研究者データベース

周東 智(シユウトウ サトシ)
薬学研究院 創薬科学部門 創薬化学分野
教授

基本情報

所属

  • 薬学研究院 創薬科学部門 創薬化学分野

職名

  • 教授

学位

  • 薬学博士(北海道大学)

ホームページURL

J-Global ID

研究キーワード

  • 有機化学   医薬品化学   Organic Chemistry   Medicinal Chemistry   

研究分野

  • ライフサイエンス / 薬系化学、創薬科学
  • ライフサイエンス / 薬系化学、創薬科学

職歴

  • 2005年04月 - 現在 北海道大学大学院薬学研究院

学歴

  •         - 1982年   北海道大学   薬学研究科   製薬化学
  •         - 1982年   北海道大学
  •         - 1980年   北海道大学   薬学部   製薬化学科
  •         - 1980年   北海道大学

所属学協会

  • アメリカ化学会   抗ウイルス療法学会   日本化学会   日本癌学会   日本薬学会   

研究活動情報

論文

  • Shota Arai, Koichi Fujiwara, Masahiro Kojima, Haruka Aoki-Saito, Masakiyo Yatomi, Tsugumichi Saito, Yasuhiko Koga, Hayato Fukuda, Mizuki Watanabe, Shigeki Matsunaga, Takeshi Hisada, Satoshi Shuto
    The Journal of Organic Chemistry 87 15 10501 - 10508 2022年08月05日
  • Haruhiro Higashida, Kazumi Furuhara, Olga Lopatina, Maria Gerasimenko, Osamu Hori, Tsuyoshi Hattori, Yasuhiko Hayashi, Stanislav M. Cherepanov, Anna A. Shabalova, Alla B. Salmina, Kana Minami, Teruko Yuhi, Chiharu Tsuji, PinYue Fu, Zhongyu Liu, Shuxin Luo, Anpei Zhang, Shigeru Yokoyama, Satoshi Shuto, Mizuki Watanabe, Koichi Fujiwara, Sei-ichi Munesue, Ai Harashima, Yasuhiko Yamamoto
    Frontiers in Neuroscience 16 2022年07月07日 
    Investigating the neurocircuit and synaptic sites of action of oxytocin (OT) in the brain is critical to the role of OT in social memory and behavior. To the same degree, it is important to understand how OT is transported to the brain from the peripheral circulation. To date, of these, many studies provide evidence that CD38, CD157, and receptor for advanced glycation end-products (RAGE) act as regulators of OT concentrations in the brain and blood. It has been shown that RAGE facilitates the uptake of OT in mother’s milk from the digestive tract to the cell surface of intestinal epithelial cells to the body fluid and subsequently into circulation in male mice. RAGE has been shown to recruit circulatory OT into the brain from blood at the endothelial cell surface of neurovascular units. Therefore, it can be said that extracellular OT concentrations in the brain (hypothalamus) could be determined by the transport of OT by RAGE from the circulation and release of OT from oxytocinergic neurons by CD38 and CD157 in mice. In addition, it has recently been found that gavage application of a precursor of nicotinamide adenine dinucleotide, nicotinamide riboside, for 12 days can increase brain OT in mice. Here, we review the evaluation of the new concept that RAGE is involved in the regulation of OT dynamics at the interface between the brain, blood, and intestine in the living body, mainly by summarizing our recent results due to the limited number of publications on related topics. And we also review other possible routes of OT recruitment to the brain.
  • Keisuke Mitsui, Maria E K Lie, Naoki Saito, Koichi Fujiwara, Mizuki Watanabe, Petrine Wellendorph, Satoshi Shuto
    Organic letters 24 23 4151 - 4154 2022年06月17日 
    Novel γ-aminobutyric acid (GABA) analogues 3-5, having a bicyclo[3.1.0]hexene, [4.1.0]heptane, or [4.1.0]heptene backbone, respectively, were designed from the bioactive form analysis of the previous inhibitor 2 with a bicyclo[3.1.0]hexane backbone. Compounds 3-5 and 2 were synthesized from a common 1,7-diene intermediate 6 using ring-closing metathesis (RCM) to construct the key bicyclo backbones. Compounds 3-5 strongly inhibit betaine/GABA transporter 1 (BGT1) uptake, but compound 4 stands out with its selective low micromolar potency.
  • Tomohiko Shimizu, Tsugumichi Saito, Haruka Aoki-Saito, Shuichi Okada, Hiroyuki Ikeda, Takashi Nakakura, Hayato Fukuda, Syota Arai, Kouichi Fujiwara, Yasuyo Nakajima, Kazuhiro Horiguchi, Sayaka Yamada, Emi Ishida, Takeshi Hisada, Satoshi Shuto, Masanobu Yamada
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology 36 3 e22188  2022年03月 
    Obesity-associated type 2 diabetes mellitus is associated with the development of insulin resistance. Among several metabolites, resolvins that are metabolites of eicosapentaenoic acid have been shown to exert insulin-sensitizing effects; however, the role of resolvin E3 (RvE3) in glucose metabolism has not been studied. In this study, the effect of RvE3 on glucose metabolism in mice with high-fat diet-induced obesity and 3T3L1 adipocytes was studied. C57BL/6 mice fed a high-fat diet were administered RvE3, for which insulin tolerance, oral glucose tolerance tests, and the homeostasis model assessment of insulin resistance, were performed. RvE3 treatment significantly improved insulin sensitivity and glucose tolerance and regulated protein kinase B (Akt) phosphorylation in the adipose tissue. Moreover, RvE3 treatment enhanced the insulin-stimulated glucose transporter 4 (Glut4) translocation, glucose uptake, phosphatidylinositol-3-kinase (PI3K) activity, and Akt phosphorylation in 3T3L1 adipocytes, whereas a PI3K inhibitor inhibited the enhanced insulin-stimulated glucose uptake induced by RvE3. These findings indicate that RvE3 likely improves insulin sensitivity, resulting in the upregulation of glucose uptake in adipocytes by activating the PI3K/Akt signaling pathways. Collectively, the findings of this study show that RvE3 may play a role in glucose homeostasis and could be used as a potential therapeutic target for developing treatments for obesity-associated diabetes.
  • Shun Aoki, Satoshi Deyama, Rinako Sugie, Kohei Ishimura, Hayato Fukuda, Satoshi Shuto, Masabumi Minami, Katsuyuki Kaneda
    Behavioural brain research 418 113676 - 113676 2022年02月10日 
    Resolvin E1 (RvE1) is an anti-inflammatory lipid mediator derived from eicosapentaenoic acid. We previously demonstrated that intracerebroventricular (i.c.v.) and intra-medial prefrontal cortex (mPFC) infusions of RvE1 produce antidepressant-like effects in a lipopolysaccharide-induced depression mouse model. To further confirm the antidepressant-like effect of RvE1, the present study examined whether RvE1 ameliorated depression-like behavior induced by repeated injections of prednisolone (PSL), a synthetic glucocorticoid, in male ICR mice. We first ascertained whether repeated subcutaneous treatment with PSL (50 mg/kg, once a day) affected locomotor activity and anxiety-like behavior in the open field test (OFT; after a 5-day PSL treatment) and induced depression-like behavior in the tail suspension test (TST; after a 6-day PSL treatment) and forced swim test (FST; after a 7-day PSL treatment). Repeated PSL injections significantly increased immobility in the FST, which was not ameliorated by acute desipramine treatment (30 mg/kg, i.p.), but not in the TST, without affecting locomotor activity and anxiety-like behavior in the OFT. Subsequently, we investigated the therapeutic effects of i.c.v. (1 ng) and intra-mPFC (50 pg/side) infusions of RvE1 in the repeated PSL-induced depression mouse model using the OFT and FST after 5- and 6-day PSL treatments, respectively. The repeated PSL-induced increase in immobility in the FST was significantly attenuated by both i.c.v. and intra-mPFC infusions of RvE1 without affecting the locomotor activity and anxiety-like behavior. In addition, a single i.c.v. infusion of RvE1 immediately before the first or fourth injection of PSL also attenuated PSL-induced depression-like behavior in the FST, suggesting the preventive effect of RvE1. These results indicate that RvE1 produces antidepressant-like effects in a mouse model of repeated PSL-induced depression.
  • Hiroe Suzuki, Takahisa Otsuka, Natsuko Hitora-Imamura, Kohei Ishimura, Hayato Fukuda, Koichi Fujiwara, Satoshi Shuto, Satoshi Deyama, Masabumi Minami
    Biological and Pharmaceutical Bulletin 44 10 1548 - 1550 2021年10月01日
  • Stefanie Kickinger, Maria E. K. Lie, Akihiro Suemasa, Anas Al-Khawaja, Koichi Fujiwara, Mizuki Watanabe, Kristine S. Wilhelmsen, Christina B. Falk-Petersen, Bente Frølund, Satoshi Shuto, Gerhard F. Ecker, Petrine Wellendorph
    Frontiers in Chemistry 9 2021年09月14日 
    The betaine/GABA transporter 1 (BGT1) is a member of the GABA transporter (GAT) family with still elusive function, largely due to a lack of potent and selective tool compounds. Based on modeling, we here present the design, synthesis and pharmacological evaluation of five novel conformationally restricted cyclic GABA analogs related to the previously reported highly potent and selective BGT1 inhibitor (1S,2S,5R)-5-aminobicyclo[3.1.0]hexane-2-carboxylic acid (bicyclo-GABA). Using [3H]GABA radioligand uptake assays at the four human GATs recombinantly expressed in mammalian cell lines, we identified bicyclo-GABA and its N-methylated analog (2) as the most potent and selective BGT1 inhibitors. Additional pharmacological characterization in a fluorescence-based membrane potential assay showed that bicyclo-GABA and 2 are competitive inhibitors, not substrates, at BGT1, which was validated by a Schild analysis for bicyclo-GABA (pKB value of 6.4). To further elaborate on the selectivity profile both compounds were tested at recombinant α1β2γ2 GABAA receptors. Whereas bicyclo-GABA showed low micromolar agonistic activity, the N-methylated 2 was completely devoid of activity at GABAA receptors. To further reveal the binding mode of bicyclo-GABA and 2 binding hypotheses of the compounds were obtained from in silico-guided mutagenesis studies followed by pharmacological evaluation at selected BGT1 mutants. This identified the non-conserved BGT1 residues Q299 and E52 as the molecular determinants driving BGT1 activity and selectivity. The binding mode of bicyclo-GABA was further validated by the introduction of activity into the corresponding GAT3 mutant L314Q (38 times potency increase cf. wildtype). Altogether, our data reveal the molecular determinants for the activity of bicyclic GABA analogs, that despite their small size act as competitive inhibitors of BGT1. These compounds may serve as valuable tools to selectively and potently target BGT1 in order to decipher its elusive pharmacological role in the brain and periphery such as the liver and kidneys.
  • Yuta Sato, Naoko Oyobe, Takao Ogawa, Sayo Suzuki, Hiroshi Aoyama, Tomonori Nakamura, Hiromichi Fujioka, Satoshi Shuto, Mitsuhiro Arisawa
    ACS Medicinal Chemistry Letters 12 9 1464 - 1469 2021年09月09日
  • 齋藤 悠, 佐藤 真季子, 古賀 康彦, 矢冨 正清, 鶴巻 寛朗, 齋藤 従道, 山口 彩, 山口 公一, 澤田 友里, 原 健一郎, 砂長 則明, 前野 敏孝, 石塚 全, 福田 隼, 周東 智, 久田 剛志
    アレルギー 70 6-7 875 - 875 (一社)日本アレルギー学会 2021年08月
  • TOHRU OBATA, SARA SHIRATANI, TOMOMI NADA, YAYOI KASAYA, MITSUHIRO ARISAWA, SATOSHI SHUTO, MOTOHIRO TANAKA
    Anticancer Research 41 5 2287 - 2296 2021年05月
  • 佐藤 真季子, 齋藤 悠, 鶴巻 寛朗, 矢冨 正清, 古賀 康彦, 砂長 則明, 石塚 全, 土橋 邦生, 周東 智, 前野 敏孝, 久田 剛志
    日本呼吸器学会誌 10 増刊 134 - 134 (一社)日本呼吸器学会 2021年04月
  • Hiroyuki Miyachi, Kayoko Kanamitsu, Mayumi Ishii, Eri Watanabe, Akira Katsuyama, Satoko Otsuguro, Fumika Yakushiji, Mizuki Watanabe, Kouhei Matsui, Yukina Sato, Satoshi Shuto, Takashi Tadokoro, Shunsuke Kita, Takanori Matsumaru, Akira Matsuda, Tomoyasu Hirose, Masato Iwatsuki, Yasuteru Shigeta, Tetsuo Nagano, Hirotatsu Kojima, Satoshi Ichikawa, Toshiaki Sunazuka, Katsumi Maenaka
    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 37 2021年04月 [査読有り]
     
    To develop methodology to predict the potential druggability of middle molecules, we examined the structure, solubility, and permeability relationships of a diverse library (HKDL ver.1) consisting of 510 molecules (359 natural product derivatives, 76 non-natural products, 46 natural products, and 29 non-natural product de-rivatives). The library included peptides, depsipeptides, macrolides, and lignans, and 476 of the 510 compounds had a molecular weight in the range of 500?2000 Da. The solubility and passive diffusion velocity of the middle molecules were assessed using the parallel artificial membrane permeability assay (PAMPA). Quantitative values of solubility of 471 molecules and passive diffusion velocity of 287 molecules were obtained, and their corre-lations with the structural features of the molecules were examined. Based on the results, we propose a method to predict the passive diffusion characteristics of middle molecules from their three-dimensional structural features.
  • Ryota Nakajima, Hiroyuki Oono, Keiko Kumazawa, Tomohide Ida, Jun Hirata, Ryan D. White, Xiaoshan Min, Angel Guzman-Perez, Zhulun Wang, Antony Symons, Sanjay K. Singh, Srinivasa Reddy Mothe, Sergei Belyakov, Anjan Chakrabarti, Satoshi Shuto
    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 36 2021年03月 [査読有り]
     
    The retinoic acid receptor-related orphan nuclear receptor gamma t (ROR gamma t), which is a promising therapeutic target for immune diseases, is a major transcription factor of genes related to psoriasis pathogenesis, such as interleukin (IL)-17A, IL-22, and IL-23R. Inspired by the co-crystal structure of ROR gamma t, a 6-oxo-4-phenyl-hexanoic acid derivative 6a was designed, synthesized, and identified as a ligand of ROR gamma t. The structure-activity relationship (SAR) studies in 6a, which focus on the improvement of its membrane permeability profile by introducing chlorine atoms, led to finding 12a, which has a potent ROR gamma t inhibitory activity and a favorable pharmacokinetic profile.
  • Kohei Ishimura, Hayato Fukuda, Koichi Fujiwara, Ryuta Muromoto, Koki Hirashima, Yuto Murakami, Mizuki Watanabe, Jun Ishihara, Tadashi Matsuda, Satoshi Shuto
    ACS MEDICINAL CHEMISTRY LETTERS 12 2 256 - 261 2021年02月 [査読有り]
     
    RvE1 (1) is an endogenous lipid mediator with very potent anti-inflammatory activity, which is due to the inhibition of neutrophil chemotaxis and inflammatory cytokine production and the promotion of macrophage phagocytosis. On the basis of the conformational analysis of RvE1, we designed its four cyclopropane congeners (2a-d), in which the conformationally flexible terminal C1-C4 moiety of RvE1 was rigidified by introducing stereoisomeric cyclopropanes. The four congeners and also RvE1 were efficiently synthesized via a common synthetic route. The evaluation of the anti-inflammatory effects of the compounds in mice resulted in the identification of trans-beta-CP-RvE1 (2d), which was significantly more active than RvE1, as a potential lead for antiinflammatory drugs of a novel mechanism of action.
  • Stefanie Kickinger, Maria E K Lie, Akihiro Suemasa, Anas Al-Khawaja, Koichi Fujiwara, Mizuki Watanabe, Kristine S Wilhelmsen, Christina B Falk-Petersen, Bente Frølund, Satoshi Shuto, Gerhard F Ecker, Petrine Wellendorph
    Frontiers in chemistry 9 736457 - 736457 2021年 
    The betaine/GABA transporter 1 (BGT1) is a member of the GABA transporter (GAT) family with still elusive function, largely due to a lack of potent and selective tool compounds. Based on modeling, we here present the design, synthesis and pharmacological evaluation of five novel conformationally restricted cyclic GABA analogs related to the previously reported highly potent and selective BGT1 inhibitor (1S,2S,5R)-5-aminobicyclo[3.1.0]hexane-2-carboxylic acid (bicyclo-GABA). Using [3H]GABA radioligand uptake assays at the four human GATs recombinantly expressed in mammalian cell lines, we identified bicyclo-GABA and its N-methylated analog (2) as the most potent and selective BGT1 inhibitors. Additional pharmacological characterization in a fluorescence-based membrane potential assay showed that bicyclo-GABA and 2 are competitive inhibitors, not substrates, at BGT1, which was validated by a Schild analysis for bicyclo-GABA (pK B value of 6.4). To further elaborate on the selectivity profile both compounds were tested at recombinant α1β2γ2 GABAA receptors. Whereas bicyclo-GABA showed low micromolar agonistic activity, the N-methylated 2 was completely devoid of activity at GABAA receptors. To further reveal the binding mode of bicyclo-GABA and 2 binding hypotheses of the compounds were obtained from in silico-guided mutagenesis studies followed by pharmacological evaluation at selected BGT1 mutants. This identified the non-conserved BGT1 residues Q299 and E52 as the molecular determinants driving BGT1 activity and selectivity. The binding mode of bicyclo-GABA was further validated by the introduction of activity into the corresponding GAT3 mutant L314Q (38 times potency increase cf. wildtype). Altogether, our data reveal the molecular determinants for the activity of bicyclic GABA analogs, that despite their small size act as competitive inhibitors of BGT1. These compounds may serve as valuable tools to selectively and potently target BGT1 in order to decipher its elusive pharmacological role in the brain and periphery such as the liver and kidneys.
  • Hiroe Suzuki, Takahisa Otsuka, Natsuko Hitora-Imamura, Kohei Ishimura, Hayato Fukuda, Koichi Fujiwara, Satoshi Shuto, Satoshi Deyama, Masabumi Minami
    Biological & pharmaceutical bulletin 44 10 1548 - 1550 2021年 
    The antidepressant effect of eicosapentaenoic acid-derived bioactive lipid, resolvin E1 (RvE1), was examined in a murine model of chronic pain-induced depression using a tail suspension test. Because RvE1 reportedly possesses agonistic activity on a chemerin receptor ChemR23, we also examined the antidepressant effect of chemerin. Two weeks after surgery for unilateral spared nerve injury to prepare neuropathic pain model mice, immobility time was measured in a tail suspension test. Chronic pain significantly increased immobility time, and this depression-like behavior was attenuated by intracerebroventricular injection of RvE1 (1 ng) or chemerin (500 ng). These results demonstrate that RvE1 exerts an antidepressant effect in a murine model of chronic pain-induced depression, which is likely to be via ChemR23. RvE1 and its receptor may be promising targets to develop novel antidepressants.
  • Hayato Fukuda, Hiroyuki Ikeda, Ryuta Muromoto, Koki Hirashima, Kohei Ishimura, Koichi Fujiwara, Haruka Aoki-Saito, Takeshi Hisada, Mizuki Watanabe, Jun Ishihara, Tadashi Matsuda, Satoshi Shuto
    JOURNAL OF ORGANIC CHEMISTRY 85 21 14190 - 14200 2020年11月 [査読有り]
     
    We synthesized RvE3 and its deoxy derivatives, 17-deoxy-RvE3 and 18-deoxy-RvE3, by a common route via Sonogashira coupling as a key step. The evaluation of their anti-inflammatory activities revealed that 18-deoxy-RvE3 was remarkably more potent than the parent RvE3 and significantly active at a 300 fg dose in mice; additionally, 17-deoxy-RvE3 was significantly less potent than the parent RvE3. For the first time, we found that the 17-hydroxy group of RvE3 is very important for anti-inflammatory activity.
  • 佐藤 真季子, 齋藤 悠, 鶴巻 寛朗, 矢冨 正清, 古賀 康彦, 砂長 則明, 前野 敏孝, 石塚 全, 柳川 正隆, 佐甲 靖志, 阿部 充宏, 土橋 邦生, 周東 智, 久田 剛志
    アレルギー 69 臨時増刊号 296 - 296 (一社)日本アレルギー学会 2020年10月
  • Megumi Yamamoto, Rie Yanagisawa, Atsushi Sakai, Masaki Mogi, Satoshi Shuto, Masachika Shudo, Hazuki Kashiwagi, Megumi Kudo, Masaaki Nakamura, Mineshi Sakamoto
    JOURNAL OF APPLIED TOXICOLOGY 41 6 928 - 940 2020年10月 [査読有り]
     
    We compared the toxicokinetics of methylmercury (MeHg) in KK-Ay type 2 diabetic mice and C57BL/6J mice to evaluate how metabolic changes associated with diabetes affect MeHg toxicokinetics. A single dose of MeHg (0.2, 1, or 5 mg mercury/kg) was administered orally to 12-week-old KK-Ay and C57BL/6J male mice. Total mercury concentrations in plasma, blood cells, whole blood, and tissues (brain, kidneys, liver, and pancreas) were measured after 4, 7, 11, and 14 days. The volume of distribution/bioavailability and the elimination rate constant per day were higher in KK-Ay mice, while the terminal elimination half-life was lower in almost all samples of KK-Ay mice. The area under the curve was lower in all blood and almost all tissue samples from KK-Ay mice. Total clearance/bioavailability was lower in all blood and tissue samples of KK-Ay mice at all MeHg doses. These results indicate that MeHg is more rapidly absorbed by, and eliminated from, the blood cells, brain, liver, kidney, and pancreas of KK-Ay mice under the experimental conditions. Different patterns of tissue-to-plasma and tissue-to-whole blood partition coefficients suggest that notable differences in MeHg transfer between plasma and blood cells affect its distribution in tissues of the two mouse strains. These findings are useful to understand the selective distribution of MeHg to target organs and the sensitivity to MeHg in pathological states.
  • Masakiyo Yatomi, Yasuhiko Koga, Haruka Saito, Makiko Sato, Hiroaki Tsurumaki, Kenichiro Hara, Noriaki Sunaga, Toshitaka Maeno, Hiroyuki Ikeda, Hayato Fukuda, Shouta Arai, Koichi Fujiwara, Satoshi Shuto, Takeshi Hisada
    EUROPEAN RESPIRATORY JOURNAL 56 2020年09月
  • Shaomeng Wang, Gunda Georg, Minoru Ishikawa, Tomohiko Ohwada, Satoshi Shuto, Takayoshi Suzuki
    JOURNAL OF MEDICINAL CHEMISTRY 63 17 8877 - 8879 2020年09月 [査読有り]
  • 佐藤 真季子, 齋藤 悠, 古賀 康彦, 矢冨 正清, 鶴巻 寛朗, 前野 敏孝, 石塚 全, 土橋 邦生, 砂長 則明, 周東 智, 山田 正信, 久田 剛志
    日本呼吸器学会誌 9 増刊 323 - 323 (一社)日本呼吸器学会 2020年08月
  • 佐藤 真季子, 齋藤 悠, 古賀 康彦, 矢冨 正清, 鶴巻 寛朗, 前野 敏孝, 石塚 全, 土橋 邦生, 砂長 則明, 周東 智, 山田 正信, 久田 剛志
    日本呼吸器学会誌 9 増刊 323 - 323 (一社)日本呼吸器学会 2020年08月
  • Mizuki Watanabe, Takaaki Kobayashi, Yoshihiko Ito, Shizuo Yamada, Satoshi Shuto
    MOLECULES 25 16 2020年08月 [査読有り]
     
    We designed and synthesized conformationally rigid histamine analogues with a bicyclo[3.1.0]hexane scaffold. All the compounds were selectively bound to the H(3)receptor subtype over the H(4)receptor subtype. Notably, compound7showed potent binding affinity and over 100-fold selectivity for the H(3)receptors (K-i= 5.6 nM for H(3)and 602 nM for H-4). These results suggest that the conformationally rigid bicyclo[3.1.0]hexane structure can be a useful scaffold for developing potent ligands selective for the target biomolecules.
  • Rika Okuma, Tomoki Kuwahara, Takafumi Yoshikane, Mizuki Watanabe, Patricia Dranchak, James Inglese, Satoshi Shuto, Yuki Goto, Hiroaki Suga
    Chemistry, an Asian journal 15 17 2631 - 2636 2020年07月07日 [査読有り][通常論文]
     
    Here we report construction of an mRNA-encoded library of thioether-closed macrocyclic peptides by using an N -chloroacetyl-cyclopropane-containing exotic initiator whose structure is more constrained than the ordinary N -chloroacetyl-α-amino acid initiators. The use of such an initiator has led to a macrocycle library with significantly suppressed population of lariat-shaped species compared with the conventional libraries. We previously used a conventional library and identified a small lariat thioether-macrocycle with a tail peptide with a C-terminal free Cys whose sidechain plays an essential role in potent inhibitory activity against a parasitic model enzyme, phosphoglycerate mutase. On the other hand, the cyclopropane-containing macrocycle library has yielded a larger thioether-macrocycle lacking a free Cys residue, which exhibits potent inhibitory activity to the same enzyme with a different mode of action. This result indicates that such a cyclopropane-containing macrocycle library would allow us to access mechanistically distinct macrocycles.
  • Ryota Nakajima, Hiroyuki Oono, Sakae Sugiyama, Yohei Matsueda, Tomohide Ida, Shinji Kakuda, Jun Hirata, Atsushi Baba, Akito Makino, Ryo Matsuyama, Ryan D. White, Ryan P. Wurz, Youngsook Shin, Xiaoshan Min, Angel Guzman-Perez, Zhulun Wang, Antony Symons, Sanjay K. Singh, Srinivasa Reddy Mothe, Sergei Belyakov, Anjan Chakrabarti, Satoshi Shuto
    ACS MEDICINAL CHEMISTRY LETTERS 11 4 528 - 534 2020年04月 [査読有り]
     
    The retinoic acid receptor-related orphan nuclear receptor gamma t (ROR gamma t), a promising therapeutic target, is a major transcription factor of genes related to psoriasis pathogenesis such as interleukin (IL)-17A, IL-22, and IL-23R. On the basis of the Xray cocrystal structure of ROR gamma t with 1a, an analogue of the known piperazine ROR gamma t inverse agonist 1, triazolopyridine derivatives of 1 were designed and synthesized, and analogue 3a was found to be a potent ROR gamma t inverse agonist. Structure-activity relationship studies on 3a, focusing on the treatment of its metabolically unstable cyclopentyl ring and the central piperazine core, led to a novel analogue, namely, 6-methyl-N-(7-methyl-8-(((2S,4S)-2methyl-1-(4,4,4-trifluoro-3-(trifluoromethyl) butanoyl)piperidin-4-yl)oxy)[1,2,4]triazolo[1,5-a]pyridin-6-yl)nicotinamide (5a), which exhibited strong ROR.t inhibitory activity and a favorable pharmacokinetic profile. Moreover, the in vitro and in vivo evaluation of 5a in a human whole-blood assay and a mouse IL-18/23-induced cytokine expression model revealed its robust and dose-dependent inhibitory effect on IL-17A production.
  • Yuto Murakami, Hayato Fukuda, Ryuta Muromoto, Koki Hirashima, Kohei Ishimura, Koichi Fujiwara, Jun Ishihara, Tadashi Matsuda, Mizuki Watanabe, Satoshi Shuto
    ACS MEDICINAL CHEMISTRY LETTERS 11 4 479 - 484 2020年04月 [査読有り][通常論文]
     
    Resolvins (Rvs) are highly potent anti-inflammatory lipid mediators that are chemically and biologically unstable because of their polyunsaturated structures. To address this issue, we designed benzene congeners of RvE2, i.e., o-, m-, and p-BZ-RvE2s, as stable equivalents of RvE2 by replacing the unstable skipped diene moiety with a benzene ring on the basis of computational conformation studies and synthesized these congeners via a short common route through two Stille couplings. o-BZ-RvE2 exhibited more potent anti-inflammatory activity and much higher metabolic stability than RvE2. Thus, o-BZ-RvE2 was identified as a stable equivalent of RvE2, which is useful as a lead for anti-inflammatory drugs with a new mechanism of action as well as a biotool for investigating RvE2-mediated inflammation resolving pathways.
  • シクロプロパン鎖導入環状ペプチド化合物の膜透過性および吸収性の評価
    加藤 七海, 植村 真衣, 松井 耕平, 渡邉 瑞貴, 武隈 洋, 周東 智, 菅原 満
    日本薬学会年会要旨集 140年会 27Z - pm13 (公社)日本薬学会 2020年03月
  • シクロプロパン鎖導入環状ペプチド化合物の膜透過性および吸収性の評価
    加藤 七海, 植村 真衣, 松井 耕平, 渡邉 瑞貴, 武隈 洋, 周東 智, 菅原 満
    日本薬学会年会要旨集 140年会 27Z - pm13 (公社)日本薬学会 2020年03月
  • Daichi Fushihara, Hayato Fukuda, Hiroshi Abe, Satoshi Shuto
    NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS 39 1-3 471 - 471 2020年02月 [査読有り]
  • Akihiko Tanimura, Satoshi Shuto
    Methods in molecular biology (Clifton, N.J.) 2091 137 - 144 2020年 
    We present a novel method, termed competitive fluorescent ligand assay for inositol 1,4,5-trisphosphate (CFLA-IP3), to measure inositol 1,4,5-trisphosphate (IP3). This method is based on fluorescence resonance energy transfer (FRET) between two fluorescent molecules, a fluorescent IP3-binding protein and its fluorescent ligand. Binding of these fluorescent molecules generates a FRET signal, and the IP3-dependent decrease in the FRET signal due to displacement of the fluorescent ligand is detected by fluorescence microscopy.
  • Yasuaki Kimura, Zhaoma Shu, Mika Ito, Naoko Abe, Kosuke Nakamoto, Fumiaki Tomoike, Satoshi Shuto, Yoshihiro Ito, Hiroshi Abe
    Chemical Communications 2019年12月 [査読有り][通常論文]
  • Keisuke Yamamoto, Tomohiro Tamura, Rina Nakamura, Shintaro Hosoe, Masahiro Matsubara, Keiko Nagata, Hiroshi Kodaira, Takeshi Uemori, Yuichi Takahashi, Michihiko Suzuki, Jun-ichi Saito, Kimihisa Ueno, Satoshi Shuto
    BIOORGANIC & MEDICINAL CHEMISTRY 27 22 2019年11月 
    We previously identified dibenzooxepine derivative 1 as a potent PPAR. ligand with a unique binding mode owing to its non-thiazolidinedione scaffold. However, while 1 showed remarkably potent MKN-45 gastric cancer cell aggregation activity, an indicator of cancer differentiation-inducing activity induced by PPAR. activation, we recognized that 1 was metabolically unstable. In the present study, we identified a metabolically soft spot, and successfully discovered 3-fluoro dibenzooxepine derivative 9 with better metabolic stability. Further optimization provided imidazo[1,2-alpha]pyridine derivative 17, which showed potent MKN-45 gastric cancer cell aggregation activity and excellent PK profiles compared with 9. Compound 17 exerted a growth inhibitory effect on AsPC-1/AG1 pancreatic tumor in mice. Furthermore, the decrease in the hematocrit (an indicator of localized edema, a serious adverse effect of PPAR gamma ligands) was tolerable even with oral administration at 200 mg/kg in healthy mice.
  • Sato M, Aoki-Saito H, Fukuda H, Ikeda H, Koga Y, Yatomi M, Tsurumaki H, Maeno T, Saito T, Nakakura T, Mori T, Yanagawa M, Abe M, Sako Y, Dobashi K, Ishizuka T, Yamada M, Shuto S, Hisada T
    FASEB journal 33 11 12750 - 12759 2019年11月 [査読有り][通常論文]
     
    We investigated the effects of resolvin E (RvE) 1, RvE2, and RvE3 on IL-4- and IL-33-stimulated bone marrow-derived dendritic cells (BMDCs) from house dust mite (HDM)-sensitized mice. We also investigated the role of RvE3 in a murine model of HDM-induced airway inflammation. In vitro, BMDCs from HDM-sensitized mice were stimulated with IL-4 and IL-33 and then treated with RvE1, RvE2, RvE3, or vehicle. RvE1, RvE2, and RvE3 suppressed IL-23 release from BMDCs. In vivo, RvE3 administrated to HDM-sensitized and challenged mice in the resolution phase promoted a decline in total numbers of inflammatory cells and eosinophils, reduced levels of IL-23 and IL-17 in lavage fluid, and suppressed IL-23 and IL-17A mRNA expression in lung and peribronchial lymph nodes. RvE3 also reduced resistance in the lungs of HDM-sensitized mice. A NanoBiT β-arrestin recruitment assay using human embryonic kidney 293 cells revealed that pretreatment with RvE3 suppressed the leukotriene B4 (LTB4)-induced β-arrestin 2 binding to LTB4 receptor 1 (BLT1R), indicating that RvE3 antagonistically interacts with BLT1R. Collectively, these findings indicate that RvE3 facilitates the resolution of allergic airway inflammation, partly by regulating BLT1R activity and selective cytokine release by dendritic cells. Our results accordingly identify RvE3 as a potential therapeutic target for the management of asthma.-Sato, M., Aoki-Saito, H., Fukuda, H., Ikeda, H., Koga, Y., Yatomi, M., Tsurumaki, H., Maeno, T., Saito, T., Nakakura, T., Mori, T., Yanagawa, M., Abe, M., Sako, Y., Dobashi, K., Ishizuka, T., Yamada, M., Shuto, S., Hisada, T. Resolvin E3 attenuates allergic airway inflammation via the interleukin-23-interleukin-17A pathway.
  • Cherepanov SM, Miura R, Shabalova AA, Ichinose W, Yokoyama S, Fukuda H, Watanabe M, Higashida H, Shuto S
    Bioorganic & medicinal chemistry 27 15 3358 - 3363 2019年08月 [査読有り][通常論文]
  • Fushihara D, Fukuda H, Abe H, Shuto S
    Nucleosides, nucleotides & nucleic acids 1 - 21 2019年06月 [査読有り][通常論文]
  • 佐藤 真季子, 齋藤 悠, 古賀 康彦, 矢冨 正清, 竹原 和孝, 前野 敏孝, 石塚 全, 土橋 邦生, 中倉 敬, 池田 紘之, 福田 隼, 森 哲哉, 周東 智, 山田 正信, 久田 剛志
    アレルギー 68 4-5 507 - 507 (一社)日本アレルギー学会 2019年05月 [査読有り][通常論文]
  • Wataru Ichinose, Stanislav M Cherepanov, Anna A Shabalova, Shigeru Yokoyama, Teruko Yuhi, Hiroaki Yamaguchi, Ayu Watanabe, Yasuhiko Yamamoto, Hiroshi Okamoto, Shinichi Horike, Junpei Terakawa, Takiko Daikoku, Mizuki Watanabe, Nariyasu Mano, Haruhiro Higashida, Satoshi Shuto
    Journal of medicinal chemistry 62 7 3297 - 3310 2019年04月11日 [査読有り][通常論文]
     
    The nonapeptide hormone oxytocin (OT) has pivotal brain roles in social recognition and interaction and is thus a promising therapeutic drug for social deficits. Because of its peptide structure, however, OT is rapidly eliminated from the bloodstream, which decreases its potential therapeutic effects in the brain. We found that newly synthesized OT analogues in which the Pro7 of OT was replaced with N-( p-fluorobenzyl)glycine (2) or N-(3-hydroxypropyl)glycine (5) exhibited highly potent binding affinities for OT receptors and Ca2+ mobilization effects by selectively activating OT receptors over vasopressin receptors in HEK cells, where 2 was identified as a superagonist ( EMax = 131%) for OT receptors. Furthermore, the two OT analogues had a remarkably long-acting effect, up to 16-24 h, on recovery from impaired social behaviors in two strains of CD38 knockout mice that exhibit autism spectrum disorder-like social behavioral deficits, whereas the effect of OT itself rapidly diminished.
  • Yuko Shishido, Fumiaki Tomoike, Keiko Kuwata, Haruka Fujikawa, Yoshitaka Sekido, Yuko Murakami-Tonami, Tomoshi Kameda, Naoko Abe, Yasuaki Kimura, Satoshi Shuto, Hiroshi Abe
    Chembiochem : a European journal of chemical biology 20 7 900 - 905 2019年04月01日 [査読有り][通常論文]
     
    Glutathione S-transferase π (GSTP1-1 ) is overexpressed in many types of cancer and is involved in drug resistance. Therefore, GSTP1-1 is an important target in cancer therapy, and many GST inhibitors have been reported. We had previously developed an irreversible inhibitor, GS-ESF, as an effective GST inhibitor; however, its cellular permeability was too low for it to be used in inhibiting intracellular GST. We have now developed new irreversible inhibitors by introducing sulfonyl fluoride (SF) into chloronitrobenzene (CNB). The mechanism of action was revealed to be that CNBSF first reacts with glutathione (GSH) through an aromatic substitution in the cell, then the sulfonyl group on the GSH conjugate with CNBSF reacts with Tyr108 of GST to form a sulfonyl ester bond. Our new inhibitor irreversible inhibited GSTP1-1 both in vitro and in cellulo with a long duration of action.
  • 膜透過性を有するGST共有結合性阻害剤の開発
    友池 史明, 宍戸 裕子, 藤川 遥加, 木村 康明, 桑田 啓子, 村上 優子, 福井 健二, 関戸 好孝, 矢野 貴人, 亀田 倫史, 周東 智, 阿部 洋
    日本薬学会年会要旨集 139年会 2 80 - 80 (公社)日本薬学会 2019年03月
  • 佐藤 真季子, 齋藤 悠, 鶴巻 寛朗, 矢冨 正清, 古賀 康彦, 竹原 和孝, 石塚 全, 中倉 敬, 池田 紘之, 福田 隼, 周東 智, 森 哲哉, 土橋 邦生, 山田 正信, 久田 剛志
    日本呼吸器学会誌 8 増刊 313 - 313 (一社)日本呼吸器学会 2019年03月 [査読有り][通常論文]
  • レゾルビンE1はfMLFが誘導するヒト好中球の活性酸素産生を増強する
    海野 雄加, 佐藤 義則, 永川 茂, 鴨志田 剛, 西田 智, 上田 たかね, 祖母井 庸之, 斧 康雄, 周東 智, 福田 隼, 石村 航平, 渡邉 瑞貴, 池田 紘之
    感染症学雑誌 93 臨増 400 - 400 (一社)日本感染症学会 2019年03月 [査読有り][通常論文]
  • Minami Takaaki, Fukuda Kohtaro, Hoshiya Naoyuki, Fukuda Hayato, Watanabe Mizuki, Shuto Satoshi
    ORGANIC LETTERS 21 3 656 - 659 2019年02月01日 [査読有り][通常論文]
  • レゾルビンによる好中球活性化のプライミング反応
    海野 雄加, 佐藤 義則, 永川 茂, 鴨志田 剛, 西田 智, 上田 たかね, 祖母井 庸之, 斧 康雄, 周東 智, 福田 隼, 石村 航平, 渡邉 瑞貴, 池田 紘之
    感染症学雑誌 93 1 71 - 71 (一社)日本感染症学会 2019年01月 [査読有り][通常論文]
  • Takahisa Taniguchi, Nozomi Saito, Ryohei Doi, Arato Kimoto, Naoyuki Hoshiya, Katsumasa Fujiki, Satoshi Shuto, Hiromichi Fujioka, Mitsuhiro Arisawa, Yoshihiro Sato
    Chemistry Letters 48 11 1406 - 1409 2019年 [査読有り][通常論文]
     
    © 2019 The Chemical Society of Japan A hydrocarboxylation reaction of alkyne or styrene derivatives with CO2 proceeded smoothly by using an air-stable nano-sized nickel catalyst supported on sulfur-modified gold (SANi), giving functionalized acrylic acids and phenylpropionic acids including an anti-inflammatory drug, Flurbiprofen. Notably, SANi could be recycled several times without a significant decrease of the yield.
  • Mizuki Watanabe, Takaaki Kobayashi, Yoshihiko Ito, Hayato Fukuda, Shizuo Yamada, Mitsuhiro Arisawa, Satoshi Shuto
    Bioorganic and Medicinal Chemistry Letters 28 23-24 3630 - 3633 2018年12月15日 [査読有り][通常論文]
     
    © 2018 Elsevier Ltd We previously designed and synthesized a series of histamine analogues with an imidazolylcyclopropane scaffold and identified potent non-selective antagonists for histamine H3 and H4 receptor subtypes. In this study, to develop H4 selective ligands, we newly designed and synthesized cyclopropane-based derivatives having an indole, benzimidazole, or piperazine structure, which are components of representative H4 selective antagonists such as JNJ7777120 and JNJ10191584. Among the synthesized derivatives, imidazolylcyclopropanes 12 and 13 conjugated with a benzimidazole showed binding affinity to the H3 and H4 receptors comparable to that of a well-known non-selective H3/H4 antagonist, thioperamide. These results suggest that the binding modes of the cyclopropane-based H3/H4 ligands in the H4 receptor can be different from those of the indole/benzimidazole-piperazine derivatives.
  • Yamamoto Keisuke, Tamura Tomohiro, Henmi Kazuki, Kuboyama Takeshi, Yanagisawa Arata, Matsubara Masahiro, Takahashi Yuichi, Suzuki Michihiko, Saito Jun-ichi, Ueno Kimihisa, Shuto Satoshi
    JOURNAL OF MEDICINAL CHEMISTRY 61 22 10067 - 10083 2018年11月22日 [査読有り][通常論文]
     
    A novel class of PPAR gamma ligand 1 (EC50 = 197 nM) with a dibenzoazepin scaffold was identified through high-throughput screening campaign. To avoid the synthetically trouble-some chiral center of 1, its conformational analysis using the MacroModel was conducted, focusing on conformational flip of the tricyclic ring and the conformational restriction by the methyl group at the chiral center. On the basis of this analysis, scaffold hopping of dibenzoazepine into dibenzo[b,e]oxepine by replacing the chiral structures with the corresponding olefinic E/Z isomers was performed. Consequently, dibenzo[b,e]oxepine scaffold 9 was developed showing extremely potent PPAR gamma reporter activity (EC50 = 2.4 nM, efficacy = 9.5%) as well as differentiation-inducing activity against a gastric cancer cell line MKN-45 that was more potent than any other well-known PPAR gamma agonists in vitro (94% at 30 nM). The X-ray crystal structure analysis of 9 complexed with PPAR gamma showed that it had a unique binding mode to PPAR gamma ligand-binding domain that differed from that of any other PPAR gamma agonists identified thus far.
  • Sato Makiko, Aoki-Saito Haruka, Fukuda Hayato, Koga Yasuhiko, Yatomi Masakiyo, Tsurumaki Hiroaki, Nakakura Takashi, Yamada Masanobu, Shuto Satoshi, Hisada Takeshi
    RESPIROLOGY 23 217  2018年11月 [査読有り][通常論文]
  • Oda K, Mori N, Okumi M, Furusawa M, Ishiguro M, Inoue K, Shuto S, Unagami K, Ishida H, Tanabe K, Murakami T
    Drug metabolism and pharmacokinetics 33 5 232 - 239 2018年10月 [査読有り][通常論文]
     
    The cellular uptake of mizoribine (MZR), an immunosuppressant, and metabolism of MZR to MZR-5'- monophosphate (MZRP), an active metabolite, were evaluated in L5178Y-R mouse lymphoma cells and peripheral blood mononuclear cells (PBMCs) of rats and kidney transplant recipients (KTRs, n = 22). Real-time PCR analysis revealed the expression of ENT1 and ENT2 mRNAs, but not of CNTs, in L5178Y-R cells and rat's PBMCs. In L5178Y-R cells, the uptake of MZR was suppressed by adenosine, a substrate for ENT1 and ENT2, but not by 5-(4-nitrobenzyl)-6-thioinosine (0.1 μM), an ENT1 inhibitor. Saturable metabolism of MZR to MZRP was observed. In rats, peak plasma concentrations of MZR and peak concentrations of MZR and MZRP in PBMCs were observed 3 h after oral administration. MZR disappeared from PBMCs in parallel with plasma MZR, but the disappearance of MZRP from PBMCs appeared to be slow. In KTRs, the mean plasma concentration of MZR 3-4 h after ingestion was 3.14 μg/ml and the mean MZRP concentration in PBMCs was 16.8% of MZR, reflecting the involvement of ENT in the uptake of MZR. A linear relationship was observed between plasma MZR concentrations ranging from 1 to 6 μg/ml and PBMC's MZRP concentrations ranging from 90 to 200 ng/ml.
  • Sato Makiko, Aoki-Saito Haruka, Fukuda Hayato, Ikeda Hiroyuki, Koga Yasuhiko, Yatomi Masakiyo, Tsurumaki Hiroaki, Hachisu Yoshimasa, Nakakura Takashi, Mori Tetsuya, Dobashi Kunio, Yamada Masanobu, Shuto Satoshi, Hisada Takeshi
    EUROPEAN RESPIRATORY JOURNAL 52 2018年09月15日 [査読有り][通常論文]
  • Deyama Satoshi, Shimoda Kento, Ikeda Hiroyuki, Fukuda Hayato, Shuto Satoshi, Minami Masabumi
    JOURNAL OF PHARMACOLOGICAL SCIENCES 138 1 86 - 88 2018年09月 [査読有り][通常論文]
  • Ryutaro Kanada, Makoto Tanabe, Ryuta Muromoto, Yukina Sato, Tomoki Kuwahara, Hayato Fukuda, Mitsuhiro Arisawa, Tadashi Matsuda, Mizuki Watanabe, Satoshi Shuto
    Journal of Organic Chemistry 83 15 7672 - 7682 2018年08月03日 [査読有り][通常論文]
     
    © 2018 American Chemical Society. Conformationally restricted analogues of SPD-304, the first small-molecule TNFα inhibitor, in which two heteroaryl groups, indole and chromone, are connected by chiral methyl- or ethyl-cis-cyclopropane, were designed. Synthesis of these molecules was achieved via Suzuki-Miyaura or Stille coupling reactions with chiral bromomethylenecyclopropane or iodovinyl-cis-cyclopropane as the substrate, both of which were prepared from chiral methylenecyclopropane as a common intermediate, constructing the heteroaryl-methyl or -ethyl-cis-cyclopropane structures as key steps. This study presents an efficient synthesis of a series of chiral cis-cyclopropane conjugates with two heteroaryl groups.
  • Suemasa A, Watanabe M, Kobayashi T, Suzuki H, Fukuda H, Minami M, Shuto S
    Bioorganic & medicinal chemistry letters 28 20 3395 - 3399 2018年08月 [査読有り][通常論文]
  • Yuka Unno, Yoshinori Sato, Hayato Fukuda, Kohei Ishimura, Hiroyuki Ikeda, Mizuki Watanabe, Shigeru Tansho-Nagakawa, Tsuneyuki Ubagai, Satoshi Shuto, Yasuo Ono
    FEBS letters 592 16 2706 - 2715 2018年08月 [査読有り][通常論文]
     
    E-series resolvins are biosynthesized from eicosapentaenoic acid during the resolution phase of acute inflammation and enhance inflammation resolution. However, the role of E-series resolvins in inflammation resolution is not yet known. Herein, we show that in human polymorphonuclear neutrophils (PMNs), resolvin E1 (RvE1) selectively enhances reactive oxygen species (ROS) generation induced by N-formylmethionyl-leucyl-phenylalanine. The RvE1-mediated enhancement is eliminated by a pan-antagonist of leukotriene B4 (LTB4) receptors, LY255283, or an NADPH oxidase inhibitor, diphenyleneiodonium. Thus, RvE1 enhances NADPH oxidase-mediated ROS generation via LTB4 receptors. Unlike RvE1, resolvins E2 and E3 do not show such activation of PMNs. Our findings suggest that RvE1 contributes to regulation of ROS generation, in accordance with the inflammatory state of the host.
  • Unno Y, Sato Y, Fukuda H, Ishimura K, Ikeda H, Watanabe M, Tansho-Nagakawa S, Ubagai T, Shuto S, Ono Y
    FEBS letters 2018年08月 [査読有り][通常論文]
  • Anindita Paulina D, Sasaki Michihito, Okada Kazuma, Ito Naoto, Sugiyama Makoto, Saito-Tarashima Noriko, Minakawa Noriaki, Shuto Satoshi, Otsuguro Satoko, Ichikawa Satoshi, Matsuda Akira, Maenaka Katsumi, Orba Yasuko, Sawa Hirofumi
    ANTIVIRAL RESEARCH 154 1 - 9 2018年06月 [査読有り][通常論文]
     
    Rabies remains an invariably fatal neurological disease despite the availability of a preventive vaccination and post-exposure prophylaxis that must be immediately administered to the exposed individual before symptom onset. There is no effective medication for treatment during the symptomatic phase. Ribavirin, a guanine nucleoside analog, is a potent inhibitor of rabies virus (RABV) replication in vitro but lacks clinical efficacy. Therefore, we attempted to identify potential ribavirin analogs with comparable or superior anti-RABV activity. Antiviral activity and cytotoxicity of the compounds were initially examined in human neuroblastoma cells. Among the tested compounds, two exhibited a 5- to 27-fold higher anti-RABV activity than ribavirin. Examination of the anti-RABV mechanisms of action of the compounds using time-of-addition and minigenome assays revealed that they inhibited viral genome replication and transcription. Addition of exogenous guanosine to RABV-infected cells diminished the antiviral activity of the compounds, suggesting that they are involved in guanosine triphosphate (GTP) pool depletion by inhibiting inosine monophosphate dehydrogenase (IMPDH). Taken together, our findings underline the potency of nucleoside analogs as a class of antiviral compounds for the development of novel agents against RABV.
  • Shuhei Kawamura, Yoshihiko Ito, Takatsugu Hirokawa, Eriko Hikiyama, Shizuo Yamada, Satoshi Shuto
    Journal of Medicinal Chemistry 61 9 4020 - 4029 2018年05月10日 [査読有り][通常論文]
     
    We hypothesized that if drug localization can be restricted to a particular subcellular domain where their target proteins reside, the drugs could bind to their target proteins without being metabolized and/or excreted, which would significantly extend the half-life of the corresponding drug-target complex. Thus, we designed ligand-phospholipid conjugates in which the ligand is conjugated with a phospholipid through a polyethylene glycol linker to restrict the subcellular localization of the ligand in the vicinity of the lipid bilayer. Here, we present the design, synthesis, pharmacological activity, and binding mode analysis of ligand-phospholipid conjugates with muscarinic acetylcholine receptors as the target proteins. These results demonstrate that ligand-phospholipid conjugation can be a versatile strategy for developing long-acting ligands that bind to membrane proteins in drug discovery.
  • 佐藤 真季子, 齋藤 悠, 古賀 康彦, 矢冨 正清, 鶴巻 寛朗, 蜂巣 克昌, 前野 敏孝, 石塚 全, 土橋 邦生, 中倉 敬, 池田 紘之, 福田 隼, 周東 智, 久田 剛志
    アレルギー 67 4-5 654 - 654 (一社)日本アレルギー学会 2018年05月 [査読有り][通常論文]
  • EPA由来新規抗炎症性代謝産物の糖代謝における検討
    清水 智彦, 齋藤 従道, 福田 隼, 石村 航平, 池田 紘之, 岡田 純一, 澁澤 良, 下田 容子, 笠井 裕子, 大崎 綾, 山田 英二郎, 岡田 秀一, 周東 智, 山田 正信
    糖尿病 61 Suppl.1 S - 421 (一社)日本糖尿病学会 2018年04月 [査読有り][通常論文]
  • Kimura Yasuaki, Maruyama Hideto, Oikawa Ryota, Hayakawa Mayu, Abe Naoko, Tsuji Genichiro, Matsuda Akira, Shuto Satoshi, Ito Yoshihiro, Abe Hiroshi
    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 255 2018年03月18日 [査読有り][通常論文]
  • Shishido Yuko, Tomoike Fumiaki, Kimura Yasuaki, Kuwata Keiko, Yano Takato, Fukui Kenji, Fujikawa Haruka, Sekido Yoshitaka, Murakami-Tonami Yuko, Kameda Tomoshi, Shuto Satoshi, Abe Hiroshi
    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 255 2018年03月18日 [査読有り][通常論文]
  • 佐藤 真季子, 齋藤 悠, 古賀 康彦, 小野 昭浩, 矢冨 正清, 鶴巻 寛朗, 蜂巣 克昌, 前野 敏孝, 石塚 全, 土橋 邦生, 中倉 敬, 岡島 史和, 池田 紘之, 福田 隼, 周東 智, 久田 剛志
    日本呼吸器学会誌 7 増刊 137 - 137 (一社)日本呼吸器学会 2018年03月 [査読有り][通常論文]
  • Shuto Satoshi
    CHEMICAL & PHARMACEUTICAL BULLETIN 66 2 155 - 161 2018年02月 [査読有り][通常論文]
  • Shuto S
    Chemical & pharmaceutical bulletin 66 2 155 - 161 2018年 [査読有り][通常論文]
  • Satoshi Deyama, Kento Shimoda, Hiroe Suzuki, Yuka Ishikawa, Kohei Ishimura, Hayato Fukuda, Natsuko Hitora-Imamura, Soichiro Ide, Masamichi Satoh, Katsuyuki Kaneda, Satoshi Shuto, Masabumi Minami
    Psychopharmacology 235 1 329 - 336 2018年01月01日 [査読有り][通常論文]
     
    Rationale: Resolvins are bioactive lipid mediators that are generated from docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). We recently demonstrated that the DHA-derived resolvins D1 and D2 exert antidepressant effects. However, whether the EPA-derived resolvins E1 (RvE1) and E2 (RvE2) produce antidepressant effects is not clear. Objectives: We examined the antidepressant effects of RvE1/RvE2 in a murine lipopolysaccharide (LPS)-induced depression model using the tail suspension and forced swim tests. RvE1/RvE2 reportedly possesses both chemerin receptor ChemR23 agonistic activity and leukotriene B4 receptor BLT1 antagonistic activity. Therefore, we investigated the receptor involved in its antidepressant effects. We also examined the roles of the mammalian target of rapamycin complex 1 (mTORC1) in the antidepressant effect of RvE1 as well as the effects of RvE1 infusions into the medial prefrontal cortex (mPFC) and hippocampal dentate gyrus (DG) on LPS-induced depression-like behaviors. Results: Intracerebroventricular infusions of RvE1 (1 ng)/RvE2 (10 ng) produced significant antidepressant effects. An intracerebroventricular infusion of chemerin (500 ng), but not U75302 (a BLT1 antagonist 10 or 50 ng), produced antidepressant effects. Intraperitoneal rapamycin (an mTORC1 inhibitor 10 mg/kg) blocked the antidepressant effect of intracerebroventricular RvE1. Bilateral intra-mPFC and intra-DG infusions of RvE1 (50 pg/side) exerted antidepressant effects. Conclusions: The results of this study demonstrate that (1) RvE1/RvE2 produce antidepressant effects likely via ChemR23, (2) mTORC1 signaling mediates the antidepressant effect of RvE1, and (3) mPFC and DG are the key brain regions involved in these actions. RvE1/RvE2 and their receptors may be promising targets for the development of novel antidepressants.
  • Satoshi Shuto
    Chemical and Pharmaceutical Bulletin 66 2 116  2018年 [査読有り][通常論文]
  • グルタチオン-S-トランスフェラーゼを標的とした共有結合性阻害剤の開発
    宍戸 裕子, 藤川 遥加, 友池 史明, 木村 康明, 桑田 啓子, 村上 優子, 福井 健二, 関戸 好孝, 矢野 貴人, 周東 智, 阿部 洋
    生命科学系学会合同年次大会 2017年度 [3P - 0205] 生命科学系学会合同年次大会運営事務局 2017年12月
  • Stanislav M Cherepanov, Shirin Akther, Tomoko Nishimura, Anna A Shabalova, Akira Mizuno, Wataru Ichinose, Satoshi Shuto, Yasuhiko Yamamoto, Shigeru Yokoyama, Haruhiro Higashida
    Brain sciences 7 10 2017年10月16日 [査読有り][通常論文]
     
    Oxytocin (OT) is a nonapeptide that plays an important role in social behavior. Nasal administration of OT has been shown to improve trust in healthy humans and social interaction in autistic subjects. As is consistent with the nature of a peptide, OT has some unfavorable characteristics: it has a short half-life in plasma and shows poor permeability across the blood-brain barrier. Analogs with long-lasting effects may overcome these drawbacks. To this end, we have synthesized three analogs: lipo-oxytocin-1 (LOT-1), in which two palmitoyl groups are conjugated to the cysteine and tyrosine residues, lipo-oxytocin-2 (LOT-2) and lipo-oxytocin-3 (LOT-3), which include one palmitoyl group conjugated at the cysteine or tyrosine residue, respectively. The following behavioral deficits were observed in CD38 knockout (CD38-/-) mice: a lack of paternal nurturing in CD38-/- sires, decreased ability for social recognition, and decreased sucrose consumption. OT demonstrated the ability to recover these disturbances to the level of wild-type mice for 30 min after injection. LOT-2 and LOT-3 partially recovered the behaviors for a short period. Conversely, LOT-1 restored the behavioral parameters, not for 30 min, but for 24 h. These data suggest that the lipidation of OT has some therapeutic benefits, and LOT-1 would be most useful because of its long-last activity.
  • Yuko Shishido, Fumiaki Tomoike, Yasuaki Kimura, Keiko Kuwata, Takato Yano, Kenji Fukui, Haruka Fujikawa, Yoshitaka Sekido, Yuko Murakami-Tonami, Tomoshi Kameda, Satoshi Shuto, Hiroshi Abe
    CHEMICAL COMMUNICATIONS 53 81 11138 - 11141 2017年10月 [査読有り][通常論文]
     
    We herein report the first covalent G-site-binding inhibitor for GST, GS-ESF (1), which irreversibly inhibited the GSTP1-1 function. LC-MS/MS and X-ray structure analyses of the covalently linked GST-inhibitor complex suggested that 1 reacted with Tyr108 of GSTP1-1. The mechanism of covalent bond formation was discussed based on MD simulation results.
  • Akira Mizuno, Kouhei Matsui, Satoshi Shuto
    CHEMISTRY-A EUROPEAN JOURNAL 23 58 14394 - 14409 2017年10月 [査読有り][通常論文]
     
    Peptidomimetics, non-natural mimicries of bioactive peptides, comprise an important class of drug molecules. The essence of the peptidomimetic design is to mimic the key conformation assumed by the bioactive peptides upon binding to their targets. Regulation of the conformation of peptidomimetics is important not only to enhance target binding affinity and selectivity, but also to confer cell-membrane permeability for targeting protein-protein interactions in cells. The rational design of peptidomimetics with suitable three-dimensional structures is challenging, however, due to the inherent flexibility of peptides and their dynamic conformational changes upon binding to the target biomolecules. In this Minireview, a three-dimensional structural diversity-oriented strategy based on the characteristic structural features of cyclopropane to address this challenging issue in peptidomimetic chemistry is described.
  • Kuwahara Tomoki, Mizuno Akira, Fukuda Hayato, Watanabe Mizuki, Shuto Satoshi
    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 254 2017年08月20日 [査読有り][通常論文]
  • Satoshi Takano, Takayoshi Tsuzuki, Takashi Murayama, Tomoshi Kameda, Yasuhiro Kumaki, Takashi Sakurai, Hayato Fukuda, Mizuki Watanabe, Mitsuhiro Arisawa, Satoshi Shuto
    Journal of Medicinal Chemistry 60 13 5868 - 5875 2017年07月13日 [査読有り][通常論文]
     
    © 2017 American Chemical Society. A series of 8-substituted analogues of cyclic ADP-4-thioribose (cADPtR, 3), which is a stable equivalent of Ca2+-mobilizing second messenger cyclic ADP-ribose (cADPR, 1), were designed as potential pharmacological tools for studies on cADPR-modulated Ca2+ signaling pathways. These 8-amino analogue (8-NH2-cADPtR, 4), 8-azido analogue (8-N3-cADPtR, 5), and 8-chloro analogue (8-Cl-cADPtR, 6) were efficiently synthesized, where the stereoselective N1-β-thioribosyladenine ring closure reaction via an α/β-equilibrium of the 1-aminothioribose derivative and construction of the characteristic 18-membered pyrophosphate ring by Ag+-promoted activation of a phenyl phosphorothioate type substrate were the two key steps. Although 8-NH2-cADPR (2) is a well-known potent antagonist against cADPR-inducing Ca2+-release, the 4-thioribose congener 8-NH2-cADPtR turned out unexpectedly to be a full agonist in sea urchin egg homogenate evaluation system. This important finding suggested that the ring-oxygen in the N1-ribose of cADPR analogues is essential for the antagonistic activity in the Ca2+-signaling pathway, which can contribute to clarify the structure-agonist/antagonist activity relationship.
  • Hideto Maruyama, Ryota Oikawa, Mayu Hayakawa, Shono Takamori, Yasuaki Kimura, Naoko Abe, Genichiro Tsuji, Akira Matsuda, Satoshi Shuto, Yoshihiro Ito, Hiroshi Abe
    NUCLEIC ACIDS RESEARCH 45 12 7042 - 7048 2017年07月 [査読有り][通常論文]
     
    We developed a new approach for chemical ligation of oligonucleotides using the electrophilic phosphorothioester (EPT) group. A nucleophilic phosphorothioate group on oligonucleotides was converted into the EPT group by treatment with Sanger's reagent (1-fluoro-2,4-dinitrobenzene). EPT oligonucleotides can be isolated, stored frozen, and used for the ligation reaction. The reaction of the EPT oligonucleotide and an amino-modified oligonucleotide took place without any extra reagents at pH 7.0-8.0 at room temperature, and resulted in a ligation product with a phosphoramidate bond with a 39-85% yield. Thismethod has potential uses in biotechnology and chemical biology.
  • John C. Walton, Ryutaro Kanada, Takeaki Iwamoto, Satoshi Shuto, Hiroshi Abe
    JOURNAL OF ORGANIC CHEMISTRY 82 13 6886 - 6894 2017年07月 [査読有り][通常論文]
     
    5- to 6-member ring enlargements of 3-oxa-2-silacyclopentylmethyl to 4-oxa-3-silacyclohexyl radicals were investigated by EPR spectroscopy and QM computations of model indano-oxasilacyclopentane and oxasilinanyl compounds. Both experimental and computational evidence favored a mechanism via a concerted 1,2-migration of the "tethered" Si-group. Thus, the "forbidden" 1,2-Si-group migration from carbon to carbon becomes allowed when the Si-group is "tethered". The EPR data from 3-oxa-2-silacyclopentylmethyl radicals disclosed ground state conformations having semioccupied p-orbitals close to antiperiplanar with respect to their beta-Si-C bonds, but indicated Si-hyperconjugation (beta-silicon effect) was insignificant in radicals. Kinetic data was obtained by the steady state EPR method for ring enlargement of indano-3-oxa-2-silacyclopentylmethyl radicals. The scope of the novel rearrangement in terms of other ring types and sizes, as well as the analogous 1,2-migration of "tethered" C-centered groups, was explored computationally.
  • Takanori Matsumaru, Makoto Inai, Kana Ishigami, Toshiki Iwamatsu, Hiroshi Maita, Satoko Otsuguro, Takao Nomura, Akira Matsuda, Satoshi Ichikawa, Masahiro Sakaitani, Satoshi Shuto, Katsumi Maenaka, Toshiyuki Kan
    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 27 10 2144 - 2147 2017年05月 [査読有り][通常論文]
     
    We accomplished divergent synthesis of potent kinase inhibitor BAY 61-3606 (1) and 27 derivatives via conjugation of imidazo[1,2-c]pyrimidine and indole ring compounds with aromatic (including pyridine) derivatives by means of palladium-catalyzed cross-coupling reaction. Spleen tyrosine kinase (Syk) and germinal center kinase (Gck, MAP4K2) inhibition assays showed that some of the synthesized compounds were selective Gck inhibitors. (C) 2017 Elsevier Ltd. All rights reserved.
  • Yasuhiro Wada, Seiji Nakano, Akifumi Morimoto, Ken-ichi Kasahara, Takahiko Hayashi, Yoshio Takada, Hiroko Suzuki, Michiko Niwa-Sakai, Shigeki Ohashi, Mutsuhiro Mori, Takatsugu Hirokawa, Satoshi Shuto
    JOURNAL OF MEDICINAL CHEMISTRY 60 8 3252 - 3265 2017年04月 [査読有り][通常論文]
     
    We previously discovered that indazole derivative 8 was a highly selective beta(3)-adrenergic receptor (beta(3)-AR) agonist, but it appeared to be metabolically unstable. To improve metabolic stability, further optimization of this scaffold was carried out. We focused on the sulfonamide moiety of this scaffold, which resulted in the discovery of compound 15 as a highly potent beta(3)-AR agonist (EC50 = 18 nM) being inactive to beta(1)-, beta(2)-, and alpha(1A)-AR (beta(1)/beta(3), beta(2)/beta(3), and alpha(1A)/beta(3) > 556-fold). Compound 15 showed dose-dependent beta(3)-AR-mediated responses in marmoset urinary bladder smooth muscle, had a desirable metabolic stability and pharmacokinetic profile (Cmax and AUC), and did not obviously affect heart rate or mean blood pressure when administered intravenously (3 mg/kg) to anesthetized rats. Thus, compound 15 is a highly potent, selective, and orally available beta(3)-AR agonist, which may serve as a candidate drug for the treatment of overactive bladder without off-target-based cardiovascular side effects.
  • Naoyuki Hoshiya, Moemi Kondo, Hayato Fukuda, Mitsuhiro Arisawa, Jun’ichi Uenishi, Satoshi Shuto
    Journal of Organic Chemistry 82 5 2535 - 2544 2017年03月03日 [査読有り][通常論文]
     
    © 2017 American Chemical Society. Here we report the construction of highly functionalized chiral 1,1,2,3-tetrasubstituted arylcyclopropanes of medicinal chemical importance using Pd(II)-catalyzed arylation via directing group-mediated C(sp3)-H activation. The key aspect for the effective arylation was control of the substrate conformation based on the characteristic steric and stereoelectronic features of cyclopropane by manipulating the protecting group at the hydroxyl. The arylation with good functional group tolerance is pivotal as the first entry to chiral 1,1,2,3-tetrasubstituted arylcyclopropanes with wide variety of aryl groups, including heteroaryl groups.
  • Kouhei Matsui, Yasuto Kido, Ryosuke Watari, Yousuke Kashima, Yutaka Yoshida, Satoshi Shuto
    CHEMISTRY-A EUROPEAN JOURNAL 23 13 3034 - 3041 2017年03月 [査読有り][通常論文]
     
    The conformation of cyclic peptides is closely related to their physicochemical and biological properties, but their rational design to obtain a conformation with the desired properties is difficult. Herein, we present a new strategy by using conformationally restricted cyclopropane tethers (CPTs) to control the conformation and improve the cell permeability of cyclic peptides regardless of the amino acid sequence. Newly designed cis-or trans-CPTs with three-dimensional structural diversity were introduced into a model cyclic peptide, and the relationship between the conformation of the cyclic peptides and their cell permeability was analyzed. Peptides containing a CPT exhibited conformational diversity due to the characteristic steric feature of cyclopropane, among which peptides containing a CPT, cis-NfCf had remarkably higher cell permeability than peptides containing other CPTs-even superior to that of cyclosporine A, a known permeable cyclic peptide.
  • Stanislav M Cherepanov, Shigeru Yokoyama, Akira Mizuno, Wataru Ichinose, Olga Lopatina, Anna A Shabalova, Alla B Salmina, Yasuhiko Yamamoto, Hiroshi Okamoto, Satoshi Shuto, Haruhiro Higashida
    Pharmacology research & perspectives 5 1 e00290  2017年02月 [査読有り][通常論文]
     
    Oxytocin (OT) is a neuroendocrine nonapeptide that plays an important role in social memory and behavior. Nasal administration of OT has been shown to improve trust in healthy humans and social interaction in autistic subjects in some clinical trials. As a central nervous system (CNS) drug, however, OT has two unfavorable characteristics: OT is short-acting and shows poor permeability across the blood-brain barrier, because it exists in charged form in the plasma and has short half-life. To overcome these drawbacks, an analog with long-lasting effects is required. We previously synthesized the analog, lipo-oxytocin-1 (LOT-1), in which two palmitoyl groups are conjugated to the cysteine and tyrosine residues. In this study, we synthesized and evaluated the analogs lipo-oxytocin-2 (LOT-2) and lipo-oxytocin-3 (LOT-3), which feature the conjugation of one palmitoyl group at the cysteine and tyrosine residues, respectively. In human embryonic kidney-293 cells overexpressing human OT receptors, these three LOTs demonstrated comparably weak effects on the elevation of intracellular free calcium concentrations after OT receptor activation, compared to the effects of OT. The three LOTs and OT exhibited different time-dependent effects on recovery from impaired pup retrieval behavior in sires of CD38-knockout mice. Sires treated with LOT-1 showed the strongest effect, whereas others had no or little effects at 24 h after injection. These results indicated that LOTs have structure-specific agonistic effects, and suggest that lipidation of OT might have therapeutic benefits for social impairment.
  • Akira Mizuno, Tomoshi Kameda, Tomoki Kuwahara, Hideyuki Endoh, Yoshihiko Ito, Shizuo Yamada, Kimiko Hasegawa, Akihito Yamano, Mizuki Watanabe, Mitsuhiro Arisawa, Satoshi Shuto
    Chemistry - A European Journal 23 13 3159 - 3168 2017年 [査読有り][通常論文]
     
    © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Detailed conformational analyses of our previously reported cyclopropane-based peptidomimetics and conformational analysis-driven ligand optimization are described. Computational calculations and X-ray crystallography showed that the characteristic features of cyclopropane function effectively to constrain the molecular conformation in a three-dimensionally diverse manner. Subsequent principal component analysis revealed that the diversity covers the broad chemical space filled by peptide secondary structures in terms of both main-chain and side-chain conformations. Based on these analyses, a lead stereoisomer targeting melanocortin receptors was identified, and its potency and subtype selectivity were improved by further derivatization. The presented strategy is effective not only for designing non-peptidic ligands from a peptide ligand but also for the rational optimization of these ligands based on the plausible target-binding conformation without requiring the three- dimensional structural information of the target and its peptide ligands.
  • Isamu Sugimoto, Tohru Kambe, Tomotaka Okino, Tetsuo Obitsu, Nobukazu Ohta, Taihei Nishiyama, Akihiro Kinoshita, Taku Fujimoto, Hiromu Egashira, Shinsaku Yamane, Satoshi Shuto, Kousuke Tan, Toru Maruyama
    ACS MEDICINAL CHEMISTRY LETTERS 8 1 107 - 112 2017年01月 [査読有り][通常論文]
     
    A novel series of prostaglandin analogues with a seven-membered ring scaffold was designed, synthesized, and evaluated for the functional activation of prostaglandin receptors to identify potent and subtype-selective FP and EP3 dual agonists. Starting from the prostacyclin derivative 5b, a nonselective agonist for prostaglandin receptors, replacement of the core structure with an octahydro-2H-cyclopenta[b]oxepine scaffold led to the discovery of the potent and selective FP and EP3 dual agonist 11b as a lead compound for the development of an antiglaucoma agent.
  • Hayato Fukuda, Ryuta Muromoto, Yuuki Takakura, Kohei Ishimura, Ryutaro Kanada, Daichi Fushihara, Makoto Tanabe, Kotaro Matsubara, Toru Hirao, Koki Hirashima, Hiroshi Abe, Mitsuhiro Arisawa, Tadashi Matsuda, Satoshi Shuto
    Organic Letters 18 24 6224 - 6227 2016年12月16日 [査読有り][通常論文]
     
    © 2016 American Chemical Society. Lipid chemical mediator resolvins with highly potent anti-inflammatory activity can be leads to develop novel anti-inflammatory drugs; however, they are unstable in oxygen due to their characteristic polyunsaturated structures. To solve the problem, CP-RvE2 has been designed and synthesized in which the cis-olefin of RvE2 was replaced with a cyclopropane. CP-RvE2s were much more stable than RvE2 against autoxidation and equipotent or more potent than RvE2. CP-RvE2s were successfully identified as stable equivalents of RvE2.
  • Tai Oura, Kaori Murata, Takao Morita, Akihiro Nezu, Mitsuhiro Arisawa, Satoshi Shuto, Akihiko Tanimura
    ChemBioChem 17 16 1509 - 1512 2016年08月17日 [査読有り][通常論文]
     
    © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Based on the results of our previous adenophostin A structure–activity relationship studies, two fluorescent inositol 1,4,5-trisphosphate (IP3) receptor ligands, fluorescent adenophostin A (FADA) and fluorescent low-affinity ligand (FLL), were designed. Binding of the fluorescent ligands to the fluorescent IP3 sensor in protein-expressing cells caused FRET. This principle was extended to a cell-free assay system by using the fluorescent IP3 sensor bound to agarose beads. The effect of FLL on the FRET signal was reduced by subsequent addition of IP3. The IC50 values of IP3 on the FRET signals were 139.7 and 352.1 nm for 30 and 100 nm FLL, respectively. This method allowed quantitative measurement of IP3 concentrations below 10 nm and was applied to measure cytosolic IP3 concentrations in COS-7 cells and to examine the potency of synthesized adenophostin A analogues.
  • Takatoshi Sato, Mizuki Watanabe, Takayoshi Tsuzuki, Satoshi Takano, Takashi Murayama, Takashi Sakurai, Tomoshi Kameda, Hayato Fukuda, Mitsuhiro Arisawa, Satoshi Shuto
    Journal of Medicinal Chemistry 59 15 7282 - 7286 2016年08月11日 [査読有り][通常論文]
     
    © 2016 American Chemical Society. Cyclic adenosine diphosphate-carbocyclic-ribose (cADPcR, 2) is a stable equivalent of cyclic adenosine diphosphate-ribose (cADPR, 1), a Ca 2+ -mobilizing second messenger. On the basis of the structure-activity relationship of cADPR-related compounds and three-dimensional structural modeling of cADPcR, we designed and synthesized cyclic-ADP-4″α-azidoethyl carbocyclic-ribose (N 3 -cADPcR, 3) to demonstrate that it has a highly potent Ca 2+ -mobilizing activity (EC 50 = 24 nM). N 3 -cADPcR will be a useful precursor for the preparation of biological tools effective to investigate cADPR-mediated signaling pathways.
  • Hayato Fukuda, Saki Ito, Kenji Watari, Chihiro Mogi, Mitsuhiro Arisawa, Fumikazu Okajima, Hitoshi Kurose, Satoshi Shuto
    ACS Medicinal Chemistry Letters 7 5 493 - 497 2016年05月12日 [査読有り][通常論文]
     
    © 2016 American Chemical Society. GPR4, a pH-sensing G protein-coupled receptor, is highly expressed in endothelial cells and may be activated in myocardial infarction due the decreased tissue pH. We are interested in GPR4 antagonists as potential effective pharmacologic tools and/or drug leads for the treatment of myocardial infarction. We investigated the structure-activity relationship of a known GPR4 antagonist 1 as a lead compound to identify 3b as the first potent and selective GPR4 antagonist, whose effectiveness was demonstrated in a mouse myocardial infarction model.
  • Tomomi Nada, Yusuke Yoneshige, Yasuhiro Ii, Takashi Matsumoto, Hiromichi Fujioka, Satoshi Shuto, Mitsuhiro Arisawa
    ACS Catalysis 6 5 3168 - 3171 2016年05月06日 [査読有り][通常論文]
     
    © 2016 American Chemical Society. We have developed a novel nonmetathesis reaction, namely, ruthenium-catalyzed intramolecular [2 + 2] cycloaddition of allenamide-enes, to give heterocycles (i.e., azabicyclo[3.1.1]heptanes). This is the first example of [2 + 2] cycloaddition using a ruthenium carbene catalyst. The reaction proceeds at room temperature, but not under thermal or radical conditions.
  • Jin Kusaka, Satoshi Shuto, Yukiko Imai, Kazuki Ishikawa, Tomo Saito, Kohei Natori, Satoshi Matsuoka, Hiroshi Hara, Kouji Matsumoto
    RESEARCH IN MICROBIOLOGY 167 3 202 - 214 2016年04月 [査読有り][通常論文]
     
    The acidic phospholipid cardiolipin (CL) is localized on polar and septal membranes and plays an important physiological role in Bacillus subtilis cells. ClsA, the enzyme responsible for CL synthesis, is also localized on septal membranes. We found that GFP fusion proteins of the enzyme with NH2-terminal and internal deletions retained septal localization. However, derivatives with deletions starting from the COOH-terminus (Leu482) ceased to localize to the septum once the deletion passed the Ile residue at 448, indicating that the sequence responsible for septal localization is confined within a short distance from the COOH-terminus. Two sequences, Ile436-Leu450 and Leu466-Leu478, are predicted to individually form an amphipathic a-helix. This configuration is known as a membrane targeting sequence (MTS) and we therefore refer to them as MTS2 and MTS1, respectively. Either one has the ability to affect septal localization, and each of these sequences by itself localizes to the septum. Membrane association of the constructs of this enzyme containing the MTSs was verified by subcellular fractionation of the cells. CL synthesis, in contrast, was abolished after deleting just the last residue, Leu482, in the COOH-terminal four amino acid residue sequence, Ser-Pro-Ile-Leu, which is highly conserved among bacterial CL synthases. (C) 2015 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.
  • Kazuya Tatani, Masahiro Hiratochi, Norihiko Kikuchi, Yu Kuramochi, Shinjiro Watanabe, Yuji Yamauchi, Fumiaki Itoh, Masayulu Isaji, Satoshi Shuto
    JOURNAL OF MEDICINAL CHEMISTRY 59 8 3719 - 3731 2016年04月 [査読有り][通常論文]
     
    To test the hypothesis that inhibitors of human concentrative nucleoside transporter 2 (hCNT2) suppress increases in serum urate levels derived from dietary purines, we previously identified adenosine derivative 1 as a potent hCNT2 inhibitor (IC50 = 0.64 mu M), but further study was hampered due to its poor solubility. Here we describe the results of subsequent research to identify more soluble and more potent hCNT2 inhibitors, leading to the discovery of the benzimidazole nucleoside 22, which is the most potent hCNT2 inhibitor (IC50 = 0.062 mu M) reported to date. Compound 22 significantly suppressed the increase in plasma uric acid levels after oral administration of purine nucleosides in rats. Because compound 22 was poorly absorbed orally in rats (F = 0.51%), its pharmacologic action was mostly limited to the gastrointestinal tract. These findings suggest that inhibition of hCNT2 in the gastrointestinal tract can be a promising approach for the treatment of hyperuricemia.
  • Ichinose Wataru, Abe Hiroshi, Shuto Satoshi
    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 251 2016年03月13日 [査読有り][通常論文]
  • Suemasa Akihiro, Kobayashi Takaaki, Fukuda Hayato, Igawa Arisa, Ide Soichiro, Minami Masabumi, Shuto Satoshi
    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 251 2016年03月13日 [査読有り][通常論文]
  • Tomoaki Bessho, Tetsuya Okada, Chihiro Kimura, Takahiro Shinohara, Ai Tomiyama, Akira Imamura, Mitsuru Kuwamura, Kazuhiko Nishimura, Ko Fujimori, Satoshi Shuto, Osamu Ishibashi, Bruno Kilunga Kubata, Takashi Inui
    PLOS NEGLECTED TROPICAL DISEASES 10 1 2016年01月 [査読有り][通常論文]
     
    The metabolic pathway of purine nucleotides in parasitic protozoa is a potent drug target for treatment of parasitemia. Guanosine 5'-monophosphate reductase (GMPR), which catalyzes the deamination of guanosine 5'-monophosphate (GMP) to inosine 5'-monophosphate (IMP), plays an important role in the interconversion of purine nucleotides to maintain the intracellular balance of their concentration. However, only a few studies on protozoan GMPR have been reported at present. Herein, we identified the GMPR in Trypanosoma brucei, a causative protozoan parasite of African trypanosomiasis, and found that the GMPR proteins were consistently localized to glycosomes in T. brucei bloodstream forms. We characterized its recombinant protein to investigate the enzymatic differences between GMPRs of T. brucei and its host animals. T. brucei GMPR was distinct in having an insertion of a tandem repeat of the cystathionine beta-synthase (CBS) domain, which was absent in mammalian and bacterial GMPRs. The recombinant protein of T. brucei GMPR catalyzed the conversion of GMP to IMP in the presence of NADPH, and showed apparent affinities for both GMP and NADPH different from those of its mammalian counterparts. Interestingly, the addition of monovalent cations such as K+ and NH4+ to the enzymatic reaction increased the GMPR activity of T. brucei, whereas none of the mammalian GMPR's was affected by these cations. The monophosphate form of the purine nucleoside analog ribavirin inhibited T. brucei GMPR activity, though mammalian GMPRs showed no or only a little inhibition by it. These results suggest that the mechanism of the GMPR reaction in T. brucei is distinct from that in the host organisms. Finally, we demonstrated the inhibitory effect of ribavirin on the proliferation of trypanosomes in a dose-dependent manner, suggesting the availability of ribavirin to develop a new therapeutic agent against African trypanosomiasis.
  • Mincen Xiao, Naoyuki Hoshiya, Katsumasa Fujiki, Tetsuo Honma, Yusuke Tamenori, Satoshi Shuto, Hiromichi Fujioka, Mitsuhiro Arisawa
    Chemical and Pharmaceutical Bulletin 64 8 1154 - 1160 2016年 [査読有り][通常論文]
     
    © 2016 The Pharmaceutical Society of Japan. A safe, facile and low-leaching (up to 0.17 ppm) sulfur-modified glass-supported palladium nanoparticle catalyst has been developed for the Suzuki-Miyaura coupling of aryl halides with aryl boronic acids. Most notably, this catalyst was highly recyclable and could be used up to 10 times without any discernible decrease in its activity.
  • Naoyuki Hoshiya, Katsumasa Fujiki, Takahisa Taniguchi, Tetsuo Honma, Yusuke Tamenori, Mincen Xiao, Nozomi Saito, Mami Yokoyama, Akira Ishii, Hiromichi Fujioka, Satoshi Shuto, Yoshihiro Sato, Mitsuhiro Arisawa
    Advanced Synthesis and Catalysis 358 15 2449 - 2459 2016年 [査読有り][通常論文]
     
    © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim We have developed a conceptually and methodologically novel self-assembled multilayer nickel nanoparticle (NP) catalyst – sulfur-modified gold-supported Ni NPs (SANi) – for organic synthesis. The SANi catalyst was easily prepared through a three-step procedure involving simultaneous in situ metal NP and nanospace organization. This unique method does not require any conventional preformed template for immobilizing and stabilizing NPs. SANi catalyzes carbon-carbon bond-forming cross-coupling, Kumada coupling, and Negishi coupling reactions under ligand-free conditions and can be used repeatedly for these reactions. Physical analysis of SANi showed that the active species in these reactions are self-assembled multilayer zerovalent Ni NPs with a size of ∼3 nm. (Figure presented.).
  • Tomoaki Bessho, Tetsuya Okada, Chihiro Kimura, Takahiro Shinohara, Ai Tomiyama, Akira Imamura, Mitsuru Kuwamura, Kazuhiko Nishimura, Ko Fujimori, Satoshi Shuto, Osamu Ishibashi, Bruno Kilunga Kubata, Takashi Inui
    PLoS neglected tropical diseases 10 1 e0004339  2016年01月 [査読有り][通常論文]
     
    The metabolic pathway of purine nucleotides in parasitic protozoa is a potent drug target for treatment of parasitemia. Guanosine 5'-monophosphate reductase (GMPR), which catalyzes the deamination of guanosine 5'-monophosphate (GMP) to inosine 5'-monophosphate (IMP), plays an important role in the interconversion of purine nucleotides to maintain the intracellular balance of their concentration. However, only a few studies on protozoan GMPR have been reported at present. Herein, we identified the GMPR in Trypanosoma brucei, a causative protozoan parasite of African trypanosomiasis, and found that the GMPR proteins were consistently localized to glycosomes in T. brucei bloodstream forms. We characterized its recombinant protein to investigate the enzymatic differences between GMPRs of T. brucei and its host animals. T. brucei GMPR was distinct in having an insertion of a tandem repeat of the cystathionine β-synthase (CBS) domain, which was absent in mammalian and bacterial GMPRs. The recombinant protein of T. brucei GMPR catalyzed the conversion of GMP to IMP in the presence of NADPH, and showed apparent affinities for both GMP and NADPH different from those of its mammalian counterparts. Interestingly, the addition of monovalent cations such as K+ and NH4+ to the enzymatic reaction increased the GMPR activity of T. brucei, whereas none of the mammalian GMPR's was affected by these cations. The monophosphate form of the purine nucleoside analog ribavirin inhibited T. brucei GMPR activity, though mammalian GMPRs showed no or only a little inhibition by it. These results suggest that the mechanism of the GMPR reaction in T. brucei is distinct from that in the host organisms. Finally, we demonstrated the inhibitory effect of ribavirin on the proliferation of trypanosomes in a dose-dependent manner, suggesting the availability of ribavirin to develop a new therapeutic agent against African trypanosomiasis.
  • Naoyuki Hoshiya, Kei Takenaka, Satoshi Shuto, Jun'ichi Uenishi
    ORGANIC LETTERS 18 1 48 - 51 2016年01月 [査読有り][通常論文]
     
    A Pd(OAc)(2)-catalyzed alkylation reaction of the tertiary carbon of chiral cydopropane substrates with alkyl iodides and bromides via C(sp(3))-H activation has been developed. This is an elusive example of a C-H activation-mediated alkylation of tertiary carbon to effectively construct a quaternary carbon center. The alkylation proceeded with various alkyl halides, including those of functional groups, to provide a variety of chiral cis- and trans-1,1,2,-trialkyl substituted cydopropanes of medicinal chemical importance.
  • Yuki Fujii, Tsunayoshi Takehara, Takeyuki Suzuki, Hiromichi Fujioka, Satoshi Shuto, Mitsuhiro Arisawa
    Advanced Synthesis and Catalysis 357 18 4055 - 4062 2015年12月14日 [査読有り][通常論文]
     
    © 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. N-Alkyl-N-(2-vinylbenzyl)prop-2-en-1-amine derivatives undergo a one-pot olefin isomerization/aliphatic enamine ring-closing metathesis (RCM)/oxidation/1,3-dipolar cycloaddition sequence with the ruthenium complex, Ru(CO)HCl(PPh3)3, a second generation Hoveyda-Grubbs catalyst, and a 1,3-dipolarophile. Overall, in a single operation the reaction sequence converts simple benzylamine derivatives into isoindolo[1,2-a]isoquinolines with a π-conjugated four-ring system, through three unique ruthenium-catalyzed transformations.
  • Naoko Abe, Ken Matsumoto, Mizuki Nishihara, Yukiko Nakano, Aya Shibata, Hideto Maruyama, Satoshi Shuto, Akira Matsuda, Minoru Yoshida, Yoshihiro Ito, Hiroshi Abe
    SCIENTIFIC REPORTS 5 2015年11月 [査読有り][通常論文]
     
    We recently reported that circular RNA is efficiently translated by a rolling circle amplification (RCA) mechanism in a cell-free Escherichia coli translation system. Recent studies have shown that circular RNAs composed of exonic sequences are abundant in human cells. However, whether these circular RNAs can be translated into proteins within cells remains unclear. In this study, we prepared circular RNAs with an infinite open reading frame and tested their translation in eukaryotic systems. Circular RNAs were translated into long proteins in rabbit reticulocyte lysate in the absence of any particular element for internal ribosome entry, a poly-A tail, or a cap structure. The translation systems in eukaryote can accept much simpler RNA as a template for protein synthesis by cyclisation. Here, we demonstrated that the circular RNA is efficiently translated in living human cells to produce abundant protein product by RCA mechanism. These findings suggest that translation of exonic circular RNAs present in human cells is more probable than previously thought.
  • 細胞膜親和性の高いアンカー修飾トルテロジンの受容体結合特性
    伊藤 由彦, 引山 恵梨子, 川村 周平, 周東 智, 尾上 誠良, 山田 静雄
    日本排尿機能学会誌 26 1 166 - 166 (一社)日本排尿機能学会 2015年09月
  • Yasuhiro Wada, Hiromitsu Shirahashi, Taisuke Iwanami, Masami Ogawa, Seiji Nakano, Akifumi Morirnoto, Ken-ichi Kasahara, Eiichi Tanaka, Yoshio Takada, Shigeki Ohashi, Mutsuhiro Mori, Satoshi Shuto
    JOURNAL OF MEDICINAL CHEMISTRY 58 15 6048 - 6057 2015年08月 [査読有り][通常論文]
     
    Novel indazole derivatives were prepared and evaluated for their biological activity and cardiovascular safety profile as human A-adrenergic receptor (AR) agonists. Although the initial hit compound 5 exhibited significant beta(3)-AR agonistic activity (EC50 = 21 nM), it also exhibited agonistic activity at the alpha(1A)-AR (EC50 = 219 nM, selectivity: alpha(1A)/beta(3) = 10-fold). The major metabolite of 5, which was an oxidative product at the indazole 3-methyl moiety, gave a clue to a strategy for improvement of the selectivity for beta(3)-AR agonistic activity versus au-AR agonistic activity. Thus, modification of the 3-substituent of the indazole moiety effectively improved the selectivity to develop compound 11 with potent beta(3)-AR agonistic activity (EC50 = 13 nM) and high selectivity (alpha(1A)/beta(3) = >769-fold). Compound 11 was also inactive toward beta(1) and beta(2)-ARs and showed dose dependent beta(3)-AR mediated relaxation of marmoset urinary bladder smooth muscle, while it did not obviously affect heart rate or blood pressure (iv, 3 mg/kg) in anesthetized rats.
  • Takatoshi Sato, Takayoshi Tsuzuki, Satoshi Takano, Kohtaro Kato, Hayato Fukuda, Mitsuhiro Arisawa, Satoshi Shuto
    Tetrahedron 71 33 5407 - 5413 2015年07月11日 [査読有り][通常論文]
     
    © 2015 Elsevier Ltd. All rights reserved. As a stable analog of the second messenger cyclic ADP-ribose (cADPR), we designed 4″-azidoethyl-cyclic ADP-carbocylic-ribose (N3-cADPcR). For the synthesis of N3-cADPcR, 1β-amino-2,3-O-isoproplylidene-4α-azidoethyl carbocyclic-ribose (4) having a chiral quaternary stereogenic center is required as the key unit. We successfully synthesized the desired unit 4 via construction of the quaternary stereogenic center by a radical cyclization/ring-enlargement reaction with a silicon-tethered substrate as the key step.
  • Satoshi Takano, Takayoshi Tsuzuki, Takashi Murayama, Takashi Sakurai, Hayato Fukuda, Mitsuhiro Arisawa, Satoshi Shuto
    Journal of Organic Chemistry 80 13 6619 - 6627 2015年07月02日 [査読有り][通常論文]
     
    © 2015 American Chemical Society. Cyclic ADP-carbocyclic-ribose (cADPcR, 3) is a biologically and chemically stable equivalent of cyclic ADP-ribose (cADPR, 1), a Ca2+-mobilizing second messenger. We became interested in the biological activity of the 7-deaza analogues of cADPcR, i.e., 7-deaza-cADPcR (7) and its 7-bromo derivative, i.e., 7-deaza-7-Br-cADPcR (8), because 7-deazaadenosine is an efficient bioisostere of adenosine. The synthesis of 7 and 8 required us to construct the key N1-carbocyclic-ribosyl-7-deazaadenosine structure. Therefore, we developed a general method for preparing N1-substituted 7-deazaadenosines by condensing a 2,3-disubstituted pyrrole nucleoside with amines. Using this method, we prepared the N1-carbocyclic ribosyl 7-deazaadenosine derivative 10a, from which we then synthesized the target 7-deaza-cADPcR (7) via an Ag+-promoted intramolecular condensation to construct the 18-membered pyrophosphate ring structure. The corresponding 7-bromo derivative 8, which was the first analogue of cADPR with a substitution at the 7-position, was similarly synthesized. Biological evaluation for Ca2+-mobilizing activity in the sea urchin egg homogenate system indicated that 7-deaza-cADPcR (7) and 7-deaza-7-Br-cADPcR (8) acted as a full agonist and a partial agonist, respectively.
  • Koji Takagi, Hayato Fukuda, Satoshi Shuto, Akira Otaka, Mitsuhiro Arisawa
    Advanced Synthesis and Catalysis 357 9 2119 - 2124 2015年06月01日 [査読有り][通常論文]
     
    © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. A safe, facile and low-leaching (up to 0.04ppm) method has been developed for the removal of allyl, prenyl and benzyl protecting groups from the corresponding esters, using a sulfur-modified gold-supported palladium (SAPd) nanoparticle catalyst, which is known to be non-flammable. The catalyst itself was found to be recyclable and the reaction appeared to proceed on the surface of the SAPd.
  • Ai Sasaki, Hayato Fukuda, Narumi Shiida, Nobuaki Tanaka, Ayako Furugen, Jiro Ogura, Satoshi Shuto, Nariyasu Mano, Hiroaki Yamaguchi
    ANALYTICAL AND BIOANALYTICAL CHEMISTRY 407 10 2939 - 2940 2015年04月 [査読有り][通常論文]
  • Nozomi Saito, Takahisa Taniguchi, Naoyuki Hoshiya, Satoshi Shuto, Mitsuhiro Arisawa, Yoshihiro Sato
    Green Chemistry 17 4 2358 - 2361 2015年04月 [査読有り][通常論文]
     
    © The Royal Society of Chemistry. A double carbonylation of aryl iodides with amines proceeded smoothly under an atmospheric pressure of carbon monoxide by using palladium nanoparticles (Pd NPs) leached from a sulfur-modified Au-supported palladium material (SAPd), producing α-ketoamides in good to excellent yields. This journal is
  • Nozomi Saito, Takahisa Taniguchi, Naoyuki Hoshiya, Satoshi Shuto, Mitsuhiro Arisawa, Yoshihiro Sato
    Green Chemistry 17 4 2358 - 2361 2015年04月 [査読有り][通常論文]
     
    © The Royal Society of Chemistry. A double carbonylation of aryl iodides with amines proceeded smoothly under an atmospheric pressure of carbon monoxide by using palladium nanoparticles (Pd NPs) leached from a sulfur-modified Au-supported palladium material (SAPd), producing α-ketoamides in good to excellent yields. This journal is
  • Keisuke Yotsuji, Naoyuki Hoshiya, Takaaki Kobayashi, Hayato Fukuda, Hiroshi Abe, Mitsuhiro Arisawa, Satoshi Shuto
    Advanced Synthesis and Catalysis 357 5 1022 - 1028 2015年03月23日 [査読有り][通常論文]
     
    © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. We describe a nickel-catalyzed Suzuki-Miyaura arylation of a tertiary iodocyclopropane with arylboronic acids; this is an efficient and convergent strategy for providing various enantioenriched arylcyclopropanes with a quaternary stereogenic center. This is the first metal-catalyzed coupling between a tertiary alkyl electrophile and a wide range of aromatics, including heteroaromatics. We found that the outcome of the Ni-catalyzed coupling with halides as electrophiles was dependent on the stability of the radical species formed during the reaction. The use of tert-butyl alcohol (t-BuOH) as the reaction solvent was very effective, because of its stability under the radical-generating reaction conditions.
  • Kazuya Tatani, Masahiro Hiratochi, Yoshinori Nonaka, Masayuki Isaji, Satoshi Shuto
    ACS MEDICINAL CHEMISTRY LETTERS 6 3 244 - 248 2015年03月 [査読有り][通常論文]
     
    Purine-rich foods have long been suspected as a major cause of hyperuricemia. We hypothesized that inhibition of human concentrative nucleoside transporter 2 (hCNT2) would suppress increases in serum urate levels derived from dietary purines. To test this hypothesis, the development of potent hCNT2 inhibitors was required. By modifying adenosine, an hCNT2 substrate, we successfully identified 8-aminoadenosine derivatives as a new class of hCNT2 inhibitors. Compound 12 moderately inhibited hCNT2 (IC50 = 52 +/- 3.8 mu M), and subsequent structure-activity relationship studies led to the discovery of compound 48 (IC50 = 0.64 +/- 0.19 mu M). Here we describe significant findings about structural requirements of 8-aminoadenosine derivatives for exhibiting potent hCNT2 inhibitory activity.
  • Ai Sasaki, Hayato Fukuda, Narumi Shiida, Nobuaki Tanaka, Ayako Furugen, Jiro Ogura, Satoshi Shuto, Nariyasu Mano, Hiroaki Yamaguchi
    ANALYTICAL AND BIOANALYTICAL CHEMISTRY 407 6 1625 - 1639 2015年02月 [査読有り][通常論文]
     
    The omega-6 and omega-3 polyunsaturated fatty acids (PUFAs) such as arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) are the precursors of various bioactive lipid mediators including prostaglandins, thromboxanes, leukotrienes, hydroxyeicosatetraenoic acid, isoprostanes, lipoxins, and resolvins (Rvs). These lipid mediators play important roles in various physiological and pathological processes. The quantitative determination of PUFA metabolites seems necessary for disease research and for developing biomarkers. However, there is a paucity of analytical methods for the quantification of omega-6 and omega-3 PUFA metabolites-the specialized pro-resolving mediators (SPMs) present in the human urine. We developed a method for the quantification of omega-6 and omega-3 PUFA metabolites present in human urine using ultra-performance liquid chromatography/tandem mass spectrometry (UPLC/MS/MS). The developed method shows good linearity, with a correlation coefficient > 0.99 for all of the analytes. The validation results indicate that our method is adequately reliable, accurate, and precise. The method was successfully used to examine urine samples obtained from 43 healthy volunteers. We could identify 20 PUFA metabolites, and this is the first report of the quantitative determination of RvD1, 17(R)-RvD1, 11-dehydro thromboxane B-3, RvE2, and 5(S)-HETE in human urine. The urinary 8-iso PGF(2 alpha) and PGE(2) levels were significantly higher in the men smokers than in the men nonsmokers (p < 0.05). In this study, we developed an accurate, precise, and novel analytical method for estimating the omega-6 and omega-3 PUFA metabolites, and this is the first report that the SPMs derived from EPA and DHA are present in human urine.
  • Akira Mizuno, Stanislav M Cherepanov, Yusuke Kikuchi, Azam Akm Fakhrul, Shirin Akther, Kisaburo Deguchi, Toru Yoshihara, Katsuhiko Ishihara, Satoshi Shuto, Haruhiro Higashida
    Brain sciences 5 1 3 - 13 2015年01月20日 [査読有り][通常論文]
     
    Oxytocin (OT) is a nonapeptide hormone that is secreted into the brain and blood circulation. OT has not only classical neurohormonal roles in uterine contraction and milk ejection during the reproductive phase in females, but has also been shown to have new pivotal neuromodulatory roles in social recognition and interaction in both genders. A single administration of OT through nasal spray increases mutual recognition and trust in healthy subjects and psychiatric patients, suggesting that OT is a potential therapeutic drug for autism spectrum disorders, schizophrenia, and some other psychiatric disorders. Although the mechanism is not well understood, it is likely that OT can be transported into the brain where it activates OT receptors to exert its function in the brain. However, the amount transported into the brain may be low. To ensure equivalent effects, an OT analog with long-lasting and effective blood-brain barrier penetration properties would be beneficial for use as a therapeutic drug. Here, we designed and synthesized a new oxytocin analog, lipo-oxytocin-1 (LOT-1), in which two palmitoyl groups are conjugated at the amino group of the cysteine9 residue and the phenolic hydroxyl group of the tyrosine8 residue of the OT molecule. To determine whether LOT-1 actually has an effect on the central nervous system, we examined its effects in a CD157 knockout model mouse of the non-motor psychiatric symptoms of Parkinson's disease. Similar to OT, this analog rescued anxiety-like behavior and social avoidance in the open field test with the social target in a central arena 30 min after intraperitoneal injection in CD157 knockout mice. When examined 24 h after injection, the mice treated with LOT-1 displayed more recovery than those given OT. The results suggest that LOT-1 has a functional advantage in recovery of social behavioral impairment, such as those caused by neurodegenerative diseases, autism spectrum disorders, and schizophrenia.
  • Mitsuhiro Arisawa, Atsushi Nishida, Satoshi Shuto
    Yuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry 73 3 254 - 265 2015年 [査読有り][通常論文]
     
    We have established aromatic enamide-ene metathesis to give highly substituted indole derivatives. This is a new method for the preparation of chiral 2-trans-cyclopropyl indoles, which successfully led to our H 4 antagonist candidates. Based on this findings, we also designed and synthesized conformationally restricted analogues and regioisomers of the nonsteroidal anti-inflammatory drug indomethacin. Evaluation of the inhibitory effects of these compounds on COX, P-glycoprotein, and multidrug-resistance indicated that NSAIDS modulation of multidrug resistant P-glycoprotein and multidrug-resistant protein-1 is not associated with COX-1 and COX-2 inhibitory activities.
  • Nozomi Saito, Takahisa Taniguchi, Naoyuki Hoshiya, Satoshi Shuto, Mitsuhiro Arisawa, Yoshihiro Sato
    GREEN CHEMISTRY 17 4 2358 - 2361 2015年 [査読有り][通常論文]
     
    A double carbonylation of aryl iodides with amines proceeded smoothly under an atmospheric pressure of carbon monoxide by using palladium nanoparticles (Pd NPs) leached from a sulfur-modified Au-supported palladium material (SAPd), producing alpha-ketoamides in good to excellent yields.
  • Mitsuhiro Arisawa, Mohammad Al-Amin, Tetsuo Honma, Yusuke Tamenori, Satoshi Arai, Naoyuki Hoshiya, Takatoshi Sato, Mami Yokoyama, Akira Ishii, Masaki Takeguchi, Tsuyoshi Miyazaki, Masashi Takeuchi, Tomohiro Maruko, Satoshi Shuto
    RSC Advances 5 1 676 - 683 2015年 [査読有り][通常論文]
     
    © The Royal Society of Chemistry. The structure of a recently developed Pd catalyst, named sulfur-modified gold-supported palladium (SAPd), has been determined to be composed of multi-layered Pd nanoparticles. SAPd is easily prepared by self-assembly on a sulfur-modified gold surface, and near-edge X-ray absorption fine structure (NEXAFS) analysis at the Pd K-edge determined that the Pd in SAPd is zero-valence analogous to metallic Pd. However, transmission electron microscopy (TEM) analyses and extended X-ray absorption fine structure (EXAFS) analysis clarified that SAPd has approximately 10 layers and consists of nanoparticles with a diameter less than 5 nm. High-density Pd nanoparticles were embedded without condensation. NEXAFS analysis at the S and C K-edge revealed that the organic matter containing sulfate and xylene as a major ingredient is distributed between Pd nanoparticles, and it seems to prevent condensation. These findings suggest that a highly efficient cross-coupling reaction, which was reported in earlier works, has been achieved by the high-density Pd nanoparticles. This journal is
  • Ayaka Tobo, Masayuki Tobo, Takashi Nakakura, Masashi Ebara, Hideaki Tomura, Chihiro Mogi, Dong-Soon Im, Naoya Murata, Atsushi Kuwabara, Saki Ito, Hayato Fukuda, Mitsuhiro Arisawa, Satoshi Shuto, Michio Nakaya, Hitoshi Kurose, Koichi Sato, Fumikazu Okajima
    PloS one 10 6 e0129334  2015年 [査読有り][通常論文]
     
    G protein-coupled receptor 4 (GPR4), previously proposed as the receptor for sphingosylphosphorylcholine, has recently been identified as the proton-sensing G protein-coupled receptor (GPCR) coupling to multiple intracellular signaling pathways, including the Gs protein/cAMP and G13 protein/Rho. In the present study, we characterized some imidazopyridine compounds as GPR4 modulators that modify GPR4 receptor function. In the cells that express proton-sensing GPCRs, including GPR4, OGR1, TDAG8, and G2A, extracellular acidification stimulates serum responsive element (SRE)-driven transcriptional activity, which has been shown to reflect Rho activity, with different proton sensitivities. Imidazopyridine compounds inhibited the moderately acidic pH-induced SRE activity only in GPR4-expressing cells. Acidic pH-stimulated cAMP accumulation, mRNA expression of inflammatory genes, and GPR4 internalization within GPR4-expressing cells were all inhibited by the GPR4 modulator. We further compared the inhibition property of the imidazopyridine compound with psychosine, which has been shown to selectively inhibit actions induced by proton-sensing GPCRs, including GPR4. In the GPR4 mutant, in which certain histidine residues were mutated to phenylalanine, proton sensitivity was significantly shifted to the right, and psychosine failed to further inhibit acidic pH-induced SRE activation. On the other hand, the imidazopyridine compound almost completely inhibited acidic pH-induced action in mutant GPR4. We conclude that some imidazopyridine compounds show specificity to GPR4 as negative allosteric modulators with a different action mode from psychosine, an antagonist susceptible to histidine residues, and are useful for characterizing GPR4-mediated acidic pH-induced biological actions.
  • Hisashi Shimada, Kazuhiro Haraguchi, Kumi Hotta, Tomoko Miyaike, Yasuyuki Kitagawa, Hiromichi Tanaka, Ryutaro Kaneda, Hiroshi Abe, Satoshi Shuto, Kyoko Mori, Youki Ueda, Nobuyuki Kato, Robert Snoeck, Graciela Andrei, Jan Balzarini
    BIOORGANIC & MEDICINAL CHEMISTRY 22 21 6174 - 6182 2014年11月 [査読有り][通常論文]
     
    Upon reacting 3',4'-unsaturated cytosine (8 and 9) and adenine nucleosides (13 and 14) with XeF2/BF3 center dot OEt2, the respective novel 3',4'-difluoro-3'-deoxyribofuranosyl nucleosides (10-12 and 15-18) could be obtained. Formation of anti-adducts (11, 16 and 18) revealed that the fluorination involved oxonium ions as incipient intermediates. TBDMS-protected 3',4'-unsaturated adenosine provided the beta-face adducts as sole stereoisomers whereas a-face-selectivity was observed with the TBDPS-protected adenosine 14. The evaluation of the novel 3'-deoxy-3',4'-difluororibofuranosylcytosine-(19-21) and adenine nucleosides (22-25) against antitumor and antiviral activities revealed that 3',4'-difluorocordycepin (24) was found to possess anti-HCV activity. The SI of 24 was comparable to that of the anti-HCV drug ribavirin. However, sofosbuvir, FDA-approved novel anti-HCV drug, showed better SI value. Our finding revealed that the introduction of the fluoro-substituent into the 4'-position of cordycepin derivatives decreased the cytotoxicity to the host cell with retention of the antiviral activity. (C) 2014 Elsevier Ltd. All rights reserved.
  • Aya Shibata, Yukiko Nakano, Mika Ito, Mika Araki, Jie Zhang, Yasuhiko Yoshida, Satoshi Shuto, Bengt Mannervik, Ralf Morgenstern, Yoshihiro Ito, Hiroshi Abe
    ANALYST 139 17 4382 - 4382 2014年09月 [査読有り][通常論文]
  • Takaaki Kobayashi, Akihiro Suemasa, Arisa Igawa, Soichiro Ide, Hayato Fukuda, Hiroshi Abe, Mitsuhiro Arisawa, Masabumi Minami, Satoshi Shuto
    ACS Medicinal Chemistry Letters 5 8 889 - 893 2014年08月14日 [査読有り][通常論文]
     
    On the basis of the three-dimensional diversity-oriented conformational restriction strategy using key chiral cyclopropane units, we previously identified 3 ((2S,3R)-4-amino-3,4-methanobutyric acid) with a chiral trans-cyclopropane structure as a γ-aminobutyric acid (GABA) transporter inhibitor selective for GABA transporter (GAT) subtypes GAT-3 and BGT-1 (betaine/GABA transporter-1). Further conformational restriction of 3 with the rigid bicyclo[3.1.0]hexane backbone led to the successful development of the first highly potent and selective BGT-1 inhibitor 4 (IC50 = 0.59 μM). The bioactive conformation of 3 for BGT-1 was also identified. © 2014 American Chemical Society.
  • Koji Takagi, Mohammad Al-Amin, Naoyuki Hoshiya, Johan Wouters, Hiroshi Sugimoto, Yoshitsugu Shiro, Hayato Fukuda, Satoshi Shuto, Mitsuhiro Arisawa
    Journal of Organic Chemistry 79 13 6366 - 6371 2014年07月03日 [査読有り][通常論文]
     
    A sulfur-modified gold-supported palladium material (SAPd) has been developed bearing palladium nanoparticles on its surface. Herein, we report for the first time the use of SAPd to affect a Pd-nanoparticle-catalyzed 1,7-Pd migration reaction for the synthesis of benzotriazoles via C-H bond activation. The resulting benzotriazoles were evaluated in terms of their inhibitory activity toward indoleamine 2,3-dioxygenase. © 2014 American Chemical Society.
  • Mika Ito, Satoshi Shuto, Yoshihiro Ito, Hiroshi Abe
    JOURNAL OF SYNTHETIC ORGANIC CHEMISTRY JAPAN 72 7 822 - 831 2014年07月 [査読有り][通常論文]
     
    Glutathione S-transferase (GST) are phase II enzymes that catalyze the nucleophilic attack of glutathione (GSH) to a wide range of hydrophobic and electrophilic compounds. GST is of high clinical interest in inflammation, pathophysiology and tumor drug resistance. In addition, GST is known to highly express in cancer cells. Therefore, we tried to develop new luminescent probes that can detect and image GST expression in living cells. Recently, we found that the electrophilic centre in the dinitrobenzenesulfonamide derivative is attacked by GSH and that this reaction is catalyzed by GST releasing the strong fluorophore. Based on this knowledge, we synthesized fluorescent probe, F-19 MRI probe, and bioluminogenic probe. The fluorescent probe and kinetic parameters for purified GST were giving a rate enhancement of 10(6) compared with the nonenzymatic reaction. In addition, fluorescent probe successfully image GST in living cells. The fluorescent probe is potentially useful reagent for detection of GST activity in living cells. F-19 MRI and bioluminogenic probes were synthesized using 4-acetyl-2-nitrobenzenesulfonyl group. F-19 MRI probe exhibited a peak shift of F-19 MRI signal and fluorescence enhancement in a bimodal way in response to GST activity. Bioluminogenic probe provided strong bioluminescence from GST activity. Moreover, both probes were successfully applied to the monitoring of GST expression in living E. coli cells. Successful detection of GST activity in living cells could be very useful for identifying tumor cells that overexpress GSTs.
  • Shuhei Kawamura, Yuka Unno, Akira Asai, Mitsuhiro Arisawa, Satoshi Shuto
    Bioorganic and Medicinal Chemistry 22 12 3091 - 3095 2014年06月15日 [査読有り][通常論文]
     
    Proteasome inhibitors are currently a focus of increased attention as anticancer drug candidates. We recently performed systematic structure-activity relationship studies of the peptidic natural product belactosin A and identified non-peptidic derivative 2 as a highly potent proteasome inhibitor. However, the cell growth inhibitory effect of 2 is only moderate, probably due to the biologically unstable β-lactone warhead. Peptide epoxyketones are an important class of proteasome inhibitors exhibit high potency in cellular systems based on the efficient α,β-epoxyketone warhead. Importantly, belactosin derivatives bind primarily to the primed binding site, while peptide epoxyketones bind only to the non-primed binding site of proteasome, suggesting that hybridization of them might lead to the development of a new class of proteasome inhibitors. Thus, we successfully identified a novel chemotype of proteasome inhibitors 3 and 4 by rational structure-based design, which are expected to bind to both the primed and non-primed binding sites of proteasome. © 2014 Elsevier Ltd. All rights reserved.
  • Tsuzuki T, Takano S, Sakaguchi N, Kudoh T, Murayama T, Sakurai T, Hashii M, Higashida H, Weber K, Guse AH, Kameda T, Hirokawa T, Kumaki Y, Arisawa M, Potter BV, Shuto S, Messenger, Los Angeles, Calif, Print), v
    Messenger (Los Angeles, Calif. : Print) 3 1-2 35 - 51 2014年06月 [査読有り][通常論文]
     
    Tsuzuki T, Takano S, Sakaguchi N, Kudoh T, Murayama T, Sakurai T, Hashii M, Higashida H, Weber K, Guse AH, Kameda T, Hirokawa T, Kumaki Y, Arisawa M, Potter BV, Shuto S, Messenger (Los Angeles, Calif. : Print), 2014, vol. 3, no. 1-2, pp. 35-51
  • Mitsuhiro Arisawa, Takatoshi Sato, Naoyuki Hoshiya, Mohammad Al-Amin, Yuji Kogami, Satoshi Shuto
    ACS Combinatorial Science 16 5 215 - 220 2014年05月12日 [査読有り][通常論文]
     
    A conformationally restricted privileged structure library with stereochemical diversity for a "fragment growth" methodology comprising 90 compounds was designed and systematically and efficiently synthesized using sulfur-modified Au-supported Pd (SAPd)-catalyzed ligand-free Suzuki-Miyaura coupling of vinyl iodide promoted by microwave and subsequent amidation in liquid-phase combinatorial chemistry as key reactions. Evaluation of the compounds with a 20-kinase panel indicated the usefulness of this "fragment growth" methodology for finding hit library compounds for fragment-based drug discovery. © 2014 American Chemical Society.
  • Mohammad Al-Amin, Mitsuhiro Arisawa, Satoshi Shuto, Yusuke Ano, Mamoru Tobisu, Naoto Chatani
    Advanced Synthesis and Catalysis 356 7 1631 - 1637 2014年05月05日 [査読有り][通常論文]
     
    We have developed a sulfur-modified, gold-supported palladium material (SAuPd) with palladium, Pd, nanoparticles on its surface; it is a recyclable, low-leaching Pd catalyst. Here we report, using SAuPd, the first example of Pd nanoparticle-catalyzed, unactivated C(sp3)-H bond functionalization of amides, using 8-aminoquinoline as a directing group, to yield ethynylated products. The low leaching properties of SAuPd enabled it to be recycled and reused 10 times for C(sp3)-H bond functionalization. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
  • Shuhei Kawamura, Yuka Unno, Akira Asai, Mitsuhiro Arisawa, Satoshi Shuto
    Journal of Medicinal Chemistry 57 6 2726 - 2735 2014年03月27日 [査読有り][通常論文]
     
    We previously developed highly potent proteasome inhibitor 1 (IC 50 = 5.7 nM) and its nonpeptide derivative 2 (IC50 = 29 nM) by systematic structure-activity relationship studies of the peptidic natural product belactosin A and subsequent rational topology-based scaffold hopping, respectively. Their cell growth inhibitory activities, however, were only moderate (IC50 = 1.8 μM (1) and >10 μM (2)). We therefore planned to replace the unstable β-lactone warhead with a more stable boronic acid warhead. Importantly, belactosin derivatives bind mainly to the proteasome binding site, which is different from that occupied by known peptide boronate proteasome inhibitors such as bortezomib, suggesting that their hybridization might lead to the development of novel potent inhibitors. Here we describe design, synthesis, and biological activities of the newly developed potent hybrid proteasome inhibitors. Interestingly, these hybrids, unlike bortezomib, were highly selective for proteasomes and have long residence times despite having the same boronic acid warhead. © 2014 American Chemical Society.
  • Shuhei Kawamura, Yuka Unno, Takatsugu Hirokawa, Akira Asai, Mitsuhiro Arisawa, Satoshi Shuto
    Chemical Communications 50 19 2445 - 2447 2014年03月07日 [査読有り][通常論文]
     
    Rational scaffold hopping of a natural product belactosin A derivative was successfully achieved based on the pharmacophore model constructed. The peptidic scaffold was replaced by significantly simplified non-peptidic scaffolds, by which weak belactosin A (IC50 = 1440 nM) was converted into highly potent non-peptidic inhibitors (IC50 = 26-393 nM). © 2014 The Royal Society of Chemistry.
  • Hideto Maruyama, Akira Matsuda, Satoshi Shuto, Yoshihiro Ito, Hiroshi Abe
    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 247 2014年03月 [査読有り][通常論文]
  • Aya Shibata, Hiroshi Abe, Takanori Uzawa, Yukiko Nakano, Satoshi Shuto, Yoshihiro Ito
    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 247 2014年03月 [査読有り][通常論文]
  • Hayato Fukuda, Yuuki Takakura, Kohei Ishimura, Mitsuhiro Arisawa, Satoshi Shuto
    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 247 2014年03月 [査読有り][通常論文]
  • Hideto Maruyama, Yuko Nakashima, Satoshi Shuto, Akira Matsuda, Yoshihiro Ito, Hiroshi Abe
    CHEMICAL COMMUNICATIONS 50 11 1284 - 1287 2014年 [査読有り][通常論文]
     
    Here we report a new strategy for the buildup reaction of active siRNA species from short RNA fragments in living cells using a chemical ligation reaction. This strategy could decrease undesired immune responses and provide more latitude for RNAi technology in the design and concentration of introduced RNA compared to traditional siRNA methods.
  • 柴田 綾, 鵜澤 尊規, 伊藤 嘉浩, 周東 智, 阿部 洋
    化学と生物 52 11 771 - 776 Japan Society for Bioscience, Biotechnology, and Agrochemistry 2014年
  • Aya Shibata, Yukiko Nakano, Mika Ito, Mika Araki, Jie Zhang, Yasuhiko Yoshida, Satoshi Shuto, Bengt Mannervik, Ralf Mogenstern, Yoshihiro Ito, Hiroshi Abe
    Analyst 138 24 7326 - 7330 2013年12月21日 [査読有り][通常論文]
     
    We have synthesized a series of 4-substituted-2-nitrobenzene-sulfonyl compounds for caged fluorogenic probes and conducted a Hammett plot analysis using the steady-state kinetic parameters. The results revealed that the glutathione transferase (GST) alpha catalyzed reaction was dependent on the σ value in the same way as the non-enzymatic reaction, whereas the dependence of the σ value of the GST mu and pi was not as pronounced as that of GST alpha. © 2013 The Royal Society of Chemistry.
  • Naoyuki Hoshiya, Takaaki Kobayashi, Mitsuhiro Arisawa, Satoshi Shuto
    Organic Letters 15 24 6202 - 6205 2013年12月20日 [査読有り][通常論文]
     
    Pd(II)-catalyzed tertiary C(sp3)-H arylation of cyclopropanes via directing group-mediated C-H activation for the construction of a chiral quaternary carbon center on cyclopropanes using aryl iodides as a coupling partner is reported. The arylation had a wide substrate scope and good functional group tolerance, including heteroaryl iodides, to provide various chiral arylcyclopropanes with the cis- and trans-1,1,2-trisubstituted structures. © 2013 American Chemical Society.
  • Makoto Tanabe, Mizuki Watanabe, Naoyuki Hoshiya, Akira Mizuno, Hayato Fukuda, Mitsuhiro Arisawa, Satoshi Shuto
    Journal of Organic Chemistry 78 23 11714 - 11720 2013年12月06日 [査読有り][通常論文]
     
    A preparative method for an optically active bromomethylenecyclopropane unit and its practical conversion to (Z)-cyclopropane-containing chiral compounds via Suzuki-Miyaura coupling were established. © 2013 American Chemical Society.
  • Yutaka Kubota, Yuri Kaneda, Kazuhiro Haraguchi, Mirei Mizuno, Hiroshi Abe, Satoshi Shuto, Takayuki Hamasaki, Masanori Baba, Hiromichi Tanaka
    TETRAHEDRON 69 51 10884 - 10892 2013年12月 [査読有り][通常論文]
     
    The key glycosyl donor for the target molecule 12 was prepared by two-step sequences; (1) acetalization of tert-butyldimethylsilyloxyacetaldehyde with 3-bromopropanediol, (2) DBN-initiated 13-elimination of the resulting 2-(tert-butyldimethylsilyloxy)methy1-4-bromomethy1-1,3-dioxolane 11. Electrophilic glycosidation between 12 and silylated pyrimidine nucleobase proceeded efficiently to provide a mixture of 13- and cc-anomers of the respective glycosides 14 and 15. Tin radical-mediated reduction of the bromomethyl functional group of 14 and 15 gave protected 4'-C-methyl-dioxorane uracil- 16 and thymine nucleoside 17. The respective cytosine nucleoside 18 was synthesized from 16. De-silylation of 4'-methyll',3'-dioxolane pyrimidine nucleosides 16-18 gave the target molecules. Evaluation of the anti-HIV-1 activity of the r3- and cc-anomers of the novel 4'-C-methyl-1',3'-dioxolane nucleosides 2213,a-2413,cx revealed that none of the nucleoside derivatives possess anti-viral activity against HIV-1 and show cytotoxicity against MT-4 cells at 100 pl. (C) 2013 Elsevier Ltd. All rights reserved.
  • Shibata Aya, Nakano Yukiko, Ito Mika, Araki Mika, Zhang Jie, Yoshida Yasuhiko, Shuto Satoshi, Mannervik Bengt, Mogenstern Ralf, Ito Yoshihiro, Abe Hiroshi
    The Analyst 138 24 7326 - 7330 2013年11月 [査読有り][通常論文]
     
    We havesynthesized a series of 4-substituted-2-nitrobenzene-sulfonyl compounds for caged fluorogenic probes and conducted a Hammett plot analysis using the steady-state kinetic parameters. The results revealed that the glutathione transferase (GST) alpha catalyzed reaction was dependent onthe σ value in the same way as the non-enzymatic reaction, whereas the dependence of the σ value of the GST mu and pi was not as pronounced as that of GST alpha.
  • Shuji Yonezawa, Kenichiro Fujiwara, Takahiko Yamamoto, Kazunari Hattori, Hidekuni Yamakawa, Chie Muto, Motoko Hosono, Yoshikazu Tanaka, Toru Nakano, Hiroshi Takemoto, Mitsuhiro Arisawa, Satoshi Shuto
    Bioorganic and Medicinal Chemistry 21 21 6506 - 6522 2013年11月01日 [査読有り][通常論文]
     
    For further investigation of BACE1 inhibitors using conformational restriction with sp3 hybridized carbon, we applied this approach to 6-substituted aminopyrimidone derivatives 3 to improve the inhibitory activity by reducing the entropic energy loss upon binding to BACE1. Among eight stereoisomers synthesized, [trans-(1′R,2′R),6S] isomer 6 exhibited the best BACE1 inhibitory activity, which was statistically superior to that of the corresponding ethylene linker compound (R)-3. Combinational examinations of the binding mode of 6 were performed, which included isothermal titration calorimetry (ITC), X-ray crystallographic structure analysis and theoretical calculations, to clarify the effect of our conformational restriction approach. From the ITC measurement, the binding entropy of 6 was found to be ∼0.5 kcal larger than that of (R)-3, which is considered to be affected by conformational restriction with a cyclopropane ring. © 2013 Elsevier Ltd. All rights reserved.
  • Shuhei Kawamura, Yuka Unno, Akira Asai, Mitsuhiro Arisawa, Satoshi Shuto
    Organic and Biomolecular Chemistry 11 38 6615 - 6622 2013年10月14日 [査読有り][通常論文]
     
    The belactosin A analog 2a, having the unnatural cis-cyclopropane structure instead of the trans-cyclopropane structure in belactosin A, is a much more potent proteasome inhibitor than belactosin A. However, its cell growth inhibitory effect is rather lower than that expected from its remarkable proteasome inhibitory effect, probably due to its instability under cellular conditions. We hypothesized that the instability of 2a was due to chemical and enzymatic hydrolysis of the strained β-lactone moiety. Thus, to increase the stability of 2a by chemical modification, its analogs with a sterically more hindered β-lactone moiety and/or cyclopropylic strain-based conformational restriction were designed and synthesized, resulting in the identification of a stabilized analog 6a as a proteasome inhibitor with cell growth inhibitory effects. Our findings suggest that the chemical and biological stability of 2a is significantly affected by the steric hindrance around its β-lactone carbonyl moiety and the conformational flexibility of the molecule. © 2013 The Royal Society of Chemistry.
  • Shibata Aya, Uzawa Takanori, Nakashima Yuko, Ito Mika, Nakano Yukiko, Shuto Satoshi, Ito Yoshihiro, Abe Hiroshi
    Journal of the American Chemical Society 135 38 14172 - 14178 2013年09月 [査読有り][通常論文]
     
    Oligonucleotide-templated reactions are powerful tools for the detection of nucleic acid sequences.One of the major scientific challenges associated with this technique is the rational design of non-enzyme-mediated catalytic templated reactions capable of multiple turnovers that provide high levels of signal amplification. Herein, we reportthe development of a nucleophilic aromatic substitution reaction-triggered fluorescent probe. The probe underwent a rapid templated reaction without any of the undesired background reactions. The fluorogenic reaction conducted in the presence of a template provided a 223-fold increase in fluorescence after 30 s compared with the nontemplated reaction. The probe provided an efficient level of signal amplification that ultimately enabled particularly sensitive levels of detection. Assuming a simple model for the templated reactions, it was possible to estimate the rate constants of the chemical reaction in the presence and in the absence of the template. From these kinetic analyses, it was possible to confirm that an efficient turnover cycle had been achieved, on the basis of the dramatic enhancement in the rate of the chemical reaction considered
  • Kazuaki Nakada, Mamie Yoshikawa, Soichiro Ide, Akihiro Suemasa, Shuhei Kawamura, Takaaki Kobayashi, Eiji Masuda, Yoshihiko Ito, Wataru Hayakawa, Takahiro Katayama, Shizuo Yamada, Mitsuhiro Arisawa, Masabumi Minami, Satoshi Shuto
    Bioorganic and Medicinal Chemistry 21 17 4938 - 4950 2013年09月01日 [査読有り][通常論文]
     
    A series of cyclopropane-based conformationally restricted γ-aminobutyric acid (GABA) analogs with stereochemical diversity, that is, the trans- and cis-2,3-methano analogs Ia and Ib and their enantiomers ent-Ia and ent-Ib, and also the trans- and cis-3,4-methano analogs IIa and IIb and their enantiomers ent-IIa and ent-Iib, were synthesized from the chiral cyclopropane units Type-a and Type-b that we developed. These analogs were systematically evaluated with four GABA transporter (GAT) subtypes. The trans-3,4-methano analog IIa had inhibitory effects on GAT3 (IC50 = 23.9 μM) and betaine-GABA transporter1 (5.48 μM), indicating its potential as an effective lead compound for the development of potent GAT inhibitors due to its hydrophilic and low molecular weight properties and excellent ligand efficiency. © 2013 Elsevier Ltd. All rights reserved.
  • Aya Shibata, Takanori Uzawa, Yuko Nakashima, Mika Ito, Yukiko Nakano, Satoshi Shuto, Yoshihiro Ito, Hiroshi Abe
    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 135 38 14172 - 14178 2013年09月 [査読有り][通常論文]
     
    Oligonucleotide-templated reactions are powerful tools for the detection of nucleic acid sequences. One of the major scientific challenges associated with this technique is the rational design of non-enzyme-mediated catalytic templated reactions capable of multiple turnovers that provide high levels of signal amplification. Herein, we report the development of a nucleophilic aromatic substitution reaction-triggered fluorescent probe. The probe underwent a rapid templated reaction without any of the undesired background reactions. The fluorogenic reaction conducted in the presence of a template provided a 223-fold increase in fluorescence after 30 s compared with the nontemplated reaction. The probe provided an efficient level of signal amplification that ultimately enabled particularly sensitive levels of detection. Assuming a simple model for the templated reactions, it was possible to estimate the rate constants of the chemical reaction in the presence and in the absence of the template. From these kinetic analyses, it was possible to confirm that an efficient turnover cycle had been achieved, on the basis of the dramatic enhancement in the rate of the chemical reaction considered to be the rate-determining step. With maximized turnover efficiency, it was demonstrated that the probe could offer a high turnover number of 1500 times to enable sensitive levels of detection with a detection limit of 0.5 pM in the catalytic templated reactions.
  • Mohammad Al-Amin, Satoshi Arai, Naoyoki Hoshiya, Tetsuo Honma, Yusuke Tamenori, Takatoshi Sato, Mami Yokoyama, Akira Ishii, Masashi Takeuchi, Tomohiro Maruko, Satoshi Shuto, Mitsuhiro Arisawa
    Journal of Organic Chemistry 78 15 7575 - 7581 2013年08月02日 [査読有り][通常論文]
     
    An improved process for the preparation of sulfur-modified gold-supported palladium material [SAPd, second generation] is presented. The developed preparation method is safer and generates less heat (aqueous Na 2S2O8 and H2SO4) for sulfur fixation on a gold surface, and it is superior to the previous method of preparing SAPd (first generation), which requires the use of the more heat-generating and dangerous piranha solution (concentrated H 2SO4 and 35% H2O2) in the sulfur fixation step. This safer and improved preparation method is particularly important for the mass production of SAPd (second generation) for which the catalytic activity was examined in ligand-free Buchwald-Hartwig cross-coupling reactions. The catalytic activities were the same between the first and second generation SAPds in aromatic aminations, but the lower palladium leaching properties and safer preparative method of second generation SAPd are a significant improvement over the first generation SAPd. © 2013 American Chemical Society.
  • Shuhei Kawamura, Yuka Unno, Motohiro Tanaka, Takuma Sasaki, Akihito Yamano, Takatsugu Hirokawa, Tomoshi Kameda, Akira Asai, Mitsuhiro Arisawa, Satoshi Shuto
    Journal of Medicinal Chemistry 56 14 5829 - 5842 2013年07月25日 [査読有り][通常論文]
     
    To develop potent covalent inhibitors, the noncovalent interactions around the transition state to form covalent bonding should be optimized because the potency of the inhibitor can be depending on the energy of the transition state. Here, we report an efficient analysis of the noncovalent binding mode of a potent covalent proteasome inhibitor 3a around the transition state by a combined use of the chemical approach, i.e., the cyclopropylic strain-based conformational restriction, and the computational docking approach. Furthermore, we calculated the binding energy of a series of salinosporamide derivatives in the predicted noncovalent complex around the transition state with the simulation model of proteasome constructed in this study, which was well correlated to their pIC50. Thus, the proposed docking methods to predict the noncovalent binding mode around the transition state of covalent inhibitors will be helpful toward the development of covalent inhibitors. © 2013 American Chemical Society.
  • Tatsuki Yasuda, Yusuke Kaji, Tomohiro Agatsuma, Takeshi Niki, Mitsuhiro Arisawa, Satoshi Shuto, Hiroyoshi Ariga, Sanae M.M. Iguchi-Ariga
    Biochemical and Biophysical Research Communications 436 2 289 - 294 2013年06月28日 [査読有り][通常論文]
     
    DJ-1, a product of the DJ-1/PARK7 gene, has been suggested to play various functions involved in transcriptional regulation, protease activity, anti-oxidative stress activity, and regulation of mitochondrial complex I. Such a variety of functions of DJ-1 are supposed to be realized through interactions with different partner proteins. Among the candidates for DJ-1-partner proteins detected in TOF-MAS analyses of the cellular proteins co-immunoprecipitated with DJ-1, we focused here pyrroline-5-carboxylate reductase 1, PYCR1, a final key enzyme for proline biosynthesis. DJ-1 directly bound to PYCR1 in vivo and in vitro. DJ-1 and PYCR1 colocalized in mitochondria, and both were suggested to be involved in regulation of mitochondrial membrane potential, but differently. DJ-1 enhanced the enzymatic activity of PYCR1 in vitro. The cells knocked down for DJ-1 and PYCR1 showed lower viability under oxidative stress conditions. No additive nor synergistic results were obtained for the cells that had been knocked down for both DJ-1 and PYCR1, suggesting that DJ-1 and PYCR1 are on the same pathway of anti-oxidative stress protection of the cells. © 2013 Elsevier Inc.
  • Takayoshi Tsuzuki, Natsumi Sakaguchi, Takashi Kudoh, Satoshi Takano, Masato Uehara, Takashi Murayama, Takashi Sakurai, Minako Hashii, Haruhiro Higashida, Karin Weber, Andreas H. Guse, Tomoshi Kameda, Takatsugu Hirokawa, Yasuhiro Kumaki, Barry V.L. Potter, Hayato Fukuda, Mitsuhiro Arisawa, Satoshi Shuto
    Angewandte Chemie - International Edition 52 26 6633 - 6637 2013年06月24日 [査読有り][通常論文]
     
    Oh, what a difference an S makes: A thioribose analogue (cADPtR, see scheme) of cyclic ADP-ribose (cADPR) was synthesized that is stable and has structural and electrostatic features similar to those of cADPR. cADPtR is the first stable equivalent of cADPR that is as active as cADPR in various cellular systems, making it useful for investigating Ca2+ ion-release signaling pathways. © 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
  • Christelle Moreau, Qun Liu, Richard Graeff, Gerd K. Wagner, Mark P. Thomas, Joanna M. Swarbrick, Satoshi Shuto, Hon Cheung Lee, Quan Hao, Barry V. L. Potter
    PLoS ONE 8 6 2013年06月19日 [査読有り][通常論文]
     
    Few inhibitors exist for CD38, a multifunctional enzyme catalyzing the formation and metabolism of the Ca2+-mobilizing second messenger cyclic adenosine 5′-diphosphoribose (cADPR). Synthetic, non-hydrolyzable ligands can facilitate structure-based inhibitor design. Molecular docking was used to reproduce the crystallographic binding mode of cyclic inosine 5′-diphosphoribose (N1-cIDPR) with CD38, revealing an exploitable pocket and predicting the potential to introduce an extra hydrogen bond interaction with Asp-155. The purine C-8 position of N1-cIDPR (IC50 276 μM) was extended with an amino or diaminobutane group and the 8-modified compounds were evaluated against CD38-catalyzed cADPR hydrolysis. Crystallography of an 8-amino N1-cIDPR:CD38 complex confirmed the predicted interaction with Asp-155, together with a second H-bond from a realigned Glu-146, rationalizing the improved inhibition (IC50 56 μM). Crystallography of a complex of cyclic ADP-carbocyclic ribose (cADPcR, IC50 129 μM) with CD38 illustrated that Glu-146 hydrogen bonds with the ligand N6-amino group. Both 8-amino N1-cIDPR and cADPcR bind deep in the active site reaching the catalytic residue Glu-226, and mimicking the likely location of cADPR during catalysis. Substantial overlap of the N1-cIDPR "northern" ribose monophosphate and the cADPcR carbocyclic ribose monophosphate regions suggests that this area is crucial for inhibitor design, leading to a new compound series of N1-inosine 5′-monophosphates (N1-IMPs). These small fragments inhibit hydrolysis of cADPR more efficiently than the parent cyclic compounds, with the best in the series demonstrating potent inhibition (IC50 = 7.6 μM). The lower molecular weight and relative simplicity of these compounds compared to cADPR make them attractive as a starting point for further inhibitor design. © 2013 Moreau et al.
  • Shuji Yonezawa, Hidekuni Yamakawa, Chie Muto, Motoko Hosono, Takahiko Yamamoto, Kazunari Hattori, Masahiro Sakagami, Hiroko Togame, Yoshikazu Tanaka, Toru Nakano, Hiroshi Takemoto, Mitsuhiro Arisawa, Satoshi Shuto
    Bioorganic and Medicinal Chemistry Letters 23 10 2912 - 2915 2013年05月15日 [査読有り][通常論文]
     
    To improve the efficacy of the conformationally restricted BACE1 inhibitors, structural modifications were investigated using two strategies: (a) modification of the terminal aromatic ring and (b) insertion of a spacer between the aromatic rings. In the latter approach, another type of inhibitor 17 bearing an ethylene spacer between two aromatic rings was found to exhibit good BACE1 inhibitory activity, while the corresponding conformationally unrestricted compound 25 showed no activity. This result revealed an interesting effect of a conformational restriction with a cyclopropane ring. © 2013 Elsevier Ltd. All rights reserved.
  • Shuhei Kawamura, Yuka Unno, Anja List, Akirai Mizuno, Motohiro Tanaka, Takuma Sasaki, Mitsuhiro Arisawa, Akira Asai, Michael Groll, Satoshi Shuto
    Journal of Medicinal Chemistry 56 9 3689 - 3700 2013年05月09日 [査読有り][通常論文]
     
    The natural product belactosin A (1) with a trans-cyclopropane structure is a useful prototype compound for developing potent proteasome (core particle, CP) inhibitors. To date, 1 and its analogues are the only CP ligands that bind to both the nonprimed S1 pocket as well as the primed substrate binding channel; however, these molecules harbor a high IC50 value of more than 1 μM. We have performed structure-activity relationship studies, thereby elucidating unnatural cis-cyclopropane derivatives of 1 that exhibit high potency to primarily block the chymotrypsin-like active site of the human constitutive (cCP) and immunoproteasome (iCP). The most active compound 3e reversibly inhibits cCP and iCP similarly with an IC50 of 5.7 nM. X-ray crystallographic analysis of the yeast proteasome in complex with 3e revealed that the ligand is accommodated predominantly into the primed substrate binding channel and covalently binds to the active site threonine residue via its β-lactone ring-opening. © 2013 American Chemical Society.
  • Tomoaki Bessho, Shoko Morii, Toshihide Kusumoto, Takahiro Shinohara, Masanori Noda, Susumu Uchiyama, Satoshi Shuto, Shigenori Nishimura, Appolinaire Djikeng, Michael Duszenko, Samuel K. Martin, Takashi Inui, Kilunga B. Kubata
    PARASITOLOGY 140 6 735 - 745 2013年05月 [査読有り][通常論文]
     
    There is an alarming rate of human African trypanosomiasis recrudescence in many parts of sub-Saharan Africa. Yet, the disease has no successful chemotherapy. Trypanosoma lacks the enzymatic machinery for the de novo synthesis of purine nucleotides, and is critically dependent on salvage mechanisms. Inosine 5'-monophosphate dehydrogenase (IMPDH) is responsible for the rate-limiting step in guanine nucleotide metabolism. Here, we characterize recombinant Trypanosoma brucei IMPDH (TbIMPDH) to investigate the enzymatic differences between TbIMPDH and host IMPDH. Size-exclusion chromatography and analytical ultracentrifugation sedimentation velocity experiments reveal that TbIMPDH forms a heptamer, different from type 1 and 2 mammalian tetrameric IMPDHs. Kinetic analysis reveals calculated K-m values of 30 and 1300 mu M for IMP and NAD, respectively. The obtained K-m value of TbIMPDH for NAD is approximately 20-200-fold higher than that of mammalian enzymes and indicative of a different NAD binding mode between trypanosomal and mammalian IMPDHs. Inhibition studies show K-i values of 3.2 mu M, 21 nM and 3.3 nM for ribavirin 5'-monophosphate, mycophenolic acid and mizoribine 5'-monophosphate, respectively. Our results show that TbIMPDH is different from its mammalian counterpart and thus may be a good target for further studies on anti-trypanosomal drugs.
  • Mohammad Al-Amin, Masayoshi Akimoto, Tsuyoshi Tameno, Yuuta Ohki, Naoyuki Takahashi, Naoyuki Hoshiya, Satoshi Shuto, Mitsuhiro Arisawa
    Green Chemistry 15 5 1142 - 1145 2013年05月 [査読有り][通常論文]
     
    We designed Suzuki-Miyaura cross-coupling reactions in conjunction with sulfur-modified Au-supported Pd material (SAPd) and two types of microwaves, single-mode and multi-mode. The entire microwave-facilitated process provided advantages over conventional heating in that reactivity of the less reactive arylbromides was induced and the reaction time was reduced. © 2013 The Royal Society of Chemistry.
  • Akira Mizuno, Shiho Miura, Mizuki Watanabe, Yoshihiko Ito, Shizuo Yamada, Takenao Odagami, Yuji Kogami, Mitsuhiro Arisawa, Satoshi Shuto
    Organic Letters 15 7 1686 - 1689 2013年04月 [査読有り][通常論文]
     
    Conformationally restricted peptidomimetics comprising eight stereoisomeric scaffolds with three-dimensional structural diversity were designed based on the structural features of cyclopropane, that is, cyclopropylic strain, which mimic wide-ranging tetrapeptide conformations covering β-turns through β-strands. Stereoselective synthesis of the designed peptidomimetics led to the identification of nonpeptidic melanocortin-4 receptor ligands. © 2013 American Chemical Society.
  • Frédéric Picard-Jean, Isabelle Bougie, Satoshi Shuto, Martin Bisaillon
    PLoS ONE 8 1 2013年01月17日 [査読有り][通常論文]
     
    Mizoribine monophosphate (MZP) is a specific inhibitor of the cellular inosine-5′-monophosphate dehydrogenase (IMPDH), the enzyme catalyzing the rate-limiting step of de novo guanine nucleotide biosynthesis. MZP is a highly potent antagonistic inhibitor of IMPDH that blocks the proliferation of T and B lymphocytes that use the de novo pathway of guanine nucleotide synthesis almost exclusively. In the present study, we investigated the ability of MZP to directly inhibit the human RNA capping enzyme (HCE), a protein harboring both RNA 5′-triphosphatase and RNA guanylyltransferase activities. HCE is involved in the synthesis of the cap structure found at the 5′ end of eukaryotic mRNAs, which is critical for the splicing of the cap-proximal intron, the transport of mRNAs from the nucleus to the cytoplasm, and for both the stability and translation of mRNAs. Our biochemical studies provide the first insight that MZP can inhibit the formation of the RNA cap structure catalyzed by HCE. In the presence of MZP, the RNA 5′-triphosphatase activity appears to be relatively unaffected while the RNA guanylyltransferase activity is inhibited, indicating that the RNA guanylyltransferase activity is the main target of MZP inhibition. Kinetic studies reveal that MZP is a non-competitive inhibitor that likely targets an allosteric site on HCE. Mizoribine also impairs mRNA capping in living cells, which could account for the global mechanism of action of this therapeutic agent. Together, our study clearly demonstrates that mizoribine monophosphate inhibits the human RNA guanylyltransferase in vitro and impair mRNA capping in cellulo. © 2013 Picard-Jean et al.
  • Akihiko Tanimura, Tetsuya Mochizuki, Takao Morita, Akihiro Nezu, Yosuke Tojyo, Mitsuhiro Arisawa, Satoshi Shuto
    Journal of Biotechnology 167 3 248 - 254 2013年 [査読有り][通常論文]
     
    Inositol 1,4,5-trisphosphate (IP3) receptors consist of three subtypes: IP3R1, IP3R2, and IP3R3. Although numerous IP3 receptor ligands have been synthesized, none of the subtype-selective ligands are known. We have developed a simple fluorescence method to examine the subtype selectivity of IP3 receptor ligands using FRET-based IP3 biosensors LIBRAvI, LIBRAvII, and LIBRAvIII. The addition of IP3 or adenophostin A (ADA) to permeabilized biosensor-expressing cells increased the fluorescence ratios of these biosensors in a concentration-dependent manner, and the potency of ADA relative to that of IP3 in terms of the changes in the fluorescence ratios of LIBRAvI, LIBRAvII, and LIBRAvIII was 43-, 22-, and 28-fold, respectively. This fluorescence-based method further showed that several ADA analogs had significant differences with respect to subtype selectivity and potency. These results highlight the important role played by the O-glycosidic structure of ADA in the selectivity of the ligands for IP3R1, as evidenced by the modified selectivity following replacement of the 5'-hydroxyl with a phenyl or phenethyl group. We also found that one ADA analog 5'-deoxy-5'-phenyladenophostin A possessed a partial agonistic effect on IP3R1. Together, the novel fluorescent methods described herein are useful for the evaluation of properties of IP3R ligands, including potency, efficacy, and subtype selectivity. © 2013 Elsevier B.V.
  • Shuji Yonezawa, Takahiko Yamamoto, Hidekuni Yamakawa, Chie Muto, Motoko Hosono, Kazunari Hattori, Kenichi Higashino, Takashi Yutsudo, Hideo Iwamoto, Yutaka Kondo, Masahiro Sakagami, Hiroko Togame, Yoshikazu Tanaka, Toru Nakano, Hiroshi Takemoto, Mitsuhiro Arisawa, Satoshi Shuto
    Journal of Medicinal Chemistry 55 20 8838 - 8858 2012年10月25日 [査読有り][通常論文]
     
    Improvement of a drugs binding activity using the conformational restriction approach with sp3 hybridized carbon is becoming a key strategy in drug discovery. We applied this approach to BACE1 inhibitors and designed four stereoisomeric cyclopropane compounds in which the ethylene linker of a known amidine-type inhibitor 2 was replaced with chiral cyclopropane rings. The synthesis and biologic evaluation of these compounds revealed that the cis-(1S,2R) isomer 6 exhibited the most potent BACE1 inhibitory activity among them. X-ray structure analysis of the complex of 6 and BACE1 revealed that its unique binding mode is due to the apparent CH-π interaction between the rigid cyclopropane ring and the Tyr71 side chain. A derivatization study using 6 as a lead molecule led to the development of highly potent inhibitors in which the structure-activity relationship as well as the binding mode of the compounds clearly differ from those of known amidine-type inhibitors. © 2012 American Chemical Society.
  • Mitsuhiro Arisawa, Yayoi Kasaya, Tohru Obata, Takuma Sasaki, Tomonori Nakamura, Takuya Araki, Koujirou Yamamoto, Akito Sasaki, Akihito Yamano, Mika Ito, Hiroshi Abe, Yoshihiro Ito, Satoshi Shuto
    Journal of Medicinal Chemistry 55 18 8152 - 8163 2012年09月27日 [査読有り][通常論文]
     
    We designed and synthesized conformationally restricted analogues and regioisomers of the nonsteroidal anti-inflammatory drug indomethacin. Evaluation of the inhibitory effects of these compounds on COX, P-glycoprotein, and multidrug resistance indicated that NSAIDS modulation of multidrug-resistant P-glycoprotein and multidrug-resistant protein-1 is not associated with COX-1 and COX-2 inhibitory activities. © 2012 American Chemical Society.
  • Mika Ito, Aya Shibata, Hiroshi Abe, Jie Zhang, Ralf Morgenstern, Satoshi Shuto, Yoshihiro Ito
    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 244 2012年08月 [査読有り][通常論文]
  • Ito Mika, Shibata Aya, Zhang Jie, Hiroshima Michio, Sako Yasushi, Nakano Yukiko, Kojima-Aikawa Kyoko, Mannervik Bengt, Shuto Satoshi, Ito Yoshihiro, Morgenstern Ralf, Abe Hiroshi
    Chembiochem : a European journal of chemical biology 13 10 1428 - 1432 2012年07月 [査読有り][通常論文]
  • Hitoshi Miyakoshi, Seiji Miyahara, Tatsushi Yokogawa, Kanji Endoh, Toshiharu Muto, Wakako Yano, Takeshi Wakasa, Hiroyuki Ueno, Khoon Tee Chong, Junko Taguchi, Makoto Nomura, Yayoi Takao, Akio Fujioka, Akihiro Hashimoto, Kenjirou Itou, Keisuke Yamamura, Satoshi Shuto, Hideko Nagasawa, Masayoshi Fukuoka
    JOURNAL OF MEDICINAL CHEMISTRY 55 14 6427 - 6437 2012年07月 [査読有り][通常論文]
     
    Deoxyuridine triphosphatase (dUTPase) has emerged as a potential target for drug development as a 5-fluorouracil-based combination chemotherapy. We describe the design and synthesis of a novel class of human dUTPase inhibitors, 1,2,3-triazole-containing uracil derivatives. Compound 45a, which possesses 1,5-disubstituted 1,2,3-triazole moiety that mimics the amide bond of tert-amide-containing inhibitor 6b locked in a cis conformation showed potent inhibitory activity, and its structure activity relationship studies led us to the discovery of highly potent inhibitors 48c and 50c (IC50 = similar to 0.029 mu M). These derivatives dramatically enhanced the growth inhibition activity of 5fluoro-2'-deoxyuridine against HeLa S3 cells in vitro (EC50 = similar to 0.05 mu M). In addition, compound 50c exhibited a markedly improved pharmacokinetic profile as a result of the introduction of a benzylic hydroxy group and significantly enhanced the antitumor activity of 5-fluorouracil against human breast cancer MX-1 xenograft model in mice. These data indicate that 50c is a promising candidate for combination cancer chemotherapies with TS inhibitors.
  • Mika Ito, Aya Shibata, Jie Zhang, Michio Hiroshima, Yasushi Sako, Yukiko Nakano, Kyoko Kojima-Aikawa, Bengt Mannervik, Satoshi Shuto, Yoshihiro Ito, Ralf Morgenstern, Hiroshi Abe
    CHEMBIOCHEM 13 10 1428 - 1432 2012年07月 [査読有り][通常論文]
  • Abe Hiroshi, Abe Naoko, Shibata Aya, Ito Keiji, Tanaka Yoshiyuki, Ito Mika, Saneyoshi Hisao, Shuto Satoshi, Ito Yoshihiro
    Angewandte Chemie (International ed. in English) 51 26 6475 - 6479 2012年06月 [査読有り][通常論文]
     
    Equal-opportunity dissolver: By attaching polyethylene glycol at its 5'end, DNA (PEG-DNA) can be solubilized in various organic solvents and was shown to formG-quadruplexes by CD spectroscopy. A complex containing iron(III) protoporphyrin IX (hemin) and G-quadruplex-forming PEG-DNA catalyzed an oxidative reaction in methanol (see scheme).
  • Takao Ogawa, Tomonori Nakamura, Takuya Araki, Koujirou Yamamoto, Satoshi Shuto, Mitsuhiro Arisawa
    European Journal of Organic Chemistry 16 3084 - 3087 2012年06月 [査読有り][通常論文]
     
    Ru-catalyzed cycloisomerization of a 1,3-diene and the alkene of an N-dienyl-2-vinylaniline substrate proceeded smoothly, leading to a 3-exomethylene-2-vinylindole derivative in good yield. This useful synthon was successfully applied to the total synthesis of (±)-cinchonaminone. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
  • Seiji Miyahara, Hitoshi Miyakoshi, Tatsushi Yokogawa, Khoon Tee Chong, Junko Taguchi, Toshiharu Muto, Kanji Endoh, Wakako Yano, Takeshi Wakasa, Hiroyuki Ueno, Yayoi Takao, Fujioka Akio, Akihiro Hashimoto, Kenjirou Itou, Keisuke Yamamura, Makoto Nomura, Hideko Nagasawa, Satoshi Shuto, Masayoshi Fukuoka
    JOURNAL OF MEDICINAL CHEMISTRY 55 11 5483 - 5496 2012年06月 [査読有り][通常論文]
     
    Human deoxyuridine triphosphatase (dUTPase) inhibition is a promising approach to enhance the efficacy of thymidylate synthase (TS) inhibitor based chemotherapy. In this study, we describe the discovery of a novel class of human dUTPase inhibitors based on the conformation restriction strategy. On the basis of the X-ray cocrystal structure of dUTPase and its inhibitor compound 7, we designed and synthesized two conformation restricted analogues, i.e., compounds 8 and 9. These compounds exhibited increased in vitro potency compared with the parent compound 7. Further structure activity relationship (SAR) studies identified a compound 43 with the highest in vitro potency (IC50 = 39 nM, EC50 = 66 nM). Furthermore, compound 43 had a favorable oral PK profile and exhibited potent antitumor activity in combination with 5-fluorouracil (5-FU) in the MX-1 breast cancer xenograft model. These results suggested that a dUTPase inhibitor may have potential for clinical usage.
  • Hitoshi Miyakoshi, Seiji Miyahara, Tatsushi Yokogawa, Khoon Tee Chong, Junko Taguchi, Kanji Endoh, Wakako Yano, Takeshi Wakasa, Hiroyuki Ueno, Yayoi Takao, Makoto Nomura, Satoshi Shuto, Hideko Nagasawa, Masayoshi Fukuoka
    JOURNAL OF MEDICINAL CHEMISTRY 55 7 2960 - 2969 2012年04月 [査読有り][通常論文]
     
    Recently, deoxyuridine triphosphatase (dUTPase) has emerged as a potential target for drug development as part of a new strategy of 5-fluorouracil-based combination chemotherapy. We have initiated a program to develop potent drug-like dUTPase inhibitors based on structure activity relationship (SAR) studies of uracil derivatives. N-Carbonylpyrrolidine- and N-sulfonylpyrrolidine-containing uracils were found to be promising scaffolds that led us to human dUTPase inhibitors (12k) having excellent potencies (IC50 = 0.15 mu M). The X-ray structure of a complex of 16a and human dUTPase revealed a unique binding mode wherein its uracil ring and phenyl ring occupy a uracil recognition region and a hydrophobic region, respectively, and are stacked on each other. Compounds 12a and 16a markedly enhanced the growth inhibition activity of 5-fluoro-2'-deoxyuridine against HeLa S3 cells in vitro (EC50 = 0.27-0.30 mu M), suggesting that our novel dUTPase inhibitors could contribute to the development of chemotherapeutic strategies when used in combination with TS inhibitors.
  • Seiji Miyahara, Hitoshi Miyakoshi, Tatsushi Yokogawa, Khoon Tee Chong, Junko Taguchi, Toshiharu Muto, Kanji Endoh, Wakako Yano, Takeshi Wakasa, Hiroyuki Ueno, Yayoi Takao, Fujioka Akio, Akihiro Hashimoto, Kenjirou Itou, Keisuke Yamamura, Makoto Nomura, Hideko Nagasawa, Satoshi Shuto, Masayoshi Fukuoka
    JOURNAL OF MEDICINAL CHEMISTRY 55 7 2970 - 2980 2012年04月 [査読有り][通常論文]
     
    Inhibition of human deoxyuridine triphosphatase (dUTPase) has been identified as a promising approach to enhance the efficacy of 5-fluorouracil (5-FU)-based chemotherapy. This study describes the development of a novel class of dUTPase inhibitors based on the structure-activity relationship (SAR) studies of uracil derivatives. Starting from the weak inhibitor 7 (IC50 = 100 mu M), we developed compound 26, which is the most potent human dUTPase inhibitor (IC50 = 0.021 mu M) reported to date. Not only does compound 26 significantly enhance the growth inhibition activity of 5-fluoro-2'-deoxyuridine (FdUrd) against HeLa S3 cells in vitro (EC50 = 0.075 mu M) but also shows robust antitumor activity against MX-1 breast cancer xenograft model in mice when administered orally with a continuous infusion of 5-FU. This is the first in vivo evidence that human dUTPase inhibitors enhance the antitumor activity of TS inhibitors. On the basis of these findings, it was concluded that compound 26 is a promising candidate for clinical development.
  • Mizuki Watanabe, Takaaki Kobayashi, Takatsugu Hirokawa, Akira Yoshida, Yoshihiko Ito, Shizuo Yamada, Naoki Orimoto, Yasundo Yamasaki, Mitsuhiro Arisawa, Satoshi Shuto
    Organic and Biomolecular Chemistry 10 4 736 - 745 2012年01月28日 [査読有り][通常論文]
     
    The stereochemical diversity-oriented conformational restriction strategy can be an efficient method for developing specific ligands for drug target proteins. To develop potent histamine H 3 and/or H 4 receptor ligands, a series of conformationally restricted analogs of histamine with a chiral trans- or cis-4-amino-2,3-methano-1-(1H-imidazol-4-yl)butane structure was designed based on this strategy. These stereochemically diverse compounds were synthesized from previously developed versatile chiral cyclopropane units. Among these analogs, a trans-cyclopropane-type compound, (2S,3R)-4-(4-chlorobenzylamino)-2,3-methano-1-(1H-imidazol-4-yl)butane (5b), has remarkable antagonistic activity to both the H 3 (K i = 4.4 nM) and H 4 (K i = 5.5 nM) receptors, and a cis-cyclopropane-type compound, (2R,3R)-4-amino-2,3-methano-1-(1H-imidazol-4-yl) butane (6a), is a potent and selective H 3 receptor partial agonist (K i = 5.4 nM). Although (2S,3R)-4-amino-2,3-methano-1-(1H-imidazol-4- yl)butane (5a) does not have a hydrophobic group which the usual H 3 receptor antagonists have, it was found to be a potent H 3 receptor antagonist (K i = 20.1 nM). Thus, a variety of compounds with different pharmacological properties depending on the cyclopropane backbones and also on the side-chain functional groups were identified. In addition to the previously used 1,2-methanobutane backbone, the 2,3-methanobutane backbone also worked effectively as a cyclopropane-based conformational restriction structure. Therefore, the combination of these two cyclopropane backbones increases the stereochemical and three-dimensional diversity of compounds in this strategy, which can provide a variety of useful compounds with different pharmacological properties. © 2012 The Royal Society of Chemistry.
  • Hiroshi Abe, Naoko Abe, Aya Shibata, Keiji Ito, Yoshiyuki Tanaka, Mika Ito, Hisao Saneyoshi, Satoshi Shuto, Yoshihiro Ito
    ANGEWANDTE CHEMIE-INTERNATIONAL EDITION 51 26 6475 - 6479 2012年 [査読有り][通常論文]
  • Mizuki Watanabe, Kazuya Yamaguchi, Wei Tang, Keisuke Yoshida, Richard B. Silverman, Mitsuhiro Arisawa, Satoshi Shuto
    Bioorganic and Medicinal Chemistry 19 20 5984 - 5988 2011年10月15日 [査読有り][通常論文]
     
    A series of optically active stereoisomers of 3,4-methanoarginine (1-4 and ent-1-ent-4) with trans/cis, d/l, and syn/anti stereochemical diversity, the side-chains of which were restricted in various special arrangements, was designed as biologically useful arginine mimetics. These conformationally restricted arginine analogues were synthesized effectively by using a series of chiral 3,4-methanoamino acid equivalents (7-10 and ent-7-ent-10) as the key synthetic units. Their biological evaluation with three isoforms of nitric oxide synthase showed that trans-3,4-methano-l-syn-arginine (2) was a good substrate, having close potency to l-arginine, and isoforms selectivities were also similar to those of l-arginine. © 2011 Elsevier Ltd. All rights reserved.
  • Zhang Jie, ShibataAya, Ito Mika, Shuto Satoshi, Ito Yoshihiro, Mannervik Bengt, Abe Hiroshi, Morgenstern Ralf
    Journal of the American Chemical Society 133 35 14109 - 14119 2011年09月 [査読有り][通常論文]
     
    Glutathione transferases (GSTs) are used in biotechnology applications as fusion partners for facile purification and are also overexpressed in certain tumors. Consequently, there is a need for sensitive detection of the enzymes. Here we describe a general strategy for the synthesis and characterization of novel fluorogenic substrates forGSTs. The substrates were synthesized by introducing an electrophilic sulfonamide linkage to fluorescent molecules containing an amino group [e.g., 2,4-dinitrobenzenesulfonamide (DNs) derivatives of coumarin, cresyl violet, and rhodamine]. The derivatives were essentially nonfluorescent, and upon GST catalyzed cleavage of the dinitrobenzenesulfonamide, free fluorophore is released (and 1-glutathionyl-2,4-dinitrobenzene + SO(2)). All the coumarin-, cresyl violet- and rhodamine-based fluorogenic probes turned out to be good substrates for most GSTs, especially for GSTA(1-1), in terms of strong fluorescence increases (71-1200-fold), high k(cat)/K(m) values (10(4)-10(7) M(-1) s(-1)) and significant rate enhancements (10(6)-10(9)-fold). The substrates were successfully applied to quantitate very low levels of GST activity in cell extracts and DNs-cresyl
  • Jie Zhang, Aya Shibata, Mika Ito, Satoshi Shuto, Yoshihiro Ito, Bengt Mannervik, Hiroshi Abe, Ralf Morgenstern
    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 133 35 14109 - 14119 2011年09月 [査読有り][通常論文]
     
    Glutathione transferases (GSTs) are used in biotechnology applications as fusion partners for facile purification and are also overexpressed in certain tumors. Consequently, there is a need for sensitive detection of the enzymes. Here we describe a general strategy for the synthesis and characterization of novel fluorogenic substrates for GSTs. The substrates were synthesized by introducing an electrophilic sulfonamide linkage to fluorescent molecules containing an amino group [e.g., 2,4-dinitrobenzenesulfonamide (DNs) derivatives of coumarin, cresyl violet, and rhodamine]. The derivatives were essentially nonfluorescent, and upon GST catalyzed cleavage of the dinitrobenzenesulfonamide, free fluorophore is released (and 1-glutathionyl-2,4-dinitrobenzene + SO(2)). All the coumarin-, cresyl violet- and rhodamine-based fluorogenic probes turned out to be good substrates for most GSTs, especially for GSTA(1-1), in terms of strong fluorescence increases (71-1200-fold), high k(cat)/K(m) values (10(4)-10(7) M(-1) s(-1)) and significant rate enhancements (10(6)-10(9)-fold). The substrates were successfully applied to quantitate very low levels of GST activity in cell extracts and DNs-cresyl violet was also successfully applied to the imaging of microsomal MGST(1) activity in living cells. The cresyl violet stained cells retained their fluorescence after fixation, which is a very useful property. In summary, we describe a general and versatile strategy to generate fluorogenic GST substrates, some of them providing the most sensitive assays so far described for GSTs.
  • Naoyuki Hoshiya, Satoshi Shuto, Mitsuhiro Arisawa
    Advanced Synthesis and Catalysis 353 5 743 - 748 2011年03月28日 [査読有り][通常論文]
     
    The actual active species of the recently developed sulfur-modified, gold-supported palladium material, S-modified Au-supported Pd (SAPd), with one of the lowest Pd-releasing levels and high recyclability in the Suzuki-Miyaura coupling, was investigated. Also, SAPd was found to work repeatedly as an excellent Pd reservoir for liquid-phase combinatorial synthesis. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
  • Takaaki Kobayashi, Mitsuhiro Arisawa, Satoshi Shuto
    Organic and Biomolecular Chemistry 9 4 1219 - 1224 2011年02月21日 [査読有り][通常論文]
     
    A synthetic method for bicyclic heterocycles, such as indole, benzofuran and chromene derivatives bearing a chiral cyclopropane at the 2-position, was established using isomerization of a terminal olefin and enamide-ene or diene metathesis. This route can also be applied to chiral 2-cyclopropylquinoline synthesis (both cis and trans). © 2011 The Royal Society of Chemistry.
  • Katarina Johansson, Mika Ito, Carolien M, S. Schophuizen, Sherin Mathew T, Vanina D. Heuser, Jie Zhang, Miyuki Shimoji, Marie Vahter, Wee Han Ang, Paul J. Dyson, Aya Shibata, Satoshi Shuto, Yoshihiro, Ito, Hiroshi Abe, Ralf Morgenstern
    Molecular Pharmaceutics 8 5 1698 - 1708 2011年 [査読有り][通常論文]
  • Mitsuhiro Arisawa, Naoyuki Hoshiya, Satoshi Shuto
    Yuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry 68 9 920 - 929 2010年09月 [査読有り][通常論文]
     
    In an effort to create reusable, Pd-leach-free catalysts, many heterogeneous catalysts have been developed with Pd immobilized on supports such as activated carbon, inorganic solids and polymers. Yet few of these immobilized Pd catalysts for C-C bond formations can claim both high recyclability (>10 times) and low Pd-leaching (<1ppm). We successfully developed a practical Pd material, SGPd (Sulfur-modified GaAs(001) supported Pd) and SAPd (Sulfur-modified Au supported Pd) whose Pd was immobilized on sulfur-modified GaAs(001) or Au, respectively. With the lowest Pd-releasing levels and high recyclability, this is one of the best Pd materials thus far developed. It became clear that actual active species is released Pd in the reaction mixture through detailed mechanistic experiments. Because it leaches extremely low levels of Pd into reaction mixtures, removal of the residual Pd is unnecessary especially using SAPd, even in syntheses involving pharmaceutical ingredients.
  • Takaaki Kobayashi, Mitsuhiro Arisawa, Satoshi Shuto
    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 240 2010年08月 [査読有り][通常論文]
  • Naoyuki Hoshiya, Masahiko Shimoda, Hideki Yoshikawa, Yoshiyuki Yamashita, Satoshi Shuto, Mitsuhiro Arisawa
    Journal of the American Chemical Society 132 21 7270 - 7272 2010年06月02日 [査読有り][通常論文]
     
    We have found in the SR-HXPS measurement of Piranha-treated Au(111)/mica that the gold surface underwent sulfur modification during this treatment, which was believed to have only removed impurities from the gold surface. We also successfully developed a practical Pd material, SAPd, whose Pd was immobilized on sulfur-modified Au. With the lowest Pd-releasing levels and high recyclability, this is one of the best Pd materials thus far developed. Because it leaches extremely low levels of Pd into reaction mixtures, removal of the residual Pd is unnecessary using SAPd, even in syntheses involving pharmaceutical ingredients.
  • Mizuki Watanabe, Takatsugu Hirokawa, Takaaki Kobayashi, Akira Yoshida, Yoshihiko Ito, Shizuo Yamada, Naoki Orimoto, Yasundo Yamasaki, Mitsuhiro Arisawa, Satoshi Shuto
    Journal of Medicinal Chemistry 53 9 3585 - 3593 2010年05月13日 [査読有り][通常論文]
     
    We previously identified the highly potent histamine H3 receptor antagonists (1R,2S)-2-[2-(4-chlorobenzylamino)ethyl]-1-(1H-imidazol-4-yl) cyclopropane (1) and its enantiomer ent-1. Although the conformations of 1 and ent-1 are restricted by the central cyclopropane ring, the 2-(4- chlorobenzylamino)ethyl side chain essential for the H3 receptor binding may somewhat freely rotate. To investigate the bioactive conformation, the 1′-ethyl-substituted derivatives 2a and 2b and their enantiomers ent-2a and ent-2b were designed as side chain conformation-restricted analogues of 1 and ent-1, based on the cyclopropylic strain. These compounds were synthesized, and their analysis by NMR and calculations suggested that the side chain moiety was effectively restricted in a syn-form or an anti-form by the cyclopropylic strain as expected. Pharmacological evaluation and docking simulation showed that the bioactive conformations of 1 and ent-1 appear to be the syn-form and the anti-form, respectively. Thus, the cyclopropylic strain can be effectively used for conformational restriction of the side chain moiety of cyclopropane compounds. © 2010 American Chemical Society.
  • Tetsuya Mochizuki, Akihiko Tanimura, Akihiro Nezu, Mika Ito, Hiroshi Abe, Yoshihiro Ito, Mitsuhiro Arisawa, Satoshi Shuto
    Tetrahedron Letters 51 6 977 - 979 2010年02月10日 [査読有り][通常論文]
     
    Indole derivatives 3a and 3b of adenophostin A (2) in which the adenine of 2 was replaced with indole or 4-fluoroindole was designed as potential inositol trisphosphate receptor ligands. These target compounds were successfully synthesized from the key disaccharide unit 6. Biological evaluation showed that 3b selectively activates IP3R1, a subtype of IP3 receptors. © 2009 Elsevier Ltd. All rights reserved.
  • Takaaki Kobayashi, Mizuki Watanabe, Akira Yoshida, Shizuo Yamada, Mika Ito, Hiroshi Abe, Yoshihiro Ito, Mituhiro Arisawa, Satoshi Shuto
    Bioorganic and Medicinal Chemistry 18 3 1076 - 1082 2010年02月01日 [査読有り][通常論文]
     
    On the basis of the previous results on a histamine H4 receptor agonist 4-methylhistamine and a cyclopropane-based conformationally restricted analog CEIC (3) with potent H3/H4 receptor antagonistic effect, 4-methylhistamine analogs 4 and 5 of CEIC were designed and synthesized. Compound 4 showed strong affinity (Ki = 38.7 nM) for the H3 receptor, which was more potent than a well-known H3 antagonist thioperamide. Stable tautomer and conformation of 3 and 4, which can affect the pharmacological activity, were analyzed by ab initio calculations. © 2009 Elsevier Ltd. All rights reserved.
  • Akira Ishii, Hiroki Asano, Mami Yokoyama, Shiro Tsukamoto, Satoshi Shuto, Mitsuhiro Arisawa
    Physica Status Solidi (C) Current Topics in Solid State Physics 7 2 359 - 361 2010年 [査読有り][通常論文]
     
    The density functional calculation is performed to determine the structure of the reused palladium catalyst on sulphur terminated GaAs(001) surface for the Heck reaction. The DFT calculation has been done for S-terminated GaAs(001) surface with and without As of the topmost layer. The difference the two model of the S-terminated GaAs(001) is very small. Since, for both case, the binding energy of palladium atom is stronger due to the co-adsorption of sulphur, the role of sulphur is to make the binding of palladium stronger. Moreover, the heights of the position of the adsorbed palladium atom for both model cases are lower than sulphur atom on the surface. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
  • Naoyuki Hoshiya, Nobuhiro Isomura, Masahiko Shimoda, Hideki Yoshikawa, Yoshiyuki Yamashita, Kanji Iizuka, Shiro Tsukamoto, Satoshi Shuto, Mitsuhiro Arisawa
    ChemCatChem 1 2 279 - 285 2009年10月05日 [査読有り][通常論文]
     
    A newly developed, environmentally benign palladium catalyst supported on gallium arsenide, {Pd}-S-GaAs (001), has both the lowest recorded leaching and high recyclability for Suzuki- Miyaura coupling. Measurements of the catalyst surface by synchrotron radiation X-ray photoelectron spectroscopy show a relationship between the surface and the activity of the catalyst. Since {Pd}-S-GaAs(001) makes efficient use of the rare metal Pd, it is a useful palladium catalyst from an atomeconomical perspective. Two heterogeneity tests clarify that the presence of immobilized palladium on S-GaAs is important for higher catalytic activity. © 2009 Wiley-VCH Verlag GmbH& Co. KGaA, Weinheim.
  • Yayoi Kasaya, Kosuke Hoshi, Yukiyoshi Terada, Atsushi Nishida, Satoshi Shuto, Mitsuhiro Arisawa
    European Journal of Organic Chemistry 27 4606 - 4613 2009年09月 [査読有り][通常論文]
     
    A. steric and electronic effect: on enamide/ene metathesis, a novel preparation of 2-substituted indoles and 3-substituted indoles using enamide-ene metathesis as a key reaction, and its application to the synthesis of indoniethacin are described. © Wiley-VCH Verlag GmbH & Co. KGaA.
  • Akitsugu Takada, Hiroyuki Kamiya, Satoshi Shuto, Akira Matsuda, Hideyoshi Harashima
    INTERNATIONAL JOURNAL OF PHARMACEUTICS 377 1-2 52 - 59 2009年07月 [査読有り][通常論文]
     
    The efficacy of an antitumor nucleoside, 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine (3'-ethynylcytidine, ECyd), was analyzed in vitro and in vivo. The in vivo antitumor effect of ECyd encapsulated into long-circulating liposomes was also examined. Based on pharmacokinetic (PK) and pharmacodynamic (PD) analyses, a model that quantitatively explains the in vivo effects of ECyd was proposed, using the concept of minimum effective concentration. The model suggests that ECyd followed a time-dependent mechanism of action in vivo, and that availability of ECyd in tumor tissue was highly important. To improve the availability of ECyd, its phospholipid derivatives were synthesized and encapsulated into long-circulating liposomes, which increased the antitumor effect. These results indicate that it is very important to design carriers of antitumor drugs based on PK-PD modeling. (C) 2009 Elsevier B.V. All rights reserved.
  • Keisuke Yoshida, Kazuya Yamaguchi, Akira Mizuno, Yuka Unno, Akira Asai, Takayuki Sone, Hideyoshi Yokosawa, Akira Matsuda, Mitsuhiro Arisawa, Satoshi Shuto
    Organic and Biomolecular Chemistry 7 9 1868 - 1877 2009年 [査読有り][通常論文]
     
    The development of potent proteasome inhibitors based on the stereochemical diversity-oriented strategy using a conformationally rigid cyclopropane structure was investigated. Thus, a series of stereo- and regioisomeric analogs of belactosin A (2), a cyclopropane amino acid (methanoamino acid)-containing tripeptidic proteasome inhibitor, were designed, in which the central cyclopropane amino acid part was replaced with the corresponding stereo- or regioisomer. Using a series of stereoisomeric cyclopropane amino acid equivalents with the cis/trans, D/L, and syn/anti stereochemical diversity, which were previously developed by us, as key units, the target compounds were successfully synthesized. Biological evaluation showed that, as expected, compound activity changed depending on the stereochemistry of the central cyclopropane amino acid part: the trans/L-syn-isomer 7 and the cis/L-anti-isomer 9 were more than twice as potent as natural belactosin A (trans/L-anti-isomer). Furthermore, the tripeptidic compound 13, the synthetic precursor for the unnatural cis/L-anti-isomer 9, was identified as a highly potent proteasome inhibitor. This compound, which is 20 times as potent as belactosin A and is even more potent than the well-known inhibitor lactacystin (4), may be an effective lead for developing clinically useful anticancer drugs. These results show that the stereochemical diversity-oriented approach can be a powerful strategy for the development of highly active compounds in medicinal chemical studies. © 2009 The Royal Society of Chemistry.
  • Takashi Kudoh, Takashi Murayama, Minako Hashii, Haruhiro Higashida, Takashi Sakurai, Clarisse Maechling, Bernard Spiess, Karin Weber, Andreas H. Guse, Barry V.L. Potter, Mitsuhiro Arisawa, Akira Matsuda, Satoshi Shuto
    Tetrahedron 64 41 9754 - 9765 2008年10月06日 [査読有り][通常論文]
     
    We previously developed cyclic ADP-carbocyclic-ribose (cADPcR, 3a) as a stable mimic of cyclic ADP-ribose (cADPR, 1), a Ca2+-mobilizing second messenger. The unsaturated carbocyclic-ribose analogs of cADPR, i.e., 4″,6″-didehydro-cADPcR (8a) and its inosine congener 4″,6″-didehydro-cIDPcR (8b) were newly designed and successfully synthesized using the key intramolecular condensation reaction with S-phenyl phosphorothioate-type substrates. The Ca2+-mobilizing potency of the compounds was examined in sea urchin egg homogenates, NG108-15 neuronal cells, and permeabilized Jurkat T-lymphocytes, which may indicate that 4″,6″-didehydro-cADPcR is the first cADPR analog selectively active in T cells. Acid-base behavior and conformation of 8a were also investigated and compared with those of cADPcR. © 2008 Elsevier Ltd. All rights reserved.
  • Kazuya Yamaguchi, Yuji Kazuta, Kazufumi Hirano, Shizuo Yamada, Akira Matsuda, Satoshi Shuto
    BIOORGANIC & MEDICINAL CHEMISTRY 16 19 8875 - 8881 2008年10月 [査読有り][通常論文]
     
    A series of the cyclopropane-based conformationally restricted analogs of haloperidol were designed as potential antidopaminergic agents and were effectively synthesized using highly stereoselective Grignard reaction with tert-butanesulfinyl imines as the key step. Pharmacological evaluation of the compounds showed that the conformational restriction method can effectively work for improving the pharmacological selectivity of a parent compound and also for investigating the bioactive conformation. (C) 2008 Elsevier Ltd. All rights reserved.
  • Rabbani M. Gulam, Masahiro Hamada, Ikuko Takamiya, Masahiko Shimoda, Satoshi Shuto, Atsushi Nishida, Shiro Tsukamoto, Mitsuhiro Arisawa
    Bulletin of the Chemical Society of Japan 81 8 1012 - 1018 2008年08月15日 [査読有り][通常論文]
     
    Chelated tethering ligands were confined on a Au(111) substrate, and the confinement of the ligands was confirmed by X-ray photoelectron spectroscopy (XPS). Palladium was anchored to the ligands to construct heterogeneous (Pd)-L-Au(111) catalysts (L = ligand). A (Pd)-Au(111) catalyst was also prepared by adsorbing the Pd complex directly on the Au(111) substrate without a tethering ligand. Both types of catalysts were used in the Mizoroki-Heck reaction to evaluate their catalytic activities. The tether-ligated Pd catalyst (Pd)-L-Au(111) activity decreased with recycling, whereas the (Pd)-Au(111) catalyst was quite stable upon reuse. The surfaces of both catalyst types were evaluated using XPS to determine the presence of tethering ligands and/or Pd on the Au(111). The ligands of the tether-ligated Pd catalysts could not be detected on the Au(111) surface after the Mizoroki-Heck reaction, which suggests weak bonding of the S-Au by which the ligand is bound to the Au(111) substrate. © 2008 The Chemical Society of Japan.
  • Keisuke Yoshida, Kazuya Yamaguchi, Takayuki Sone, Yuka Unno, Akira Asai, Hideyoshi Yokosawa, Akira Matsuda, Mitsuhiro Arisawa, Satoshi Shuto
    ORGANIC LETTERS 10 16 3571 - 3574 2008年08月 
    A series of chiral 2,3- and 3,4-methanoamino acid equivalents of stereochernical diversity were designed and synthesized from our chiral cyclopropane units, using a diastereoselective Grignard addition with (R)- or (S)-t-butanesulfinyl imines as the key step. These equivalents were converted into the proteasome inhibitor belactosin A and its cis-cyclopropane stereoisomer. The unnatural cis-isomer was shown to be more than twice as potent as belactosin A as a proteasome inhibitor.
  • Natsumi Sakaguchi, Takashi Kudoh, Takayoshi Tsuzuki, Takashi Murayama, Takashi Sakurai, Akira Matsuda, Mitsuhiro Arisawa, Satoshi Shuto
    Bioorganic and Medicinal Chemistry Letters 18 13 3814 - 3818 2008年07月01日 [査読有り][通常論文]
     
    The 5″-branched cyclic ADP-carbocyclic-ribose derivatives were designed and synthesized. These target compounds were identified as the first antagonists of cADPR without a substituent at the adenine 8-position, and were shown to be stable due to the N1-carbocyclic-ribosyl structure. © 2008 Elsevier Ltd. All rights reserved.
  • Takashi Kudoh, Karin Weber, Andreas H. Guse, Barry V.L. Potter, Minako Hashii, Haruhiro Higashida, Mitsuhiro Arisawa, Akira Matsuda, Satoshi Shuto
    Tetrahedron Letters 49 25 3976 - 3979 2008年06月16日 [査読有り][通常論文]
     
    4″,6″-Didehydro-cADPcR (3), an unsaturated carbocyclic ribose analog of a Ca2+-mobilizing second messenger cyclic ADP-ribose (cADPR), was designed and successfully synthesized using a key intramolecular condensation reaction forming the 18-membered pyrophosphate ring structure with a S-phenyl phosphorothioate-type substrate. Biological evaluation showed that 4″,6″-didehydro-cADPcR is a potent Ca2+-mobilizing agent in T cells. © 2008 Elsevier Ltd. All rights reserved.
  • Tomohiro Asai, Souichiro Miyazawa, Noriyuki Maeda, Kentaro Hatanaka, Yasufumi Katanasaka, Kosuke Shimizu, Satoshi Shuto, Naoto Oku
    CANCER SCIENCE 99 5 1029 - 1033 2008年05月 [査読有り][通常論文]
     
    Causing damage to angiogenic vessels is a promising approach for cancer chemotherapy. The present study is a codification of a designed liposomal drug delivery system (DDS) for antineovascular therapy (ANET) with 2'-C-cyano-2'-deoxy-1-beta-D-arabino-pentofuranosylcytosine (CNDAC). The authors have previously reported that liposomalized 5'-O-dipalmitoylphosphatidyl CNDAC (DPP-CNDAC), a phospholipid derivative of the novel antitumor nucleoside CNDAC, is quite useful for ANET. DPP-CNDAC liposomes modified with APRPG, a peptide having affinity toward angiogenic vessels, efficiently suppressed tumor growth by damaging angiogenic endothelial cells. In the present study, the authors masked the hydrophilic moiety of DPP-CNDAC, namely, CNDAC, on the liposomal surface with APRPG-polyethyleneglycol (PEG) conjugate to improve the availability of DPP-CNDAC liposomes. The use of the APRPG-PEG conjugate attenuated the negative zeta-potential of the DPP-CNDAC liposomes and reduced the agglutinability of them in the presence of serum. These effects improved the blood level of DPP-CNDAC liposomes in colon 26 NL-17 tumor-bearing BALB/c male mice, resulting in enhanced accumulation of them in the tumor. Laser scanning microscopic observations indicated that APRPG-PEG-modified DPP-CNDAC liposomes (LipCNDAC/APRPG-PEG) colocalized with angiogenic vessels and strongly induced apoptosis of tumor cells, whereas PEG-modified DPP-CNDAC liposomes (LipCNDAC/PEG) did not. In fact, LipCNDAC/APRPG-PEG suppressed the tumor growth more strongly compared to LipCNDAC/PEG and increased significantly the life span of the mice. The present study is a good example of an effective liposomal DDS for ANET that is characterized by: (i) phospholipid derivatization of a certain anticancer drug to suit the liposomal formulation; (ii) PEG-shielding for masking undesirable properties of the drug on the liposomal surface; and (iii) active targeting to angiogenic endothelial cells using a specific probe.
  • Keisuke Yoshida, Kazuya Yamaguchi, Takayuki Sone, Yuka Unno, Akira Asai, Hideyoshi Yokosawa, Akira Matsuda, Mitsuhiro Arisawa, Satoshi Shuto
    Organic Letters 10 16 3571 - 3574 2008年 [査読有り][通常論文]
     
    (Chemical Equation Presented) A series of chiral 2,3- and 3,4-methanoamino acid equivalents of stereochemical diversity were designed and synthesized from our chiral cyclopropane units, using a diastereoselective Grignard addition with (R)- or (S)-t-butanesulfinyl imines as the key step. These equivalents were converted into the proteasome inhibitor belactosin A and its cis-cyclopropane stereoisomer. The unnatural cis-isomer was shown to be more than twice as potent as belactosin A as a proteasome inhibitor. © 2008 American Chemical Society.
  • Satoshi Shuto, Satoshi Ichikawa, Hiroshi Abe, Akira Matsuda
    JOURNAL OF SYNTHETIC ORGANIC CHEMISTRY JAPAN 66 1 50 - 60 2008年01月 [査読有り][通常論文]
     
    Despite considerable progress and extensive effort, a general method for highly stereoselective glycosylation particularly for the 1,2-cis-glycosylation has not yet been developed and therefore is required. The alpha/beta-stereo selectivity in glycosylation can be affected by the steric and stereoelectronic (anomeric) effects around the anomeric center, which depend on the conformation of the glycosyl donor substrates. Therefore, we hypothesized that highly alpha- and beta-selective glycosylation can be realized by employing conformationally restricted substrates. We showed that the alpha/beta-stereoselectivity was significantly increased by the conformational restriction and was completely inverted by changing the substrate conformation from the C-4(1)-form into the C-1(4)-form in radical and nucleophilic C-glycosylation reactions as well as in O-glycosylation reactions. The conformational restriction of substrates also effectively facilitates the alpha- and beta-selective radical cyclization reaction at the anomeric position. Using the method, C-glucoside trisphosphates designed as Ca2+-mobilizing agents were successfully,synthesized.
  • Satoshi Shuto, Jin Kusaka, Hiroshi Hara, Kouji Matsumoto
    GENES & GENETIC SYSTEMS 82 6 519 - 519 2007年12月 [査読有り][通常論文]
  • Mizoki Watanabe, Yuji Kazuta, Mitsuhiro Arisawa, Akira Matsuda, Satoshi Shuto
    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 234 2007年08月 [査読有り][通常論文]
  • Takashi Kudoh, Takashi Murayama, Akira Matsuda, Satoshi Shuto
    BIOORGANIC & MEDICINAL CHEMISTRY 15 8 3032 - 3040 2007年04月 [査読有り][通常論文]
     
    We previously showed that 3 ''-deoxy-cyclic ADP-carbocyclic-ribose (3 ''-deoxy-cADPcR, 4) is a stable and highly potent analogue of cyclic ADP-ribose (cADPR, 1), a Ca2+-mobilizing second messenger. From these results, we designed and synthesized other 3 ''-modified analogues of cADPcR having a substituent at the 8-position and found that this modification at the 8-position made them partial agonists. Among these compounds, 8-NH2-3 ''-deoxy-cADPcR (10) was identified as a potent partial agonist with an EC50 value of 17 nM. (c) 2007 Published by Elsevier Ltd.
  • Oxytocin released from mouse hypothalamus and nerve endings by extracellular application of beta-NAD+ and cyclic ADP ribose.
    Jin D, Liu, X.-X, Lopatina, O, Hashii, M, Yokoyama, S, Koizumi, K, Amina, S, Shuto, S, Shiraishi, Y, Tanaka, S, Higashida, H
    Nat. Protocols. (Protocols Network) 204  2007年 [査読無し][通常論文]
  • 有澤光弘, 塚本史郎, 下田正彦, 荒川泰彦, 周東智, 西田篤司
    ケミカルエンジニヤリング 51 12 945 - 951 2006年12月01日 [査読無し][通常論文]
  • Yukari Kudo, Satoshi Shuto, Jin Kusaka, Hiroshi Hara, Kouji Matsumoto
    GENES & GENETIC SYSTEMS 81 6 434 - 434 2006年12月 [査読有り][通常論文]
  • Tetsuya Kodama, Akira Matsuda, Satoshi Shuto
    TETRAHEDRON 62 42 10011 - 10017 2006年10月 [査読有り][通常論文]
     
    The first synthesis of 1 '-fluoronucleosides, which has long been synthetic targets as the potential antimetabolites, was achieved. Electrophilic fluorination of the 1 '-position occurred to form an anomeric mixture of l-fluorouridine derivatives, when the lithium enolate, prepared from 3 ',5 '-O-tetraisopropyldisiloxane-1,3-diyl (TIPDS)-protected 2 '-ketouridine (10) and LiHMDS, was treated with an electrophilic fluorinating agent such as NFSI (13). Subsequent reduction of the 2 '-keto-moiety of the resulting beta-nucleoside gave the protected 1 '-fluorouridine 16 and its arabino-type congener 17. Alternatively, nucleophilic fluorination was also successful. Thus, treatment of 2 ',3 ',5 '-tri-O-acetyl-1 '-phenylselenouridine (20) with DAST/NBS produced the 1 '-fluorouridine triacetate (21) and its alpha-anomer 22. (c) 2006 Elsevier Ltd. All rights reserved.
  • Tetsuya Mochizuki, Yoshihiko Kondo, Hiroshi Abe, Stephen C. Tovey, Skarlatos G. Dedos, Colin W. Taylor, Michael Paul, Barry V. L. Potter, Akira Matsuda, Satoshi Shuto
    JOURNAL OF MEDICINAL CHEMISTRY 49 19 5750 - 5758 2006年09月 [査読有り][通常論文]
     
    Previous structure-activity relationship studies of adenophostin A, a potent IP3 receptor agonist, led us to design the novel adenophostin A analogues 5a-c, conjugating an aromatic group at the 5'-position to develop useful IP3 receptor ligands. The common key intermediate, a D-ribosyl alpha-D-glucoside 10 alpha, was stereoselectively synthesized by a glycosidation with the 1-sulfinylglucoside donor 11, which was conformationally restricted by a 3,4-O-cyclic diketal protecting group. After introduction of an aromatic group at the 5-position of the ribose moiety, an adenine base was stereoselectively introduced at the anomeric beta-position to form 7a-c, where the tetra-O-i-butyryl donors 9a-c were significantly more effective than the corresponding O-acetyl donor. Thus, the target compounds 5a-c were synthesized via phosphorylation of the 2', 3", and 4"-hydroxyls. The potencies of compounds 5a-c for Ca2+ release were shown to be indistinguishable from that of adenophostin A, indicating that bulky substitutions at the 5'-position of adenophostin A are well-tolerated in the receptor binding. This biological activity of 5a-c can be rationalized by molecular modeling using the ligand binding domain of the IP3 receptor.
  • Mizuki Watanabe, Yuji Kazuta, Hideki Hayashi, Shizuo Yamada, Akira Matsuda, Satoshi Shuto
    JOURNAL OF MEDICINAL CHEMISTRY 49 18 5587 - 5596 2006年09月 [査読有り][通常論文]
     
    The stereochemical diversity-oriented conformational restriction strategy can be an efficient method for developing specific ligands for drug target proteins, especially in cases where neither the bioactive conformation nor the pharmacophore is known. To develop potent H-3 and H-4 receptor antagonists, a series of conformationally restricted analogues of histamine with a chiral cis- or trans-cyclopropane structure were designed on the basis of this strategy. These target compounds with stereochemical diversity were synthesized from the versatile chiral cyclopropane units ( 1S, 2R)- and ( 1R, 2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-formylcyclopropane ( 6 and 7, respectively) or their enantiomers ent-6 and ent-7. Pharmacological profiles of these conformationally restricted analogues were shown to be different depending on the cyclopropane backbones. Among the analogues, ( 1R, 2S)-2-[ 2-( 4-chlorobenzylamino) ethyl]-1-( 1H-imidazol-4- yl) cyclopropane ( 11a) with the ( 1R)-trans-cyclopropane structure has remarkable antagonistic activity to both the H-3 ( K-i = 8.4 nM) and H-4 ( K-i = 7.6 nM) receptors. The enantiomer of 11a, i.e., ent-11a, with the ( 1S)- trans-cyclopropane structure turned out to be a highly potent and selective H-3 receptor antagonist with a K-i of 3.6 nM. Conversely, ( 1R, 2R)-2-[( 4-chlorobenzylamino) methyl]-1-( 1H-imidazol-4- yl) cyclopropane ( 10a) with the ( 1R)- trans structure was selective for the H-4 receptor ( K-i) 118 nM) compared to the H-3 receptor ( K-i > 10(3) nM). Thus, a variety of compounds with different pharmacological profiles have been developed. These results show that when the structure of the target protein is unknown, the stereochemical diversity-oriented approach can be a powerful strategy in medicinal chemical studies.
  • Watanabe Mizuki, Kazuta Yuji, Hayashi Hideki, Yamada Shizuo, Matsuda Akira, Shuto Satoshi
    International Symposium on the Chemistry of Natural Products 2006 "P - 253" 天然有機化合物討論会 2006年07月23日
  • Natsumi Sakaguchi, Shinpei Hirano, Akira Matsuda, Satoshi Shuto
    ORGANIC LETTERS 8 15 3291 - 3294 2006年07月 [査読有り][通常論文]
     
    The 2-bromobenzylidene group, designed as a novel protecting/radical-translocating (PRT) group, proved to be effective for an unusual 1,6-hydrogen transfer reaction. Using this PRT group, 4-branched ribose derivatives were stereoselectively prepared.
  • Tetsuya Kodama, Satoshi Shuto, Akira Matsuda
    TETRAHEDRON LETTERS 47 26 4429 - 4432 2006年06月 [査読有り][通常論文]
     
    Treatment of the V-lithium enolate, prepared from a 2'-ketouridine derivative, with NFSI. followed by reduction of the 2'-keto-moiety gave the corresponding 1'-fluorouridine derivative and its arabino-type congener. Thus, the first synthesis of 1'-fluoronucleosides was achieved. (c) 2006 Elsevier Ltd. All rights reserved.
  • S Ichikawa, N Minakawa, S Shuto, M Tanaka, T Sasaki, A Matsuda
    ORGANIC & BIOMOLECULAR CHEMISTRY 4 7 1284 - 1296 2006年 [査読有り][通常論文]
     
    3'-beta-Carbamoylmethylcytidine (CAMC) and its derivatives were synthesized using an intramolecular Reformatsky-type reaction promoted by SmI2 as the key step. In vitro tumor cell growth inhibitory activity was evaluated and CAMC was found to exhibit potent cytotoxicity against various human tumor cell lines. From a structure - activity relationship study it was postulated that the cytotoxic mechanism of action of CAMC did not require phosphorylation at the 5'-hydroxyl group. This study provides a novel strategy for the development of a new type of antitumor nucleoside.
  • Masaru Terauchi, Hiroshi Abe, Stephen C. Tovey, Skarlatos G. Dedos, Colin W. Taylor, Michael Paul, Melanie Trusselle, Barry V. L. Potter, Akira Matsuda, Satoshi Shuto
    Journal of Medicinal Chemistry 49 1900 - 1909 2006年 [査読有り][通常論文]
  • Tetsuya Mochizuki, Yoshihiko Kondo, Hiroshi Abe, Collin W. Taylor, Barry V. L. Potter, Akira Matsuda, Satoshi Shuto
    Organic Letters 8 1455 - 1458 2006年 [査読有り][通常論文]
  • Takashi Kudoh, Akira Matsuda, Satoshi Shuto, Takashi Murayama, Yasuo Ogawa
    NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS 25 4-6 583 - 599 2006年 [査読有り][通常論文]
     
    We previously showed that 3'-deoxy-cyclic ADP-carbocyclic-ribose (3'-deoxy-cADPcR, 3) is a stable and highly potent analogue of cyclic ADP-ribose (cADPR, 1), a Ca2+-mobilizing second messenger. From these results, we newly designed another 3"-modified analogues of cADPcR and identified the N1-"xylo"-type carbocyclic analogue, i.e., cADPcX (4), as one of the most potent cADPR-related compounds reported so far.
  • M Terauchi, A Matsuda, S Shuto
    TETRAHEDRON LETTERS 46 38 6555 - 6558 2005年09月 [査読有り][通常論文]
     
    An efficient method for preparing beta-C-glucosides using radical cyclization with a temporary connecting silicon tether was developed. In this reaction, conformational restriction of the substrates to the unusual C-1(4)-form is essential for the cyclization to occur. (c) 2005 Published by Elsevier Ltd.
  • M Sukeda, A Matsuda, S Shuto
    TETRAHEDRON 61 33 7865 - 7873 2005年08月 [査読有り][通常論文]
     
    In order to develop an efficient method for the regio- and stereoselective introduction of a carbon substituent, a radical hydrogen abstraction-cyclization using 1- and 2-bromovinylsilyl groups as bifunctional tethers was studied. Although, the selective introduction of a carbon substituent at the position P to the hydroxyl was unsuccessful, a carbon substituent was introduced with the 2-bromovinylsilyl ethers via a hydrogen abstraction-cyclization. These reactions were analyzed based on the bond dissociation energies obtained by theoretical calculations. (c) 2005 Elsevier Ltd. All rights reserved.
  • T Kudoh, M Fukuoka, S Shuto, A Matsuda
    NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS 24 5-7 655 - 658 2005年 [査読有り][通常論文]
     
    Several cyclic ADP-carbocyclic-ribose analogs 3-10 modified in the N-1-carbocyclic-ribose moiety were synthesized. Their Ca2+-releasing activity was estimated in sea urchin eggs to show that the 3"-deoxy analog 6 shows 5 times more potent activity than cADPcR, but the 2",3"-didieoxy-2",3"-unsunsaturated analog 3 has very weak activity. We also calculated their stable conformation and found that 3 and 6 were significantly different in their stable conformation.
  • C Takagi, M Sukeda, HS Kim, Y Wataya, S Yabe, Y Kitade, A Matsuda, S Shuto
    ORGANIC & BIOMOLECULAR CHEMISTRY 3 7 1245 - 1251 2005年 [査読有り][通常論文]
     
    5'-Methylenearisteromycin (5) and its 2-fluoro derivative 6, which were designed as antimalarial agents because of their AdoHcy hydrolase inhibition, were synthesized from D-ribose, using a stereoselective intramolecular radical cyclization as the key step to construct the carbocyclic structure. These compounds were evaluated as AdoHcy hydrolase inhibitors with the recombinant human and malarial parasite enzymes. Although 5 and 6 were both potent inhibitors of the malarial parasite AdoHcy hydrolase, the 2-fluoro derivative 6 proved to be superior due to its lower inhibitory effect on the human enzyme. In addition, 6 was identified as a potent antimalarial agent using an in vitro assay system with Plasmodium falciparum.
  • Kudoh T, Murayama T, Matsuda A, Shuto S
    Nucleic acids symposium series (2004) 49 25 - 26 2005年 [査読有り][通常論文]
  • Masaru Terauchi, Yumi Yahiro, Hiroshi Abe, Satoshi Ichikawa, Stephen C. Tovey, Skarlatos G. Dedos, Colin W. Taylor, Barry. V. L. Potter, Akira Matsuda, Satoshi Shuto
    Tetrahedron 61 3697 - 3707 2005年 [査読有り][通常論文]
  • KUDOH Takashi, FUKUOKA Masayoshi, ICHIKAWA Satoshi, MURAYAMA Takashi, OGAWA Yasuo, HASHII Minako, HIGASHIDA Haruhiro, KUNERTH Svenja, WEBER Karin, GUSE Andreas H, POTTER Barry V. L, MATSUDA Akira, SHUTO Satoshi
    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 127 24 8846 - 8855 2005年 [査読無し][通常論文]
  • HASHII Minako, SHUTO Satoshi, FUKUOKA Masayoshi, KUDOH Takashi, MATSUDA Akira, HIGASHIDA Haruhiro
    JOURNAL OF NEUROCHEMISTRY 94 2 316 - 323 Blackwell Publishing 2005年 [査読無し][通常論文]
     
    金沢大学大学院医学系研究科We synthesized analogs modified in the ribose unit (ribose linked to N1 of adenine) of cyclic ADP-ribose (cADPR), a Ca2+-mobilizing second messenger. The biological activities of these analogs were determined in NG108-15 neuroblastoma × glioma hybrid cells that were pre-loaded with fura-2 acetoxymethylester and subjected to whole-cell patch-clamp. Application of the hydrolysis-resistant cyclic ADP-carbocyclicribose (cADPcR) through patch pipettes potentiated elevation of the cytoplasmic free Ca2+ concentration ([Ca2+]i) at the depolarized membrane potential. The increase in [Ca2+]i evoked upon sustained membrane depolarization was significantly larger in cADPcR-infused cells than in non-infused cells and its degree was equivalent to or significantly greater than that induced by cADPR or β-NAD+. 8-chloro-cADPcR and two inosine congeners (cyclic IDP-carbocyclic-ribose and 8-bromo-cyclic IDP-carbocyclic-ribose) did not induce effects similar to those of cADPcR or cADPR. Instead, 8-chloro-cADPcR together with cADPR or cADPcR caused inhibition of the depolarization-induced [Ca2+]i increase as compared with either cADPR or cADPcR alone. These results demonstrated that our cADPR analogs have agonistic or antagonistic effects on the depolarization-induced [Ca2+]i increase and suggested the presence of functional reciprocal coupling between ryanodine receptors and voltage-activated Ca 2+ channels via cADPR in mammalian neuronal cells. © 2005 International Society for Neurochemistry.
  • Y Yamamoto, S Shuto, Y Tamura, T Kodama, S Hoshika, S Ichikawa, Y Ueno, E Ohtsuka, Y Komatsu, A Matsuda
    BIOCHEMISTRY 43 27 8690 - 8699 2004年07月 [査読有り][通常論文]
     
    Components that form stable hairpin loops are highly useful for the development of functional DNA and RNA molecules. We have designed and synthesized a sugar-modified thymidine analogue, 3'-deoxy-4'-C-(2-hydroxyethyl)thymidine (X), as a nucleosidic loop component stabilizing the hairpin structure. The ODNs I-1-4, 5'-d[CGAACG-X-n-CGTTCG]-3' (I-1, n = 1; I-2, n = 2; I-3, n = 3; I-4, n = 4), forming the hairpin loop structures, of which the loop moiety consisted of the analogue X, and also the corresponding unmodified ODNs II-1-4, 5'-d[CGAACG-T-n-CGTTCG]-3' (II-1, n = 1; II-2, n = 2; II-3, n = 3; II-4, n = 4), having a thymidine loop, were synthesized by the phosphoramidite method. The melting temperatures (T m) of the ODNs I-1-4 containing X in the loop moiety at 5 muM were 67.1, 68.1, 73.0, and 69.3 degreesC, respectively, and those of the control natural ODNs II-1-4 were 65.3, 67.0, 69.2, and 68.8 degreesC, respectively. Thus, the ODNs I-1-4 formed a more thermally stable hairpin than the corresponding unmodified ODNs II-1-4 having an equal number of loop residues. The hairpin structures of the modified ODNs I-1-4 and the unmodified ODNs II-1-4 were investigated by CD spectroscopy and molecular mechanics calculations. These results showed that the 4'-branched nucleoside X can stabilize hairpin structures when it is present in the loop moiety, probably due to the flexibility of the one-carbon-elongated 4'-branched structure.
  • S Shuto, A Matsuda
    CURRENT MEDICINAL CHEMISTRY 11 7 827 - 845 2004年04月 [査読有り][通常論文]
     
    Cyclic ADP-ribose (cADPR), a general mediator involved in Ca2+ signaling, has the characteristic 18-membered ring consisting of an adenine, two riboses and a pyrophosphate, in which the two primary hydroxyl groups of the riboses are linked by a pyrophosphate unit. This review focuses on the chemical synthetic studies of cADPR analogs. These analogs have been used quite effectively in proving tHe mechanism of cADPR-mediated Ca2+ signaling pathways. These analogs are also expected to be lead structures for the development of drugs. Although cADPR analogs can be synthesized by enzymatic and chemo-enzymatic methods using ADP-ribosyl cyclase, the analogs obtained by these methods are limited due to the substrate-specificity of the enzymes. Consequently, chemical synthetic methods providing a greater variety of cADPR analogs are required. Chemical synthetic studies have demonstrated that the construction of the large 18-membered ring structure is quite difficult. Another problem encountered in the synthesis is the construction of the N1-substituted purine nucleoside structure. The N1-substituted inosine derivatives were prepared by condensation between the N1-(2,4-dinitrophenyl)inosine derivatives and the appropriate amines. For the preparation of the N1-substituted adenosine structures, condensation of the 4-cyano-5-(alkoxymethyleneamino)imidazole nucleosides with the appropriate amines was found to be effective. The first chemical construction of the 18-membered ring was achieved using a bisphosphate-type substrate conformationally restricted in the cyclized product-like syn-form around the N9-glycosyl linkage; however, the yield was inadequate. The key 18-membereding construction was significantly improved by employing the phenylthiophosphate-type substrates. When the substrates were activated by AgNO3 or I-2 in the presence of molecular sieves in pyridine, the corresponding 18-membered ring products were obtained in high yields. Using this method as the key step, the chemically and biologically stable cADPR mimic, cADP-carbocyclic-ribose (cADPcR), was synthesized. This method has been applied subsequently to the synthesis of various cADPR analogs.
  • Satoshi Shuto, Masaru Terauchi, YumiYahiro, Hiroshi Abe, Satoshi Ichikawa, Akira Matsuda
    Tetrahedron Letters 45 6819  2004年 [査読有り][通常論文]
  • H Abe, M Terauchi, A Matsuda, S Shuto
    JOURNAL OF ORGANIC CHEMISTRY 68 19 7439 - 7447 2003年09月 [査読有り][通常論文]
     
    We previously theorized that, since the stereoselectivity of anomeric radical reactions is significantly influenced by the kinetic anomeric effect, which can be controlled by restricting the conformation of the radical intermediate, the proper conformational restriction of the pyranose ring of the substrates would therefore make highly alpha- and beta-stereoselective anomeric radical reactions possible. This theory was based on our previous results of the anomeric radical reactions with D-xylose derivatives as the substrates. We herein report the anomeric radical deuteration reactions with the conformationally restricted 1-phenylseleno-D-glucose derivatives, 2g and 3g, restricted in a C-4(1)-conformation by an beta-cyclic diketal moiety, and 4g, 5g, 6g, 7g, and 8g, restricted in a C-1(4)-conformation by bulky O-silyl protecting groups. The radical deuterations with Bu3SnD, using the C-4(1)-restricted substrates 2g and 3g, afforded the corresponding alpha-products (alpha/beta = 98:2) highly stereoselectively, whereas the C-1(4)-restricted substrate 6g, having a trigonal (sp(2)) carbon substituent, i.e., -CHO, at the 5-position, selectively gave the beta-products (alpha/beta = 0: 100). Thus, the stereoselectivity was significantly increased by the conformational restriction and was completely inverted by changing the substrate conformation from the C-4(1)-form to the C-1(4)-form. On the other hand, the deuterations with the C-1(4)-restricted substrates 4g and 5g showed that the 1,5-steric effect due to the tetrahedral carbon substituent (-CH2OTIPS or -CH2OH) at the 5-axial position dominantly prevented the hydride transfer from the beta-face competing with the kinetic anomeric effect. This study suggests that, depending on the restricted conformation of the substrates to the C-4(1)- or the C-1(4)-form, the alpha- or beta-products would be obtained highly stereoselectively via anomeric radical reactions of hexopyranoses.
  • M Sukeda, S Ichikawa, A Matsuda, S Shuto
    JOURNAL OF ORGANIC CHEMISTRY 68 9 3465 - 3475 2003年05月 [査読有り][通常論文]
     
    A novel radical method for the stereoselective introduction of an ethynyl group has been developed. When a solution of ethynyldimethylsilyl (EDMS) or [2-(trimethylsilyl)ethynyl]dimethylsilyl (TEDMS) ethers of trans-2-iodoindanol was treated with Et3B followed by tetrabutylammonium fluoride in toluene, atom transfer 5-exo-cyclization and subsequent elimination occurred to give cis-2-ethynylindanol in high yield. The method was shown to be useful in the introduction of an ethynyl group in various five- and six-membered-ring iodohydrins. Furthermore, 2'-deoxy-2'-C-ethynyl-uridine (6) and -cytidine (7), which were designed as novel antimetabolites, were readily synthesized by using this method as the key step. This would be the first example in which a radical reaction was used for introducing an ethynyl group.
  • Y Kazuta, H Abe, T Yamamoto, A Matsuda, S Shuto
    JOURNAL OF ORGANIC CHEMISTRY 68 9 3511 - 3521 2003年05月 [査読有り][通常論文]
     
    The stereoselective hydride reduction of the cis- and trans-substituted cyclopropyl ketones was systematically investigated using a series of structurally simplified substrates, trans-[tert-butyldiphenylsilyloxymethyl]cyclopropyl ketones la-a and trans- (benzyloxymethyl)cyclopropyl methyl ketone (2), and the corresponding cis congeners 3a,b,e and 4. The results showed that, not only in the reduction of the cis-substituted cyclopropyl ketones but also in that of the trans-substituted ketones, high stereoselectivity can be realized when the substrate has a bulky substituent on the cyclopropane ring, even though it is attached to the position trans to the acyl moiety. Ab initio calculations based on the density functional theory (DFT) of cyclopropyl ketones showed that (1) the bisected s-cis and s-trans conformers were the only two minimum energy conformers; while the s-cis conformer was more stable than the s-trans and (2) a bulky alkyl group in the acyl moiety and a cis substituent on the cyclopropane ring made the bisected s-cis conformer much more stable. On the basis of these calculations and experimental results, it is likely that the more stable the bisected s-cis conformer of the substrate, the more stereoselective the hydride reduction. Thus, the stereochemistry can be explained by hydride attack on the bisected s-cis conformation of the substrate from the less-hindered face. The predictability of the stereochemical results is predicated on the bisected s-cis transition-state model, which is very important from the viewpoint of synthetic organic chemistry.
  • Y Kazuta, K Hirano, K Natsume, S Yamada, R Kimura, SI Matsumoto, K Furuichi, A Matsuda, S Shuto
    JOURNAL OF MEDICINAL CHEMISTRY 46 10 1980 - 1988 2003年05月 [査読有り][通常論文]
     
    A series of cyclopropane-based conformationally restricted analogues of histamine, the "folded" cis-analogues, i.e., (1S,2R)-2-(aminomethyl)-1-(1H-imidazol-4-yl)cyclopropane (11), (1S,2S)-2-(2-aminoethyl)-1-(1H-imidazol-4-yl)cyclopropane (13), and their enantiomers ent-11 and ent-13, and the "extended" trans-analogues, i.e., (1R,2R)-2-(aminomethyl)-1-(1H-imidazol-4-yl)cyclopropane (12) and its enantiomer ent-12, were designed as histamine H-3 receptor agonists. These target compounds were synthesized from the versatile chiral cyclopropane units, (1S,2R)- and (1R,2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-formylcyclopropane (14 and 15, respectively) or their enantiomers ent-14 and ent-15. Among the conformationally restricted analogues, the "folded" analogue 13 (AEIC) having the cis-cyclopropane structure was identified as a potent H-3 receptor agonist, which showed a significant binding affinity (K-i = 1.31 +/- 0.16 nM) and had an agonist effect (EC50 value of 10 +/- 3 nM) on the receptor. This compound owes its importance to being the first highly selective H-3 receptor agonist to have virtually no effect on the H-4 subtype receptor. These studies showed that the cis-cyclopropane structure is very effective in the conformational restriction of histamine to improve the specific binding to the histamine H-3 receptor.
  • M Nomura, S Shuto, A Matsuda
    BIOORGANIC & MEDICINAL CHEMISTRY 11 11 2453 - 2461 2003年05月 [査読有り][通常論文]
     
    We have designed and synthesized the acetal derivatives of 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine (ECyd, 1), the 2',3'-O-nitrobenzylidene derivatives 2 and 3 and the 5'-O-(alkoxy)(nitrophenyl)methyl derivatives 6-10 as potential prodrugs of ECyd. These prodrugs can be selectively activated in tumor tissues via a bio-reduction hydrolysis mechanism owing to the characteristic properties of tumor tissues, such as hypoxia and lower pH. Although the 2',3'-O-(4-nitrobenzylidene) derivatives 2 and 3 were converted bio-reductively into the corresponding 4-aminobenzylidene derivatives by rat S-9 mix, the reduction products, that is, the corresponding amino congeners 4 and 5, proved to be rather stable in an aqueous solution at pH 6.5 used as a pH model for acidic tumor tissues. In contrast, the 5'-O-(alkoxy)(4-nitropheny)methyl derivatives 6-8 were also reduced by rat S-9 mix to the corresponding amino congeners 11-13, which were hydrolyzed to release ECyd more effectively at pH 6.5 than at pH 7.4. Accordingly, the acyclic acetals 6-8 may be efficient prodrugs of ECyd, that are effectively reduced under physiological conditions releasing ECyd in acidic tumor tissues. (C) 2003 Elsevier Science Ltd. All rights reserved.
  • L Gan, MR Seyedsayamdost, S Shuto, A Matsuda, GA Petsko, L Hedstrom
    BIOCHEMISTRY 42 4 857 - 863 2003年02月 [査読有り][通常論文]
     
    Mizoribine monophosphate (MZP) is the active metabolite of the immunosuppressive agent mizoribine and a potent inhibitor of IMP dehydrogenase (IMPDH). This enzyme catalyzes the oxidation of IMP to XMP with the concomitant reduction of NAD via a covalent intermediate at Cys319 (E-XMP*). Surprisingly, mutational analysis indicates that MZP is a transition state analogue although its structure does not resemble that of the expected transition state. Here we report the X-ray crystal structure of the E(.)MZP complex at 2.0 Angstrom resolution that reveals a transition state-like structure and solves the mechanistic puzzle of the IMPDH reaction. The protein assumes a new conformation where a flap folds into the NAD site and MZP, Cys319, and a water molecule are arranged in a geometry resembling the transition state. The water appears to be activated by interactions with a conserved Arg418-Tyr419 dyad. Mutagenesis experiments confirm that this new closed conformation is required for the hydrolysis of E-XMP*, but not for the reduction of NAD. The closed conformation provides a structural explanation for the differences in drug selectivity and catalytic efficiency of IMPDH isozymes.
  • S Tamura, H Abe, A Matsuda, S Shuto
    ANGEWANDTE CHEMIE-INTERNATIONAL EDITION 42 9 1021 - + 2003年 [査読有り][通常論文]
  • T Kodama, S Shuto, S Ichikawa, A Matsuda
    JOURNAL OF ORGANIC CHEMISTRY 67 22 7706 - 7715 2002年11月 [査読有り][通常論文]
     
    Since V-branched nucleosides are biologically important targets in medicinal chemistry, more efficient methods for preparing them are required. The 1'alpha-branched uridine derivatives were successfully synthesized via a samarium diiodide (SmI2)-promoted aldol reaction. Treatment of the 1'alpha-phenylseleno-2'-ketouridine derivative 6, readily prepared from uridine, with SmI2 at -78 degreesC in THF reductively cleaved the anomeric Se-C bond to generate the corresponding samarium enolate, which was highly stereoselectively condensed with aldehydes, such as PhCHO, MeCHO, i-PrCHO, or (CH2O)(n), to give the corresponding 1'alpha-1"S-branched products 12a-d. This is the first time an enolate has been generated by reductively cleaving a C-Se bond. The highly selective stereochemical results suggest that the aldol reaction proceeds via a chelation-controlled transition state. When an excess of aldehyde was used and the reaction mixture was gradually warmed, the tandem aldol-Tishchenko reaction proceeded to give the "arabino-type" nucleosides 14a-c, having a 2'-"up" hydroxyl and 1'alpha-1"S-branched chain. 1'alpha-Hydroxymethyluridine (21), which is the uracil version of the antitumor antibiotic angustmycin C, was synthesized from the aldol reaction product 10.
  • N Atsumi, Y Ueno, M Kanazaki, S Shuto, A Matsuda
    BIOORGANIC & MEDICINAL CHEMISTRY 10 9 2933 - 2939 2002年09月 [査読有り][通常論文]
     
    In order to develop novel antigene molecules forming thermally stable triplexes with target DNAs and having nuclease resistance properties, e synthesized oligodeoxynucleotides (ODNs) with various lengths of aminoalkyl-linkers at the 4'alpha position of thymidine and the aminoethyl-linker at the 4'alpha position of 2'-deoxy-5-methylcytidine. Thermal stability of triplexes between these ODNs and a DNA duplex was studied by thermal denaturation. The ODNs containing the nucleoside 2 with the aminoethyl-tinker or the nucleoside 3 with the aminopropyl-linker thermally stabilized the triplexes, whereas the ODNs containing the nucleoside I with the aminomethyl-linker or the nucleoside 4 with the 2-[N-(2-aminoethyl)carbamoyl]oxy]ethyl-linker thermally destabilized the triplexes. The ODNs containing 2 were the most efficient at stabilizing the triplexes with the target DNA. The ODNs containing 4'alpha-C-(2-aminoethyl)-2'-deoxy-5-methylcytidine (5) also efficiently stabilized the triplexes with the target DNA. Stability of the ODN containing 5 to nucleolytic hydrolysis by snake venom phosphodiesterase (a 3'-exonuclease) was Studied. It was found that the ODN containing 5 was more resistant to nucleolytic digestion by the enzyme than all unmodified ODN. In a previous paper, we reported that the ODNs containing 2 were more resistant to nucleolytic digestion by DNase I (an endonuclease) than the Unmodified ODNs. Thus, it was found that the ODNs containing 4'alpha-C-(2-aminoethyl)-2'-deoxynucleosides were good candidates for antigene molecules. (C) 2002 Elsevier Science Ltd. All rights reserved.
  • AH Guse, C Cakir-Kiefer, M Fukuoka, S Shuto, K Weber, VC Bailey, A Matsuda, GW Mayr, N Oppenheimer, F Schuber, BVL Potter
    BIOCHEMISTRY 41 21 6744 - 6751 2002年05月 [査読有り][通常論文]
     
    Three novel analogues modified in the "northern" ribose (ribose linked to NI of adenine) of the Ca2+ mobilizing second messenger cyclic adenosine diphosphoribose, termed 2"-NH2-cyclic adenosine diphosphoribose, cyclic adenosine diphospho-carbocyclic-ribose, and 8-NH2-cyclic adenosine diphospho-carbocyclic-ribose, were synthesized (chemoenzymatically and by total synthesis) and spectroscopically characterized, and the pK(a) values for the 6-amino/imino transition were determined in two cases. The biological activity of these analogues was determined in permeabilized human Jurkat T-lymphocytes. 2"-NH2-cyclic adenosine diphosphoribose mediated Ca2+ release was slightly more potent than that of the endogenous cyclic adenosine diphosphoribose in terms of the concentration - reponse relationship. Both compounds released Ca2+ from the same intracellular Ca2+ pool. In addition, the control compound 2"-NH2-adenosine diphosphoribose was almost without effect. In contrast, only at much higher concentrations (greater than or equal to 50 muM) did the "northern" carbocyclic analogue, cyclic adenosine diphospho-carbocyclic-ribose, significantly release Ca2+ from permeabilized T cells, whereas the previously reported "southern" carbocyclic analogue, cyclic aristeromycin diphosphoribose, was slightly more active than the endogenous cyclic adenosine diphosphoribose. Likewise, 8-NH2-cyclic adenosine diphospho-carbocyclic-ribose, expected to antagonize Ca2+ release as demonstrated previously for 8-NH2-cyclic adenosine diphosphoribose, did not inhibit cyclic adenosine diphosphoribose mediated Ca2+ release. This indicates that the 2"-NH2-group substitutes well for the 2"-OH-group it replaces; it may be oriented toward the outside of the putative cyclic adenosine diphosphoribose receptor binding domain and/or it can potentially also engage in H bonding interactions with residues of that domain. In sharp contrast to this, replacement of the endocyclic furanose oxygen atom by CH2 in a carbocyclic system obviously interferes with a crucial element of interaction between cyclic adenosine diphosphoribose and its receptor in T-lymphocytes.
  • Y Kazuta, A Matsuda, S Shuto
    JOURNAL OF ORGANIC CHEMISTRY 67 5 1669 - 1677 2002年03月 [査読有り][通常論文]
     
    The cyclopropane ring can be used effectively in restricting the conformation of biologically active compounds to improve activity and also to investigate bioactive conformations. We designed (1S,2R)and (1R,2R)-2-aminomethyl-1-(1H-imidazol-4-yl)cyclopropanes (1 and 2, respectively) and their enantiomers (ent-1 and ent-2) as conformationally restricted analogues of histamine. The four types of chiral cyclopropanes bearing two differentially functionalized carbon substituents in a cis or trans relationship on a cyclopropane ring, (1S,2R)-2-(tert-butyldiphenylsilyloxy)methyl-l-formylcyclopropane (7) and (1-R,2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-fonnylcyclopropane (8) and their enantiomers (ent-7 and ent-8), were developed as the key intermediates for synthesizing 1, 2, ent-1, and ent-2. The reaction between (R)-epichlorohydrin [(R)-12] and phenylsulfonylacetonitrile (13a) in the presence of NaOEt in EtOH followed by treatment with acid gave the chiral cyclopropane lactone 11a with 98% ee in 82% yield. Compound 11a was converted into both the cis- and transchiral cyclopropane units 7 and 8, respectively, via reductive desulfonylation with Mg/MeOH as the key step. The corresponding enantiomers, the cis-substituted ent-7 and the trans-substituted ent-8, were also prepared starting from (S)-epichlorohydrin [(S)-12]. The four conformationally restricted target histamine analogues 1, 2, ent-1, and ent-2 were successfully synthesized from 7, 8, ent-7, and ent-8, respectively. The chiral cyclopropane units 7, 8, ent-7, and ent-8 should be useful as versatile intermediates for synthesizing various compounds having an asymmetric cyclopropane structure.
  • S Shuto, M Kanazaki, Sugimoto, I, S Ichikawa, Y Nagasawa, Y Ueno, H Abe, N Minakawa, M Sukeda, T Kodama, M Nomura, A Matsuda
    RECENT ADVANCES IN NUCLEOSIDES: CHEMISTRY AND CHEMOTHERAPY 21 - 55 2002年 [査読有り][通常論文]
  • S Shuto, N Minakawa, S Niizuma, HS Kim, Y Wataya, A Matsuda
    JOURNAL OF MEDICINAL CHEMISTRY 45 3 748 - 751 2002年01月 [査読有り][通常論文]
     
    An improved method for the synthesis of (6'R)-6'-C-methylneplanocin A (RMNPA, 2), a potent S-adenosyl-L-homocysteine (AdoHcy) hydrolase inhibitor, was developed via a chelation-controlled stereoselective addition of MeTiCl3 to the neplanocin A 6'-aldehyde derivative 6. Compound 2 effectively inhibited the growth of malaria parasites both in vitro and in vivo. The antimalarial EC50 value of 2 against Plasmodium berghei in mice was 1.0 mg/kg/day, which was superior to that of chloroquine (EC50 = 1.8 mg/kg/day).
  • M Sukeda, S Ichikawa, A Matsuda, S Shuto
    ANGEWANDTE CHEMIE-INTERNATIONAL EDITION 41 24 4748 - 4750 2002年 [査読有り][通常論文]
  • Shuto S, Mochizuki T, Abe H, Kondo Y, Matsuda A
    Nucleic acids research. Supplement (2001) 2 23 - 24 2002年 [査読有り][通常論文]
  • S Shuto, G Horne, RD Marwood, BVL Potter
    CHEMISTRY-A EUROPEAN JOURNAL 7 22 4937 - 4946 2001年11月 [査読有り][通常論文]
     
    The adenophostins exhibit approximately 10-100 times higher receptor binding and Ca2+ mobilising potencies in comparison with the natural second messenger D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P-3]. Despite many synthetic attempts to determine the minimal structural requirement for this unusual behaviour of the adenophostins, few related simplified analogues displaying higher activity than that of Ins(1.4,5)P-3 have been reported. However, biological evaluation of such analogues has revealed that one of the key factors for the enhanced biological activity is the adenine moiety. To further understand the effect that the adenine base has upon the activity of the adenophostins, congeners in which this functionality is replaced by uracil, benzimidazole, 2-methoxynaphthalene, 4-methylanisole and 4-methylnaphthalene using the common intermediate 1,2-di-O-acetyl-5-O-benzyl-3-O-(3,4-di-O-acetyl-2,6-di-O-benzyl-alpha -D-glucopyranosyl)-ribofuranose have been synthesised using a base replacement strategy. The synthesis of the uracil and benzimidazole analogues was achieved using the Vorbruggen condensation procedure. The 1'-C-glycosidic analogues were prepared using Friedel-Crafts type C-aryl glycosidation reactions. Phosphate groups were introduced using the phosphoramidite method with subsequent removal of all-benzyl protecting groups by catalytic hydrogenation or catalytic hydrogen transfer. Apart from one analogue with an alpha -glycosidic linkage all compounds were more potent than Ins(1,4,5)P-3 and most tended more towards adenophostin in activity. These analogues will be valuable tools to unravel the role that the adenine moiety plays in the potent activity of the adenophostins and demonstrate that this strategy is effective at producing highly potent ligands.
  • Shigeo Uchino, Wakako Watanabe, Takeshi Nakamura, Satoshi Shuto, Yuji Kazuta, Akira Matsuda, Sadayo Nakajima-Iijima, Yoshihisa Kudo, Shinichi Kohsaka, Masayoshi Mishina
    FEBS Letters 506 2 117 - 122 2001年10月05日 [査読有り][通常論文]
     
    To develop an assay system that allows the N-methyl-D-aspartate (NMDA) receptor subtype-selective antagonistic potency of drugs, we have established Chinese hamster ovary cell lines expressing the four NMDA receptor subtypes (GluRε1/ζ1-GluRε4/ζ1) heat-indelibly. Using these clonal cells, we found that a novel antagonist, (1S,2R)-1-phenyl-2[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide, was less selective for the GluRε1/ζ1: the IC50 values for the GluRε1/ζ1-GluRε4/ζ1 were 41.7, 13.3, 12.6 and 11.5 μM, respectively, while two well-known antagonists, DL-2-amino-5-phosphonovaleric acid and ifenprodil, showed the known potency and selectivity for each subtype. Thus, the established clonal cells are of use in characterizing the pharmacological properties of drugs that act on NMDA receptors. © 2001 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.
  • S Shuto, M Fukuoka, H Abe, A Matsuda
    NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS 20 4-7 461 - 470 2001年 [査読有り][通常論文]
     
    We designed novel Ca2+-mobilizing purine nucleotides, cyclic ADP-carbocyclicribose 4, and its inosine congener 5, and C-glycosidic adenophostin A 6. In the synthesis of cADPR analogs, the intramolecular condensation to form the pyrophosphate linkage should be the key step. We developed an efficient method for forming such an intramolecular pyrophosphate linkage by the activation of the phenylthiophosphate group with I-2 or AgNO3. Using this method, we achieved to synthesize the target compounds 4 and 5. The synthesis of C-glycosidic analog 6 of adenophostin A was achieved using a temporary silicon-tethered radical coupling reaction for constructing (3'alpha, 1 " alpha)-C-glycosidic structure as the key step.
  • M Fukuoka, S Shuto, N Minakawa, Y Ueno, A Matsuda
    NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS 20 4-7 1355 - 1358 2001年 [査読有り][通常論文]
     
    An efficient synthesis of cyclic ADP-carbocyclic-ribose (2), as a stable mimic for cyclic ADP-ribose, was achieved. Treatment of N-1-carbocyclic-ribosyladenosine bisphosphate derivative 10 with AgNO3 in the presence of molecular sieves 3A in pyridine gave the desired cyclic product in 93% yield, which was deprotected to give the target cyclic ADP-carbocyclic-ribose (2).
  • Asai T, Shuto S, Matsuda A, Kakiuchi T, Ohba H, Tsukada H, Oku N
    Cancer Lett. 162 162 49 - 56 2001年 [査読有り][通常論文]
  • S Shuto, M Fukuoka, A Matsuda
    JOURNAL OF SYNTHETIC ORGANIC CHEMISTRY JAPAN 58 12 1144 - 1154 2000年12月 [査読有り][通常論文]
     
    Cyclic ADP-ribose (cADPR, 1) is a newly discovered general mediator involved in Ca2+ signaling. The synthesis of cADPR analogs has been extensively studied by enzymatic and chemo-enzymatic methods using ADP-ribosylcyclase, due to their biological importance. ADP-ribosylcyclase from Aplysia Californica mediates the intramolecular ribosylation of NAD(+) and some modified NAD(+), which are prepared chemically or enzymatically, at the N-1-position of the purine moiety to yield cADPR or the corresponding analogs. However, the analogs that can be obtained by this method are limited due to the substrate-specificity of the enzyme. We developed an efficient method for the chemical synthesis of cADPR analogs and synthesized cyclic ADP-carbocyclic-ribose (cADPcR 2) and its inosine congener (3, cIDPcR) as stable mimics of cADPR, in which an oxygen atom in the ribose ring of cADPR is replaced by a methylene group. Biological activities of cADPR and its analogs were also described.
  • M Kashiwayanagi, K Tatani, S Shuto, A Matsuda
    EUROPEAN JOURNAL OF NEUROSCIENCE 12 2 606 - 612 2000年02月 [査読有り][通常論文]
     
    Using the whole-cell mode of the patch-clamp technique, we recorded inward currents in response to inositol-1,4,5-trisphosphate (IP3) and adenophostin analogues in turtle olfactory sensory neurons. Dialysis of IP3 into the neurons induced inward currents with an increase in membrane conductance in a dose-dependent manner under the voltage-clamp conditions (holding potential -70 mV). The application of Ca2+-free Ringer solution to neurons previously dialysed with IP3 induced inward currents that were reversibly inhibited by application of Na+, Ca2+-free Ringer solution, normal Ringer solution or 10 mu m ruthenium red. Dialysis of the adenophostin analogues, novel IP3 receptor ligands, also induced inward currents with an increase in membrane conductance. The magnitude of the responses to the adenophostin analogues varied among these derivatives. The application of Ca2+-free Ringer solution to neurons previously dialysed with the adenophostin analogues induced inward currents that were inhibited by the application of normal Ringer solution. The reversal potential of inward currents induced by an adenophostin analogue was similar to that induced by IP3, suggesting that inward currents induced by the adenophostin analogue were generated by a similar ionic mechanism to that induced by IP3. The present study demonstrated that IP3-mediated transduction pathways exist in turtle olfactory receptor neurons and that adenophostin analogues act as agonists of IP3.
  • S Shuto, K Haramuishi, M Fukuoka, A Matsuda
    JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1 21 3603 - 3609 2000年 [査読有り][通常論文]
     
    The imidazole nucleoside bredinin (mizoribine) is a clinically useful immunosuppressant. Derivatization of bredinin by the usual nucleoside chemistry is often troublesome due to the unusual zwitterionic structure of the base moiety. We achieve the synthesis of 5'-modified analogs of bredinin via a novel photochemical imidazole ring-cleavage reaction as the key step. When a solution of 2',3'-O-isopropylidenebredinin 5 in 0.1 M AcOH is irradiated with a high-pressure mercury lamp, an imidazole ring-cleavage reaction occurs to give the 2-aminomalonamide riboside derivative 16 in 71% yield. Appropriate modifications of the 5'-position of 16 and subsequent condensation with (EtO)(3)CH to reconstruct the imidazole base moiety follow. Using this imidazole ring-cleavage-reconstruction strategy, some biologically important 5'-modified bredinin analogs, i.e., the 5'-phosphate 2, the 5'-deoxy derivative 3, and the 5'-O-aminopropylcarbamate 4 are efficiently synthesized.
  • M. Fukuoka, S. Shuto, N. Minakawa, Y. Ueno, A. Matsuda
    Nucleic acids symposium series 42 11 - 12 1999年01月01日 [査読無し][通常論文]
     
    An efficient synthesis of cyclic IDP-carbocyclic-ribose, as a stable mimic for cyclic ADP-ribose, was achieved. 8-Bromo-N1-carbocyclic-ribosylinosine derivative 10, prepared from N1-(2,4-dinitrophenyl)inosine derivative 5 and an optically active carbocyclic amine 6, was converted to 8-bromo-N1-carbocyclic-ribosylinosine bisphosphate derivative 15. Treatment of 15 with I2 in the presence of molecular sieves in pyridine gave the desired cyclic product 16 quantitatively, which was deprotected and reductively debrominated to give the target cyclic IDP-carbocyclic-ribose (3).
  • S Shuto, M Kanazaki, S Ichikawa, N Minakawa, A Matsuda
    JOURNAL OF ORGANIC CHEMISTRY 63 3 746 - 754 1998年02月 [査読有り][通常論文]
     
    An efficient method for the synthesis of 4'alpha-branched 2'-deoxyadenosines starting from 2'-deoxyadenosine has been developed utilizing a novel radical cyclization reaction with a silicon tether. The radical reaction of 4'beta-phenylseleno)-3'-O-diphenylvinylsilyl adeninenucleoside derivative 17 with Bu3SnH and AIBN, followed by Tamao oxidation, gave selectively either the 4'alpha-(2-hydroxyethyl) derivative 21 or 4'alpha-(1-hydroxyethyl) derivative 19, depending on the reaction conditions. With a lower Bu3SnH concentration, the reaction gave the 4'alpha-(2-hydroxyethyl) derivative 21, via a 6-endo-radical cyclized product 20, as the sole product in 72% yield. The reaction of 17 in the presence of excess Bu3SnH gave 19 quantitatively, via a 5-exo-cyclized product 18, as a diastereomeric mixture. The reaction mechanism was examined using Bu3SnD. The results demonstrated that the 5-exo cyclized (3-oxa-2-silacyclopentyl)methyl radical (C) was formed initially which was trapped when the concentration of Bu3SnH(D) was high enough. With lower concentrations of Bu3SnH(D), radical C rearranged into the ring-enlarged 4-oxa-3-silacyclohexyl radical (D) which was then trapped with Bu3SnH(D) to give endo-cyclized product F.
  • Dirk Daelemans, Anne-Mieke Vandamme, Satoshi Shuto, Akira Matsuda, Erik De Clercq
    Nucleosides and Nucleotides 17 1-3 479 - 486 1998年 [査読有り][通常論文]
     
    The R- and S-isomers of 6'-C-neplanocin A analogues, which are all known as inhibitors of S-adenosylhomocysteine (AdoHcy) hydrolase, were studied for their inhibitory effects on Human Immunodeficiency Virus type 1 (HIV-1) replication and HIV-1 Tat-mediated transactivation. The R-isomers showed much greater activity against AdoHcy hydrolase than the S-isomers. The same differential activity was observed against the HIV-1 replication and the Tat transactivation.
  • AEA Hassan, N Nishizono, N Minakawa, S Shuto, A Matsuda
    JOURNAL OF ORGANIC CHEMISTRY 61 18 6261 - 6267 1996年09月 [査読有り][通常論文]
     
    The Wittig reaction of 1-[3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-beta-D-erythro-pentofuranos-2-ulosyl]uracil (6) with Ph(3)P=CHCN afforded (Z)-2'-cyanomethylene derivative 7 exclusively. The (E)-isomer was accessed from its (Z)-isomer through a sequence of addition of thiophenol to the 2'-cyanomethylene moiety of the (Z)-isomer from the alpha-face, selectively, and stereoselective oxidative syn-elimination of the resulting adduct. The diastereofacial selectivity of the benzenethiolate addition to the cyanomethylene moiety was found to be influenced by participation of the 2-carbonyl group at the base moiety and steric hindrance of the sugar protecting groups. Although nucleophilic addition reactions at the 2'-position of 6 have been well-known to occur from the alpha-face selectively, treatment of 7 with LiSPh in THF unexpectedly afforded a mixture of alpha- and beta-phenylthio derivatives 8 and 9 in almost equal ratio. Furthermore, an unusual beta-facial selective addition was observed on treatments of 7 with PhSAlMe(2) in CH2Cl2 or wit LiSPh in the presence of Mg(ClO4)(2) in THF. On the other hand, when (Z)-2'-(cyanomethylene)-5'-O-triisopropylsilyl derivative 10 was treated with LiSPh, the alpha-phenylthio derivative 13 was obtained predominantly (89:11). Oxidation of 8 with m-chloroperbenzoic acid (m-CPBA) in CH2Cl2 and pyrolysis of the resulting sulfoxides afforded the (Z)-isomer 7 exclusively. Treatment of 13 with m-CPBA under the same conditions afforded the desired (E)-cyanomethylene derivatives 18 as a major product (E:Z = 14:1) in good yield. Deprotection of 18 by the standard procedures furnished (E)-2'-(cyanomethylene)-2'-deoxyuridine (5).
  • S SHUTO, T OBARA, Y KOSUGI, Y SAITO, M TORIYA, S YAGINUMA, S SHIGETA, A MATSUDA
    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 4 4 605 - 608 1994年02月 [査読有り][通常論文]
     
    (6'R)- and (6'S)-6'-C-methyl-3-deazaneplanocin A's were synthesized from D-ribose as anti-RNA virus agents. Of these compounds, (6'R)-6'-C-methyl-3-deazaneplanocin A (4b) showed the greatest anti-RNA virus activity in vitro. It was found that the 6'R-configuration was essential for the antiviral activity of 6'-C-methylneplanocin A derivatives.
  • H AWANO, S SHUTO, M BABA, T KIRA, S SHIGETA, A MATSUDA
    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 4 2 367 - 370 1994年01月 [査読有り][通常論文]
     
    (2'S)-2'-deoxy-2'-C-methyl-5-halogenopyrimidine nucleosides were designed and synthesized as anti-herpes virus agents. Of these compounds, (2'S)-2'-deoxy-2'-C-methyl-5-iodouridine (SMIU, 9e) showed the greatest anti-HSV-l activity in vitro while showing no cytotoxicity. SMIU is a candidate drug for clinical treatment of herpes virus infection disease.
  • S SHUTO, H ITOH, T OBARA, K NAKAGAMI, M YASO, S YAGINUMA, M TSUJINO, T SAITO, A MATSUDA, T UEDA
    NUCLEOSIDES & NUCLEOTIDES 11 2-4 437 - 446 1992年 [査読有り][通常論文]
     
    A novel series of neplanocin analogues, 6'-(3-sn-phosphatidyl)neplanocin As bearing a variety of fatty acyl or alkyl residues in the glyceride moiety (2b-2h), were synthesized by means of phospholipase D-catalyzed transphosphatidylation. Among them, 2b, 2c, and 2e each exhibited significant antitumor effect against P388 leukemia in mice, which evidently surpassed that of parent compound neplanocin A.
  • M ARITA, T OKUMOTO, T SAITO, Y HOSHINO, K FUKUKAWA, S SHUTO, M TSUJINO, H SAKAKIBARA, M OHNO
    CARBOHYDRATE RESEARCH 171 233-258 233 - 258 1987年12月 [査読無し][通常論文]
  • Satoshi Shuto, Sigeyuki Imamura, Kiyofumi Fukukawa, Hideo Sakakibara, Junichi Murase
    Chemical and Pharmaceutical Bulletin 35 1 447 - 449 1987年 [査読有り][通常論文]
     
    Phospholipase D from Streptomyces effectively catalyzed the transfer reaction of the phosphatidyl residue from phosphatidylcholines to the primary hydroxyl group of homoserine in a two-phase system. Various phosphatidylhomoserines were easily prepared in good yields by this reaction. © 1987, The Pharmaceutical Society of Japan. All rights reserved.
  • S SHUTO, S UEDA, S IMAMURA, K FUKUKAWA, A MATSUDA, T UEDA
    TETRAHEDRON LETTERS 28 2 199 - 202 1987年 [査読無し][通常論文]
  • Kiyofumi Fukukawa, Satoshi Shuto, Takao Hirano, Tohru Ueda
    Chemical and Pharmaceutical Bulletin 34 9 3653 - 3657 1986年 [査読有り][通常論文]
     
    Photolysis of l-β-D-ribofuranosyl-5-aminoimidazole-4-carboxamide (AICA-riboside) gave 2-amino-A-(β-D-ribofuranosyl)malondiamide, which was cyclized by treatment with ethyl orthoformate to furnish l-β-D-ribofuranosyl-5-hydroxyimidazole-4-carboxamide (bredinin), a potent immunosuppressive nucleoside antibiotic. © 1986, The Pharmaceutical Society of Japan. All rights reserved.
  • Tomoharu Sano, Satoshi Shuto, Hideo Inoue, Tohru Ueda
    Chemical and Pharmaceutical Bulletin 33 9 3617 - 3622 1985年 [査読有り][通常論文]
     
    The reaction of methylenetriphenylphosphorane with 2’-keto-3’,5’-O-(tetraisopropyldisil-oxane-l,3-diyl)uridine afforded the 2’-methyleneuridine (1). Oxidation of 1 with osmium tetroxide and tert-butyl hydroperoxide or N-methylmorpholine-N-oxide afforded a mixture of a 2’-hydroxymethyluridine (2) and its arabinosyl isomer. Oxidation at lower temperature gave the former as the main product. Compound 2 was converted to the 5-bromo-2’-iodomethyl derivative (3) through the 2’-mesyloxy compound, and 3 was treated with tri-n-butyltin hydride to give the 6,2’-methano-cyclo-5,6-dihydro derivative (4). Compound 4 was dehydrobrominated and deprotected to furnish 6,2’-methano-cyclouridine, a uridine fixed in high-anti conformation. Some results on the synthesis and cleavage of the 2’-spiro-epoxy derivative prepared from the 2’-ketouridine are also presented. © 1985, The Pharmaceutical Society of Japan. All rights reserved.
  • T UEDA, S SHUTO, M SATOH, H INOUE
    NUCLEOSIDES & NUCLEOTIDES 4 3 401 - 409 1985年 [査読無し][通常論文]
  • Kiyofumi Fukukawa, Satoshi Shuto, Takao Hirano, Tohru Ueda
    Chemical and Pharmaceutical Bulletin 32 4 1644 - 1646 1984年 [査読有り][通常論文]
     
    A novel synthesis of bredinin by the conversion of AICA-riboside through a photo-degradation product is described. © 1984, The Pharmaceutical Society of Japan. All rights reserved.
  • T UEDA, H USUI, S SHUTO, H INOUE
    CHEMICAL & PHARMACEUTICAL BULLETIN 32 9 3410 - 3416 1984年 [査読有り][通常論文]
  • S SHUTO, T IWANO, H INOUE, T UEDA
    NUCLEOSIDES & NUCLEOTIDES 1 3 263 - 273 1982年 [査読無し][通常論文]
  • T UEDA, S SHUTO
    HETEROCYCLES 17 95-98 95 - 98 1982年 [査読無し][通常論文]

書籍

  • 臨床医薬品化学研究会 (担当:共著範囲:モルヒネ関連薬の化学、アルツハイマー治療薬の化学(p159-p165))
    化学同人 2021年04月 (ISBN: 9784759820546) iv, 261p
  • スタンダード薬学シリーズII ・化学系薬学 II.生体分子・医薬品の化学による理解
    周東 智 (担当:共著範囲:酵素阻害剤とその害様式.)
    東京化学同人 2016年
  • ペプチド医薬の最前線
    周東 智 (担当:共著範囲:シクロプロパンの立体的および立体電子的特性に基づくペプチドミメティックの創製)
    2012年
  • 有機医薬分子論
    周東 智 (担当:単著)
    2011年11月
  • ベーシック薬学教科書シリーズ・薬理学
    周東 智 (担当:共著範囲:化学療法薬(抗がん薬))
    化学同人 2009年
  • 新規抗RNAウイルス薬の設計と作用機序
    抗ウイルス化学療法の進歩 1993年

その他活動・業績

  • 青木 駿, 出山 諭司, 石村 航平, 福田 隼, 周東 智, 南 雅文, 金田 勝幸 日本薬理学会年会要旨集 93 (0) 2 -P-178 2020年 [査読無し][通常論文]
     

    We have recently demonstrated that infusion of eicosapentaenoic acid-derived resolvin E1 (RvE1) into the medial prefrontal cortex (mPFC) exerts antidepressant effects via brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) release and subsequent activation of mechanistic target of rapamycin complex 1 (mTORC1) in a murine lipopolysaccharide (LPS)-induced depression model. In the present study, we examined the roles of BDNF/VEGF release and mTORC1 activation within the mPFC in the antidepressant actions of intranasal (i.n.) administration of RvE1 in LPS-induced depression model mice using the tail suspension and forced swim tests. The results demonstrate that the antidepressant effects of i.n. RvE1 are completely blocked by intraperitoneal injection of an AMPA receptor antagonist NBQX or an L-type voltage-dependent Ca2+ channel (L-VDCC) blocker verapamil. We also demonstrate that the antidepressant effects of i.n. RvE1 are blocked by intra-mPFC infusion of a BDNF neutralizing antibody (nAb), a VEGF nAb or an mTORC1 inhibitor rapamycin. Together, the current results suggest that the antidepressant actions of i.n. RvE1 are mediated by BDNF/VEGF release which is probably caused by activation of AMPA receptors and L-VDCCs, and subsequent activation of mTORC1 in the mPFC.

  • 炎症収束脂質レゾルビンE2のスキップジエン構造をベンゼン環で置換した安定等価体創製研究
    村上 侑斗, 福田 隼, 石村 航平, 平島 洸基, 室本 竜太, 渡邉 瑞貴, 松田 正, 周東 智 日本薬学会年会要旨集 139年会 (2) 96 -96 2019年03月 [査読無し][通常論文]
  • 青木駿, 出山諭司, 石村航平, 福田隼, 福田隼, 周東智, 南雅文, 金田勝幸 次世代を担う創薬・医療薬理シンポジウムプログラム・要旨集 2019 2019年
  • 杉山洸, 一ノ瀬亘, 渡邉瑞貴, 広川貴次, 周東智 日本薬学会年会要旨集(CD-ROM) 139th 2019年
  • 桑原智希, 水野彰, 渡邉瑞貴, 竹内恒, 広川貴次, 浅井章良, 周東智 日本薬学会年会要旨集(CD-ROM) 139th 2019年
  • 出山 諭司, 石村 航平, 福田 隼, 周東 智, 南 雅文, 金田 勝幸 日本薬理学会年会要旨集 92 (0) 2 -P-029 2019年 [査読無し][通常論文]
     

    We have recently demonstrated that infusion of eicosapentaenoic acid-derived resolvin E1 (RvE1; 50 pg/side) into the medial prefrontal cortex (mPFC) exerts antidepressant effect in a murine lipopolysaccharide (LPS)-induced depression model. In the present study, we examined the roles of brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and their downstream mTORC1 in the antidepressant actions of intra-mPFC RvE1 infusion in LPS-induced depression model mice using the tail suspension and forced swim tests. The results demonstrate that the antidepressant effects of intra-mPFC RvE1 infusion are completely blocked by co-infusion of a BDNF neutralizing antibody (nAb), a VEGF nAb or an mTORC1 inhibitor rapamycin. We also demonstrate that the antidepressant effects of intra-mPFC BDNF or VEGF infusion are blocked by co-infusion of rapamycin. Together, the current results indicate that BDNF/VEGF release and subsequent activation of mTORC1 in the mPFC are required for the antidepressant actions of RvE1.

  • 佐藤晋平, 福田隼, 渡邉瑞貴, 周東智 反応と合成の進歩シンポジウム講演要旨集 44th 12 2018年10月15日 [査読無し][通常論文]
  • 南貴覚, 福多洸太朗, 星谷尚亨, 福田隼, 渡邉瑞貴, 周東智 反応と合成の進歩シンポジウム講演要旨集 44th 107 2018年10月15日 [査読無し][通常論文]
  • EPA由来新規抗炎症性代謝産物(レゾルビンE3)の糖代謝における検討
    清水 智彦, 齋藤 従道, 福田 隼, 石村 航平, 池田 紘之, 岡田 純一, 澁澤 良, 下田 容子, 笠井 裕子, 大崎 綾, 山田 英二郎, 岡田 秀一, 周東 智, 山田 正信 日本内分泌学会雑誌 94 (1) 359 -359 2018年04月 [査読無し][通常論文]
  • レゾルビンE1およびレゾルビンE2の抗うつ作用機序
    鈴木 博惠, 出山 諭司, 霜田 健斗, 石川 由香, 石村 航平, 福田 隼, 人羅 菜津子[今村], 井手 聡一郎, 佐藤 公道, 金田 勝幸, 周東 智, 南 雅文 日本薬学会年会要旨集 138年会 (3) 146 -146 2018年03月 [査読無し][通常論文]
  • レゾルビンE1およびレゾルビンE2の抗うつ作用機序
    鈴木 博惠, 出山 諭司, 霜田 健斗, 石川 由香, 石村 航平, 福田 隼, 人羅 菜津子, 井手 聡一郎, 佐藤 公道, 金田 勝幸, 周東 智, 南 雅文 日本薬学会年会要旨集 138年会 (3) 146 -146 2018年03月 [査読無し][通常論文]
  • 山田圭恭, 一ノ瀬亘, 福田隼, 渡邉瑞貴, 周東智 日本薬学会年会要旨集(CD-ROM) 138th ROMBUNNO.26L‐am03S 2018年 [査読無し][通常論文]
  • 植村真衣, 加藤七海, 松井耕平, 桑原智希, 渡邉瑞貴, 福田隼, 武隈洋, 菅原満, 周東智 日本薬学会年会要旨集(CD-ROM) 138th (2) ROMBUNNO.26X‐pm08S -116 2018年 [査読無し][通常論文]
  • 末政亮大, 中田和彰, 小林嵩明, 福田隼, 渡邉瑞貴, 井手聡一郎, 人羅菜津子, 南雅文, 周東智 日本薬学会年会要旨集(CD-ROM) 138th ROMBUNNO.26X‐am04 2018年 [査読無し][通常論文]
  • グルタチオン-S-トランスフェラーゼを標的とした共有結合性阻害剤の開発
    宍戸 裕子, 藤川 遥加, 友池 史明, 木村 康明, 桑田 啓子, 村上 優子, 福井 健二, 関戸 好孝, 矢野 貴人, 周東 智, 阿部 洋 生命科学系学会合同年次大会 2017年度 [3P -0205] 2017年12月 [査読無し][通常論文]
  • 桑原智希, 植村真衣, 水野彰, 一ノ瀬亘, 松井耕平, 福田隼, 渡邉瑞貴, 周東智 反応と合成の進歩シンポジウム講演要旨集 43rd 149 2017年10月16日 [査読無し][通常論文]
  • 山田真輝, 金田龍太郎, 高木耕治, 福田隼人, 渡邉瑞貴, 周東智 複素環化学討論会講演要旨集 47th 82 2017年10月10日 [査読無し][通常論文]
  • In vitroでの狂犬病ウイルスに対する5-エチニル-1-リボフラノシルイミダゾール-4-カルボキサミド(EICAR)の抗ウイルス活性に関する検討(Examination of antiviral activity of 5-ethynyl-1-ribofuranosylimidazole-4-carboxamide(EICAR) against rabies virus in vitro)
    Anindita Paulina Duhita, 佐々木 道仁, 伊藤 直人, 杉山 誠, 南川 典昭, 周東 智, 乙黒 聡子, 市川 聡, 松田 彰, 前仲 勝実, 大場 靖子, 澤 洋文 日本獣医学会学術集会講演要旨集 160回 390 -390 2017年08月 [査読無し][通常論文]
  • Examination of antiviral activity of 5-ethynyl-1-ribofuranosylimidazole-4-carboxamide(EICAR) against rabies virus in vitro(和訳中)
    Anindita Paulina Duhita, 佐々木 道仁, 伊藤 直人, 杉山 誠, 南川 典昭, 周東 智, 乙黒 聡子, 市川 聡, 松田 彰, 前仲 勝実, 大場 靖子, 澤 洋文 日本獣医学会学術集会講演要旨集 160回 390 -390 2017年08月 [査読無し][通常論文]
  • 南貴覚, 福多洸太朗, 星谷直亨, 福田隼, 渡邉瑞貴, 周東智 万有札幌シンポジウム 29th 47 2017年07月01日 [査読無し][通常論文]
  • 石村航平, 福田隼, 室本竜太, 平島洸基, 渡邉瑞貴, 松田正, 周東智 次世代を担う有機化学シンポジウム講演要旨集 15th 26‐27 2017年05月19日 [査読無し][通常論文]
  • 新規脂質メディエーターの糖代謝に関する研究
    齋藤 従道, 清水 智彦, 澁澤 良, 下田 容子, 多賀谷 裕子, 大崎 綾, 山田 英二郎, 石村 航平, 池田 紘之, 福田 隼, 周東 智, 岡田 秀一, 山田 正信 糖尿病 60 (Suppl.1) S -460 2017年04月 [査読無し][通常論文]
  • 宍戸 裕子, 藤川 遥加, 木村 康明, 友池 史明, 桑田 啓子, 矢野 貴人, 福井 健二, 関戸 好孝, 村上 優子, 周東 智, 阿部 洋 日本薬学会年会要旨集 137年会 (2) 68 -68 2017年03月 [査読無し][通常論文]
  • 伏原大地, 福田隼, 阿部洋, 周東智 日本薬学会年会要旨集(CD-ROM) 137th ROMBUNNO.26S‐pm10S 2017年 [査読無し][通常論文]
  • 松原光太郎, 池田紘之, 石村航平, 平島洸基, 室本竜太, 松田正, 福田隼, 渡邉瑞貴, 周東智 日本薬学会年会要旨集(CD-ROM) 137th ROMBUNNO.27R‐am10S 2017年 [査読無し][通常論文]
  • 佐藤晋平, 福田隼, 渡邉瑞貴, 周東智 日本薬学会年会要旨集(CD-ROM) 137th ROMBUNNO.27S‐pm09S 2017年 [査読無し][通常論文]
  • 植村真衣, 松井耕平, 桑原智希, 渡邉瑞貴, 福田隼, 加藤七海, 武隈洋, 菅原満, 周東智 日本薬学会年会要旨集(CD-ROM) 137th (2) ROMBUNNO.27R‐am11S -120 2017年 [査読無し][通常論文]
  • 池田紘之, 福田隼, 高倉夕季, 石村航平, 平島洸基, 平尾徹, 室本竜太, 渡邉瑞貴, 松田正, 周東智 メディシナルケミストリーシンポジウム講演要旨集 34th 143 2016年11月11日 [査読無し][通常論文]
  • 渡邉瑞貴, 大浦泰, 森川優輝, 福田隼, 森田貴雄, 谷村明彦, 周東智 反応と合成の進歩シンポジウム講演要旨集 42nd 11 2016年10月21日 [査読無し][通常論文]
  • 桑原智希, 水野彰, 福田隼, 渡邉瑞貴, 神田敦宏, 石田晋, 周東智 万有生命科学振興国際交流財団札幌シンポジウム 28th 61 2016年07月02日 [査読無し][通常論文]
  • 末政亮大, 中田和彰, 小林嵩明, 福田隼, 渡邉瑞貴, 柴野さや子, 井川ありさ, 井手聡一郎, 南雅文, 周東智 次世代を担う有機化学シンポジウム講演要旨集 14th 28‐29 2016年05月19日 [査読無し][通常論文]
  • 佐藤孝行, 井川ありさ, 圓山智嘉史, 末政亮大, 小林嵩明, 有澤光弘, 井手聡一郎, 周東智, 南雅文 次世代を担う創薬・医療薬理シンポジウムプログラム・要旨集 2016 2016年
  • 佐藤孝行, 井川ありさ, 圓山智嘉史, 末政亮大, 小林嵩明, 有澤光弘, 井手聡一郎, 周東智, 南雅文 日本薬学会年会要旨集(CD-ROM) 136th 2016年
  • 和田康弘, 和田康弘, 白橋浩光, 岩並泰資, 小川雅巳, 中野誠志, 森本晃史, 笠原憲一, 田中英一, 林高彦, 高田美生, 鈴木寛子, 丹羽(酒井)美智子, 大橋茂樹, 森睦博, 広川貴次, 広川貴次, 広川貴次, 周東智 メディシナルケミストリーシンポジウム講演要旨集 34th 2016年
  • 池田紘之, 石村航平, 福田隼, 周東智 日本薬学会年会要旨集(CD-ROM) 136th ROMBUNNO.29T‐PM04S 2016年 [査読無し][通常論文]
  • 近藤萌美, 星谷尚亨, 福田隼, 有澤光弘, 周東智 複素環化学討論会講演要旨集 45th 129 -130 2015年11月02日 [査読無し][通常論文]
  • 三浦梨紗子, 川村周平, 一ノ瀬亘, 福田隼, 伊藤由彦, 引山恵梨子, 山田静雄, 広川貴次, 周東智 メディシナルケミストリーシンポジウム講演要旨集 33rd 95 2015年11月01日 [査読無し][通常論文]
  • 石村航平, 福田隼, 高倉夕季, 金田龍太郎, 平尾徹, 平島洸基, 室本竜太, 松田正, 阿部洋, 周東智 メディシナルケミストリーシンポジウム講演要旨集 33rd 78 2015年11月01日 [査読無し][通常論文]
  • 福田隼, 高倉夕季, 石村航平, 金田龍太郎, 平尾徹, 平島洸基, 室本竜太, 松田正, 阿部洋, 有澤光弘, 周東智 反応と合成の進歩シンポジウム講演要旨集 41st 37 2015年10月09日 [査読無し][通常論文]
  • 佐藤耀, 川村周平, 平尾徹, 室本竜太, 福田隼, 阿部洋, 松田正, 周東智 万有生命科学振興国際交流財団札幌シンポジウム 27th 42 2015年07月04日 [査読無し][通常論文]
  • レゾルビンE2の抗うつ作用に関する検討
    霜田 健斗, 出山 諭司, 井手 聡一郎, 福田 隼, 周東 智, 南 雅文 日本薬学会年会要旨集 135年会 (3) 193 -193 2015年03月 [査読無し][通常論文]
  • 金田龍太郎, 杉本勇, 岩本武明, 福田隼, 阿部洋, 阿部洋, 周東智 日本薬学会年会要旨集(CD-ROM) 135th ROMBUNNO.26I-PM12S 2015年 [査読無し][通常論文]
  • 桑原智希, 水野彰, 福田隼, 阿部洋, 阿部洋, 周東智 日本薬学会年会要旨集(CD-ROM) 135th ROMBUNNO.28I-PM11S 2015年 [査読無し][通常論文]
  • 佐藤耀, 川村周平, 平尾徹, 室本竜太, 福田隼, 阿部洋, 阿部洋, 松田正, 周東智 日本薬学会年会要旨集(CD-ROM) 135th ROMBUNNO.28T-AM12S 2015年 [査読無し][通常論文]
  • 近藤萌美, 星谷尚亨, 福田隼, 周東智 日本薬学会年会要旨集(CD-ROM) 135th ROMBUNNO.28C-PM03S 2015年 [査読無し][通常論文]
  • 石村航平, 福田隼, 高倉夕季, 阿部洋, 阿部洋, 周東智 日本薬学会年会要旨集(CD-ROM) 135th ROMBUNNO.28H-PM05S 2015年 [査読無し][通常論文]
  • 末政亮大, 小林嵩明, 井川ありさ, 福田隼, 阿部洋, 井手聡一郎, 南雅文, 周東智 メディシナルケミストリーシンポジウム講演要旨集 32nd 71 2014年11月07日 [査読無し][通常論文]
  • 星谷尚亨, 四辻慶佑, 小林嵩明, 福田隼, 阿部洋, 有澤光弘, 周東智 反応と合成の進歩シンポジウム講演要旨集 40th 94 2014年10月22日 [査読無し][通常論文]
  • 高木耕治, 福田隼, 阿部洋, 周東智, 大高章, 有澤光弘 反応と合成の進歩シンポジウム講演要旨集 40th 145 2014年10月22日 [査読無し][通常論文]
  • 藤居由基, 加藤宏茂, 福田隼, 阿部洋, 藤岡弘道, 周東智, 有澤光弘 複素環化学討論会講演要旨集 44th 227 -228 2014年08月25日 [査読無し][通常論文]
  • 末政亮大, 中田和彰, 小林嵩明, 井川ありさ, 福田隼, 阿部洋, 有澤光弘, 井手聡一郎, 南雅文, 周東智 万有生命科学振興国際交流財団札幌シンポジウム 26th 64 2014年07月05日 [査読無し][通常論文]
  • 海野雄加, 周東智, 浅井章良 日本がん分子標的治療学会学術集会プログラム・抄録集 18th 97 2014年05月29日 [査読無し][通常論文]
  • 海野雄加, 川村周平, 周東智, 浅井章良 日本分子生物学会年会プログラム・要旨集(Web) 37th 2P-0829 (WEB ONLY) 2014年 [査読無し][通常論文]
  • 高木耕治, 星谷尚亨, 杉本宏, 城宜嗣, 福田隼, 周東智, 有澤光弘 日本薬学会年会要旨集(CD-ROM) 134th ROMBUNNO.28T-AM09 2014年 [査読無し][通常論文]
  • 遠藤秀幸, 水野彰, 阿部洋, 福田隼, 小松康雄, 周東智 日本薬学会年会要旨集(CD-ROM) 134th ROMBUNNO.28Y-PM07 2014年 [査読無し][通常論文]
  • 高倉夕季, 福田隼, 石村航平, 田辺真人, 有澤光弘, 周東智 日本薬学会年会要旨集(CD-ROM) 134th ROMBUNNO.28N-PM08 2014年 [査読無し][通常論文]
  • 海野雄加, 川村周平, 有澤光弘, 浅井章良, 周東智 メディシナルケミストリーシンポジウム講演要旨集 31st 142 2013年11月01日 [査読無し][通常論文]
  • 川村周平, 海野雄加, 浅井章良, 有澤光弘, 周東智 反応と合成の進歩シンポジウム講演要旨集 39th 14 2013年10月15日 [査読無し][通常論文]
  • 四辻慶佑, 小林嵩明, 星谷尚亨, 福田隼, 有澤光弘, 周東智 複素環化学討論会講演要旨集 43rd 29 -30 2013年10月01日 [査読無し][通常論文]
  • 四辻慶佑, 小林嵩明, 福田隼, 有澤光弘, 周東智 万有生命科学振興国際交流財団札幌シンポジウム 25th 63 2013年07月06日 [査読無し][通常論文]
  • MIZUNO Akira, MIURA Shiho, WATANABE Mizuki, KAMEDA Tomoshi, ARISAWA Mitsuhiro, SHUTO Satoshi Peptide science : proceedings of the ... Japanese Peptide Symposium 2012 9 -10 2013年03月01日
  • Mitsuhiro Arisawa, Yuki Fujii, Hiroshige Kato, Hayato Fukuda, Takashi Matsumoto, Mika Ito, Hiroshi Abe, Yoshihiro Ito, Satoshi Shuto Angewandte Chemie - International Edition 52 (3) 1003 -1007 2013年01月14日 [査読有り][通常論文]
     
    The one-pot tandem reaction of N-alkyl-N-allyl-2-vinylaniline derivatives with benzo- or naphthoquinones and a ruthenium-alkylidene catalyst leads to isoindolo[2,1-a]quinolines in a variety of colors, which can be altered by exchanging the substituent on the core heterocycle (see scheme). This reaction offers a new synthetic method for π-conjugated small molecules from simple aniline derivatives. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
  • 藤居由基, 加藤宏茂, 福田隼, 伊藤美香, 阿部洋, 伊藤嘉浩, 有澤光弘, 周東智 日本薬学会年会要旨集(CD-ROM) 133rd ROMBUNNO.30N-PM43 2013年 [査読無し][通常論文]
  • Mami Yokoyamay, Akira Ishii, Mitsuhiro Arisawa, Satoshi Shuto e-Journal of Surface Science and Nanotechnology 10 630 -632 2012年12月01日 [査読有り][通常論文]
     
    The actual active species of the recently developed S-modified Au-supported Au-supported Pd (SAPd), with one of the lowest Pd-releasing levels and high recyclability in the Suzuki-Miyaura coupling, was investigated. Also SAPd was found to work repeatedly as an excellent Pd reservoir for liquid-phase combinatorial synthesis. In order to develop more effective catalysts, it is essential to understand the function of the OH-group around Pd of SAPd. © 2012 The Surface Science Society of Japan.
  • 有澤光弘, MOHAMMAD Al‐Amin, 星谷尚亨, 佐藤隆俊, 福田隼, 周東智, 本間徹生, 為則雄祐 反応と合成の進歩シンポジウム講演要旨集 38th 190 -191 2012年10月15日 [査読無し][通常論文]
  • 田辺真人, 渡邉瑞貴, 水野彰, 有澤光弘, 周東智 複素環化学討論会講演要旨集 42nd 355 -356 2012年09月30日 [査読無し][通常論文]
  • 有澤 光弘, 石井 晃, 周東 智 觸媒 = Catalyst 54 (3) 197 -202 2012年04月10日
  • Mohammad Al-Amin, Tetsuo Honma, Naoyuki Hoshiya, Satoshi Shuto, Mitsuhiro Arisawa Advanced Synthesis and Catalysis 354 (6) 1061 -1068 2012年04月 [査読有り][通常論文]
     
    A stable heterogeneous catalyst precursor, sulfur-modified gold-supported palladium material (SAPd), has proved to be an excellent source of leached, ligand-free, Pd for the amination of aryl bromides and chlorides. The reaction-enabling catalyst is provided in situ as leached Pd in low catalyst loading (0.21±0.02mol%). This allows the precatalyst (SAPd) to be filtered off and used for a minimum of ten reaction cycles without loss of catalytic activity. SAPd released only trace amounts, less than 0.6ppm, of highly active Pd during the reaction without any aggregation. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
  • 田辺真人, 渡邉瑞貴, 水野彰, 有澤光弘, 周東智 日本薬学会年会要旨集 132nd (2) 136 2012年03月05日 [査読無し][通常論文]
  • Hiroshige Kato, Tatsuya Ishigame, Nobuhiro Oshima, Naoyuki Hoshiya, Ken Shimawaki, Mitsuhiro Arisawa, Satoshi Shuto Advanced Synthesis and Catalysis 353 (14-15) 2676 -2680 2011年10月 [査読有り][通常論文]
     
    We have developed a one-pot ring-closing metathesis (RCM)/oxidation methodology to yield various 2-quinolines from 2-vinyl-N-allylaniline derivatives. This is a first example of an oxidation involving methylene (CH2) groups with modified Grubbs-type ruthenium complexes. Hence, this adds an example of a non-methathesis reaction using a ruthenium carbene catalyst. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
  • 田辺真人, 渡邉瑞貴, 水野彰, 有澤光弘, 周東智 万有生命科学振興国際交流財団札幌シンポジウム 23rd 59 2011年07月02日 [査読無し][通常論文]
  • Mitsuhiro Arisawa, Yayoi Kasaya, Tohru Obata, Takuma Sasaki, Mika Ito, Hiroshi Abe, Yoshihiro Ito, Akihito Yamano, Satoshi Shuto ACS Medicinal Chemistry Letters 2 (5) 353 -357 2011年05月12日 [査読有り][通常論文]
     
    Conformationally restricted indomethacin analogues were designed and prepared from the corresponding 2-substituted indoles, which were synthesized by a one-pot isomerization/enamide-ene metathesis as the key reaction. Conformational analysis by calculations, NMR studies, and X-ray crystallography suggested that these analogues were conformationally restricted in the s-cis or the s-trans form due to the 2-substituent as expected. Their biological activities on cyclooxygenase-1 (COX-1) inhibition, cyclooxygenase-2 (COX-2) inhibition, and modulation of MRP-1-mediated multidrug resistance (MDR) are described. Some of these indomethacin analogues enhanced doxorubicin cytotoxicity, although they do not have any COX inhibitory activity, which suggests that the MDR-modulating effect of an NSAID can be unassociated with its COX-inhibitory activity. This may be an entry into the combination chemotherapy of doxorubicin with a MDR modulator. © 2011 American Chemical Society.
  • 川村周平, 海野雄加, 田中基裕, 佐々木琢磨, 浅井章良, 有澤光弘, 周東智 日本薬学会年会要旨集 131st (2) 133 2011年03月05日 [査読無し][通常論文]
  • 田辺真人, 渡邉瑞貴, 水野彰, 有澤光弘, 周東智 日本薬学会年会要旨集 131st (2) 87 2011年03月05日 [査読無し][通常論文]
  • 海野雄加, 中野慎太郎, 川村周平, 有澤光弘, 周東智, 浅井章良 日本分子生物学会年会プログラム・要旨集(Web) 34th 4P-0237 (WEB ONLY) 2011年 [査読無し][通常論文]
  • Naoyuki Hoshiya, Satoshi Shuto, Mitsuhiro Arisawa ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 240 2010年08月 [査読無し][通常論文]
  • K. Kobayashi Journal of Applied Physics 108 (2) 2010年07月15日 [査読有り][通常論文]
     
    We present studies on the structure and chemical states of a catalyst developed by immobilizing palladium on S-terminated GaAs(001). Hard x-ray photoelectron spectroscopy (HX-PES) of core-level and valence band photoemission consistently indicates that the organopalladium molecules are reduced on the surface yielding Pd nanoparticles with a metallic nature. This finding is supported by high-resolution observations using scanning electron microscopy and backscattered electron image. HX-PES results also reveal that a portion of S atoms forming the S-termination is oxidized during the formation of Pd nanoparticles. © 2010 American Institute of Physics.
  • 小林嵩明, 渡辺瑞貴, 広川貴次, 吉田徳, 伊藤由彦, 山田静雄, 有澤光弘, 周東智 メディシナルケミストリーシンポジウム講演要旨集 28th 2009年
  • Kouki Kajihara, Mitsuhiro Arisawa, Satoshi Shuto Journal of Organic Chemistry 73 (23) 9494 -9496 2008年12月05日 [査読有り][通常論文]
     
    (Chemical Equation Presented) A facile method for N-deallylation at the amide nitrogen of peptides is described. One-pot deallylation of a substrate through ruthenium hydride-catalyzed terminal olefin isomerization and subsequent ozonolysis gave the corresponding deallylated product under mild conditions. © 2008 American Chemical Society.
  • 吉田佳右, 山口和也, 曽根孝之, 横沢英良, 松田彰, 有澤光弘, 周東智, 海野雄加, 浅井章良 メディシナルケミストリーシンポジウム講演要旨集 26th 160 -161 2007年11月09日 [査読無し][通常論文]
  • YOSHIDA Keisuke, YAMAGUCHI Kazuya, ARISAWA Mitsuhiro, MATSUDA Akira, SHUTO Satoshi Peptide science : proceedings of the ... Japanese Peptide Symposium 2006 184 -185 2007年03月01日
  • The first synthesis of 1'-fluoronucleosides.
    Tetsuya Kodama, Akira Matsuda, Satoshi Shuto Nucleic Acids Symp Ser 50 3-4 2006年12月08日 [査読無し][通常論文]
  • Stable hairpins having a loop consisting of 3'-deoxy-4'-C-(2-hydroxyethyl)thymidines.
    Satoshi Shuto, Yutaka Tamura, Yuji Yamamoto, Tetsuya Kodama, Shuichi Hoshika, Satoshi Ichikawa, Yoshihito Ueno, Eiko Ohtsuka, Yasuo Komatsu, Akira Matsuda Nucleic Acids Symp Ser 48 67-68 2006年12月08日 [査読無し][通常論文]
  • Natsumi Sakaguchi, Takashi Kudoh, Takashi Murayama, Mitsuhiro Arisawa, Akira Matsuda, Satoshi Shuto Nucleic acids symposium series (2004) (50) 119 -120 2006年 [査読有り][通常論文]
     
    5''-Branched cyclic ADP-carbocyclic-riboses (4 and 5) were designed as biological tools for identifying the target proteins of cyclic ADP-ribose, an intracellular Ca(2+)-mobilizing second messenger. One of the targets, 4, successfully synthesized.
  • 渡邉瑞貴, 数田雄二, 林秀樹, 山田静雄, 松田彰, 周東智 メディシナルケミストリーシンポジウム講演要旨集 24th 200 -201 2005年11月10日 [査読無し][通常論文]
  • Takagi,T, Sukeda,M, Kim,H.-S, Wataya,Y, Kitade,Y, Matsuda,A, Shuto. S Org. Biomol. Chem., 2005年 [査読無し][通常論文]
  • Y Kazuta, H Abe, A Matsuda, S Shuto JOURNAL OF ORGANIC CHEMISTRY 69 (26) 9143 -9150 2004年12月 [査読無し][通常論文]
     
    We previously found that Grignard addition to a C-cyclopropylaldonitrone, C-[cis-2-(N,N-diethyl-carbamoyl)-trans-2-phenylcyclopropyl]-N-benzylaldonitrone (1), stereoselectively gave the antiproduct 3, in which the stereoselectivity was particularly high when MgBr2 was the additive. In this study, the reaction pathway was investigated in detail. The stereoselective addition was initially thought to occur via either a 1,5-chelation-controlled or a bisected s-trans conformation-controlled pathway. However, Grignard addition to a nonchelating silyl ether-type substrate, C-[cis-2-(tert-butyldiphenylsilyloxymethyl)-trans-2-phenylcyclopropyl]-N-benzylaldonitrone (7), also gave the antiproduct 9 with high stereoselectivity suggesting that chelation is not important in the reaction. Theoretical calculations of C-cyclopropylaldonitrones showed that the coordination of Mg2+ at the nitrone oxygen significantly stabilizes the bisected s-trans conformer due to the effective hyper-conjugation between the,pi* of the nitrone C=N bond and the electron-donating cyclopropane orbitals. This kind of orbital interaction is able to stabilize the transition state of the nucleophilic addition and is maximized in the bisected conformation, in which the orbitals of the forming bond and the cyclopropane C-C bond are in an almost planar arrangement. Thus, the high stereoselectivity can be explained by nucleophilic attack on the less hindered side of the C=N bond of the substrates in the Mg2+-coordinated bisected s-trans conformation.
  • M Terauchi, H Abe, A Matsuda, S Shuto ORGANIC LETTERS 6 (21) 3751 -3754 2004年10月 [査読無し][通常論文]
     
    The reduction of glyconolactols having an anomeric carbon substituent by Et3SiH/TMSOTf proceeded with complete stereoselectivity to produce the corresponding beta-C-glycosides when the substrates were conformationally restricted in the C-4(1)-chair form by a 3,4-O-cyclic diketal or a 4,6-O-benzylidene protecting group. Thus, the efficient construction beta-C-glycosides was achieved on the basis of the conformation restriction strategy.
  • Y Yamamoto, S Shuto, Y Tamura, T Kodama, S Hoshika, S Ichikawa, Y Ueno, E Ohtsuka, Y Komatsu, A Matsuda BIOCHEMISTRY 43 (27) 8690 -8699 2004年07月 [査読無し][通常論文]
     
    Components that form stable hairpin loops are highly useful for the development of functional DNA and RNA molecules. We have designed and synthesized a sugar-modified thymidine analogue, 3'-deoxy-4'-C-(2-hydroxyethyl)thymidine (X), as a nucleosidic loop component stabilizing the hairpin structure. The ODNs I-1-4, 5'-d[CGAACG-X-n-CGTTCG]-3' (I-1, n = 1; I-2, n = 2; I-3, n = 3; I-4, n = 4), forming the hairpin loop structures, of which the loop moiety consisted of the analogue X, and also the corresponding unmodified ODNs II-1-4, 5'-d[CGAACG-T-n-CGTTCG]-3' (II-1, n = 1; II-2, n = 2; II-3, n = 3; II-4, n = 4), having a thymidine loop, were synthesized by the phosphoramidite method. The melting temperatures (T m) of the ODNs I-1-4 containing X in the loop moiety at 5 muM were 67.1, 68.1, 73.0, and 69.3 degreesC, respectively, and those of the control natural ODNs II-1-4 were 65.3, 67.0, 69.2, and 68.8 degreesC, respectively. Thus, the ODNs I-1-4 formed a more thermally stable hairpin than the corresponding unmodified ODNs II-1-4 having an equal number of loop residues. The hairpin structures of the modified ODNs I-1-4 and the unmodified ODNs II-1-4 were investigated by CD spectroscopy and molecular mechanics calculations. These results showed that the 4'-branched nucleoside X can stabilize hairpin structures when it is present in the loop moiety, probably due to the flexibility of the one-carbon-elongated 4'-branched structure.
  • Y Kazuta, H Abe, T Yamamoto, A Matsuda, S Shuto TETRAHEDRON 60 (31) 6689 -6703 2004年07月 [査読無し][通常論文]
     
    The addition reaction of carbon nucleophiles to cis-substituted cyclopropanecarbaldehydes was systematically investigated. Ab initio calculations of model cyclopropanecarbaldehydes suggested that the bisected s-cis and s-trans conformers are the only two minimum energy conformers, which are stabilized due to the pi-donating stereoelectronic effect of the cyclopropane ring. The experimental results of a series of substrates, that is, cyclopropanecarbaldehydes 1-5 bearing a cis-(tert-butyldiphenyisilyloxy)methyl group, a cis-benzyloxymethyl group, a cis-(p-methoxybenzyloxy)methyl group, cis-N,N-diethylcarbamoyl and trans-phenyl groups, and cis-(tert-butyldiphenylsilyloxy)methyl and trans-phenyl groups, respectively, showed that highly anti-selective Grignard additions could be realized. It turned out that it occurred via an unusual 7-membered 1,4-chelation-controlled pathway. Highly stereoselective Grignard addition via the chelation-controlled pathway occurred even in the reaction of the usually non-chelating silyl ether-type substrate 5. The results have great importance because the 1,4-chelation-controlled stereoselective addition reactions can indeed be realized. Under non-chelation conditions, the syn-products were produced with moderate stereoselectivity, which are likely to be formed via the bisected s-cis conformation-like transition state stabilized by the characteristic orbital interaction. These reactions, especially the chelation-controlled reaction, should be useful because of their t stereoselectivity and stereochemical predictability. (C) 2004 Elsevier Ltd. All rights reserved.
  • H Dozol, C Maechling, R Graff, A Matsuda, S Shuto, B Spiess BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS 1671 (1-3) 1 -8 2004年03月 [査読無し][通常論文]
     
    Four adenophostin analogues lacking the adenine moiety were subjected to P-31- and H-1-NMR titrations in order to determine the acid-base behaviour of the individual ionisable groups of the molecules and the complex interplay of intramolecular interactions resulting from the protonation process. For the two trisphosphorylated compounds, the curve pattern of the phosphorus nuclei corresponds to the superimposition of the titration curves of a monophosphorylated polyol and a polyol carrying two vicinal phosphates, suggesting that the two phosphate moieties behave independently. Also, the general shape of H-1-NMR titration curves of the studied compounds is very close to that of adenophostin A, indicating that the adenine moiety does not specifically interact with the phosphorylated sugar moieties. The curves show, however, that both trisphosphorylated compounds adopt slightly different preferential conformations which could contribute to explain the difference in their affinity for Ins(1,4,5)P-3 receptor. Their macroscopic as well as the microscopic protonation constants are higher than those of adenophostin A, indicating that the adenine moiety plays a base-weakening effect on the phosphate groups. Further analysis of the microscopic protonation constants confirms that the compound whose conformation is the closest to that of adenophostin A also shows the highest biological activity. The two bisphosphorylated analogues studied behave very similarly, suggesting that the deletion of the hydroxymethyl group on the pentafuranosyl ring only weakly influences the protonation process of the phosphate groups that bear the glucopyranose moiety. (C) 2004 Elsevier B.V. All rights reserved.
  • Y Ohmori, A Yamashita, R Tsujita, T Yamamoto, K Taniuchi, A Matsuda, S Shuto JOURNAL OF MEDICINAL CHEMISTRY 46 (25) 5326 -5333 2003年12月 [査読無し][通常論文]
     
    A series of conformationally restricted analogues of milnacipran, a weak NMDA receptor antagonist, were designed by a method based on allylic strain. The conformational analysis study showed that the allylic-strain-based conformational restriction indeed occurred and that the affinity for the NMDA receptor was efficiently improved by the conformational restriction.
  • K Yamaguchi, Y Kazuta, H Abe, A Matsuda, S Shuto JOURNAL OF ORGANIC CHEMISTRY 68 (24) 9255 -9262 2003年11月 [査読無し][通常論文]
     
    (1S,2S)-, (1S,2R)-, and (1R,2S)-1-(2,4-Dimethylphenyl)piperazyl-2-phenylcyclopropane (2a, 3, and ent-3, respectively), which were designed as conformationally restricted analogues of haloperidol (1), a clinically effective antipsychotic agent, were synthesized from chiral epichlorohydrins using the Barton reductive radical decarboxylation as the key step. (1S,2R)-1-(tert-Butyldiphenylsilyloxy)methyl-2-carboxy-2-phenylcyclopropane (5), which was prepared from (S)-epichlorohydrin ((S)-7), was converted into its N-hydroxypyridine-2-thione ester 12, the substrate for the reductive radical decarboxylation. When 12 was treated with TMS(3)SiH in the presence of Et(3)B or AIBN, the decarboxylation and subsequent hydride attack on the cyclopropyl radical intermediate from the side opposite to the bulky silyloxymethyl moiety occurred, resulting in selective formation of the corresponding reductive decarboxylation product 4-cis with the cis-cyclopropane structure. From 4-cis, the cis-cyclopropane-type target compound 3 was readily synthesized. Starting from (R)epichlorohydrin ((R)-7), ent-3 was similarly synthesized. Epimerization of the cyclopropanecarboxamide ent-16-cis, a synthetic intermediate for ent-3, on treatment with a base prepared from Bu(2)Mg and i-Pr(2)NH in THF occurred effectively to give the corresponding trans isomer 16-trans, which was converted into 2a with the trans-cyclopropane structure.
  • S Shuto, M Fukuoka, T Kudoh, C Garnham, A Galione, BVL Potter, A Matsuda JOURNAL OF MEDICINAL CHEMISTRY 46 (22) 4741 -4749 2003年10月 [査読無し][通常論文]
     
    Cyclic ADP-carbocyclic-ribose (cADPcR, 2) is a biologically and chemically stable equivalent of cyclic ADP-ribose (cADPR, 1), a Ca2+-mobilizing second messenger. In this study, a series of 8-substituted analogues of cADPcR, namely the 8-chloro analogue 6 (8-Cl-cADPcR), the 8-azido analogue 7 (8-N-3-cADPcR), the 8-amino analogue 8 (8-NH2-cADPcR), and the 8-phenylthio analogue 9 (8-SPh-cADPcR), were designed as effective pharmacological tools for studies on cADPR-modulated Ca2+ signaling pathways. These target compounds were synthesized by a convergent route via 8-Cl-cADPcR bisacetonide (14) as the common intermediate, in which a method for forming the intramolecular pyrophosphate linkage by activation of the phenylthiophosphate type substrate 15 with AgNO3 to produce 14 was used as the key step. The carbocyclic analogues were tested for activity in the sea urchin egg homogenate system. Compounds were assessed for their calcium-mobilizing effects and their ability to cross-desensitize with calcium release induced by a normally maximal concentration of cADPR, as well as cADPR antagonism of cADPR-evoked calcium release. While cADPcR was 3-4 times more potent than cADPR, the 8-substituted analogues were less efficacious, with 8-SPh-cADPcR largely acting as a competitive antagonist. Most surprisingly, given that 8-N-3-cADPR and 8-NH2-CADPR are known as potent antagonists, 8-N3-cADPcR and 8-NH2-cADPcR were full agonists, but ca. 80 and 2 times less potent than cADPR, respectively. These data contribute to developing structure-activity relationships for the interaction of cADPR with its receptor.
  • H Abe, M Terauchi, A Matsuda, S Shuto JOURNAL OF ORGANIC CHEMISTRY 68 (19) 7439 -7447 2003年09月 [査読無し][通常論文]
     
    We previously theorized that, since the stereoselectivity of anomeric radical reactions is significantly influenced by the kinetic anomeric effect, which can be controlled by restricting the conformation of the radical intermediate, the proper conformational restriction of the pyranose ring of the substrates would therefore make highly alpha- and beta-stereoselective anomeric radical reactions possible. This theory was based on our previous results of the anomeric radical reactions with D-xylose derivatives as the substrates. We herein report the anomeric radical deuteration reactions with the conformationally restricted 1-phenylseleno-D-glucose derivatives, 2g and 3g, restricted in a C-4(1)-conformation by an beta-cyclic diketal moiety, and 4g, 5g, 6g, 7g, and 8g, restricted in a C-1(4)-conformation by bulky O-silyl protecting groups. The radical deuterations with Bu3SnD, using the C-4(1)-restricted substrates 2g and 3g, afforded the corresponding alpha-products (alpha/beta = 98:2) highly stereoselectively, whereas the C-1(4)-restricted substrate 6g, having a trigonal (sp(2)) carbon substituent, i.e., -CHO, at the 5-position, selectively gave the beta-products (alpha/beta = 0: 100). Thus, the stereoselectivity was significantly increased by the conformational restriction and was completely inverted by changing the substrate conformation from the C-4(1)-form to the C-1(4)-form. On the other hand, the deuterations with the C-1(4)-restricted substrates 4g and 5g showed that the 1,5-steric effect due to the tetrahedral carbon substituent (-CH2OTIPS or -CH2OH) at the 5-axial position dominantly prevented the hydride transfer from the beta-face competing with the kinetic anomeric effect. This study suggests that, depending on the restricted conformation of the substrates to the C-4(1)- or the C-1(4)-form, the alpha- or beta-products would be obtained highly stereoselectively via anomeric radical reactions of hexopyranoses.
  • Synthesis and radiacal reaction of 1'-phenylselenonucleosides.
    Tetsuya Kodama, Satoshi Shuto, Makoto Nomura, Akira Matsuda Nucleic Acids Symp Ser 44 109-110 2003年08月09日 [査読無し][通常論文]
  • M Nomura, S Shuto, A Matsuda BIOORGANIC & MEDICINAL CHEMISTRY 11 (11) 2453 -2461 2003年05月 [査読無し][通常論文]
     
    We have designed and synthesized the acetal derivatives of 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine (ECyd, 1), the 2',3'-O-nitrobenzylidene derivatives 2 and 3 and the 5'-O-(alkoxy)(nitrophenyl)methyl derivatives 6-10 as potential prodrugs of ECyd. These prodrugs can be selectively activated in tumor tissues via a bio-reduction hydrolysis mechanism owing to the characteristic properties of tumor tissues, such as hypoxia and lower pH. Although the 2',3'-O-(4-nitrobenzylidene) derivatives 2 and 3 were converted bio-reductively into the corresponding 4-aminobenzylidene derivatives by rat S-9 mix, the reduction products, that is, the corresponding amino congeners 4 and 5, proved to be rather stable in an aqueous solution at pH 6.5 used as a pH model for acidic tumor tissues. In contrast, the 5'-O-(alkoxy)(4-nitropheny)methyl derivatives 6-8 were also reduced by rat S-9 mix to the corresponding amino congeners 11-13, which were hydrolyzed to release ECyd more effectively at pH 6.5 than at pH 7.4. Accordingly, the acyclic acetals 6-8 may be efficient prodrugs of ECyd, that are effectively reduced under physiological conditions releasing ECyd in acidic tumor tissues. (C) 2003 Elsevier Science Ltd. All rights reserved.
  • Y Kazuta, H Abe, T Yamamoto, A Matsuda, S Shuto JOURNAL OF ORGANIC CHEMISTRY 68 (9) 3511 -3521 2003年05月 [査読無し][通常論文]
     
    The stereoselective hydride reduction of the cis- and trans-substituted cyclopropyl ketones was systematically investigated using a series of structurally simplified substrates, trans-[tert-butyldiphenylsilyloxymethyl]cyclopropyl ketones la-a and trans- (benzyloxymethyl)cyclopropyl methyl ketone (2), and the corresponding cis congeners 3a,b,e and 4. The results showed that, not only in the reduction of the cis-substituted cyclopropyl ketones but also in that of the trans-substituted ketones, high stereoselectivity can be realized when the substrate has a bulky substituent on the cyclopropane ring, even though it is attached to the position trans to the acyl moiety. Ab initio calculations based on the density functional theory (DFT) of cyclopropyl ketones showed that (1) the bisected s-cis and s-trans conformers were the only two minimum energy conformers; while the s-cis conformer was more stable than the s-trans and (2) a bulky alkyl group in the acyl moiety and a cis substituent on the cyclopropane ring made the bisected s-cis conformer much more stable. On the basis of these calculations and experimental results, it is likely that the more stable the bisected s-cis conformer of the substrate, the more stereoselective the hydride reduction. Thus, the stereochemistry can be explained by hydride attack on the bisected s-cis conformation of the substrate from the less-hindered face. The predictability of the stereochemical results is predicated on the bisected s-cis transition-state model, which is very important from the viewpoint of synthetic organic chemistry.
  • M Sukeda, S Ichikawa, A Matsuda, S Shuto JOURNAL OF ORGANIC CHEMISTRY 68 (9) 3465 -3475 2003年05月 [査読無し][通常論文]
     
    A novel radical method for the stereoselective introduction of an ethynyl group has been developed. When a solution of ethynyldimethylsilyl (EDMS) or [2-(trimethylsilyl)ethynyl]dimethylsilyl (TEDMS) ethers of trans-2-iodoindanol was treated with Et3B followed by tetrabutylammonium fluoride in toluene, atom transfer 5-exo-cyclization and subsequent elimination occurred to give cis-2-ethynylindanol in high yield. The method was shown to be useful in the introduction of an ethynyl group in various five- and six-membered-ring iodohydrins. Furthermore, 2'-deoxy-2'-C-ethynyl-uridine (6) and -cytidine (7), which were designed as novel antimetabolites, were readily synthesized by using this method as the key step. This would be the first example in which a radical reaction was used for introducing an ethynyl group.
  • Y Kazuta, K Hirano, K Natsume, S Yamada, R Kimura, SI Matsumoto, K Furuichi, A Matsuda, S Shuto JOURNAL OF MEDICINAL CHEMISTRY 46 (10) 1980 -1988 2003年05月 [査読無し][通常論文]
     
    A series of cyclopropane-based conformationally restricted analogues of histamine, the "folded" cis-analogues, i.e., (1S,2R)-2-(aminomethyl)-1-(1H-imidazol-4-yl)cyclopropane (11), (1S,2S)-2-(2-aminoethyl)-1-(1H-imidazol-4-yl)cyclopropane (13), and their enantiomers ent-11 and ent-13, and the "extended" trans-analogues, i.e., (1R,2R)-2-(aminomethyl)-1-(1H-imidazol-4-yl)cyclopropane (12) and its enantiomer ent-12, were designed as histamine H-3 receptor agonists. These target compounds were synthesized from the versatile chiral cyclopropane units, (1S,2R)- and (1R,2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-formylcyclopropane (14 and 15, respectively) or their enantiomers ent-14 and ent-15. Among the conformationally restricted analogues, the "folded" analogue 13 (AEIC) having the cis-cyclopropane structure was identified as a potent H-3 receptor agonist, which showed a significant binding affinity (K-i = 1.31 +/- 0.16 nM) and had an agonist effect (EC50 value of 10 +/- 3 nM) on the receptor. This compound owes its importance to being the first highly selective H-3 receptor agonist to have virtually no effect on the H-4 subtype receptor. These studies showed that the cis-cyclopropane structure is very effective in the conformational restriction of histamine to improve the specific binding to the histamine H-3 receptor.
  • L Gan, MR Seyedsayamdost, S Shuto, A Matsuda, GA Petsko, L Hedstrom BIOCHEMISTRY 42 (4) 857 -863 2003年02月 [査読無し][通常論文]
     
    Mizoribine monophosphate (MZP) is the active metabolite of the immunosuppressive agent mizoribine and a potent inhibitor of IMP dehydrogenase (IMPDH). This enzyme catalyzes the oxidation of IMP to XMP with the concomitant reduction of NAD via a covalent intermediate at Cys319 (E-XMP*). Surprisingly, mutational analysis indicates that MZP is a transition state analogue although its structure does not resemble that of the expected transition state. Here we report the X-ray crystal structure of the E(.)MZP complex at 2.0 Angstrom resolution that reveals a transition state-like structure and solves the mechanistic puzzle of the IMPDH reaction. The protein assumes a new conformation where a flap folds into the NAD site and MZP, Cys319, and a water molecule are arranged in a geometry resembling the transition state. The water appears to be activated by interactions with a conserved Arg418-Tyr419 dyad. Mutagenesis experiments confirm that this new closed conformation is required for the hydrolysis of E-XMP*, but not for the reduction of NAD. The closed conformation provides a structural explanation for the differences in drug selectivity and catalytic efficiency of IMPDH isozymes.
  • S Tamura, H Abe, A Matsuda, S Shuto ANGEWANDTE CHEMIE-INTERNATIONAL EDITION 42 (9) 1021 -+ 2003年 [査読無し][通常論文]
  • Y Kazuta, R Tsujita, K Yamashita, S Uchino, S Kohsaka, A Matsuda, S Shuto BIOORGANIC & MEDICINAL CHEMISTRY 10 (12) 3829 -3848 2002年12月 [査読無し][通常論文]
     
    (1S,2R)-1-Phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide (PPDC. 4a). which is a conformationally restricted analogue of antidepressant milnacipran [(+/-)-1]. is a new class of potent noncompetitive NMDA receptor antagonists. A series of PPDC analogues modified at the 1-phenyl moiety. that is, the analogue 6 lacking 1-phenyl group, the 1-(fluorophenyl) analogues 4b,c.d. the 1-(methylphenyl) analogues 4e-g and the 1-(naphthyl) analogues 4h.i were synthesized. Analogue 6. lacking the 1-phenyl group. was completely inactive showing that the aromatic moiety is essential for the NMDA receptor binding. Among the analogues synthesized, the 1-o-fluorophenyl and 1-m-fluorophenyl analogues 4b and 4c showed potent affinities for the NMDA receptor [IC50=0.16+/-0.001 muM (4b), 0.15+/-0.02 muM (4c)]. which were improved to some extent compared to those of the parent compound PPDC (IC50=0.20+/-0.02 muM). On the other hand, compounds 4b and 4c showed none of the 5-HT-uptake inhibitors effect, while PPDC turned out to be a weak 5-HT-uptake inhibitor. (C) 2002 Elsevier Science Ltd. All rights reserved.
  • N Atsumi, Y Ueno, M Kanazaki, S Shuto, A Matsuda BIOORGANIC & MEDICINAL CHEMISTRY 10 (9) 2933 -2939 2002年09月 [査読無し][通常論文]
     
    In order to develop novel antigene molecules forming thermally stable triplexes with target DNAs and having nuclease resistance properties, e synthesized oligodeoxynucleotides (ODNs) with various lengths of aminoalkyl-linkers at the 4'alpha position of thymidine and the aminoethyl-linker at the 4'alpha position of 2'-deoxy-5-methylcytidine. Thermal stability of triplexes between these ODNs and a DNA duplex was studied by thermal denaturation. The ODNs containing the nucleoside 2 with the aminoethyl-tinker or the nucleoside 3 with the aminopropyl-linker thermally stabilized the triplexes, whereas the ODNs containing the nucleoside I with the aminomethyl-linker or the nucleoside 4 with the 2-[N-(2-aminoethyl)carbamoyl]oxy]ethyl-linker thermally destabilized the triplexes. The ODNs containing 2 were the most efficient at stabilizing the triplexes with the target DNA. The ODNs containing 4'alpha-C-(2-aminoethyl)-2'-deoxy-5-methylcytidine (5) also efficiently stabilized the triplexes with the target DNA. Stability of the ODN containing 5 to nucleolytic hydrolysis by snake venom phosphodiesterase (a 3'-exonuclease) was Studied. It was found that the ODN containing 5 was more resistant to nucleolytic digestion by the enzyme than all unmodified ODN. In a previous paper, we reported that the ODNs containing 2 were more resistant to nucleolytic digestion by DNase I (an endonuclease) than the Unmodified ODNs. Thus, it was found that the ODNs containing 4'alpha-C-(2-aminoethyl)-2'-deoxynucleosides were good candidates for antigene molecules. (C) 2002 Elsevier Science Ltd. All rights reserved.
  • S Ono, K Ogawa, K Yamashita, T Yamamoto, Y Kazuta, A Matsuda, S Shuto CHEMICAL & PHARMACEUTICAL BULLETIN 50 (7) 966 -968 2002年07月 [査読無し][通常論文]
     
    (1S,2R)-1-Phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide (2b, PPDC), a new class of potent N-methyl-D-aspartic acid (NMDA) receptor antagonist, was designed based on a new method for restricting the conformation of compounds having a cyclopropane ring. The three-dimensional structures of PPDC obtained by the three different methods of X-ray crystallographic analysis, usual MM2-calculations in vacuum, and MM2 calculations based on the nuclear Overhauser effect (NOE) data in D2O are similar, which are In accord with that hypothesized. These results suggest that this conformational restriction method is particularly effective in designing novel biologically active molecules.
  • T Asai, K Shimizu, M Kondo, K Kuromi, K Watanabe, K Ogino, T Taki, S Shuto, A Matsuda, N Oku FEBS LETTERS 520 (1-3) 167 -170 2002年06月 [査読無し][通常論文]
     
    We previously reported that liposomalized 5'-O-dipalmitoylphosphatidyl 2'-C-cyano-2'-deoxy-1-beta-D-arabinopentofuranosylcytosine (DPP-CNDAC), a hydropbobized derivative of the novel antitumor nucleoside CNDAC, is quite useful for cancer therapy. On the other hand, for anti-neovascular therapy, we recently isolated peptides homing to angiogenic vessels from a phage-displayed random peptide library, and observed that peptide-modified liposomal adriamycin strongly suppressed tumor growth, perhaps through damaging angiogenic endothelial cells. In the present study, we modified DPP-CNDAC-liposomes with one of the angiogenic homing peptides, APRPG, and examined their antitumor activity. Three doses of APRPG-modified DPP-CNDAC-liposomes (15 mg/kg as CNDAC) strongly inhibited tumor growth compared with the same number of doses of unmodified DPP-CNDAC-liposomes. The life span was increased 31.8%, with one completely cured mouse out of the six mice treated. Since the accumulation of liposomes in the tumor tissue was not so much different between APRPG-liposomes and non-modified liposomes, the enhanced therapeutic efficacy may be explained as the alteration of targets, i.e. APRPG-modified DPP-CNDAC-liposomes caused tumor growth suppression through damage of angiogenic endothelial cells. Anti-neovascular therapy promises no drug resistance, and should be effective against essentially any kind of solid tumor; and thus the present results demonstrate another benefit of the therapy, namely, high efficacy of cancer treatment. (C) 2002 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.
  • Y Kazuta, R Tsujita, K Ogawa, T Hokonohara, K Yamashita, K Morino, A Matsuda, S Shuto BIOORGANIC & MEDICINAL CHEMISTRY 10 (6) 1777 -1791 2002年06月 [査読無し][通常論文]
     
    (IS,2R)-1-Phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide (PPDC, 4a), which is a conformationally restricted analogue of the antidepressant milnacipran [(+/-)-1], represents a new class of potent NMDA receptor antagonists. A series of PPDC analogues modified at the carbamoyl moiety were synthesized. Among these, (IS,2R)-l-phenyl-2-[(S)-l-aminopropyl]-N,N-dipropylcyclopropanecarboxamide (4d) was identified as the most potent NMDA receptor antagonist in this series and clearly reduced the MMDA receptor mediated potentiation of rat hippocampal slices, a model of long-term potentiation (LTP). The three-dimensional structure of 4d was also analyzed in detail to clarify the receptor-binding conformation. (C) 2002 Elsevier Science Ltd. All rights reserved.
  • AH Guse, C Cakir-Kiefer, M Fukuoka, S Shuto, K Weber, VC Bailey, A Matsuda, GW Mayr, N Oppenheimer, F Schuber, BVL Potter BIOCHEMISTRY 41 (21) 6744 -6751 2002年05月 [査読無し][通常論文]
     
    Three novel analogues modified in the "northern" ribose (ribose linked to NI of adenine) of the Ca2+ mobilizing second messenger cyclic adenosine diphosphoribose, termed 2"-NH2-cyclic adenosine diphosphoribose, cyclic adenosine diphospho-carbocyclic-ribose, and 8-NH2-cyclic adenosine diphospho-carbocyclic-ribose, were synthesized (chemoenzymatically and by total synthesis) and spectroscopically characterized, and the pK(a) values for the 6-amino/imino transition were determined in two cases. The biological activity of these analogues was determined in permeabilized human Jurkat T-lymphocytes. 2"-NH2-cyclic adenosine diphosphoribose mediated Ca2+ release was slightly more potent than that of the endogenous cyclic adenosine diphosphoribose in terms of the concentration - reponse relationship. Both compounds released Ca2+ from the same intracellular Ca2+ pool. In addition, the control compound 2"-NH2-adenosine diphosphoribose was almost without effect. In contrast, only at much higher concentrations (greater than or equal to 50 muM) did the "northern" carbocyclic analogue, cyclic adenosine diphospho-carbocyclic-ribose, significantly release Ca2+ from permeabilized T cells, whereas the previously reported "southern" carbocyclic analogue, cyclic aristeromycin diphosphoribose, was slightly more active than the endogenous cyclic adenosine diphosphoribose. Likewise, 8-NH2-cyclic adenosine diphospho-carbocyclic-ribose, expected to antagonize Ca2+ release as demonstrated previously for 8-NH2-cyclic adenosine diphosphoribose, did not inhibit cyclic adenosine diphosphoribose mediated Ca2+ release. This indicates that the 2"-NH2-group substitutes well for the 2"-OH-group it replaces; it may be oriented toward the outside of the putative cyclic adenosine diphosphoribose receptor binding domain and/or it can potentially also engage in H bonding interactions with residues of that domain. In sharp contrast to this, replacement of the endocyclic furanose oxygen atom by CH2 in a carbocyclic system obviously interferes with a crucial element of interaction between cyclic adenosine diphosphoribose and its receptor in T-lymphocytes.
  • Y Kazuta, A Matsuda, S Shuto JOURNAL OF ORGANIC CHEMISTRY 67 (5) 1669 -1677 2002年03月 [査読無し][通常論文]
     
    The cyclopropane ring can be used effectively in restricting the conformation of biologically active compounds to improve activity and also to investigate bioactive conformations. We designed (1S,2R)and (1R,2R)-2-aminomethyl-1-(1H-imidazol-4-yl)cyclopropanes (1 and 2, respectively) and their enantiomers (ent-1 and ent-2) as conformationally restricted analogues of histamine. The four types of chiral cyclopropanes bearing two differentially functionalized carbon substituents in a cis or trans relationship on a cyclopropane ring, (1S,2R)-2-(tert-butyldiphenylsilyloxy)methyl-l-formylcyclopropane (7) and (1-R,2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-fonnylcyclopropane (8) and their enantiomers (ent-7 and ent-8), were developed as the key intermediates for synthesizing 1, 2, ent-1, and ent-2. The reaction between (R)-epichlorohydrin [(R)-12] and phenylsulfonylacetonitrile (13a) in the presence of NaOEt in EtOH followed by treatment with acid gave the chiral cyclopropane lactone 11a with 98% ee in 82% yield. Compound 11a was converted into both the cis- and transchiral cyclopropane units 7 and 8, respectively, via reductive desulfonylation with Mg/MeOH as the key step. The corresponding enantiomers, the cis-substituted ent-7 and the trans-substituted ent-8, were also prepared starting from (S)-epichlorohydrin [(S)-12]. The four conformationally restricted target histamine analogues 1, 2, ent-1, and ent-2 were successfully synthesized from 7, 8, ent-7, and ent-8, respectively. The chiral cyclopropane units 7, 8, ent-7, and ent-8 should be useful as versatile intermediates for synthesizing various compounds having an asymmetric cyclopropane structure.
  • M Nomura, T Sato, M Washinosu, M Tanaka, T Asao, S Shuto, A Matsuda TETRAHEDRON 58 (7) 1279 -1288 2002年02月 [査読無し][通常論文]
     
    A practical synthetic route to the antitumor nucleoside, 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine (ECyd, 1) from 1,2-O-isopropylidene-D-xylofuranose (3) has been developed. Since most of the compounds were obtained as crystals, the target ECyd was prepared without any chromatographic purification in 31% overall yield from compound 3. The isobutyryloxy group was found to be an effective leaving group at the anomeric position of the 3-beta-C-ethynyl glycosyl donors in the key Vorbruggen glycosylation reaction. Using a similar procedure without chromatographic purification, the uracil congener EUrd [1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)uracil (2), which also has a potent antitumor effect, was synthesized from 3 in 39% overall yield. (C) 2002 Elsevier Science Ltd. All rights reserved.
  • M Sukeda, S Ichikawa, A Matsuda, S Shuto ANGEWANDTE CHEMIE-INTERNATIONAL EDITION 41 (24) 4748 -4750 2002年 [査読無し][通常論文]
  • Y Kazuta, R Tsujita, S Uchino, N Kamiyama, D Mochizuki, K Yamashita, Y Ohmori, A Yamashita, T Yamamoto, S Kohsaka, A Matsuda, S Shuto JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1 2002 (9) 1199 -1212 2002年 [査読無し][通常論文]
     
    (1S,2R)-1-Phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide (2b), which is a conformationally restricted analog of the antidepressant milnacipran [(+/-)-1], is a new class of potent NMDA (N-methyl-D-aspartic acid) receptor antagonists. A series of analogs of 2b modified at the 1'-position were designed and synthesized starting from (R)-epichlorohydrin via the key intermediate an optically active cyclopropanecarbaldehyde derivative 8 with a (1S,2R)-configuration. Among these analogs, (1S,2R)-1-phenyl-2-[(S)-1-aminobut-3-enyl]-N, N-diethylcyclopropanecarboxamide (2i) and (1S,2R)-1-phenyl-2-[(S)-1-aminobut-3-ynyl]-N,N-diethylcyclopropanecarboxamide (2j) were identified as more potent NMDA receptor antagonists than 2b. The subtype selectivity of 2i and 2j together with 2b was investigated to show that 2i inhibited the GluRepsilon3/zeta1 and GluRepsilon4/zeta1 subtypes four times more strongly than GluRepsilon1/zeta1 and GluRepsilon2/zeta1 subtypes. Compound 2i is the first GluRepsilon3/zeta1 and GluRepsilon4/zeta1 subtype-selective antagonist, while the selectivity is not so high.
  • S Shuto, N Minakawa, S Niizuma, HS Kim, Y Wataya, A Matsuda JOURNAL OF MEDICINAL CHEMISTRY 45 (3) 748 -751 2002年01月 [査読無し][通常論文]
     
    An improved method for the synthesis of (6'R)-6'-C-methylneplanocin A (RMNPA, 2), a potent S-adenosyl-L-homocysteine (AdoHcy) hydrolase inhibitor, was developed via a chelation-controlled stereoselective addition of MeTiCl3 to the neplanocin A 6'-aldehyde derivative 6. Compound 2 effectively inhibited the growth of malaria parasites both in vitro and in vivo. The antimalarial EC50 value of 2 against Plasmodium berghei in mice was 1.0 mg/kg/day, which was superior to that of chloroquine (EC50 = 1.8 mg/kg/day).
  • Shuto, S, Niizuma, S, Minakawa, N, Kim, H.-S, Wataya, Y, Matsuda, A J. Med. Chem., 2002年 [査読無し][通常論文]
  • S Shuto, M Fukuoka, A Manikowsky, Y Ueno, T Nakano, R Kuroda, H Kuroda, A Matsuda JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 123 (36) 8750 -8759 2001年09月 [査読無し][通常論文]
     
    The synthesis of cyclic ADP-carbocyclic-ribose (cADPcR, 4) designed as a stable mimic of cyclic ADP-ribose (cADPR, 1), a Ca2+-mobilizing second messenger, was achieved using as the key step a condensation reaction with the phenylthiophosphate-type substrate 14 to form an intramolecular pyrophosphate linkage. The N-1-carbocyclic-ribosyladenosine derivative 16 was prepared via the condensation between the imidazole nucleoside derivative 17, prepared from AICA-riboside (19), and the readilv available optically active carbocyclic amine 18. Compound 16 was then converted to the corresponding 5 " -phosphoryl-5 ' phenylthiophosphate derivatives 14. Treatment of 14 with AgNO3 in the presence of molecular sieves (3 A) in pyridine at room temperature gave the desired cyclization product 32 in 93% yield, and subsequent acidic treatment provided the target cADPcR (4), This represents a general method for synthesizing biologically important cyclic nucleotides of this type. H-1 NMR analysis of cADPcR suggested that its conformation in aqueous medium is similar to that of cADPR. cADPcR. unlike cADPR. was stable under neutral and acidic conditions, where under basic conditions. it formed the Dimroth-rearranged N-6-cyclized product 34. cADPcR was also stable in rat brain membrane homogenate which has cADPR degradation activity. Furthermore, cADPcR was resistant to the hydrolysis by CD38 cADPR hydrolase. while cADPR was rapidly hydrolyzed under the same conditions. When cADPcR was injected into sea urchin eggs, it caused a significant release of Ca2+ in the cells, an effect considerably stronger than that of cADPR. Thus, cADPcR was identified as a stable mimic of cADPR.
  • H Abe, S Shuto, S Tamura, A Matsuda TETRAHEDRON LETTERS 42 (35) 6159 -6161 2001年08月 [査読無し][通常論文]
     
    An efficient method for preparing fully O-silylated pyranoses, which are conformationally restricted in the unusual C-1(4)-form, was developed. Thus, successive treatment of pyranosides, such as xylose and glucose derivatives, with NaH and TIPSOTf or TBSOTf in THF at room temperature gave the corresponding fully O-silylated products. (C) 2001 Elsevier Science Ltd. All rights reserved.
  • R Tateoka, H Abe, S Miyauchi, S Shuto, A Matsuda, M Kobayashi, K Miyazaki, N Kamo BIOCONJUGATE CHEMISTRY 12 (4) 485 -492 2001年07月 [査読無し][通常論文]
     
    Our previous paper [(1999) Bioconjugate Chem. 10, 24-31] pointed out that hydrophobicity of substrates/inhibitors plays an important role in the recognition by an oligopeptide transporter (PEPT1) expressed in the human intestinal epithelial cell line Caco-8. To determine the significance of that hydrophobicity, we have now synthesized dipeptide analogues conjugating the E-amino group of Lys in Val-Lys with aliphatic carboxylic acids: acetic acid (C2), propanoic acid (C3), pentanoic acid (C5), hexanoic acid (C6), and decanoic acid (C10). The affinities of these conjugates were estimated by their inhibition of the accumulation rate of Gly-Sar, a well-established substrate for PEPT1. With the increase in length of the hydrocarbon chain of the conjugates, i.e., in the hydrophobicity of the conjugates, the inhibition strengthened. Dixon-Webb plot analysis of the inhibition by the C10-conjugated dipeptide showed competitive inhibition. The trans-stimulation effect of Val-Lys conjugated to C10 or C5 on the uptake of Ceftibuten was observed using rat brush border membrane vesicles. This findings showed that these conjugates are transportable substrates. These results confirmed that the hydrophobicity of substrates/inhibitor is one of the factors in the recognition by PEPT1.
  • T Kodama, S Shuto, M Nomura, A Matsuda CHEMISTRY-A EUROPEAN JOURNAL 7 (11) 2332 -2340 2001年06月 [査読無し][通常論文]
     
    The 1'alpha -phenylselenouridine derivative 13 was successfully synthesized hv enolization of the 3',5'-O-TIPDS-2'-ketouridine 8, and was subjected to a radical reaction with a vinylsilyl tether-an efficient procedure for preparing 1'alpha -branched-chain sugar pyrimidine nucleosides. Successive treatment of 8 with LiHMDS and PhSeCl in THF at < - 70<degrees> C gave the desired 1'-phenylseleno products in 85% yield as an anomeric mixture of the 1'alpha -product 11 and the 1'beta -product 12 (11/12 = 2.5:1). Highly stereoselective reduction at the 2'-carbonyl of the 1'alpha -product 11 occurred from the beta -face by using NaBH4/CeCl3 in MeOH, and subsequent introduction of a dimethylvinylsilyl tether at the 2'-hydroxyl gave the radical reaction substrate 14. The photochemical radical atom-transfer reaction of 14 by using a high-pressure mercury lamp proceeded effectively in benzene to give the exo-cyclized PhSe-transferred product 18, in which (PhSe)(2) proved to be essential as an additive for radical atom-transfer cyclization reactions. Subsequent phenylseleno-group elimination of 18 gave the sugar-protected 1'alpha -vinyluridine. With this procedure, 1'alpha -vinyluridine (22) and -cytidine (25), designed to be potential antitumor agents, were successfully synthesized. This study is the first example of functionalization at the anomeric 1'-position of a nucleoside by starting from a natural nucleoside to produce a ribo-type 1'-modified nucleoside.
  • S Shuto, Sugimoto, I, A Matsuda JOURNAL OF SYNTHETIC ORGANIC CHEMISTRY JAPAN 59 (6) 589 -598 2001年06月 [査読無し][通常論文]
     
    We developed a regio- and stereoselective method for introducing l-hydroxyethyl, 2-hydroxyethyl, and vinyl groups at the position beta to a hydroxyl group in halohydrins or alpha -phenylselenoalkanols using an intramolecular radical cyclisation reaction with a dimethyl- or diphenylvinylsilyl group as a temporary connecting radical-acceptor tether (Scheme 14). Thus, when a vinylsilyl ether of halohydrins or alpha -phenylselenoalkanols (A) was subjected to the radical reaction with Bu3SnH/AIBN, the selective introduction of both l-hydroxyethyl and 2-hydroxyethyl groups can be achieved, depending on the concentration of Bu3SnH in the reaction system, via a 5-exo-cyclization intermediate E or a B-endo-cyclization intermediate F, respectively, after oxidative ring-cleavage by treating the cyclization products under Tamao oxidation conditions. A vinyl group can also be introduced by photo-irradiating the vinylsilyl ether A in the presence of (Bu3Sn)(2), and then treating the resulting atom-transfer 5-exo-cyclization product I with fluoride ion. The mechanistic studies showed that the kinetically favored 5-exo-cyclized radical C, formed from radical B, was trapped when the concentration of Bu3SnH was high enough to give E. At lower concentrations of Bu3SnH and higher reaction temperatures, radical C rearranged into the more stable ring-enlarged 4-oxa-3-silacyclohexyl radical D, which was then trapped with Bu3SnH to give F. The ring-enlarging rearrangement was experimentally proved to occur via a pentavalent-like silicon-bridging transition state X (Scheme 9). This radical reaction with a vinylsilyl tether has been successfully applied to the synthesis of biologically important 4'-branched-chain sugar nucleosides and C-glycosides.
  • Correa, V, AM Riley, S Shuto, G Horne, EP Nerou, RD Marwood, BVL Potter, CW Taylor MOLECULAR PHARMACOLOGY 59 (5) 1206 -1215 2001年05月 [査読無し][通常論文]
     
    Adenophostin A is the most potent known agonist of inositol 1,4,5-trisphosphate (InsP(3)) receptors. Ca2(+) release from permeabilized hepatocytes was 9.9 +/- 1.6-fold more sensitive to adenophostin A (EC50, 14.7 +/- 2.4 nM) than to InsP(3) (145 +/- 10 nM), consistent with the greater affinity of adenophostin A for hepatic InsP(3) receptors (K-d = 0.48 +/- 0.06 and 3.09 +/- 0.33 nM, respectively). Here, we systematically modify the structures of the glucose, ribose, and adenine moieties of adenophostin A and use Ca2(+) release and binding assays to define their contributions to high-affinity binding. Progressive trimming of the adenine of adenophostin A reduced potency, but it fell below that of InsP(3) only after complete removal of the adenine. Even after substantial modifications of the adenine (to uracil or even unrelated aromatic rings, retaining the beta -orientation), the analogs were more potent than InsP(3). The only analog with an alpha -ribosyl linkage had massively decreased potency. The 2'-phosphate on the ribose ring of adenophostin A was essential and optimally active when present on a five-membered ring in a position stereochemically equivalent to its location in adenophostin A. Xylo-adenophostin, where xylose replaces the glucose ring of adenophostin A, was only slightly less potent than adenophostin A, whereas manno-adenophostin (mannose replacing glucose) had similar potency to InsP(3). These results are consistent with the relatively minor role of the 3-hydroxyl of InsP(3) (the equivalent is absent from xylo-adenophostin) and greater role of the equatorial 6-hydroxyl (the equivalent is axial in manno-adenophostin). This is the first comprehensive analysis of all the key structural elements of adenophostin A, and it provides a working model for the design of related high-affinity ligands of InsP(3) receptors.
  • S Shuto, K Yoshii, A Matsuda JAPANESE JOURNAL OF PHARMACOLOGY 85 (3) 207 -213 2001年03月 [査読無し][通常論文]
     
    We have found that milnacipran, a clinically useful antidepressant due to its inhibition of the re-uptake of serotonin (5-HT) and noradrenaline, is also a non-competitive NMDA-receptor antagonist. Based on the cyclopropane structure of milnacipran, conformationally restricted analogs were designed and synthesized. Of these analogs, (1S,2R)-1-phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide (PPDC) is 30-fold stronger than milnacipran as an NMDA-receptor antagonist with virtually no inhibitory effect on the neurotransmitter re-uptake. PPDC was identified as a new class of NMDA-receptor antagonist because it has a mode of action different from that of the previous antagonists; it selectivly binds the GluR epsilon3/GluR zeta1 and GluR epsilon4/GluR zeta1 subtype receptors in an agonist-independent allosteric manner. Functional assays of PPDC with the Xenopus oocytes system and cultured mouse neurons under voltage-clamp conditions confirmed that it acts as a potent NMDA-receptor antagonist. PPDC effectively protected against NMDA-induced neurotoxicity in both cultured mouse cerebral cortex and delayed neuronal death in a gerbil ischemic model. It was also active in a reserpine-treated mouse Parkinsons disease model. Thus, PPDC may be a candidate for a clinically useful NMDA-receptor antagonist, since the development of previous NMDA-receptor antagonists as drugs has been hindered by various undesirable side effects.
  • 周東 智, 杉本 勇, 松田 彰 有合化 59 (6) 589 -598 2001年 [査読無し][通常論文]
     
    We developed a regio- and stereoselective method for introducing 1-hydroxyethyl, 2-hydroxyethyl, and vinyl groups at the position β to a hydroxyl group in halohydrins or α-phenylselenoalkanols using an intramolecular radical cyclization reaction with a dimethyl- or diphenylvinylsilyl group as a temporary connecting radical-acceptor tether (Scheme 14). Thus, when a vinylsilyl ether of halohydrins or α-phenylselenoalkanols (A) was subjected to the radical reaction with Bu3SnH/AIBN, the selective introduction of both 1-hydroxyethyl and 2-hydroxyethyl groups can be achieved, depending on the concentration of Bu3SnH in the reaction system, via a 5-exo-cyclization intermediate E, or a 6-endo-cyclization intermediate F, respectively, after oxidative ring-cleavage by treating the cyclization products under Tamao oxidation conditions. A vinyl group can also be introduced by photo-irradiating the vinylsilyl ether A in the presence of (Bu3Sn)2, and then t reating the resulting atom-transfer 5-exo-cyclization product I with fluoride ion. The mechanistic studies showed that the kinetically favored 5-exo-cyclized radical C, formed from radical B, was trapped when the concentration of Bu3SnH was high enough to give E. At lower concentrations of Bu3SnH and higher reaction temperatures, radical C rearranged into the more stable ring-enlarged 4-oxa-3-silacyclohexyl radical D, which was then trapped with Bu3SnH to give F. The ring-enlarging rearrangement was experimentally proved to occur via a pentavalent-like silicon-bridging transition state X (Scheme 9). This radical reaction with a vinylsilyl tether has been successfully applied to the synthesis of biologically important 4'-branched-chain sugar nucleosides and C-glycosides.
  • J. Am. Chem. Soc. 123 (11870-11882) 2001年 [査読無し][通常論文]
     
    Highly alfa- and beta-selective radical C-glycosylation reactions based on the conformational restriction strategy using a controlling anomeric effect. A study on the conformationミanomeric effectミstereoselectivity relationship in the anomeric radical reactions
  • Y Kazuta, S Shuto, H Abe, A Matsuda JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1 (6) 599 -604 2001年 [査読無し][通常論文]
     
    An efficient synthesis of 1-phenyl-2-[(S)-1-aminoethyl]- and 1-phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamides [1a (PEDC) and 1b (PPDC), respectively], potent NMDA receptor antagonists having a cyclopropane structure, was achieved. We have shown for the first time that C-cyclopropylaldonitrone preferentially exists in the bisected s-trans conformation, due to the characteristic stereoelectronic effects of the cyclopropane ring, by X-ray crystallographic analysis, NMR studies, and theoretical calculations. Based on these findings, the highly stereoselective addition reaction of Grignard reagents to C-cyclopropylaldonitrone 6 was developed, and the reaction was successfully used as the key step for the preparation of the NMDA receptor antagonists 1a and 1b as well as for a newly designed isopropyl-type congener 1c. The facial selectivity of the addition of Grignard reagents can be explained by the attack of the reagents from the less hindered side of the substrate in the predicted bisected s-trans conformation. This Grignard reaction is the first example of a highly stereoselective addition to a nitrone via a non-chelation controlled pathway.
  • Targeted pulmonary cancer therapy by liposomal 5'-O-dipalmitoylphosphatidyl 2'-C-cyano-2'-deoxy-l-β-D-arabiono-pentofuranosylcytosine.
    Cancer Lett. 162 49 -56 2001年 [査読無し][通常論文]
  • M Sukeda, S Shuto, Sugimoto, I, S Ichikawa, A Matsuda JOURNAL OF ORGANIC CHEMISTRY 65 (26) 8988 -8996 2000年12月 [査読無し][通常論文]
     
    Recently, we developed a regio- and stereoselective method for introducing a vinyl group at the position beta to a hydroxyl group in halohydrins or alpha -phenylselenoalkanols via a radical atom-transfer cyclization reaction with a vinylsilyl group as a temporary connecting radical-acceptor tether. The synthesis of 2'-deoxy-2'-C-vinyl- and 2'-deoxy-2'-C-hydroxymethyluridines (7 and 8, respectively) and the corresponding 2'-deoxycytidine congeners (10 and 11, respectively), which were designed as potential antitumor and/or antiviral agents, was achieved using this radical atom-transfer cyclization as the key step. When the 2'-deoxy-2'-iodo-5'-O-monomethoxytrityl (MMTr) uridine derivative 19a, bearing a vinylsilyl group at the 3'-hydroxyl group, was heated with (Me3Sn)(2) and AIBN in benzene, the corresponding radical atom-transfer product was generated, which in turn was successively treated with tetrabutylammonium fluoride and TBSCl/imidazole to give the desired 2'-deoxy-5'-O-MMTr-3'-O-TBS-2'-C-vinyluridine (25). Compound 25 was successfully converted into the target 2'-deoxy-2'-branched pyrimidine ribonucleosides 7, 8, 10, and 11.
  • S Shuto, Y Yahiro, S Ichikawa, A Matsuda JOURNAL OF ORGANIC CHEMISTRY 65 (18) 5547 -5557 2000年09月 [査読無し][通常論文]
     
    3,7-Anhydro-D-glycero-D-ido-octitol 1,5,6-trisphosphate (5) was designed as a novel IP3-receptor ligand having a C-glycosidic structure and was synthesized via a radical cyclization reaction with a temporary connecting vinylsilyl tether as the key step. The phenyl 2-O-dimethylvinylsilyl-3,4,6-tri-O-benzyl-1-seleno-beta-D-glucopyranoside (7), in the usual C-4(1)-conformation, was successively treated with Bu3SnH/AIBN and under Tamao oxidation conditions to give a mixture of five C-glycosidic products, On the other hand, similar successive treatment of the corresponding 3,4-di-O-TBS-protected substrates 13 and 24, which were in an unusual C-1(4)-conformaion due to the steric repulsion between the bulky silyl protecting groups, gave the desired 1 alpha-C-glycosides 18 and 25, respectively, as the major products. Thus, the course of the radical cyclization was effectively controlled by a change in the conformation of the pyranose ring into a C-1(4)-form due to steric repulsion between the adjacent bulky TBS-protecting groups at the 3- and 4-hydroxyl groups. From 25, the target 5 was synthesized via phosphorylation of the hydroxyls by the phosphoramidite method. The C-glycoside trisphosphate 5 has significant binding affinity for IP3 receptor of calf cerebella.
  • M Fukuoka, S Shuto, N Minakawa, Y Ueno, A Matsuda JOURNAL OF ORGANIC CHEMISTRY 65 (17) 5238 -5248 2000年08月 [査読無し][通常論文]
     
    An efficient synthesis of cyclic IDP-carbocyclic-ribose (3! and its 8-bromo derivative 6, as stable mimics of cyclic ADP-ribose, was achieved, and a condensation reaction with phenylthiophosphate-type substrate 15 or 16 to form an intramolecular pyrophosphate linkage was a key step. N-1-Carbocyclic-ribosylinosine derivative 28 and the corresponding 8-bromo congener 24 were prepared via condensation between N-1-(2,4-dinitrophenyl)inosine derivative 17 and a known optically active carbocyclic amine 18. Compounds 24 and 28 were then converted to the corresponding 5''-phosphoryl-5'-phenylthiophosphate derivatives 15 and 16, respectively, which were substrates for the condensation reaction to form an intramolecular pyrophosphate linkage. Treatment of 8-bromo substrate 15 with It or AgNO3 in the presence of molecular sieves 3A (MS 3A) in pyridine at room temperature gave the desired cyclic product 12 quantitatively, while the yield was quite low without MS. The similar reaction of 8-unsubstituted substrate 16 gave the corresponding cyclized product 32 in 81% yield. Acidic treatment of these cyclic pyrophosphates 12 and 32 readily gave the targets 6 and 3, respectively. This result suggests that the construction of N-1-substituted hypoxanthine nucleoside structures from N-1-(2, 4-dinitrophenyl)ino sine derivatives and the intramolecular condensation by activation of the phenylthiophosphate group with I-2 or AgNO3/MS 3A combine to provide a very efficient route for the synthesis of analogues of cyclic ADP-ribose such as 3 and 6. Thus, this may be an entry to a general method for synthesizing biologically important cyclic nucleotides of this type.
  • H Abe, S Shuto, A Matsuda JOURNAL OF ORGANIC CHEMISTRY 65 (14) 4315 -4325 2000年07月 [査読無し][通常論文]
     
    Synthesis of the C-glycosidic analogue 9 of adenophostin A, a very potent IP3 receptor agonist, and its uracil congener 10 was achieved via a temporary silicon-tethered radical coupling reaction as the key step. Phenyl 3,4,6-tri-O-(p-methoxybenzyl)-1-seleno-beta-D-glucopyranoside (27) and 3-deoxy3-methylene-1,2-O-isopropylidene-alpha-D-erythro (30) were connected by a dimethylsilyl tether to give the radical coupling reaction substrate 24, which was successively treated with Bu-3-SnH/AIBN in benzene and TBAF in THF to give the coupling product 25 with the desired (3a,1'a)-configuration as the major product. From 25, the targets 9 and 10 were synthesized via introduction of adenine or uracil base by Vorbruggen's method and phosphorylation of the hydroxyls by the phosphoramidite method.
  • Y Kazuta, S Shuto, A Matsuda TETRAHEDRON LETTERS 41 (28) 5373 -5377 2000年07月 [査読無し][通常論文]
     
    An efficient synthesis of PEDC (1), a potent NMDA receptor antagonist of a cyclopropane structure, was achieved. The highly stereoselective addition reaction of MeMgBr to C-cyclopropylnitrone 2, via its bisected s-trans conformation which can be predicted from the stereo-electronic effects, was developed as the key step. The s-trans conformation predominant in C-cyclopropynitrone 2 was suggested by NOE experiments. (C) 2000 Elsevier Science Ltd. All rights reserved.
  • S Shuto, M Terauchi, Y Yahiro, H Abe, S Ichikawa, A Matsuda TETRAHEDRON LETTERS 41 (21) 4151 -4155 2000年05月 [査読無し][通常論文]
     
    An efficient method for preparing both 1 alpha- and 1 beta-C-glucosides having a 3-hydroxypropyl group at the anomeric position via a radical cyclization reaction with an allylsilyl tether was developed. The stereoselectivity of the radical cyclization can be controlled by the conformation of the pyranose ring, which is effectively manipulated by the hyroxyl protecting groups. (C) 2000 Elsevier Science Ltd. All rights reserved.
  • T Kodama, S Shuto, M Nomura, A Matsuda TETRAHEDRON LETTERS 41 (19) 3643 -3646 2000年05月 [査読無し][通常論文]
     
    Synthesis of the 1'-alpha-phenylselenouridine derivative 1 alpha, a potentially useful precursor for the synthesis of a variety of 1'-modified nucleosides, was achieved via enolization of the 3',5'-O-TIPDS-2'-ketouridine 2. Successive treatment of 2 with LiHMDS and PhSeCl at less than or equal to 70 degrees C in THF gave the corresponding 1'-phenylseleno product, which was reduced stereoselectively with NaBH4/CeCl3 in MeOH to give the target compound 1 alpha. (C) 2000 Elsevier Science Ltd. All rights reserved.
  • Hiroshi Abe, Satoshi Shuto, Akira Matsuda Tetrahedron Letters 41 (14) 2391 -2394 2000年04月01日 [査読無し][通常論文]
     
    Synthesis of the C-glycosidic analog (3) of adenophostin A, a very potent IP3 receptor agonist, was achieved using a temporary silicon-tethered reductive radical coupling reaction as the key step. Radical reaction of the silaketal substrate 6 with Bu3SnH/AIBN in benzene occurred stereoselectively, and subsequent desilylation gave the desired C-glycosidic disaccharide 7 with the (3α,1'α-configuration as the major product. Compound 7 was converted into the target 3 via the introduction of an adenine base by a Vorbruggen glycosylation reaction. (C) 2000 Elsevier Science Ltd.
  • M Kanazaki, Y Ueno, S Shuto, A Matsuda JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 122 (11) 2422 -2432 2000年03月 [査読無し][通常論文]
     
    The properties of phosphodiester oligodeoxynucleotides (ODNs) containing 4'alpha-C-aminomethyl, -ethyl, -propyl, and -N-(2-aminoethyl)carbamoylthymidines (1, 2, 4, and 5) as potential antisense molecules are investigated in detail. We developed new radical chemistry with a vinylsilyl or an allylsilyl;I group as a temporary radical acceptor tether to synthesize the required 4'alpha-branched thymidines. Thus, an intramolecular radical cyclization of 4'-phenylseleno nucleosides 7a and 7b, which have a dimethylvinylsilyl and a dimethylallylsilyl group at the 3'-hydroxyl, respectively, with Bu3SnH/AIBN and subsequent Tamao oxidation provided 5'-O-[dimethoxytrityl(DMTr)]-4'alpha-C-(2-hydroxyethyl)thymidine (8a) and 5'-O-DMTr-4'alpha-C-(3-hydroxypropyl)thymidine (8b). Compounds 8a and 8b were then converted into 4'alpha-C-(2-trifluoroacetamidoethyl)thymidine 12a and 4'alpha-C-(3-trifluoroacetamidopropyl)thymid 12b, which were phosphitylated to give the phosphoramidite units 14a and 14b. The phosphoramidite units of 1 and 5 were prepared by previous methods. The nucleosides 1, 2, 1, and 5 were incorporated into the 18-mer, 5'-d[MTMTMTMTMTMTMTMTMT]-3' where M is 5-methyl-2'-deoxycytidine, instead of T at various positions. We also prepared a 21-mer ODN 29 with a mixed sequence containing five residues of 2. The ODNs containing the modified nucleosides formed more stable duplexes with complementary DNA than the corresponding unmodified ODN. These ODNs also formed stable duplexes with the complimentary RNA, The ODNs containing the modified nucleosides were significantly resistant to nucleolytic hydrolysis by both snake venom phosphodiesterase (a 3'-exonuclease) and DNase 1 (an endonuclease) and were also very stable in PBS containing 50% human serum. It is worthwhile to note that these ODNs contain natural phosphodiester linkages. Furthermore, the duplexes formed by the ODNs containing the modified nucleosides and their complementary RNAs were good substrates for Escherichia coli RNase H and HeLa cell nuclear extracts as a source of human RNase H. Thus. these ODNs were identified as candidates for antisense molecules.
  • S Shuto, Sugimoto, I, H Abe, A Matsuda JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 122 (7) 1343 -1351 2000年02月 [査読無し][通常論文]
     
    A mechanistic study was performed on a novel radical ring-enlargement reaction of (3-oxa-2-silacyclopentyl)methyl radicals into 4-oxa-3-silacyclohexyl radicals. Two pathways, one via a pentavalent silicon bridging radical transition state (or intermediate), the other via beta-elimination to give a ring-opened silyl radical, can be postulated. The radical reactions of 1 and 2, which are precursors for a (3-oxa-2-silacyclopentyl)methyl radical C' and a 4-oxa-3-silacyclohexyl radical D', respectively, showed that the ring-enlargement rearrangement of C' into D' is irreversible. H-1 NMR analysis of the radical reactions of 8a and 8b, which have an asymmetric center at silicon, indicated that the configuration at the silicon atom is retained via a pentavalent silicon-bridging radical transition state (or intermediate) during the ring-enlargement reaction. Furthermore, examination of the radical ring-enlargement reaction with a deuterium-labeled substrate 12D showed that the ring-enlargement reaction did not involve beta-elimination to give a ring-opened silyl radical. Based on these results, we conclude that the ring-enlargement reaction occurs via a pentavalent silicon-bridging radical transition state (or intermediate). This is the first experimental evidence for such a pentavalent silicon radical, which has been previously postulated to understand radical reactions of organic silicon compounds.
  • 新しいセカンドメッセンジャー・サイクリックADP-リボース(cADPR)とその誘導体の化学
    有合化 58 1144 -1154 2000年 [査読無し][通常論文]
  • RD Marwood, S Shuto, DJ Jenkins, BVL Potter CHEMICAL COMMUNICATIONS (3) 219 -220 2000年 [査読無し][通常論文]
     
    The first totally synthetic base-modified analogues of the natural product and potent d-myo-inositol 1,4,5-trisphosphate receptor agonist adenophostin A were efficiently synthesised from d-xylose and d-glucose using methodology employing base and surrogate base addition to a common disaccharide intermediate.
  • Y Sumita, M Shirato, Y Ueno, A Matsuda, S Shuto NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS 19 (1-2) 175 -187 2000年 [査読無し][通常論文]
     
    The synthesis of cyclic ADP-carbocyclic-ribose (2), as a stable mimic for cyclic ADP-ribose, was investigated. Construction of the 18-membered backbone structure was successfully achieved by condensation of the two phosphate groups of 19, possibly due to restriction of the conformation of the substrate in a syn-form using an 8-chloro substituent at the adenine moiety. SN2 reactions between an ostically active carbocyclic unit 8, which was constructed by a previously developed method, and 8-bromo-N-6-trichloroacetyl-2',3'-O-isopropylideneadenosine 9c gave N-1-carbocyclic derivative, which was deprotected to give 5',5 "-diol derivatives 18. When 18 was treated with POCl3 in PO(OEt)(3), the bromo group at the 8-position was replaced to give N-1-carbocyclic-8-chloroadenosine 5',5 "-diphosphate derivative 19 in 43% yield. Treatment of 19 with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride gave the desired intramolecular condensation product 20 in 10% yield. This Is the first chemical construction of the 18-membered backbone structure containing an intramolecular pyrophosphate linkage of a cADPR-related compound with an adenine base.
  • Inward current responses to IP3 and adenophostin-analogues in turtle olfactory sensory neurons (Jointly Worked)
    Eur. J. Neurosci. 2 606 -612 2000年 [査読無し][通常論文]
  • Correa, V, RD Marwood, S Shuto, AM Riley, DJ Jenkins, BVL Potter, CW Taylor BRITISH JOURNAL OF PHARMACOLOGY 129 U127 -U127 2000年01月 [査読無し][通常論文]
  • M Nomura, K Endo, S Shuto, A Matsuda TETRAHEDRON 55 (52) 14847 -14854 1999年12月 [査読無し][通常論文]
     
    When 1-[2,3,5-tri-O-TBS-4 alpha-formyl-beta-D-ribo-pentofuranosyl]uracil (5) was treated with (methylene)triphenylphosphorane in THF, an unusual ring-expansion reaction occurred to give a nucleoside (7) containing dihydrooxepine ring at the sugar moiety. A deuterium-label experiment showed that one carbon unit derived from the ylide was incorporated into the 5'-position of 7. A ring cleavage between the C-3' and C-4' of 5 during the reaction was suggested. (C) 1999 Elsevier Science Ltd. All rights reserved.
  • 柏柳 誠, 田谷 和也, 周東 智, 松田 彰 日本味と匂学会誌 = The Japanese journal of taste and smell research 6 (3) 343 -346 1999年12月01日 [査読無し][通常論文]
  • Sugimoto, I, S Shuto, A Matsuda SYNLETT (11) 1766 -1768 1999年11月 [査読無し][通常論文]
     
    The kinetic study of the novel ring-expansion reaction of (3-axa-2-silacyclopentyl)methyl radical into 4-oxa-3-silacyclohexyl radical with a precursor far 3-oxa-2-silacyclopentylmethyl radical 3 showed that the ring-expansion reaction is irreversible with a rate constant of 6.1 x 10(4) s(-1) at 80 degrees C.
  • S Ichikawa, S Shuto, A Matsuda JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 121 (44) 10270 -10280 1999年11月 [査読無し][通常論文]
     
    The first total synthesis of the nucleoside antibiotic herbicidin B (Ib) was achieved, where a novel aldol-type C-glycosidation reaction promoted by samarium diiodide (SmI2) was used as a key step. Treatment of methyl 3,4-O-(1,1,3,3-tetraisopropyl-1,3-disiloxanediyl)-1-phenylthio-2-ulos-beta-D-glucuronate (13) with SmI2 in THF regioselectively gave the corresponding l-enolate, which was readily trapped with 1-beta-D-xylosyladenine 5'-aldehyde derivative 7 to afford the product 19a,b as an anomeric mixture. Dehydration of the 5'-hydroxyl in 19a,b with using Burgess's inner salt gave the enone 20, which was subsequently hydrogenated to give undeculofuranuronyl adenine derivative 21. Deprotection of 21 gave a tricyclic sugar nucleoside, 23. However, it was an epimer of herbicidin B at the 6'-position. Construction of the desired 6'-alpha-configuration was achieved by using a conformational restriction strategy based on repulsion between adjacent bulky protecting groups on the pyranose ring. Thus, when methyl 3-O-tert-butyldimethylsilyl-4-O-tert-butyldimethylsilyl-4-O-tert-butyldiphenylsilyl-1-phenylthio-2-ulos-D-glucuronate (29c), the conformation of which was restricted in an unusual C-1(4)-like conformation, was used as a precursor for ulose l-enolate in the SmI2-promoted aldol reaction with 7, the desired 6'-alpha-aldol product 30c was predominantly obtained. Compound 30c was dehydrated, followed by hydrogenation of the alkenyl bond and then deprotection to form an internal ketal linkage between the 3'- and 7'-positions, which spontaneously gave herbicidin B.
  • Sugimoto, I, S Shuto, A Matsuda JOURNAL OF ORGANIC CHEMISTRY 64 (19) 7153 -7157 1999年09月 [査読無し][通常論文]
     
    A one-pot method for the stereoselective introduction of a vinyl group at the beta-position of a hydroxyl group in halohydrins or alpha-phenylselenoalkanols via an atom-transfer radical-cyclization reaction was developed. When a solution of the diphenylvinylsilyl ether of (+/-)-trans-2-iodoindanol (2a) and (Bu3Sn)(2) in benzene was irradiated with a high-pressure mercury lamp, the corresponding atom transfer 5-exo-cyclization product was produced, which in turn was treated with tetrabutylammonium fluoride to give cis-2-vinylindanol (3) in 82% yield from 2a. Similar reactions with diphenylvinylsilyl ethers of (+/-)trans-1-phenylselenoindan-2-ol (4), trans-2-iodocyclopentanol (6), and trans-2-iodocyclohexanol (8) gave the corresponding vinyl derivatives. Furthermore, this reaction was successfully applied to the synthesis of 4'alpha-C-vinylthymidine, a potent antiviral nucleoside.
  • Sugimoto, I, S Shuto, A Matsuda JOURNAL OF ORGANIC CHEMISTRY 64 (19) 7153 -7157 1999年09月 [査読無し][通常論文]
     
    A one-pot method for the stereoselective introduction of a vinyl group at the beta-position of a hydroxyl group in halohydrins or alpha-phenylselenoalkanols via an atom-transfer radical-cyclization reaction was developed. When a solution of the diphenylvinylsilyl ether of (+/-)-trans-2-iodoindanol (2a) and (Bu3Sn)(2) in benzene was irradiated with a high-pressure mercury lamp, the corresponding atom transfer 5-exo-cyclization product was produced, which in turn was treated with tetrabutylammonium fluoride to give cis-2-vinylindanol (3) in 82% yield from 2a. Similar reactions with diphenylvinylsilyl ethers of (+/-)trans-1-phenylselenoindan-2-ol (4), trans-2-iodocyclopentanol (6), and trans-2-iodocyclohexanol (8) gave the corresponding vinyl derivatives. Furthermore, this reaction was successfully applied to the synthesis of 4'alpha-C-vinylthymidine, a potent antiviral nucleoside.
  • S Shuto, N Shibuya, S Yamada, T Ohkura, R Kimura, A Matsuda CHEMICAL & PHARMACEUTICAL BULLETIN 47 (8) 1188 -1192 1999年08月 [査読無し][通常論文]
     
    Conformationally restricted analogs of baclofen (2), i.e., 5, 6, and their enantiomers ent-5, and ent-6, the conformations of which were restricted by introducing a cyclopropane ring, were designed as potential GABA(B) receptor ligands. Reaction of (R)-epichlorohydrin [(R)-7] and (4-chlorophenyl)acetonitrile in the presence of NaNH2 in benzene/tetrahydrofuran gave chiral cyclopropane derivatives 11 and 12, which were then converted into the target compounds 5 and 6, respectively. Their corresponding enantiomers, ent-5 and ent-6, were also synthesized starting from (S)-epichlorohydrin [(S)-7].
  • S Shuto, N Shibuya, S Yamada, T Ohkura, R Kimura, A Matsuda CHEMICAL & PHARMACEUTICAL BULLETIN 47 (8) 1188 -1192 1999年08月 [査読無し][通常論文]
     
    Conformationally restricted analogs of baclofen (2), i.e., 5, 6, and their enantiomers ent-5, and ent-6, the conformations of which were restricted by introducing a cyclopropane ring, were designed as potential GABA(B) receptor ligands. Reaction of (R)-epichlorohydrin [(R)-7] and (4-chlorophenyl)acetonitrile in the presence of NaNH2 in benzene/tetrahydrofuran gave chiral cyclopropane derivatives 11 and 12, which were then converted into the target compounds 5 and 6, respectively. Their corresponding enantiomers, ent-5 and ent-6, were also synthesized starting from (S)-epichlorohydrin [(S)-7].
  • Y Yahiro, S Ichikawa, S Shuto, A Matsuda TETRAHEDRON LETTERS 40 (30) 5527 -5531 1999年07月 [査読無し][通常論文]
     
    A stereoselective method for introducing a C2-unit at the 1 alpha- and 1 beta-postions of D-glucose and D-mannose, respectively, via a radical cyclization reaction with vinylsilyl group as a temporary connecting tether, was developed. The radical cyclization of D-glucose substrates was effectively facilitated by a change in the conformation of the pyranose ring into a C-1(4)-form due to steric repulsion between adjacent bulky TBS-protecting groups. (C) 1999 Elsevier Science Ltd. All rights reserved.
  • M Fukuoka, S Shuto, N Minakawa, Y Ueno, A Matsuda TETRAHEDRON LETTERS 40 (29) 5361 -5364 1999年07月 [査読無し][通常論文]
     
    An efficient synthesis of cyclic IDP-carbocyclic-ribose, as a stable mimic for cyclic ADP-ribose, was achieved. N-1-Carbocyclic-ribosylinosine derivative 15, prepared from N-1-(2,4-dinitrophenyl)inosine derivative 10 and an optically active carbocyclic amine 11, was converted to 8-bromo-N-1-carbocyclic-ribosylinosine bis-phosphate derivative 20. Treatment of 20 with I-2 in the presence of molecular sieves in pyridine gave the desired cyclic product 8 quantitatively, which was deprotected and reductively debrominated to give the target cyclic IDP-carbocyclic ribose (3). (C) 1999 Elsevier Science Ltd. All rights reserved.
  • A Ogawa, S Shuto, M Tanaka, T Sasaki, S Mori, S Shigeta, A Matsuda CHEMICAL & PHARMACEUTICAL BULLETIN 47 (7) 1000 -1005 1999年07月 [査読無し][通常論文]
     
    Pyrimidine carbocyclic nucleosides with a hydroxyamino group instead of a hydroxymethyl group at the 4'-position of the sugar moiety were designed as potential antitumor and/or antiviral agents. Pd(O)-catalyzed reactions of enantiomerically pure (+)-(1R,4S)-4-[(tert-butyldiphenylsilyl)oxy]-1-(ethoxycarbonyloxy)-2-cyclopentene (9) with N3-benzoylthymine and -uracil gave carbocyclic nucleosides 10 and 11. Subsequent Pd (O)-catalyzed reactions of N3-benzoyl-1-[(1R,4S)-4-(ethoxycarbonyloxy)-2-cyclopenten-1-yl]thymine (14) and -uracil (15) with O-benzylhydroxylamine smoothly gave the hydroxyamino-substituted carbocyclic nucleosides 16 and 17. From these nucleosides, the target compounds were prepared after deprotection or further reactions. The 2',3'-didehydro-2',3'-dideoxythymidine (D4T) analogue 20 was the most effective compound, with IC50 values of 27.3 and 34.5 mu M against KB and L1210 cells in vitro. Carbocyclic analogues of uridine and cytidine (29 and 32) were less effective than 20 against both cell lines.
  • M Nomura, S Shuto, M Tanaka, T Sasaki, S Mori, S Shigeta, A Matsuda JOURNAL OF MEDICINAL CHEMISTRY 42 (15) 2901 -2908 1999年07月 [査読無し][通常論文]
     
    A series of 4'alpha-C-branched-chain pyrimidine nucleosides was synthesized from 2'-deoxycytidine or uridine. In the 2'-deoxycytidine series, the substituent at the 4'alpha-position affected cytotoxicity against L1210 mouse leukemic cells in vitro in the order Me (23) > CN (22) > C=CH (21) > CH=CH2 (19) > Et (24) > CH=CHCl (20). However, uridine and cytidine derivatives with ethynyl and cyano groups at the 4'alpha-position did not show any cytotoxicity. The antiviral activities of these nucleosides against HSV-1, HSV-2, and. HIV-1 in vitro were also examined. Compounds 22 and 23 showed antiviral activities against HSV-1 and HSV-2 without showing significant toxicity to the host cells (MRC-5 cells). Although almost all of the nucleosides showed anti-HIV-1 activities, they were also cytotoxic to the host cells (MT-4).
  • Y Yahiro, S Ichikawa, S Shuto, A Matsuda TETRAHEDRON LETTERS 40 (30) 5527 -5531 1999年07月 [査読無し][通常論文]
     
    A stereoselective method for introducing a C2-unit at the 1 alpha- and 1 beta-postions of D-glucose and D-mannose, respectively, via a radical cyclization reaction with vinylsilyl group as a temporary connecting tether, was developed. The radical cyclization of D-glucose substrates was effectively facilitated by a change in the conformation of the pyranose ring into a C-1(4)-form due to steric repulsion between adjacent bulky TBS-protecting groups. (C) 1999 Elsevier Science Ltd. All rights reserved.
  • M Fukuoka, S Shuto, N Minakawa, Y Ueno, A Matsuda TETRAHEDRON LETTERS 40 (29) 5361 -5364 1999年07月 [査読無し][通常論文]
     
    An efficient synthesis of cyclic IDP-carbocyclic-ribose, as a stable mimic for cyclic ADP-ribose, was achieved. N-1-Carbocyclic-ribosylinosine derivative 15, prepared from N-1-(2,4-dinitrophenyl)inosine derivative 10 and an optically active carbocyclic amine 11, was converted to 8-bromo-N-1-carbocyclic-ribosylinosine bis-phosphate derivative 20. Treatment of 20 with I-2 in the presence of molecular sieves in pyridine gave the desired cyclic product 8 quantitatively, which was deprotected and reductively debrominated to give the target cyclic IDP-carbocyclic ribose (3). (C) 1999 Elsevier Science Ltd. All rights reserved.
  • A Ogawa, S Shuto, M Tanaka, T Sasaki, S Mori, S Shigeta, A Matsuda CHEMICAL & PHARMACEUTICAL BULLETIN 47 (7) 1000 -1005 1999年07月 [査読無し][通常論文]
     
    Pyrimidine carbocyclic nucleosides with a hydroxyamino group instead of a hydroxymethyl group at the 4'-position of the sugar moiety were designed as potential antitumor and/or antiviral agents. Pd(O)-catalyzed reactions of enantiomerically pure (+)-(1R,4S)-4-[(tert-butyldiphenylsilyl)oxy]-1-(ethoxycarbonyloxy)-2-cyclopentene (9) with N3-benzoylthymine and -uracil gave carbocyclic nucleosides 10 and 11. Subsequent Pd (O)-catalyzed reactions of N3-benzoyl-1-[(1R,4S)-4-(ethoxycarbonyloxy)-2-cyclopenten-1-yl]thymine (14) and -uracil (15) with O-benzylhydroxylamine smoothly gave the hydroxyamino-substituted carbocyclic nucleosides 16 and 17. From these nucleosides, the target compounds were prepared after deprotection or further reactions. The 2',3'-didehydro-2',3'-dideoxythymidine (D4T) analogue 20 was the most effective compound, with IC50 values of 27.3 and 34.5 mu M against KB and L1210 cells in vitro. Carbocyclic analogues of uridine and cytidine (29 and 32) were less effective than 20 against both cell lines.
  • M Nomura, S Shuto, M Tanaka, T Sasaki, S Mori, S Shigeta, A Matsuda JOURNAL OF MEDICINAL CHEMISTRY 42 (15) 2901 -2908 1999年07月 [査読無し][通常論文]
     
    A series of 4'alpha-C-branched-chain pyrimidine nucleosides was synthesized from 2'-deoxycytidine or uridine. In the 2'-deoxycytidine series, the substituent at the 4'alpha-position affected cytotoxicity against L1210 mouse leukemic cells in vitro in the order Me (23) > CN (22) > C=CH (21) > CH=CH2 (19) > Et (24) > CH=CHCl (20). However, uridine and cytidine derivatives with ethynyl and cyano groups at the 4'alpha-position did not show any cytotoxicity. The antiviral activities of these nucleosides against HSV-1, HSV-2, and. HIV-1 in vitro were also examined. Compounds 22 and 23 showed antiviral activities against HSV-1 and HSV-2 without showing significant toxicity to the host cells (MRC-5 cells). Although almost all of the nucleosides showed anti-HIV-1 activities, they were also cytotoxic to the host cells (MT-4).
  • 浅井 知浩, 黒羽子 孝太, 岡田 昌二, 周東 智, 粟野 博一, 松田 彰, 塚田 秀夫, 奥 直人 Drug delivery system 14 (2) 103 -108 1999年03月10日 [査読無し][通常論文]
     
    2'-<I>C</I>-cyano-2'-deoxy-1-<I>β</I>-D-<I>arabino</I>-pentofuranosylcytosine (CNDAC), a novel antitumor nucleoside antimetabolite, has a new mechanism of action for damaging tumor cells. This compound showed potent growth inhibitory activity against various kinds of human tumor cells both <I>in vitro</I> and <I>in vivo</I>. Furthermore, 5'-phosphatidylation of the compound enhanced the antitumor activity. In the present study, we liposomalized 5'-<I>O</I>-dipalmitoylphosphatidyl derivative of CNDAC (DPP-CNDAC) and investigated the effect of DPP-CNDAC incorporation on the <I>in vivo</I> behavior of these liposomes by a non-invasive method using positron emission tomography (PET). Interestingly, liposomes composed of DPP-CNDAC and cholesterol (DPP-CNDAC/CH liposomes) were observed to have a tendency to accumulate in lungs. Furthermore, this accumulation was markedly enhanced in the mice bearing lung metastatic cancer. Therefore, we attempted to use these CNDAC/CH liposomes for lung targeting and to examine the therapeutic efficacy against lung metastatic cancer. In experimental model using highly lung metastatic murine B16BL6 melanoma cells, these liposomes significantly reduced the number of lung tumor colonies as well as the size of them in a dose dependent manner. On the contrary, reduced lung colonization was not seen by use of the formulation of conventional liposomes or soluble CNDAC. These results were coincident with the data of PET analysis, and suggesting the usefulness of DPP-CNDAC/CH liposomes for curing lung metastasis.
  • Sugimoto, I, S Shuto, S Mori, S Shigeta, A Matsuda BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 9 (3) 385 -388 1999年02月 [査読無し][通常論文]
     
    A series of 4'alpha-branched thymidines was synthesized and evaluated as potential antiviral agents. 4'-Ethylthymidine (3), 4'-ethenylthymidine (5), and 4'-ethynylthymidine (6) exhibited potent anti-HSV-l and anti-HIV-1 activities with no significant cytotoxicity. (C) 1999 Elsevier Science Ltd. All rights reserved.
  • T Noguchi, K Ishii, Y Ohtubo, S Shuto, S Ono, A Matsuda, K Yoshii SYNAPSE 31 (2) 87 -96 1999年02月 [査読無し][通常論文]
     
    We investigated the blocking effect of the conformationally restricted analogs of milnacipran on NMDA receptors by recording the whole-cell currents of Xenopus oocytes injected with rat brain mRNA and the single channel currents of cultured hippocampal neurons under voltage-clamp conditions. Their protective effect against excitotoxicity was also investigated on cultured cortex neurons. All conformationally restricted analogs examined blocked activated NMDA receptors, though their structures were quite different from known NMDA receptor blockers. The analogs with a (1S, 2R, 1'S)-configuration such as PPDC ((1S, 2R)-1-phenyl-2[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide)had lower IC50 values than those with other configurations. The empirical Hill coefficients for each compound were close to unity, indicating a 1:1 stoichiometry for the block. PPDC decreased the maximum responses to both N-methyl D-aspartate (NMDA) and glycine without altering their dissociation constants. The blocking effect was enhanced on hyperpolarization. PPDC had no effects on other glutamate receptor subtypes (AMPA, kainate, and metabotropic glutamate receptors) or other neurotransmitter receptors (GABA(A), 5HT(2C), and AC(M1) receptors) produced by the oocytes. PPDC decreased the mean open time of NMDA receptors without decreasing their elementary conductance. The microscopic blocking rate constant was 2.8 X 10(7) M-ls-l. The macroscopic unblocking rate constant of PPDC was much faster than that of MK-801. Only the analogs with the (1S, 2R, 1'S)-configuration protected the cultures against NMDA-induced neurotoxicity, though they failed to protect against kainate-induced neurotoxicity. These results show that conformationally restricted analogs, at least PPDC, selectively blocked open channels of NMDA receptors. Synapse 31:87-96, 1999. (C) 1999 Wiley-Liss, Inc.
  • Sugimoto, I, S Shuto, S Mori, S Shigeta, A Matsuda BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 9 (3) 385 -388 1999年02月 [査読無し][通常論文]
     
    A series of 4'alpha-branched thymidines was synthesized and evaluated as potential antiviral agents. 4'-Ethylthymidine (3), 4'-ethenylthymidine (5), and 4'-ethynylthymidine (6) exhibited potent anti-HSV-l and anti-HIV-1 activities with no significant cytotoxicity. (C) 1999 Elsevier Science Ltd. All rights reserved.
  • T Noguchi, K Ishii, Y Ohtubo, S Shuto, S Ono, A Matsuda, K Yoshii SYNAPSE 31 (2) 87 -96 1999年02月 [査読無し][通常論文]
     
    We investigated the blocking effect of the conformationally restricted analogs of milnacipran on NMDA receptors by recording the whole-cell currents of Xenopus oocytes injected with rat brain mRNA and the single channel currents of cultured hippocampal neurons under voltage-clamp conditions. Their protective effect against excitotoxicity was also investigated on cultured cortex neurons. All conformationally restricted analogs examined blocked activated NMDA receptors, though their structures were quite different from known NMDA receptor blockers. The analogs with a (1S, 2R, 1'S)-configuration such as PPDC ((1S, 2R)-1-phenyl-2[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide)had lower IC50 values than those with other configurations. The empirical Hill coefficients for each compound were close to unity, indicating a 1:1 stoichiometry for the block. PPDC decreased the maximum responses to both N-methyl D-aspartate (NMDA) and glycine without altering their dissociation constants. The blocking effect was enhanced on hyperpolarization. PPDC had no effects on other glutamate receptor subtypes (AMPA, kainate, and metabotropic glutamate receptors) or other neurotransmitter receptors (GABA(A), 5HT(2C), and AC(M1) receptors) produced by the oocytes. PPDC decreased the mean open time of NMDA receptors without decreasing their elementary conductance. The microscopic blocking rate constant was 2.8 X 10(7) M-ls-l. The macroscopic unblocking rate constant of PPDC was much faster than that of MK-801. Only the analogs with the (1S, 2R, 1'S)-configuration protected the cultures against NMDA-induced neurotoxicity, though they failed to protect against kainate-induced neurotoxicity. These results show that conformationally restricted analogs, at least PPDC, selectively blocked open channels of NMDA receptors. Synapse 31:87-96, 1999. (C) 1999 Wiley-Liss, Inc.
  • T Mizutani, H Inagaki, D Hayasaka, S Shuto, N Minakawa, A Matsuda, H Kariwa, Takashima, I ARCHIVES OF VIROLOGY 144 (10) 1937 -1946 1999年 [査読無し][通常論文]
     
    Regulation of viral RNA levels in infected cells is considered important in the investigation of viral transcription and replication. Amounts of Borna disease virus (BDV) RNAs were increased in confluent persistently BDV-infected MDCK cells (MDCK/BDV) cells, while maintained at low levels in growing cells. The amount of 1.9-kb RNA without cap formation and polyadenylation at the 5' and 3' ends respectively were remarkably increased (200% per day) in confluent MDCK/BDV cells. Both the full-length genomic and anti-genomic RNAs were increased accompained by 1.9-kb RNA, suggesting the transcription of the 1.9-kb RNA was important for replication of BDV. Ribavirin has an inhibitory effect on replication and transcription of BDV at concentrations from 1 to 10 mu g/ml [Mizutani T et al., Arch Virol (1998) 143: 2039-2044]. BDV transcripts were decreased with ribavirin treatment and increased after its removal which indicated that ribavirin has a reversible inhibitory effect on BDV transcription. Furthermore, BDV transcription was also decreased by two agents, RMNPA and EICAR, which selectively inhibit enzyme activity related to cap formation at the 5' end of mRNA. On the contrary, when the growing MDCK/BDV cells were treated with actinomycin D, transcripts of BDV RNA were increased for 24 h. These agents and culture conditions in this study were found to be useful tools for up-and down-regulation of BDV transcription in persistently BDV-infected cells.
  • Y Ueno, M Kanazaki, S Shuto, A Matsuda NUCLEOSIDES & NUCLEOTIDES 18 (6-7) 1401 -1402 1999年 [査読無し][通常論文]
     
    To find the nuclease-resistant oligodeoxynucleotides (ODNs) with natural phosphodiester linkages, we designed and synthesized ODNs containing 4'-C-aminoalkylthymidines (1-4). We found that the ODNs containing 1, 2, 3 or 4 were more resistant to nucleolytic hydrolysis by both snake venom phosphodiesterase (a 3'-exonuclease) and DNase I (an endonuclease) than unmodified ODNs.
  • H Abe, M Satoh, S Miyauchi, S Shuto, A Matsuda, N Kamo BIOCONJUGATE CHEMISTRY 10 (1) 24 -31 1999年01月 [査読無し][通常論文]
     
    Dipeptide transporters in small intestine have a very wide substrate specificity, so that the transporter sometimes serves as a carrier for peptide-like compounds. We have synthesized dipeptide analogues conjugated at an E-amino group of Lys in Val-Lys or Lys-Sar with fluorescent compounds such as fluorescein isothiocyanate and coumarin-3-carboxylic acid. Uptakes of these peptide analogues were examined by measuring intracellular accumulations into monolayers of the human intestinal epithelial cell line Caco-2 expressing the dipeptide transporter PEPT1. Kinetic analysis and effects of addition either of uncoupler (protonophore) or by Gly-Sar, one of the good substrates of PEPT1, revealed that fluorescent dipeptides were taken up by passive diffusion. In contrast, these analogues remarkably inhibited the Gly-Sar uptake by Caco-2 cells. Among the fluorescent analogues synthesized in this paper, Vaf-Lys(Flu) was the most potent competitive inhibitor against the Gly-Sar uptake with an inhibition constant of 5 mu M. This value is the smallest among those ever reported: Val-Lys(Flu) has the highest affinity for PEPT1 among chemicals ever reported. The importance of the hydrophobic part of the substrate was pointed out.
  • H Abe, M Satoh, S Miyauchi, S Shuto, A Matsuda, N Kamo BIOCONJUGATE CHEMISTRY 10 (1) 24 -31 1999年01月 [査読無し][通常論文]
     
    Dipeptide transporters in small intestine have a very wide substrate specificity, so that the transporter sometimes serves as a carrier for peptide-like compounds. We have synthesized dipeptide analogues conjugated at an E-amino group of Lys in Val-Lys or Lys-Sar with fluorescent compounds such as fluorescein isothiocyanate and coumarin-3-carboxylic acid. Uptakes of these peptide analogues were examined by measuring intracellular accumulations into monolayers of the human intestinal epithelial cell line Caco-2 expressing the dipeptide transporter PEPT1. Kinetic analysis and effects of addition either of uncoupler (protonophore) or by Gly-Sar, one of the good substrates of PEPT1, revealed that fluorescent dipeptides were taken up by passive diffusion. In contrast, these analogues remarkably inhibited the Gly-Sar uptake by Caco-2 cells. Among the fluorescent analogues synthesized in this paper, Vaf-Lys(Flu) was the most potent competitive inhibitor against the Gly-Sar uptake with an inhibition constant of 5 mu M. This value is the smallest among those ever reported: Val-Lys(Flu) has the highest affinity for PEPT1 among chemicals ever reported. The importance of the hydrophobic part of the substrate was pointed out.
  • S Shuto, K Tatani, Y Ueno, A Matsuda JOURNAL OF ORGANIC CHEMISTRY 63 (24) 8815 -8824 1998年11月 [査読無し][通常論文]
     
    1-O-Tetrahydrofuranyl-alpha-D-glucopyranose derivatives 5-8 were designed and synthesized as novel IP3 receptor ligands. The glycosidation reactions between fluoroglycosyl donor 23 and tetrahydrofuran derivatives 11-14 as glycosyl accepters selectively gave the corresponding alpha-glycosides, which were converted into the target Compounds 5-8 via the introduction of phosphate groups using the phosphoramidite method. Among these compounds, 1-O-tetrahydrofuranyl-alpha-D-glucopyranose trisphosphate derivatives 5 and 8 significantly inhibited the binding of [H-3] IP3 to IP3 receptor from porcine cerebella, with IC50 values of 25 and 27 nM, respectively, which were comparable to the affinity of IP3 itself.
  • S Shuto, M Shirato, Y Sumita, Y Ueno, A Matsuda TETRAHEDRON LETTERS 39 (40) 7341 -7344 1998年10月 [査読無し][通常論文]
     
    Formation of symmetric 36-membered-ring product 14 was observed in the synthetic study of a stable mimic of cyclic ADP-ribose (cADPR, 1), When 8-bromo-N-1-[5-(phenylthiophosphoryl)carbocyclic-ribosyl]inosine 5'-phosphate derivative 5 was treated with AgNO3 and Et3N in N-methyl-2-pyrrolidinone-HMPA (3:1), the substrate was dimerized and cyclized to give 14 in 39% yield, (C) 1998 Elsevier Science Ltd. All rights reserved.
  • 浅井 知浩, 奥 直人, 黒羽子 孝太, 湯山 ゆきの, 岡田 昌二, 周東 智, 粟野 博一, 松田 彰 Drug delivery system 13 (5) 341 -346 1998年09月10日 [査読無し][通常論文]
     
    2'-<I>C</I>-Cyano-2'-deoxy-1-<I>β</I>-D-arabino-pentofuranosylcytosine (CNDAC) has been developed as a novel antitumor nucleoside. 5'-Dipalmitoylphosphatidyl derivative of CNDAC (DPP-CNDAC) also has a significant antitumor activity and is readily incorporated in liposomes. Therefore, to reduce the side effects and to enhance the antitumor activity, we incorporated DPP-CNDAC into reticuloendothelial systems (RES)-avoiding, long circulating, liposomes modified with palmityl-D-glucuronide (PGlcUA), which tend to accumulate passively in tumor tissues. When liposomal DPP-CNDAC modified with PGlcUA was injected intravenously into Meth A sarcoma-bearing mice, it showed higher antitumor activities and increased more the life span of mice, compared to those obtained by injection of DPP-CNDAC only or by liposomal DPP-CNDAC without PGlcUA. Thus, the incorporation of DPP-CNDAC into liposoma membrane modified with PGlcUA may be useful as a formulation of this anticancer agent.
  • S Shuto, S Ono, H Imoto, K Yoshii, A Matsuda JOURNAL OF MEDICINAL CHEMISTRY 41 (18) 3507 -3514 1998年08月 [査読無し][通常論文]
     
    Conformationally restricted analogues of (+/-)-(Z)-2-aminomethyl-1-phenyl-N, N-diethylcyclopropanecarboxamide [milnacipran, (+/-)-1] were designed on the basis of its characteristic cyclopropane structure and were synthesized enantioselectively to develop efficient NMDA receptor antagonists. Among these analogues, (1S,2R)-1-phenyl-2-[(R)-1-amino-2-propynyl]- N,N-diethylcyclopropanecarboxamide (2d) had one of the most potent affinities for the receptor, with a K-i value of 0.29 mu M. The blockade of NMDA receptor channels expressed by Xenopus oocytes by 2d was investigated in detail, and 2d was identified as a new class of open channel blocker against this receptor.
  • A Ogawa, S Shuto, O Inanami, M Kuwabara, M Tanaka, T Sasaki, A Matsuda BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 8 (14) 1913 -1918 1998年07月 [査読無し][通常論文]
     
    The design and synthesis of potential antitumor antimetabolites 2'-deoxy-2'-hydroxylaminouridine (2'-DHAU) and -cytidine (2'-DHAC) are described. We found that 2'-DHAC in neutral solution generated 2'-aminoxy radicals at room temperature. 2'-DHAC inhibited the growth of L1210 and KB cells, with IC50 values of 1.58 and 1.99 mu M, respectively, more potently than 2'-DHAU, with IC50 values of 34.5 and 27.3 mu M, respectively. 2'-DHAC was effective against 9 human cell lines, with IC50 values in the micromolar range. The in vivo antitumor activity of 2'-DHAC was also examined using the mouse leukemia P388 model, which gave a T/C value of 167%. Phosphorylation of 2'-DHAC by uridine/cytidine kinase was essential for its cytotoxicity, as suggested by a competition experiment using several common nucleosides. Inhibition of DNA synthesis was the predominant mechanism of action of 2'-DHAC, although it has a ribo-configuration. (C) 1998 Elsevier Science Ltd. All rights reserved.
  • H Hattori, E Nozawa, T Iino, Y Yoshimura, S Shuto, Y Shimamoto, M Nomura, M Fukushima, M Tanaka, T Sasaki, A Matsuda JOURNAL OF MEDICINAL CHEMISTRY 41 (15) 2892 -2902 1998年07月 [査読無し][通常論文]
     
    We previously designed 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)uracil (EUrd) and its cytosine congener (ECyd) as potential multifunctional antitumor nucleoside antimetabolites. They showed potent and broad-spectrum antitumor activity against various human and mouse tumor cells in vitro and in vivo. To clarify the structure-activity relationship of the sugar moiety, various 3'-C-carbon-substituted analogues, such as 1-propynyl, 1-butynyl, ethenyl, ethyl, and cyclopropyl derivatives, of ECyd and EUrd were synthesized. We also prepared 3'-deoxy analogues and 3'-homologues of ECyd and EUrd with different configurations to determine the role of the 3'-hydroxyl group and the length between the S'-carbon atom and the ethynyl group and a 2'-ethynyl derivative of ECyd to determine the spatial requirements of the ethynyl group. The in vitro tumor cell growth inhibitory activities of these nucleosides against mouse leukemic L1210 and human KB cells showed that ECyd and EUrd were the most potent inhibitors in the series, with IC50 values of 0.016 and 0.13 mu M for L1210 cells and 0.028 and 0.029 mu M for KB cells, respectively. Only 3'-C-1-propynyl and -ethenyl derivatives of ECyd showed greatly reduced cytotoxicity. We found that the cytotoxic activity of these nucleosides predominantly depended on their first phosphorylation by uridine/cytidine kinase.
  • K Tatani, S Shuto, Y Ueno, A Matsuda TETRAHEDRON LETTERS 39 (28) 5065 -5068 1998年07月 [査読無し][通常論文]
     
    1-O-[(3S,4R)-3-Hydroxytetrahydrofuran-4-yl]-alpha-D-glucopyranoside 3,4,3'-trisphosphate (5) was designed and synthesized as a novel IP3 receptor ligand. This compound bound strongly to IP3 receptor from porcine cerebella with an affinity comparable to that of IP3. (C) 1998 Elsevier Science Ltd. All rights reserved.
  • T Asai, K Kurohane, S Shuto, H Awano, A Matsuda, H Tsukada, Y Namba, S Okada, N Oku BIOLOGICAL & PHARMACEUTICAL BULLETIN 21 (7) 766 -771 1998年07月 [査読無し][通常論文]
     
    We previously synthesized the 5'-O-diacylphosphatidyl derivative of 2'-C-cyano-2'-deoxy-1-beta-D-arabinopentofuranosylcytosine (CNDAC), a novel antitumor nucleoside, and observed it to have a high antitumor activity. Since this compound is readily incorporated into liposomal membranes, we liposomalized the compound using a formulation for conventional and long-circulating liposomes, and investigated the antitumor activity of liposomal 5'-O-dipalmitoylphosphatidyl CNDAC (DPP-CNDAC), Long-circulating liposomes composed of DPP-CNDAC, dipalmitoylphosphatidylcholine, cholesterol and palmityl-D-glucuronide (PGlcUA) (2:2:2:1 as a molar ratio), as well as liposomes containing dipalmitoylphosphatidylglycerol (DPPG) instead of palmityl-D-glucuronide and those composed of only DPP-CNDAC, were injected intravenously into Meth A sarcoma-bearing mice. DPP-CNDAC showed suppression of tumor growth, whereas CNDAC did not at the same concentration, suggesting that 5'-phosphatidylation is useful to enhance therapeutic efficacy. Furthermore, liposomal DPP-CNDAC reduced the acute toxicity, and liposomes containing PGlcUA showed more enhanced activities of reducing tumor growth and increasing the lifetime of the mice than liposomes containing DPPG, To obtain a higher therapeutic efficacy, we injected long-circulating liposomal DPP-CNDAC 5 times. The tumor growth was suppressed to 13.2% (86.8% inhibition), and the survival time of the tumor-bearing mice increased to 128.5% with one completely cured mouse out of five. Next, the effect of DPP-CNDAC incorporation on the in vivo behavior of PGlcUA and DPPG liposomes was examined by a non-invasive method using positron emission tomography (PET), Liposomes were labeled with [2-F-18]-2-fluoro-2-deoxy-D-glucose, and administered to tumor-bearing mice. PET images and time-activity curves indicated that DPP-CNDAC/PGlcUA-liposomes tended to accumulate in tumor tissues a little bit more than DPP-CNDAC/DPPG-liposomes, although the difference between the two kinds of liposomal distribution was not as marked as between PGlcUA and DPPG liposomes, suggesting that DPP-CNDAC incorporation partly affected the liposomal behavior in vivo but that the long-circulating character of PGlcUA-liposomes might not be fully abolished. Thus, the enhanced therapeutic efficacy of long circulating liposomalized DPP-CNDAC observed here may be due to passive targeting of DPP-CNDAC to the tumor tissue, making this formulation of DPP-CNDAC useful for cancer chemotherapy.
  • S Shuto, S Niizuma, A Matsuda JOURNAL OF ORGANIC CHEMISTRY 63 (13) 4489 -4493 1998年06月 [査読無し][通常論文]
     
    One-pot conversiojn of α, β-unsaturated alcohols into the corresponding carbon-elongated dienes with a stable phosphorus ylide-BaMnO<sub>4</sub>. Synthesis of 6'-methylene derivatives of neplanocin A as potential antiviral nucleosides. New neplanocin analogues. 11.
  • S Ichikawa, S Shuto, A Matsuda TETRAHEDRON LETTERS 39 (25) 4525 -4528 1998年06月 [査読無し][通常論文]
     
    A novel aldol-type C-glycosidation reaction promoted by samarium diiodide (Sml(2)) was developed. Treatment of phenyl 3,4,6-tri-o-benzyl-1-thio-beta-D-arabino-hexopyranosid-2-ulose (6) with SmI2 in THF regioselectively gave the corresponding 1-enolate, which was readily trapped with ketones or aldehydes to afford various C-glycosides in high yields. (C) 1998 Elsevier Science Ltd. All rights reserved.
  • S Shuto, M Shirato, Y Sumita, Y Ueno, A Matsuda JOURNAL OF ORGANIC CHEMISTRY 63 (6) 1986 -1994 1998年03月 [査読無し][通常論文]
     
    Cyclic ADP-ribose (cADPR, 1) is a general mediator involved in cellular Ca2+ signaling. However, both the biological and chemical instability of cADPR limit studies on its physiological role. We designed cyclic ADP-carbocyclic-ribose (3) and its inosine congener 4 as stable mimics of cADPR and successfully synthesized 4. Starting with cyclopentadiene, the optically active carbocyclic unit 8 was constructed via enzymatic optical resolution. S(N)2 reactions of 8 with inosine derivative 7 and the 8-bromoinosine derivative 25 gave the N-1-substituted derivatives 6 and 26, which were converted to the corresponding diphosphate derivatives 5 and 22. The intramolecular condensation reactions between the two phosphate groups of 5 and 22 were investigated, Although the reaction with inosine derivative 5 did not produce any of the cyclization product 20, treatment of the corresponding 8-bromoinosine derivative 22 with EDC gave the desired intramolecular condensation product 29 in 23% yield. Thus, the significant effect of the 8-bromo group at the hypoxanthine moiety in facilitating the key intramolecular condensation reaction between the phosphate groups of the substrate 22 was recognized. This is possibly due to conformational restriction of the molecule in a syn-form around its glycosyl linkage. The 8-bromo and isopropylidene groups were removed in succession to give the target compound 4. This is the first total synthesis of this type of cyclic nucleotide.
  • Y Ueno, Y Nagasawa, Sugimoto, I, N Kojima, M Kanazaki, S Shuto, A Matsuda JOURNAL OF ORGANIC CHEMISTRY 63 (5) 1660 -1667 1998年03月 [査読無し][通常論文]
     
    The synthesis and properties of oligodeoxynucleotides (ODNs) containing 4'-C-[2-[IN-(2-aminoethyl)carbamoyl]oxy]ethyl]thymidine (3) are described. 4'alpha-(2-Hydroxyethyl)thymidine (4), which is a precursor for phosphoramidite 5, was synthesized using a newly developed intramolecular radical cyclization reaction at the 4'-position of thymidine derivative 7. The radical reaction of 4'beta-(phenylseleno)-3'-O- (dimethylvinylsilyl)thymidine derivative 7, which was prepared from thymidine in several steps, with Bu3SnH and AIBN, followed by Tamao oxidation, gave either 4'alpha-(2-hydroxyethyl) derivative 6 or 4'alpha-(1-hydroxyethyl) derivative 13, respectively. With a low Bu-3-SnH concentration, the reaction gave 6, via. 6-endo-radical-cyclized product 11, as a sole product in 87% yield. The reaction of 7 in the presence of excess Bu3SnH gave 13 in 75% yield, via 5-exo-cyclized product 12, as a diastereomeric mixture. The 4'alpha-(2-hydroxyethyl) derivative 6 was then converted into a 4'-C-[2-[IN-(2-aminoethyl)carbamoyl]oxy]ethyl]thymidine derivative 14, which was phosphitylated to give phosphoramidite 5 in 72% yield. In this study, 3 was incorporated into a nonadecamer, d[CTGGCTCAGCTCGTCTCAT]-3', and a heptadecamer, d[CTCGTACCATTCCGCTC]-3', instead of T at various positions. ODNs containing 3 were more resistant to nucleolytic hydrolysis by both snake venom phosphodiesterase (a 3'-exonuclease) and DNase I (an endonuclease) than unmodified parent ODNs, although ODNs containing 3 only slightly destabilized duplex formation with both complementary DNA and RNA strands. Furthermore, the duplex formed by an ODN containing 3 and its complementary RNA was a good substrate for Escherichia coli RNase H.
  • S Shuto, M Kanazaki, S Ichikawa, N Minakawa, A Matsuda JOURNAL OF ORGANIC CHEMISTRY 63 (3) 746 -754 1998年02月 [査読無し][通常論文]
     
    An efficient method for the synthesis of 4'alpha-branched 2'-deoxyadenosines starting from 2'-deoxyadenosine has been developed utilizing a novel radical cyclization reaction with a silicon tether. The radical reaction of 4'beta-phenylseleno)-3'-O-diphenylvinylsilyl adeninenucleoside derivative 17 with Bu3SnH and AIBN, followed by Tamao oxidation, gave selectively either the 4'alpha-(2-hydroxyethyl) derivative 21 or 4'alpha-(1-hydroxyethyl) derivative 19, depending on the reaction conditions. With a lower Bu3SnH concentration, the reaction gave the 4'alpha-(2-hydroxyethyl) derivative 21, via a 6-endo-radical cyclized product 20, as the sole product in 72% yield. The reaction of 17 in the presence of excess Bu3SnH gave 19 quantitatively, via a 5-exo-cyclized product 18, as a diastereomeric mixture. The reaction mechanism was examined using Bu3SnD. The results demonstrated that the 5-exo cyclized (3-oxa-2-silacyclopentyl)methyl radical (C) was formed initially which was trapped when the concentration of Bu3SnH(D) was high enough. With lower concentrations of Bu3SnH(D), radical C rearranged into the ring-enlarged 4-oxa-3-silacyclohexyl radical (D) which was then trapped with Bu3SnH(D) to give endo-cyclized product F.
  • D Daelemans, AM Vandamme, S Shuto, A Matsuda, E De Clercq NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS 17 (1-3) 479 -486 1998年01月 [査読無し][通常論文]
     
    The R-and S-isomers of 6'-C-neplanocin A analogues, which are all known as inhibitors of S-adenosylhomocysteine (AdoHcy) hydrolase, were studied for their inhibitory effects on Human Immunodeficiency Virus type 1 (HIV-1) replication and HIV-1 Tat-mediated transactivation. The R-isomers showed much greater activity against AdoHcy hydrolase than the S-isomers. The same differential activity was observed against the HIV-1 replication and the Tat transactivation.
  • N Niitsu, Y YamamotoYamaguchi, Y Kanatani, S Shuto, A Matsuda, M Umeda, Y Honma EXPERIMENTAL HEMATOLOGY 25 (12) 1296 -1303 1997年11月 [査読無し][通常論文]
     
    Several neplanocin A analogs were synthesized and their growth-inhibiting and differentiation-inducing activities on myelogenous leukemia cells were examined. An adenosine kinase-ineffective analog of neplanocin A was effective in inducing differentiation, suggesting that phosphorylation of the nucleoside is not essential for inducing the differentiation of leukemia cells. Neplanocin A induced functional and morphological differentiation of HL-60 cells, but did not effectively induce differentiation of NB4, a cell line derived from a leukemia patient with t(15;17). However, these cells have been known to undergo granulocytic differentiation upon treatment with all-trans retinoic acid (ATRA), and are used as a model for differentiation therapy in acute promyelocytic leukemia. Preexposure of NB4 cells to low concentrations of neplanocin A greatly enhanced the ATRA-induced differentiation of the cells, whereas representative antileukemic drugs such as cytosine arabinoside and daunomycin did not enhance this differentiation. A clinical strategy that combines intermittent treatment with neplanocin A analogs and a low dose of ATRA may increase the clinical response and decrease the adverse effects of ATRA.
  • K Kato, H Hayakawa, H Tanaka, H Kumamoto, S Shindoh, S Shuto, T Miyasaka JOURNAL OF ORGANIC CHEMISTRY 62 (20) 6833 -6841 1997年10月 [査読無し][通常論文]
     
    In spite of exclusive lithiation at the 8-position of 9-(2,3,5-tris-O-TBDMS-beta-D-ribofuranosyl)-6-chloropurine (2) with LDA, subsequent quenching of its lithiated species with Bu3SnCl (or TMSCl) results in the formation of 2-substituted products. Under optimized reaction conditions, where LTMP was us ed as a lithiating agent, 9-(2,3,5-tris-O-TBDMS-beta-D-ribofuranosyl)-6-chloro-2-(tributylstannyl)purine (11) was formed in quantitative yield. Several experiments carried out to verify the reaction mechanism suggested that an anionic stannyl (or silyl) transfer from the 8- to the 2-position had been involved. Manipulation of the 2-tributylstannyl group in 11 and in its adenine counterpart (22) has disclosed a new entry to 2-substituted purine nucleosides. This chemistry was briefly applied to the synthesis of the 2-fluoro analogue of neplanocin A.
  • S Niizuma, S Shuto, A Matsuda TETRAHEDRON 53 (40) 13621 -13632 1997年10月 [査読無し][通常論文]
     
    Synthesis of neplanocin A, a potent antiviral carbocyclic nucleoside, from adenosine was achieved. An acyclic adeninenucleoside 21, prepared from adenosine, was converted to 4'-keto acyclic derivative 27. When 27 was treated with lithiotrimethylsilyldiazomethane in THF, a C-H insertion reaction at the 1'-position proceeded to give 6'-O-TBS-2',3'-O-isopropyrideneneplanocin A (29) along with its 1'-epimer 30. (C) 1997 Elsevier Science Ltd.
  • 周東 智, 松田 彰 有機合成化学協会誌 55 (10) 868 -876 1997年10月01日 [査読無し][通常論文]
     
    Adjacent substituents on a cyclopropane ring mutually exert steric repulsion quite significantly, because they are fixed in eclipsed conformation to each other. Based on this structural feature of the cyclopropane ring, we devised a new method for restricting the conformation of cyclopropane derivatives. Using this strategy, conformationally restricted analogs of milnacipran, a useful antidepressant, were designed as potent NMDA receptor antagonists, and were synthesized highly enantioselectively from chiral epichlorohydrins. Throughout the synthetic study, we found that nucleophilic addition reactions on cyclopropylcarbaldehyde and -ketones proceeded highly stereoselectively <I>via</I> either the bisected <I>s-trans</I> or <I>s-cis</I> conformation of the cyclopropylcarbonyl derivatives. The structures of the conformationally restricted analogs detected by the X-ray crystallographic analysis suggested that their conformations can be restricted as we hypothesized.<BR>Some of the synthesized analogs were significantly effective compared with milnacipran as an NMDA receptor antagonists.
  • S Shuto, M Kanazaki, S Ichikawa, A Matsuda JOURNAL OF ORGANIC CHEMISTRY 62 (17) 5676 -5677 1997年08月 [査読無し][通常論文]
     
    A novel ring-enlargement reaction of(3-oxa-2-silacyclopentyl)methyl radicals into 4-oxa-3-silacyclohexyl radicals. Stereoselective introduction of a hydroxyethyl group via unusual 6-endo-cyclization products derived from 3-oxa-4-silahexenyl radicals, and its application to the synthesis of a 4'α-branched nucleoside.
  • S Shuto, M Kanazaki, S Ichikawa, A Matsuda JOURNAL OF ORGANIC CHEMISTRY 62 (17) 5676 -5677 1997年08月 [査読無し][通常論文]
     
    A novel ring-enlargement reaction of(3-oxa-2-silacyclopentyl)methyl radicals int 4-oxa-3-silacyclohexyl radicals. Stereoselective introduction of a hydroxyethyl group via unusual 6-endo-cyclization products derived from 3-oxa-4silahexenyl radicals, and its application to the synthesis of a 4'α-brancehd nucleoside.
  • 市川 聡, 周東 智, 松田 彰 天然有機化合物討論会講演要旨集 (39) 373 -378 1997年07月20日 [査読無し][通常論文]
     
    Herbicidins are efficient inhibitors of Xanthomonas oryzae, a bacterium which causes rice infection disease. Their structures are consist of adenine and unique furanopyranopyrane, undecose, having the intramolecular hemiacetal linkage. Our synthetic strategy is that herbicidine B (1b) is synthesized from a 2-urose unit and 5'-formyl derivative of adenosine, and the two units will be coupled by aldol-type C-glycosylation induced by SmI_2. First, we developed an efficient SmI_2-induce aldol-type C-glycosylasion reaction with 1-SPh-2-urose derivatives as donors: treatment of 1-SPh-2-urose derivative 11 with SmI_2 in THF at -78℃ gave corresponding 1-enolate which effectively reacted with cyclohexanone to afford a C-glycosides 12 in high yield (α/β=79/21). This method effectively produced 1-enolates of urose derivatives under very mild conditions. We, next, applied the C-glycosylation reaction to the synthesis of Herbicidin B. 1-SPh-2-urose 4 and aldehyde 5 were prepared from D-glucose and adenosine, respectively (Scheme 2, 3). Treatment of 4 with SmI_2 in THF at -78℃ followed by addition of aldehyde 5 gave the desired undecose nucleoside 23, the key intermediate, in 75% yield. It was shown that SmI_2-induced Aldol-type C-glycosidation was effective to the synthetic study toward Herbicidin B. The conversion of the undecose nucleoside 23 into Herbicidin B is currently under progress.
  • S Shuto, T Obara, Y Saito, K Yamashita, M Tanaka, T Sasaki, G Andrei, R Snoeck, J Neyts, E Padalko, J Balzarini, E DeClercq, A Matsuda CHEMICAL & PHARMACEUTICAL BULLETIN 45 (7) 1163 -1168 1997年07月 [査読無し][通常論文]
     
    This report describes the synthesis and antiviral effects of (6'R)-6'-C-ethnyl, -ethenyl, and -ethyl derivatives of neplanocin A (7a, 8a, and 9a, respectively) and the corresponding 6'S-diastereomers (7b, 8b, and 9b, respectively), as examples of 6'-C-substituted analogues of neplanocin A. Grignard reaction of the 6'-formyl derivative 4, which was readily prepared from neplanocin A, with ethynylmagnesium bromide gave a diastereomeric mixture of the corresponding 1,2-addition products 5a and 5b. After removal of the protecting groups, (6'R)- and (6'S)-6'-C-ethynylneplanocin A's (7a, 7b) were separated. The corresponding ethenyl derivatives 8a and 8b and ethyl derivatives 9a and 9b were prepared by catalytic hydrogenation of 7a and 7b, respectively. As compared to neplanocin A, the new neplanocin A derivatives were much weaker inhibitors of S-adenosyl-L-homocysteine hydrolase, the R-diastereomers being more inhibitory than the S-diastereomers. The decreasing order of activity was 7a>8a>7b>9a>8b>9b. The cytotoxicity (for CEM cells) followed exactly the same order. Of these compounds, (6'R)-6'-C-ethynylneplanocin A (7a, RENPA) showed an antiviral activity spectrum that was comparable to, and an antiviral specificity that was higher than, that of neplanocin A. RENPA was particularly active against those viruses (i.e. vaccinia virus, vesicular stomatitis virus) that are known to be highly sensitive to AdoHcy hydrolase inhibitors.
  • S Shuto, A Matsuda JOURNAL OF SYNTHETIC ORGANIC CHEMISTRY JAPAN 55 (3) 207 -216 1997年03月 [査読無し][通常論文]
     
    We found that phospholipase D from Streptomyces sp.(PLDP) effectively catalyzed transphosphatidylation, i.e., the regiospecific transfer of the phosphatidyl residue from phosphatidylcholines to alkanols. The scope of this enzymatic reaction was investigated in detail to develop an efficient method for preparing various phospholipid derivatives. Using this enzymatic method, 5'-O-phosphatidyl derivatives of antitumor nucleosides were successfully synthesized to identify potent antitumor drugs. 5'-O-Phosphatidyl derivatives of DMDC (2'-deoxy-2'-methylenecytidine) and CNDAC [1-(2-C -cyano-2-deoxy-beta-D-arabino-pentofuranosyl)cytosine], antitumor nucleosides developed by us, showed significant antitumor effects in mice which clearly surpassed those of parent compounds. We have also demonstrated that 5'-O-phosphatidylnucleosides can be used as a drug delivery system for lymph: 5'-O-phosphatidyl-5-fluorouridine given orally is absorbed via the deacylation-reacylation cycle, a specific pathway for natural phospholipids, to be transported selectively to the lymph.
  • S Ichikawa, S Shuto, N Minakawa, A Matsuda JOURNAL OF ORGANIC CHEMISTRY 62 (5) 1368 -1375 1997年03月 [査読無し][通常論文]
     
    A novel efficient method for the synthesis of 3'-beta-branched uridines starting from uridine was developed, in which a SmI2-promoted intramolecular Reformatsky-type reaction was effectively used. 5'-O-(Bromoacetyl)-3'-ketouridine derivatives 12, 26, and 27 were synthesized from uridine and were subjected to an intramolecular Reformatsky-type reaction. When 12, 26, and 27 were treated with 2.0 equiv of SmI2 in THF at -78 degrees C, intramolecular carbon-carbon bond formation at the 3'-beta-position proceeded smoothly to give the corresponding 3',5'-lactones 14, 28, and 29 in high yields, respectively. Treatment of 28 with NH3/MeOH gave the 3'-beta-branched uridine derivative 32 quantitatively, which was then deprotected to give 3'-C-(carbamoylmethyl)uridine (33).
  • AEA Hassan, S Shuto, A Matsuda JOURNAL OF ORGANIC CHEMISTRY 62 (1) 11 -17 1997年01月 [査読無し][通常論文]
     
    The Wittig reaction of 1-[3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-beta-D-erythro-pentofuranos-2-ulosyl]uracil (4) with Ph(3)P=CHCO(2)R (R = ethyl or tert-butyl) exclusively gave (Z)-2'-[(alkoxycarbonyl)methylene] derivatives 5 and 13, respectively, in high yields. An unusual beta-facial selectivity of thiophenol addition to the 2'-[(alkoxycarbonyl)methylene] moiety of 5 and 13 was observed, and this facial selectivity was found to be influenced by both the thiolate counter cation and the bulkiness of the alkoxy moiety. Treatment of 2'-[(ethoxycarbonyl)methylene] derivative 5 with LiSPh (1.5 equiv) in the presence of PhSH in THF selectively gave 2'beta-(phenylthio) derivative 11 in high yield along with a trace of 2'alpha-(phenylthio) derivative 10. On the other hand, when 2'-[(tert-butoxycarbonyl)methylene] derivative 13 was treated with KSPh in the presence of PhSH in dioxane/DMF, the facial selectivity was reversed to selectively give the 2'alpha-(phenylthio) adduct 14 (alpha:beta, 77:23) in 90% yield. Oxidation of 14 with m-chloroperbenzoic acid in CH2Cl2 and subsequent pyrolysis of the resulting sulfoxides exclusively gave the (Z)-isomer 13 in 92% yield. The oxidative syn-elimination of the (2'R)-2'-[(tert-butoxycarbonyl)methyl]-2'-deoxy-2'-thiophenoxy-5'-(triiso-propylsilyl)uridine (17), which was obtained from 14 in two steps, exclusively gave the desired (E)-[(tert-butoxycarbonyl)methylene] derivatives 18 in 90% yield. Deprotection of 18 gave the (E)-(carboxymethylene)-2'-deoxyuridine (3). The (Z)-(carboxymethylene)-2'-deoxyuridine (2) was synthesized from 13 in a similar manner.
  • S Shuto, T Obara, S Yaginuma, A Matsuda CHEMICAL & PHARMACEUTICAL BULLETIN 45 (1) 138 -142 1997年01月 [査読無し][通常論文]
     
    We previously synthesized (6'R)- and (6'S)-6'-C-methylneplanocin A's (2a and 2b, respectively), and found that one of them has a potent antiviral activity, though its 6'-configuration has not been confirmed, This report describes the determination of the 6'-configuration and practical preparation of the antivirally active diastereomer. The 6'-configuration of the active diastereomer was determined as R by the modified Mosher's method as well as by synthesizing 2b from the known cyclopentenone derivative 10, A practical method for preparing the 6'R-diastereomer was developed by using diastereoselective deamination with Ado deaminase as the key step, Treatment of the diastereomeric mixture of 2a and 2b, which was prepared via an addition reaction of Me(3)Al with the 6'-formyl derivative 3, with Ado deaminase from calf intestine, deaminated 2b selectively to give the corresponding (6'S)-inosine congener 5, and left the desired 2a not deaminated, After silica gel column chromatography, 2a was obtained in a pure form.
  • S Shuto, S Ono, Y Hase, Y Ueno, T Noguchi, K Yoshii, A Matsuda JOURNAL OF MEDICINAL CHEMISTRY 39 (24) 4844 -4852 1996年11月 [査読無し][通常論文]
     
    We recently demonstrated that (+/-)-(Z)-2-(aminomethyl)-1-phenyl-N,N-diethylcyclopropanecar-boxamide [milnacipran, (+/-)-1], an inhibitor of the reuptake of serotonin (5-HT), was a noncompetitive NMDA receptor antagonist. On the basis of the cyclopropane structure of (+/-)-1, conformationally restricted analogs with different stereochemistries, namely 1-phenyl-2-(1-aminoalkyl)-N,N-diethylcyclopropanecarboxamindes (2, 3, ent-2, and ent-3), were designed and synthesized. Among these analogs, 2a, 2b, and 2f, with (1S,2R,1'S)-configuration, were more efficient than milnacipran as NMDA receptor antagonists; these compounds significantly inhibited the binding of [H-3]MK-801 at IC50 = 0.35 +/- 0.08, 0.20 +/- 0.024, and 0.16 +/- 0.02 mu M, respectively, and blocked the response of voltage-clamped oocytes to NMDA, surpassing the effects of(+/-)-1. Although both the 1'-methyl analog 2a and the 1'-vinyl analog 2f, like (+/-)-1, strongly inhibited 5-HT uptake in vitro, the corresponding 1'-ethyl analog 2b was devoid of the inhibitory effect on 5-HT uptake, while it was about 30 times more potent as an NMDA receptor antagonist than (+/-)-1.
  • AEA Hassan, N Nishizono, N Minakawa, S Shuto, A Matsuda JOURNAL OF ORGANIC CHEMISTRY 61 (18) 6261 -6267 1996年09月 [査読無し][通常論文]
     
    The Wittig reaction of 1-[3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-beta-D-erythro-pentofuranos-2-ulosyl]uracil (6) with Ph(3)P=CHCN afforded (Z)-2'-cyanomethylene derivative 7 exclusively. The (E)-isomer was accessed from its (Z)-isomer through a sequence of addition of thiophenol to the 2'-cyanomethylene moiety of the (Z)-isomer from the alpha-face, selectively, and stereoselective oxidative syn-elimination of the resulting adduct. The diastereofacial selectivity of the benzenethiolate addition to the cyanomethylene moiety was found to be influenced by participation of the 2-carbonyl group at the base moiety and steric hindrance of the sugar protecting groups. Although nucleophilic addition reactions at the 2'-position of 6 have been well-known to occur from the alpha-face selectively, treatment of 7 with LiSPh in THF unexpectedly afforded a mixture of alpha- and beta-phenylthio derivatives 8 and 9 in almost equal ratio. Furthermore, an unusual beta-facial selective addition was observed on treatments of 7 with PhSAlMe(2) in CH2Cl2 or wit LiSPh in the presence of Mg(ClO4)(2) in THF. On the other hand, when (Z)-2'-(cyanomethylene)-5'-O-triisopropylsilyl derivative 10 was treated with LiSPh, the alpha-phenylthio derivative 13 was obtained predominantly (89:11). Oxidation of 8 with m-chloroperbenzoic acid (m-CPBA) in CH2Cl2 and pyrolysis of the resulting sulfoxides afforded the (Z)-isomer 7 exclusively. Treatment of 13 with m-CPBA under the same conditions afforded the desired (E)-cyanomethylene derivatives 18 as a major product (E:Z = 14:1) in good yield. Deprotection of 18 by the standard procedures furnished (E)-2'-(cyanomethylene)-2'-deoxyuridine (5).
  • S Shuto, H Awano, A Fujii, K Yamagami, A Matsuda BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 6 (18) 2177 -2182 1996年09月 [査読無し][通常論文]
     
    2'-Deoxy-2'-methylenecytidine (DMDC, 1) and its 5-fluoro congener (5-F-DMDC, 2), potent antitumor nucleosides developed by us, were efficiently converted to their 5'-phosphatidyl derivatives bearing palmitoyl residues (3 and 4, respectively) as novel antitumor phospholipids by phospholipase D-catalyzed trans-phosphatidylation. These phospholipids 3 and 4, administered i.p., remarkably prolonged the life-span of mice which were i.p.-inoculated with M5076 sarcoma, and the effects were clearly superior to that of DMDC. Compound 3 was a good substrate for phospholipase A(2) from bovine pancreas as well as phospholipase D from Streptomyces, while it was slightly hydrolyzed by phospholipase C from Bacillus cereus. Copyright (C) 1996 Elsevier Science Ltd
  • T Obara, S Shuto, Y Saito, R Snoeck, G Andrei, J Balzarini, E DeClercq, A Matsuda JOURNAL OF MEDICINAL CHEMISTRY 39 (19) 3847 -3852 1996年09月 [査読無し][通常論文]
     
    The syntheses and the antiviral activities of 2-halo derivatives of neplanocin A (1b,c), (6'R)-6'-C-methylneplanocin A (2b), and dehydroxymethylneplanocin A (3b,c) are described. S(N)2 reaction of the known cyclopentenyl units 12 and 13 with 2-haloadenines under basic conditions gave the protected carbocyclic nucleosides 14b,c and 15b,c, respectively. Starting from the cyclopentenone derivative 5, the optically active tosyloxycyclopentene derivative 11 was prepared, which was similarly condensed with 2-fluoroadenine to give the protected (6'R)-6'-C-methyl derivative 16b. Deprotection of these compounds afforded the target 2-halo derivatives of neplanocin A. Of these new compounds, 2-fluoroneplanocin A (1b) showed an antiviral potency and a spectrum that was comparable to that of neplanocin A (1a). It was particularly active against vaccinia virus, vesicular stomatitis virus, parainfluenza virus, reovirus, arenaviruses (Junin, Tacaribe), and human cytomegalovirus, i.e., those viruses that fall within the purview of the S-adenosyl-L-homocysteine hydrolase inhibitors.
  • T Kira, H Awano, S Shuto, A Matsuda, M Baba, K Konno, S Shigeta ANTIVIRAL CHEMISTRY & CHEMOTHERAPY 7 (4) 209 -212 1996年07月 [査読無し][通常論文]
     
    In this study, the anti-herpetic activities of novel 2'-methyl nucleoside analogues which were substituted at the 5 position of the pyrimidine with a halogen were investigated. The 2'-fluoro-5-iodo-aracytosine (FIAC) congeners (2'S)-2'-deoxy-2'-C-methylcytidine which were substituted with Br or I at the 5 position (SMBC or SMIC); and 2'-fluoro-5-iodo-arauridine (FIAU) congeners (2'S)-2'-deoxy-2'-C-methyluridine which were substituted with Sr or I at the 5 position (SMBU or SMIU), proved to have potent antiviral activities against herpes simplex virus type-1 (HSV-1) and varicella-zoster virus (VZV) but not against herpes simplex virus type -2 (HSV-2). SMIU has a higher selective index against HSV-1 than FIAU, and both SMIC and SMIU showed higher inhibitory effects against VZV replication than aciclovir. The four effective compounds were not inhibitory to a thymidine kinase (TK)-negative HSV-1 strain, and this result indicates that phosphorylation of the compounds by HSV or VZV -TK is necessary for the activation of these compounds.
  • S Shuto, T Obara, Y Saito, G Andrei, R Snoeck, E DeClercq, A Matsuda JOURNAL OF MEDICINAL CHEMISTRY 39 (12) 2392 -2399 1996年06月 [査読無し][通常論文]
     
    The design, synthesis, and antiviral activities of 6'-homoneplanocin A (HNPA, 3) and its congeners having nucleobases other than adenine, such as 3-deazaadenine (4), guanine (5), thymine (6), and cytosine (7), were described. Starting from the known cyclopentenone derivative 8, the optically active (mesyloxy)cyclopentene derivative 15 was prepared, which was condensed with nucleobases then deprotected to give target compounds 3-7. Of these compounds, HNPA showed an antiviral activity spectrum that was comparable to, and an antiviral specificity that was higher than, that of neplanocin A. HNPA proved particularly active against human cytomegalovirus, vaccinia virus, parainfluenza virus, vesicular stomatitis virus, and arenaviruses, which is compatible with an antiviral action targeted at S-adenosylhomocysteine hydrolase. HNPA appears to be a promising candidate drug for the treatment-of these viruses.
  • S Shuto, H Awano, N Shimazaki, K Hanaoka, A Matsuda BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 6 (9) 1021 -1024 1996年05月 [査読無し][通常論文]
     
    1-(2-C-Cyano-2-deoxy-beta-D-arabino-pentofuranosyl)cytosine (CNDAC, 1) is a potent antitumor nucleoside developed by us. A series of 5'-phosphatidyl derivatives of CNDAC bearing various fatty acyl residues, namely dimyristoyl derivative 3a, dipalmitoyl derivative 3b, distearoyl 3c, dioleoyl derivative 3d, and dilinoleoyl derivative 3e, was synthesized by phospholipase D-catalyzed transphosphatidylation. All of these 5'-phosphatidyl-CNDACs (3a-e) administered ip almost perfectly inhibited the growth of sc-implanted M5076 sarcoma in mice, and the effects were clearly superior to that of CNDAC. (C) 1996 Elsevier Science Ltd.
  • 金崎真紀子, 長沢有紀, 市川聡, 小島直, 南川典昭, 周東智, 松田彰 日本薬学会年会要旨集 116th (Pt 2) 137 1996年03月 [査読無し][通常論文]
  • S Shuto, S Ono, Y Hase, N Kamiyama, H Takada, K Yamasihita, A Matsuda JOURNAL OF ORGANIC CHEMISTRY 61 (3) 915 -923 1996年02月 [査読無し][通常論文]
     
    Adjacent substituents on a cyclopropane ring mutually exert steric repulsion quite significantly, because they are fixed in eclipsed conformation to each other. Based on this structural feature of the cyclopropane ring, conformationally restricted analogs of milnacipran (1), namely 1-phenyl-2-(1-aminoalkyl)-N,N-diethylcyclopropanecarboxamides (2, 3, ent-2, and ent-3) were designed as potent NMDA receptor antagonists and were synthesized highly enantioselectively. Reaction of (R)epichlorohydrin [(R)-5] and phenylacetonitrile (6) in the presence of NaNH2 in benzene gave a chiral cyclopropane derivative that was isolated as lactone 4 with 96% ee in 67% yield, after alkaline hydrolysis of the cyano group. The nucleophilic addition reaction of Grignard reagents to aldehyde 10, which was readily prepared from 4, proceeded highly selectively from the si-face to afford addition products 11 in high yields. Although hydride reduction of the corresponding ketone 15b, prepared from 11b, with L-Selectride also proceeded highly diastereo selectively, the facial selectivity was reversed to give the re-face addition product 11b. On the other hand, reduction of 15 with DIBAL-H afforded the si-face addition product 12 in high yields. These results suggested that these nucleophilic addition reactions proceeded via either the bisected s-trans or s-cis conformation of the cyclopropylcarbonyl derivatives. From 11 and 12, the target conformationally resticted analogs, 2 and 3, were synthesized, respectively. Starting from (S)-epichlorohydrin [(S)-5], their corresponding enantiomers, ent-a and ent-3, were also synthesized. The structures of the conformationally restricted analogs detected by the X-ray crystallographic analysis suggested that their conformations can be restricted as we hypothesized. Thus, a new method for restricting the conformation of cyclopropane derivatives has been developed.
  • H Awano, S Shuto, T Miyashita, N Ashida, H Machida, T Kira, S Shigeta, A Matsuda ARCHIV DER PHARMAZIE 329 (2) 66 -72 1996年02月 [査読無し][通常論文]
     
    Synthesis of several 5-substituted (2'S)-2'-deoxy-2'-C-methyl-cytidines (8) and -uridines (6,11) has been accomplished using radical deoxygenation of the 2'-tert-alcohols via their methyl oxalyl esters as a key reaction. Anti-herpes simplex virus type-1 and -2, and anti-varicella-zoster virus activities of the newly synthesized nucleosides were evaluated. Among them, the 5-iodouracil derivative 6e showed the most potent activity against herpes simplex virus type-1, with an EC(50) of 0.14 mu g/mL without showing cytotoxicity up to 100 mu g/mL, but had a weak activity against herpes simplex virus type-2 and no activity against varicella-zoster virus up to 50 mu g/mL in vitro. Although the 5-fluorocytosine derivative 8b had a potent anti-herpes simplex virus type-1 activity (EC(50) = 0.22 mu g/mL), it was rather cytotoxic to the CCRF-HSB-2 human T-cell line (IC50 greater than or equal to 1.0 mu g/mL).
  • Satoshi Shuto, Akira Matsuda, Atsushi Sakai, Hiromichi Itoh Drug Delivery System 11 (2) 81 -88 1996年 [査読無し][通常論文]
     
    5′-phosphatidyl-FURs, with the same backbone structure as that of natural phospholipids, in which a polar-head group of usual phospholipids is replaced by a cytotoxic nucleosides, 5-fluorouridine (FUR), were designed to be potent antitumor agents. 5′-phosphatidyl-FURs were synthesized by transphosphatidylation catalyzed by phospholipase D from phosphatidylcholines and FUR, and showed greater antitumor activity than FUR. We demonstrated that a 5′-phosphatidyl-FUR given orally was absorbed via a specific pathway for natural phospholipids, namely deacylation-reacylation cycle, to be transported highly selectively to lymph in rats, which suggested effective use of antitumor pseudo-phospholipids, in targeting chemotherapy of metastases of tumors. In fact, 5′-phosphatidyl-FUR showed significant antitumor activity both against P388 leukemia metastasized to the lymph node and P815 mastocytoma metastasized to the lever in mice. These results suggested that the pseudo-phospholipids could be recognized as phospholipids by the body. This methodology of DDS would be applicable for various antitumor agents as well as other biologically active compounds. © 1996, THE JAPAN SOCIETY OF DRUG DELIVERY SYSTEM. All rights reserved.
  • T Obara, S Shuto, Y Saito, M Toriya, K Ogawa, S Yaginuma, S Shigeta, A Matsuda NUCLEOSIDES & NUCLEOTIDES 15 (6) 1157 -1167 1996年 [査読無し][通常論文]
     
    The g-carboxylic acid derivative of neplanocin A 3 was synthesized from NPA, and was converted to the corresponding methyl ester 4 and amides 5 and 6. These were evaluated for their anti-RNA-virus activities. Of the derivatives synthesized, only 5 was active against RNA viruses within the concentration range of 0.14-4.88 mu g/mL. Compounds 3 and 5 showed a potent inhibitory effect on S-adenosylhomocysteine (AdoHcy) hydrolase from rabbit erythrocytes. Although a close correlation between the inhibitory effect of adenosine analogues on AdoHcy hydrolase and their antiviral potency has been demonstrated, 3 did not show any anti-RNA-virus activities.
  • Stereoselective synthesis of (2'S)-2'-C-alkyl-2'-deoxyuridines.
    Nucleosides Nucleotides 15 169 -191 1996年 [査読無し][通常論文]
  • S Shuto, S Ono, Y Hase, N Kamiyama, A Matsuda TETRAHEDRON LETTERS 37 (5) 641 -644 1996年01月 [査読無し][通常論文]
     
    Reaction of (R)-epichlorohydrin [(R)-5] and phenylacetonitrile (6) in the presence of NaNH2 in benzene gave a cyclopropane derivative which was isolated as lactone 4 [(1S,2R)-2-oxo-1-phenyl-3-oxabicyclo[3,1,0]hexane] of 96% e.e. in 67% yield, after alkaline hydrolysis of the cyano group. Compound 4 was readily converted to (+)-milnacipran [(+)-1], by which the absolute stereochemistry of (+)-1 was confirmed. (1S,2R)-1-Phenyl-2-[(S)-1-aminoethyl]-cyclopropane-N,N-diethylcarboxamindes (2), a conformationally restricted analog of 1, was also synthesized in high enantiomeric purity from 4. Starting from (S)-epichlorohydrin [(S)-5], their corresponding enantiomers, namely (-)-milnacipran [(-)-1] and ent-2, were also synthesized.
  • S Ono, S Shuto, A Matsuda TETRAHEDRON LETTERS 37 (2) 221 -224 1996年01月 [査読無し][通常論文]
     
    Nucleophilic addition reaction of Grignard reagents to cyclopropylcarbaldehyde 4 proceeded highly selectively from the si-face to afford 5 in high yield. Although hydride reduction of the corresponding ketone 7 with L-Selectride(R) also proceeded highly diastereoselectively, the facial selectivity was reversed to give the re-Face addition product 5. On the other hand, reduction of 7 with DIBAL-H afforded si-face addition product 6 in high yield. The result suggested that these nucleophilic addition reaction proceeded via either the bisected s-trans or s-cis conformation of the cyclopropane derivatives.
  • S Shuto, K Haramuishi, A Matsuda TETRAHEDRON LETTERS 37 (2) 187 -190 1996年01月 [査読無し][通常論文]
     
    2'-Deoxy and 5'-phosphate derivatives of bredinin (2 and 3, respectively) were synthesized. UV irradiation of bredinin with a mercury lamp in aqueous HCl gave the imidazole-ring cleavage product 7 in high yield, which was converted to 2'-deoxy derivative 13. Reconstruction of the imidazole ring of 13 with (EtO)(3)CH and subsequent deprotection afforded the desired 2'-deoxybredinin (2). Similarly, bredinin 5'-phosphate (3) was synthesized via the photo-product 17.
  • 上野義仁, 長沢有紀, 小島直, 南川典昭, 周東智, 松田彰 アンチセンスシンポジウム講演要旨集 6th 24 1996年 [査読無し][通常論文]
  • A MATSUDA, H KOSAKI, Y YOSHIMURA, S SHUTO, N ASHIDA, K KONNO, S SHIGETA BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 5 (15) 1685 -1688 1995年08月 [査読無し][通常論文]
     
    An alternative synthesis of 9-(5,6-dideoxy-beta-D-ribo-hex-5-ynofuranosyl)adenine (5), which is known to be a potent, irreversible, and time-dependent inhibitor of AdoHcy hydrolase, has been accomplished. Compound 5 had a potent antiviral activity against influenza A and B viruses as well as vesicular stomatitis virus. Since the usual inhibitors of AdoHcy hydrolase, such as neplanocin A, are inactive on both influenza viruses, the mechanism of action of 5 would be different from that of known AdoHcy hydrolase inhibitors.
  • S SHUTO, H TAKADA, D MOCHIZUKI, R TSUJITA, Y HASE, S ONO, N SHIBUYA, A MATSUDA JOURNAL OF MEDICINAL CHEMISTRY 38 (15) 2964 -2968 1995年07月 [査読無し][通常論文]
     
    (+/-)-(Z)-2-(Aminomethyl)-1-phenylcyclopropane-N,N-diethylcarboxamide (milnacipran, 1), a clinically useful antidepressant, and its derivatives were prepared by an improved method and were evaluated as NMDA receptor antagonists. Of these, milnacipran (1), its N-methyl and N,N-dimethyl derivatives, 7 and 8, respectively, and its homologue 12 at the aminomethyl moiety had binding affinity for the receptor in vitro (IC50: 1, 6.3 +/- 0.3 mu M; 7, 13 +/- 2.1 mu M; 8, 88 +/- 1.4 mu M; 12, 10 +/- 1.2 mu M). These also protected mice from NMDA-induced lethality. These compounds would be important as anovel prototype for designing potent NMDA-receptor antagonists because of their characteristic structure, which clearly differentiated them from known competitive and noncompetitive antagonists to the receptor.
  • S SHUTO, H ITOH, A SAKAI, K NAKAGAMI, S IMAMURA, A MATSUDA BIOORGANIC & MEDICINAL CHEMISTRY 3 (3) 235 -243 1995年03月 [査読無し][通常論文]
     
    5'-Phosphatidyl-5-fluorouridines, with the same backbone structure as that of natural phospholipids, in which a polar-head group of usual phospholipids is replaced by 5-fluorouridine, were designed to be potent antitumor agents. 5'-Phosphatidyl-5 fluorouridines with a variety of diacyl or dialkyl residues in the glycerol moiety, were synthesized by phospholipase D-catalyzed transphosphatidylation from the corresponding phosphatidylcholine and 5-fluorouridine. These new compounds were evaluated in mice with experimental tumors by ip and po administration. Dipalmitoyl and distearoyl derivatives 1b and 1c had the greatest antitumor activity against both P388 leukemia and Meth A fibrosarcoma in mice.
  • Development of anti-HSV screening system using suspension cell line and screening several nucleooside analogues in this method.
    Antiviral Res. 26 (A309) 1995年 [査読無し][通常論文]
  • T KIRA, A KAKEFUDA, S SHUTO, A MATSUDA, M BABA, S SHIGETA NUCLEOSIDES & NUCLEOTIDES 14 (3-5) 571 -574 1995年 [査読無し][通常論文]
     
    We examined eight isonucleoside analogues, which have variable bases at the 2' position of deoxyribose, for anti-herpes virus activities in vitro. Six of the eight compounds showed anti-herpes activity.
  • K DOI, N OKU, T TOYOTA, S SHUTO, A SAKAI, H ITOH, S OKADA BIOLOGICAL & PHARMACEUTICAL BULLETIN 17 (10) 1414 -1416 1994年10月 [査読無し][通常論文]
     
    Reticuloendothelial system (RES)-avoiding liposomes are known to accumulate in tumor tissues due to passive targeting. Dipalmitoylphosphatidylfluorouridine (DPPF), a potent antitumor agent readily incorporated into the lipid bilayer, was embedded in RES-avoiding liposomes modified with a uronic acid derivative, palmityl-D-glucuronide (PGlcUA). The therapeutic effect of DPPF in PGlcUA-liposomes was examined in tumor-bearing mice. Free or liposomal DPPF was injected intravenously into BALB/c mice bearing subcutaneously implanted Meth A sarcomas. The RES-avoiding liposomal formulation using PGlcUA was effective in reducing tumors, and prolonging survival time compared with free DPPF and also DPPF in conventional liposomes. Therefore, PGlcUA-liposomes might be of practical use as drug carriers for anticancer agents, especially their derivatives for embedding in liposomal membranes.
  • A KAKEFUDA, S SHUTO, T NAGAHATA, J SEKI, T SASAKI, A MATSUDA TETRAHEDRON 50 (34) 10167 -10182 1994年08月 [査読無し][通常論文]
     
    (2R)-2-C-(Adenin-9-yl)-1,4-anhydro-2-deoxy-D-arabitol (2) and (2R, 3R)-2-C-(adenin-9-yl)-1,4-anhydro-2,3-dideoxy-3-C-hydroxymethyl-D-arabitol (3), and their 2,6-diaminopurine analogues 4 and 5 were synthesized from corresponding 1,4-anhydro-D-ribitol derivatives, which were readily obtained from D-glucose. The corresponding guanine isonucleosides 6 and 7 were obtained from 4 and 5 by enzymatic deamination with adenosine deaminase. Pyrimidine counterparts 8 and 9 were synthesized via construction of the pyrimidine moiety from amino derivatives of the 1,4-anhydro-D-arabitol derivatives. Antiviral activity of these ring-expanded derivatives of oxetanocins towards HSV-1, HSV-2, HCMV, and HBV in vitro was examined along with their cytotoxicity against L1210 and KB cells in vitro.
  • S SHUTO, T OBARA, H ITOH, Y KOSUGI, Y SAITO, M TORIYA, S YAGINUMA, S SHIGETA, A MATSUDA CHEMICAL & PHARMACEUTICAL BULLETIN 42 (8) 1688 -1690 1994年08月 [査読無し][通常論文]
     
    2-Fluoro- and 2-chloroneplanocin A's (2 and 3) were synthesized as an adenosine deaminase resistant-equivalent of neplanocin A, and evaluated for their antitumor and antiviral activities. Of these, 2 was completely resistant to adenosine deaminase and showed more significant antitumor and antiviral activities than neplanocin A.
  • Satoshi Shuto, Takumi Obara, Yoshinori Kosugi, Yasuyoshi Saito, Minoru Toriya, Satoshi Yaginuma, Shiro Shigeta, Akira Matsuda Bioorganic and Medicinal Chemistry Letters 4 (4) 605 -608 1994年02月24日 [査読無し][通常論文]
     
    (6′R)- and (6′S-6′-C-methyl-3-deazaneplanocin A's were synthesized from D-ribose as anti-RNA virus agents. Of these compounds, (6′R)-6′-C-methyl-3-deazaneplanocin A (4b) showed the greatest anti-RNA virus activity in vitro. It was found that the 6′R-configuration was essential for the antiviral activity of 6′-C-methylneplanocin A derivatives. © 1994.
  • Hirokazu Awano, Satoshi Shuto, Masanori Baba, Toshihiko Kira, Shiro Shigeta, Akira Matsuda Bioorganic and Medicinal Chemistry Letters 4 (2) 367 -370 1994年01月20日 [査読無し][通常論文]
     
    (2′S)-2′-deoxy-2′-C-methyl-5-halogenopyrimidine nucleosides were designed and synthesized as anti-herpes virus agents. Of these compounds, (2′S)-2′-deoxy-2′-C-methyl-5-iodouridine (SMIU, 9e) showed the greatest anti-HSV-1 activity in vitro while showing no cytotoxicity. SMIU is a candidate drug for clinical treatment of herpes virus infection disease. © 1994.
  • AEA HASSAN, S SHUTO, A MATSUDA TETRAHEDRON 50 (3) 689 -700 1994年01月 [査読無し][通常論文]
     
    Nucleophilic substitution reactions of an ally] alcohol system in the 2'-deoxy-2'-methylidene pyrimidine nucleosides with various nucleophiles were investigated. The allyl alcohol system reacted with softer nucleophiles such as azide, thiophenoxide, and iodo anion through an SN2' manner to afford 2'-substituted-methyl-2',3'-didehydro-2',3'-dideoxy nucleosides, but with hard oxygen-nucleophiles such as benzoyloxy and phenoxide through an SN2 manner to afford 2'-deoxy-2'-methylidene-3'-substituted nucleosides with inversion at the 3'-position. Based on this characteristic reactivity, 2',3'-didehydro-2',3'-dideoxy-2'-phenylselenomethyl pyrimidine nucleosides 16b and 16c were synthesized. These nucleosides were converted into 3'-amino-2',3'-dideoxy-2'-methylidene pyrimidine nucleosides 3b and 3c via oxidative [2,3]-sigmatropic rearrangement of the allylic selenides as a key step The cytosine derivative 3a was also prepared h om the corresponding uracil derivative.
  • AEA HASSAN, S SHUTO, A MATSUDA NUCLEOSIDES & NUCLEOTIDES 13 (1-3) 197 -211 1994年 [査読無し][通常論文]
     
    Reaction of 2'-deoxy-2'-methylidene-5'-O-trityluridine (1) with diethylamino-sulfur trifluoride (DAST) in CH2Cl2 resulted in the formation of a mixture of (3'R)-2',3'-dideoxy-3'-fluoro-2'-methylidene derivative 3 and 2',3'-didehydro-2',3'-dideoxy-2'-fluoromethyl derivative 4 (3:4 = 1:1.5) in 65% yield. A similar treatment of 1-(2-deoxy-2-methylidene-5-O-trityl-beta-D-threo-pentofuranosyl)uracil (19) with DAST in CH2Cl2 afforded (3'S)-2',3'-dideoxy-3'-fluoro-2'-methylidene derivatives 20 and 4 in 38% and 17% yields respectively. Transformation of the uracil nucleosides 4, 12, and 20 into cytosines followed by deprotection furnished the corresponding cytidine derivatives 29, 18, and 25, respectively. The corresponding thymidine congener 27 was also synthesized in a similar manner. All of the newly synthesized nucleosides were evaluated for their inhibitory activities against HIV and for their antiproliferative activities against L1210 and KB cells.
  • A SAKAI, N MORI, S SHUTO, T SUZUKI JOURNAL OF PHARMACEUTICAL SCIENCES 82 (6) 575 -578 1993年06月 [査読無し][通常論文]
     
    Dipalmitoylphosphatidylfluorouridine (DPPF) is a potent antitumor agent that selectively gains access to the lymphatic system. To determine whether DPPF enters the lymph in an unmodified form, we administered DPPF orally to rats and analyzed lymph collected from a cannula in the thoracic duct. Although lymph was found to contain only very low levels of DPPF, two congeners of DPPF were detected at high levels. Instrumental analysis demonstrated that these congeners are 1-palmitoyl-2-arachidonoylphosphatidylfluorouridine (PAPF) and 1-palmitoyl-2-linoleoyl-phosphatidylfluorouridine (PLPF). PAPF and PLPF levels in thoracic lymph were shown to be approximately 30 times higher than those in plasma. These results suggest that DPPF is absorbed from the intestinal tract via the deacylation-reacylation cycle for the uptake of phospholipids and is selectively delivered to the lymphatic route after oral administration. DPPF is a candidate drug for the treatment of tumor metastasis, especially in cases where metastasis has occurred via the lymphatic route.
  • A SAKAI, N MORI, S SHUTO, T SUZUKI JOURNAL OF PHARMACEUTICAL SCIENCES 82 (6) 575 -578 1993年06月 [査読無し][通常論文]
     
    Dipalmitoylphosphatidylfluorouridine (DPPF) is a potent antitumor agent that selectively gains access to the lymphatic system. To determine whether DPPF enters the lymph in an unmodified form, we administered DPPF orally to rats and analyzed lymph collected from a cannula in the thoracic duct. Although lymph was found to contain only very low levels of DPPF, two congeners of DPPF were detected at high levels. Instrumental analysis demonstrated that these congeners are 1-palmitoyl-2-arachidonoylphosphatidylfluorouridine (PAPF) and 1-palmitoyl-2-linoleoyl-phosphatidylfluorouridine (PLPF). PAPF and PLPF levels in thoracic lymph were shown to be approximately 30 times higher than those in plasma. These results suggest that DPPF is absorbed from the intestinal tract via the deacylation-reacylation cycle for the uptake of phospholipids and is selectively delivered to the lymphatic route after oral administration. DPPF is a candidate drug for the treatment of tumor metastasis, especially in cases where metastasis has occurred via the lymphatic route.
  • Highly stereoselective synthesis of bicyclic-sugar adenosine derivatives via Diels-Alder reaction.
    Nucleic Acids Res. Symposium Series 29,39-40 1993年 [査読無し][通常論文]
  • S SHIGETA, S MORI, M BABA, M ITO, K HONZUMI, K NAKAMURA, H OSHITANI, Y NUMAZAKI, A MATSUDA, T OBARA, S SHUTO, E DECLERCQ ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 36 (2) 435 -439 1992年02月 [査読無し][通常論文]
     
    5-Ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide (EICAR) and 6'-(R)-6'-C-methylneplanocin A (TJ13025) are two novel antiviral agents which are targeted against IMP dehydrogenase and S-adenosylhomocysteine hydrolase, respectively. These compounds have been examined for their activities against various strains of orthomyxoviruses (influenza virus) and paramyxoviruses (parainfluenza virus, mumps virus, measles virus, and respiratory syncytial virus) in vitro. EICAR was 10- to 59-fold more active than ribavirin and TJ13025 was 32- to 330-fold more active than ribavirin against parainfluenza virus (types 2 and 3), mumps virus, and measles virus. EICAR was also more active than ribavirin against respiratory syncytial virus and influenza virus, whereas TJ13025 was virtually inactive against these viruses. The 50% virus-inhibitory concentrations of EICAR and TJ13025 were generally within the 0.1- to 1-mu-g/ml range. Although the compounds did not prove cytotoxic to stationary host cells (HeLa, Vero, MDCK, and LLCMK2) at a concentration of 200-mu-g/ml, concentrations of 4 to 13-mu-g/ml inhibited the growth of dividing cells. EICAR and TJ13025 should be further pursued as candidate drugs for the treatment of ortho- and paramyxovirus infections.
  • S SHUTO, T OBARA, M TORIYA, M HOSOYA, R SNOECK, G ANDREI, J BALZARINI, E DECLERCQ JOURNAL OF MEDICINAL CHEMISTRY 35 (2) 324 -331 1992年01月 [査読無し][通常論文]
     
    Novel neplanocin A analogues modified at the 6'-position, i.e., 6'-deoxy analogues (2, 3, 6, 9, 20), 6'-O-methylneplanocin A (15), and 6'-C-methylneplanocin A's (22a and 22b) have been synthesized and evaluated for their antiviral activity in a wide variety of DNA and RNA virus systems. These compounds showed an activity spectrum that conforms to that of S-adenosylhomocysteine hydrolase inhibitors. They were particularly active against pox- (vaccinia), paramyxo-(parainfluenza, measles, respiratory syncytial), arena- (Junin, Tacaribe), rhabdo- (vesicular stomatitis), reo-, and cytomegalovirus. In order of (increasing) antiviral activity, the compounds ranked as follows: 3 < 15 approximately 20 < 6 < 9 approximately 2 < 22a. Of the two diastereomeric forms of 22, only 22a was active; 22a surpassed neplanocin A both in antiviral potency and selectivity. Compound 22a appears to be a promising candidate drug for the treatment of pox-, paramyxo-, arena-, rhabdo-, reo-, and cytomegalovirus infections.
  • S SHUTO, S IMAMURA, K FUKUKAWA, T UEDA CHEMICAL & PHARMACEUTICAL BULLETIN 36 (12) 5020 -5023 1988年12月 [査読無し][通常論文]
  • 周東 智, 伊東 裕通, 植田 成, 今村 茂行, 福川 清史, 辻野 正俊, 松田 彰, 上田 亨 Chemical & pharmaceutical bulletin 36 (1) 209 -217 1988年01月25日 [査読無し][通常論文]
     
    Phospholipase D from Streptomyces effectively catalyzed the transfer reaction of the phosphatidyl residue from 3-sn-phosphatidylcholine to the 5'-hydroxyl group of nuclesides in a two-phase system. Thus, a variety of 5'-(3-sn-phosphatidyl)nucleosides could be readily prepared in high yields by means of this reaction. Among them, phosphatidyl-FUR (3b), phosphatidyl-Ara FC (8b), and phoshatidyl-neplanocin A (12b) each produced a significant increase in the life span mice bearing i.p.-implanted P388 leukemia, being more effective than the parent nucleosides.
  • S SHUTO, S UEDA, S IMAMURA, K FUKUKAWA, A MATSUDA, T UEDA JOURNAL OF PHARMACEUTICAL SCIENCES 76 (11) S224 -S224 1987年11月 [査読無し][通常論文]
  • H ITOH, S SHUTO, K FUKUKAWA, M TSUJINO, A MATSUDA, T UEDA JOURNAL OF PHARMACEUTICAL SCIENCES 76 (11) S220 -S220 1987年11月 [査読無し][通常論文]
  • S SHUTO, H ITOH, E ENDO, K FUKUKAWA, M TSUJINO, T UEDA CHEMICAL & PHARMACEUTICAL BULLETIN 35 (8) 3523 -3526 1987年08月 [査読無し][通常論文]

共同研究・競争的資金等の研究課題

  • RNA分解酵素・アンチセンスの細胞内分子複合体化と長鎖RNA機能制御への応用
    日本学術振興会:科学研究費助成事業 基盤研究(B)
    研究期間 : 2020年04月 -2023年03月 
    代表者 : 小松 康雄, 周東 智, 平野 悠
  • VCP化合物の最適化による新規神経保護薬の開発
    日本学術振興会:科学研究費助成事業 基盤研究(C)
    研究期間 : 2020年04月 -2023年03月 
    代表者 : 船木 智, 中川 慎介, 角家 健, 周東 智
  • 高分子間相互作用を制御する合成機能分子を論理的・効率的に創出する方法論の確立
    日本学術振興会:科学研究費助成事業 基盤研究(A)
    研究期間 : 2019年04月 -2023年03月 
    代表者 : 周東 智, 渡邉 瑞貴, 小松 康雄, 藤原 広一, 後藤 佑樹
     
    創薬においてランダムスクリーニングが汎用されている現状に鑑みると、標的分子に選択的に結合する化合物を偶然に依存することなく論理的に創出する方法論の確立は、アカデミアとしての化学系薬学が取り組むべき最重要課題である。 本研究の目的は、独自に考案したシクロプロパンの構造特性に基づく三次元多様性を鍵概念とする論理的分子設計を、タンパク質間相互作用(PPI)等の高分子間相互作用の制御へと展開することが可能であることを実証し、高分子間相互作用を制御する合成医薬創出の論理的方法論を提示することにある。また、有機合成化学に裏付けられた独自の分子設計戦略が、本研究の独創性に優れる利点である。 具体的には、1. PPIを制御できる汎用性αヘリックスミメティクスの創出、2. 高分子間相互作用制御能を有する環状ペプチドの欠点である細胞膜透過性の配座制御に基づく改善、3. 標的高親和性環状ペプチドを効率的に同定可能な革新的方法論であるRaPIDライブラリーへの三次元多様性導入によるさらなる高機能化、4. ネガマイシンをリードとする三次元多様型配座制御に基づく高活性リードスルー活性分子創出、5. シクロプロパンヌクレオシドを活用する高機能核酸の創出に取り組む。これらの課題の遂行を通して本分子設計の有用性の実証し、広範な標的分子を対象とする論理的創薬方法論を提示する。 本研究遂行を通して、偶然性に依存することのない創薬科学の発展に寄与することを目指す。既に、1-5の研究課題のそれぞれにおいて、下記進捗状況に記したような成果を得ている。特に、4. ネガマイシン関連研究での成果については、特許出願準備が完了している。
  • 日本学術振興会:科学研究費助成事業 基盤研究(B)
    研究期間 : 2016年04月 -2020年03月 
    代表者 : 石田 晋, 周東 智, 神田 敦宏
     
    生活習慣病や加齢に伴って発症・進行する網脈絡膜疾患における炎症・血管新生病態の上流では、様々な分子が病態形成に関与しており、未だ根本的な治療法の開発・疾患発症機序の解明には至っていない。我々は、これまでに受容体結合プロレニン系(RAPS)が生活習慣病での網脈絡膜疾患において(プロ)レニン受容体が炎症・血管新生病態の上流で疾患の分子病態を制御していることを報告してきた。本研究課題では、RAPSの機能解明および生理的機能への影響を最小限にしながら慢性炎症病態を抑制する阻害剤の開発を行った。
  • 日本学術振興会:科学研究費助成事業 基盤研究(A)
    研究期間 : 2015年04月 -2020年03月 
    代表者 : 周東 智, 小松 康雄, 福田 隼, 有澤 光弘, 山口 浩明, 一ノ瀬 亘
     
    シクロプロパンの構造特性に基づく三次元多様性を鍵とする分子設計法を考案し、それに基づく論理的な低分子創薬化学研究を展開した。その結果、炎症収束脂質レゾルビンE2の高活性類縁体、プロレニン阻害剤やメラノコルチン受容体阻害剤などのペプチドミメティクス、細胞膜透過性環状ペプチドやGABAトランスポーターGAT1高選択的阻害剤等を創出した。これらの結果は、分子設計法の有用性を明示する。さらに、創薬化学研究実践に資する、シクロプロパンヌクレオシドを含めた多置換光学活性シクロプロパンの合成法を種々開発した。
  • 日本学術振興会:科学研究費助成事業 基盤研究(B)
    研究期間 : 2016年04月 -2019年03月 
    代表者 : 小松 康雄, 周東 智, 平野 悠
     
    独自の手法でクロスリンクした2本鎖(CL2本鎖)を、miRNAのアンチセンス鎖に位置を変えて導入したanti-microRNA oligo(CL-AMO)を複数種類合成した。このCL-AMOを細胞内に導入し、miRNAへの影響を調べた。その結果、2本鎖構造の分子内の位置に応じ、miRNAに異なる修飾が誘導されること、また分子構造によって細胞内分布が異なる傾向が有ることを見出した。また、CL-AMOを乳がん細胞に添加した結果より、CL-AMOが従来型よりもがん細胞の増殖を長期間に渡って抑制できることを実証した。
  • 日本学術振興会:科学研究費助成事業 挑戦的萌芽研究
    研究期間 : 2016年04月 -2018年03月 
    代表者 : 周東 智, 福田 隼
     
    長時間薬理活性が持続することは、多くの治療薬において利点となる。本研究では、“リン脂質を細胞膜へのアンカー素子として活用することで、長時間リガンドを細胞膜標的分子近傍へと偏在化できる”との作業仮説の下、超長時間作用持続型医薬創出法の確立することを計画した。具体的には、“リガンド-リンカー部-リン脂質”を基本構造とするリガンド・リン脂質複合体(Ligand-Phospholipid-Conjugates, LPC)を設計・合成し、作業仮説通りに薬物動態を時空間的に制御できるか否かを、in vitro及びin vivoで評価し、本作業仮説を実証するとともに、新規創薬方法論確立への端緒を開いた。
  • 日本学術振興会:科学研究費助成事業 挑戦的萌芽研究
    研究期間 : 2015年04月 -2017年03月 
    代表者 : 南 雅文, 周東 智
     
    GABAトランスポーターのBGT-1サブタイプに選択的な阻害薬候補である化合物Bは、尾懸垂試験において抗うつ作用を有することが示めされた。GABA受容体に対する作用を検討したところ、 GABAA受容体に対して高い結合親和性を有し、アゴニストとして作用することが示された。GABAB受容体には結合しなかった。以上より、化合物Bの抗うつ作用は、BGT-1阻害活性、または 、BGT-1阻害活性とGABAA受容体アゴニスト活性の複合的な作用によることが示唆された。GABA受容体に作用せず、BGT-1のみを阻害する化合物を得るため新たに4種類の化合物を合成したが、いずれもBGT-1阻害作用を示さなかった。
  • 日本学術振興会:科学研究費助成事業 挑戦的萌芽研究
    研究期間 : 2014年04月 -2016年03月 
    代表者 : 谷村 明彦, 森田 貴雄, 根津 顕, 周東 智
     
    本研究では、IP3濃度測定の新しい原理として「競合的リガンド結合アッセイ法」を開発した。この方法は、低親和性蛍光アデノフォスチン誘導体(FLL)と蛍光IP3センサータンパク質(ECFPを連結したリガンド結合ドメイン)と言う2つの蛍光分子の結合によるFRETを利用するものである。細胞あるいはビーズを使った実験で、蛍光IP3センサータンパク質とFLLの結合がFRETを起こし、このFRETシグナルがIP3によって減少することが確認された。この方法を使って、10 nMのIP3濃度の定量的測定が可能であり、実際にCOS-7細胞の細胞内IP3濃度を測定できることが確認された。
  • 日本学術振興会:科学研究費助成事業 挑戦的萌芽研究
    研究期間 : 2013年04月 -2015年03月 
    代表者 : 周東 智, 福田 隼, 浅井 章良, 松田 正
     
    本研究では、“ホスファチジルセリン(PS)を二量化すればセリンリン酸部が常に細胞表面に露出してファゴサイトーシスを誘発する”との作業仮説に基づき、PS二量等価体を設計・合成し、実際にファゴサイトーシス誘発作用を有することを明らかにすることを期待した。その結果、合成したPS二量体含有リポソームをがん細胞へ取り込ませた結果、期待した通りにPS自体よりも効果的にPSを露出させることに成功した。
  • 日本学術振興会:科学研究費助成事業 基盤研究(B)
    研究期間 : 2012年04月 -2015年03月 
    代表者 : 周東 智, 福田 隼, 南 雅文, 東田 陽博, 広川 貴次, 有澤 光弘
     
    シクロプロパンは、分子の物理化学的性質にほとんど影響することなしに、強固に官能基の配座を制御できることに加えて、その特有の立体及び立体電子効果であるシクロプロパン歪み及び二等分配座効果を側鎖の配座制限に活用できる。このようなシクロプロパンの構造特性を活用する三次元的多様性を鍵とする独自の分子設計を基盤として、標的分子に対して選択的かつ強力に作用する薬理活性化合物を論理的かつ効率的に創出した。具体的には、創薬リードとなりうる高活性なGABAトランスポーターBGT-1阻害剤、プロテアソーム阻害剤、β-セクレターゼ(BASE)阻害剤の創出に成功した。
  • 日本学術振興会:科学研究費助成事業 挑戦的萌芽研究
    研究期間 : 2011年 -2012年 
    代表者 : 周東 智, 嶋脇 健
     
    cADPR(1)Ca2+動員を担うセカンドメッセンジャーであるcADPR(1)は非常に不安定であるので、申請者が先に開発したcADPRの安定等価体である炭素環アナログcADPcR(cADPR,2)をプロトタイプとして、ADPR標的タンパク質同定のためのバイオロジカルツールの創出を目指した。バイオロジカルツールを創出する上での鍵化合物として4"α-アジドcADPcR(3)を設計し、その合成を達成した。さらに、3が望みの生物学的機能を有することを確認した。
  • 日本学術振興会:科学研究費助成事業 基盤研究(B)
    研究期間 : 2009年 -2011年 
    代表者 : 周東 智, 有澤 光弘
     
    創薬上有用でその開発が望まれている汎用性に優れるβターンミメティックを三次元的多様性を鍵とする分子設計法に基づき考案し、その効率的かつ立体選択的合成法を開発した。βターンミメティックを基本構造としてメラノコルチン受容体リガンドを設計・合成し、その薬理活性を評価した結果、顕著な同受容体阻害活性を有する非ペプチドリガンドの創製に至った。以上の結果は本βターンミメティックの創薬上の有用性を示す。
  • 発達障害発症機序の解析と治療薬創製研究
    日本学術振興会:科学研究費助成事業 挑戦的萌芽研究
    研究期間 : 2009年 -2010年 
    代表者 : 周東 智
     
    本研究は、Ca2+動員セカンドメッセンジャーであるサイクリックADP-リボースの合成抑制に起因するオキシトシン(OT)の脳内濃度の低下が精神的発達障害の発症に関与することを実験的に明らかにし、さらに自閉症等の発達障害治療薬開発の端緒を開くことを目的とする。具体的には生物学的にも化学的にも不安定なcADPRの安定等価体をリードとして、細胞膜透過性のプロドラッグの開発を目指した。 当初細胞膜透過性のプロドラック創出のためのリード化合物として、cADPRの炭素環安定アナログではcADPcRを用いる予定であったが、三次元構造等の詳細の検討の結果から、チオリボースアナログであるcADPtRがより適切なリードになるものと判断した。本年度は、昨年度ほぼ確立した合成法を基盤としてcADPtRの合成に成功した。 cADPtRの生物活性を評価した結果、ウニ卵、マウス神経細胞、ヒトT細胞の何れにおいても、cADPRと同等あるいはそれ以上のCa2+動員活性を有することは明らかとなった。さらに、cADPRが短時間に分解されるラット脳抽出液中において全く分解されないことから、cADPtRが極めて生物学的に安定であることも確認された。以上の結果は、cADPtRが細胞膜透過性のプロドラッグのリードとして好適であることを示す成果である。
  • Ca^<2+>-動員細胞内情報伝達系機能分子の創製
    日本学術振興会:科学研究費助成事業 基盤研究(B)
    研究期間 : 2005年 -2007年 
    代表者 : 周東 智
     
    本研究は、セカンドメッセンジャーとして未だ不明な点の多いcADPRが関与する情報伝達機構を開明のためのツール、さらに創薬リード化合物となりうるcADPR類縁化合物の創製を目的とした。 cADPRの安定等価体としてサイクリックADP-カーボサイクリックリボース(cADPcR)を既に開発した。cADPcRは、ウニ卵、神経細胞においてはcADPRを凌駕する強力なCa^<2+>動員活性を示すが、T-細胞ではほとんど活性を示さない。この原因をアデニン部のpKa値またはカーボサイクリックリボース部のコンホメーションにあるものと推論し、T-細胞でも有効な類縁体として、N1-4-チオリボース体及びN1-不飽和カーボサイクリックリボース体等を設計し、その合成を計画した。 N1-不飽和カーボサイクリックリボース体の合成に成功し、T-細胞でも有効なことを確認した。N1-4-チオリボース体については、基本骨格であるN1-4-チオリボシルアデノシン構造を構築し、さらに鍵段階の大環状構造の構築に成功したので、あとは脱保護を残すのみとなった。合成完了後、生物学的評価を検討する。
  • 非イノシトール型イノシトールリン脂質ミミックの創製研究
    日本学術振興会:科学研究費助成事業 萌芽研究
    研究期間 : 2005年 -2006年 
    代表者 : 周東 智
     
    イノシトールリン脂質は細胞内シグナル伝達系の重要な因子で、細胞増殖・癌化あるいは老化等に関与する。従って、イノシトールリン脂質の等価体として機能する分子は、細胞内シグナル伝達系解析のための生物学ツールあるいは創薬リードとして有用である。本研究では、イノシトールリン脂質のmyo-イノシトール骨格をC-グルコシドでミミックしたホシファチジルC-グルコシドを設計・合成し、その生物活性、特に重要なシグナル伝達分子であるホスファチジルイノシトール3-キナーゼ(PI3K)あるいはホスソリパーゼC(PLC)に対する阻害活性を調べ、イノシトールを基本骨格としない、構造的にも機能的にも斬新なイノシトールリン脂質等価体の創製を目的とする。 D-グルコースはmyo-イノシトール同様の6員環いす型構造とトランスジオールを有することから、D-グルコース構造でPI及びPIP_2のイノシトール部をミミック可能と推論し、さらに代謝的及び化学的安定性を考慮し、C-グルコシドを骨格とするPI及びPIP_2等価体を設計した。これらは、イノシトール3位に相当する位置(グルコース5位)に水酸基が存在しないここから、この部位を認識するPI及びPIP_2の重要な代謝酵素であり、また制癌剤分子標的と想定されるPI3Kの阻害剤となることを期待した。 3,4位にリン酸基を持たない目的物の合成を目指して研究を進めた。前年度合成した、目的物の極性頭部に相当するa-C-グルコシドをアクセプターとして、ホスホリパーゼ(PLD)の触媒するホスファチジル基転移反応によりリン脂質への変換を検討した。その結果、アシル基として飽和型パルミトイル基あるいは不飽和型のオレオイイル基を有するα-C-グルコシド型PI等価体の合成に成功した。
  • 配座制御に基づく分子設計:ユビキチン/プロテアソーム系を標的とする制がん剤の創製
    日本学術振興会:科学研究費助成事業 特定領域研究
    研究期間 : 2004年 -2004年 
    代表者 : 周東 智
     
    がん細胞の分裂あるいは転移には、ユビキチン/プロテアソーム系によりp53等様々なタンパク質が細胞周期に依存的して効果的に分解されることが必須であることから、同系は新しい制がん剤分子標的と考えることができる。本研究は、最近日本で見い出されたプロテアソーム阻害剤ベラクトシンAの構造をもとに、三次元構造を重視した構造-活性相関の検討を通して高活性なプロテアソーム阻害剤を創製し、最終的には臨床利用念頭に、制がん剤としての基礎的な性質を明らかにすることを目的とする。 ベラクトシンAの構造上の中央に位置して根幹を成し、分子全体の三次元構造を規定しているシクロプロパンアミノ酸部が活性に重要と考え、この部分を変換した誘導体を種々設計した。本年度研究において、目的物合成の鍵となる、光学活性なシクロプロパンアミノ酸類の合成法の確立に成功した。先ず、入手用意な光学活性エピクロロヒドリンより、シクロプロパン骨格を構築した。シクロプロパン側鎖上のD-及びL-型アミノ酸構造の構築が課題であったが、スルフィニルイミン型基質に対するCH_2=CHMgBrの立体選択的付加反応を見出し解決した。本法により、スルフィニル部が(R)-及び(S)-型の基質を使い分けることで、D-及びL-型アミノ酸構造の立体選択的構築が可能となり、目的のシクロプロパンアミノ酸の合成法が確立した。
  • 汎用性医薬分子設計用ユニットに基づくヒスタミンH_3受容体特異的機能分子の創製
    日本学術振興会:科学研究費助成事業 基盤研究(C)
    研究期間 : 2003年 -2004年 
    代表者 : 周東 智
     
    従来より神経伝達物質ヒスタミンを内在性リガンドとする受容体としてH_1及びH_2受容体が知られており、そのアンタゴニストが抗アレルギー薬及び抗潰瘍薬として臨床利用されている。さらに、様々な薬理学的実験結果からこれらとは別のヒスタミン受容体としてH_3受容体の存在が示され、そのアゴニストあるいはアンタゴニストの医薬としての利用が期待されている。さらに最近になって第四のヒスタミン受容体H_4受容体がクローニングされ、H_3受容体と非常に配列類似性が高いことが分かった。本研究は、シクロプロパン環の構造特性に着目して開発した医薬分子設計用ユニットを用いて、今までに報告例のないH_3受容体特異的機能分子、即ちH_1及びH_2受容体のみならずH_4受容体にも作用しないH_3アゴニスト及びアンタゴニストを創製するとともに、この医薬分子設計用シクロプロパンユニットの有用性を明らかにすることを目的として研究を進めた。 "folded型"配座制限誘導体がH_3特異的アゴニストを示すことを既に明らかにした。この知見を基に、イミダゾール部とアミノ部の空間配置が受容体結合を規定すると考え、16種類のヒスタミン配座制限誘導体を設計した。なお、ある受容体の選択的なアゴニストの構造上の適当な部位に芳香環を付与することで、しばしばアンタゴニストへの機能変換が可能である(アンブレラ効果)ことから、アミノ基上に脂溶性基を導入する,ことにした。これらを合成し、薬理活性を評価した結果、目的のH_3受容体選択的なアンタゴニストを見出すことに成功した。さらに、H_4受容体に対しても選択的なアンタゴニストの創出にも成功した。これらの研究により、"extended"型の配座制限誘導体が顕著なアンタゴニスト活性を示すことが明らかになった。
  • 大環状ピロリン酸構造を持つサイクリックADP-リボース類縁化合物の効率的合成
    日本学術振興会:科学研究費助成事業 特定領域研究
    研究期間 : 2002年 -2002年 
    代表者 : 周東 智
     
    細胞内のCa^<2+>動員を担う新しいセカンドメッセンジャーとして見い出されたサイクリックADP-リボース(cADPR)関連化合物の効率的合成法を確立し、構造活性相関を明らかにし、さらに未だ不明な部分が多いCa^<2+>動員情報伝達系を解明するために有用な機能分子を創製することを目的として研究をすすめている。cADPRは化学的にも生物学的にも不安定であるが、その安定な活性等価体として設計した炭素環型誘導体サイクリックADP-カーボサイクリックリボース(cADPcR)の合成を既に達成している。 cADPcRは、推論通り化学的にも生物学的にも安定であり、かつ、cADPR自体より数倍強力なCa^<2+>動員活性物質として機能することが分かった。この知見に基づき、Ag^+によるチオフェニルリン酸の活性化を経る分子内ピロリン酸化反応を鍵段階として、種々のcADPcR類縁体の合成を検討した。^<2)>その結果、本法はcADPcR関連化合物の一般的合成法として利用できることが判明した。これら類縁体の中で、3-デオキシ体(3d-cRDPcR)が、天然物cADPRの約16倍、cADPcRに比べても5倍以上という非常に強力なCa^<2+>動員活性を持つことが明らかになった。
  • 新規ラジカル受容テザーの開発とその抗HIVヌクレオシド合成への応用
    日本学術振興会:科学研究費助成事業 基盤研究(C)
    研究期間 : 2001年 -2002年 
    代表者 : 周東 智
     
    アルケンから容易に調製可能なハロヒドリンまたはα-ゼレノアルコールの水酸基にトリチルシリルエチニルジメチルシリル(TEDMS)基をラジカル受容tetherとして導入し、アトムトランスファー条件下のラジカル反応に付すとendo-環化ラジカルがハロゲンでトラップされたエキソメチレン体が生成し、さらにフッ素イオンまたは適当な塩基で処理すると脱離反応ならびに脱TMS反応が進行する結果、エチニル基の立体選択的導入が可能と考え検討を進めた。 先ず、TEDMS基を導入したフェニルセレノインダノール誘導体をモデル基質として種々検討した結果、当初の予想通りの機構でエチニル基のone-pot導入が可能であることが確認できた。 様々な基質を用いて検討した結果、本反応は、糖等の多官能性化合物を含む5及び6員環のヨードヒドリンに適用可能であることが明かとなった。さらに本反応を鍵段階として、抗HIV活性が期待される2-エチニルヌクレオシドの合成に成功した。 なお、本反応は、ラジカル反応によるエチニル化の初めての例である。
  • 高次脳機能障害モデルの作出,新規薬効評価法の確立と創薬
    日本学術振興会:科学研究費助成事業 基盤研究(A)
    研究期間 : 2000年 -2002年 
    代表者 : 野村 靖幸, 周東 智, 村山 俊彦, 大熊 康修, 齋藤 洋, 上原 孝
     
    老化促進モデルマウス(SAM)のSAMP8系は学習記憶障害を発症する。SAMP8における記憶障害について、とくに海馬における神経栄養因子GDNF発現の加齢に伴う変化を検討した結果、SAMP8若齢期において、海馬におけるGDNF発現量は正常動物に比し、有意に減少していた。SAMP8の学習記憶障害遺伝子は未だ特定されていない。そこでSAMP8の学習記憶障害遺伝子の遺伝様式とその存在位置を特定する目的で、遺伝分析を行ったところ記憶障害責任遺伝子が単一の優性遺伝であることを示した。さらに、記憶障害責任遺伝子のQTL(量的形質遺伝子座)連鎖解析を行ない、1番染色体、12番染色体、13番染色体上に記憶障害責任遺伝子の存在する候補領域を同定した。 L型カルシウムチャネルおよびカルモジュリン拮抗作用を有するCV-159が脳虚血(MCAOモデル)によるニューロン死を保護することが明かとなった。4血管結紮一過性脳虚血モデルラットを用い、脳虚血時に海馬で発現が変化する遺伝子の単離・同定を検討する目的で、Differential Display法を用いて検討した結果、脳虚血後発現が減少する遺伝子としてphosphatidylinositol 4-kinase(PI4-K)を単離した。免疫組織学的検討において、PI4-Kの海馬における発現は、脳虚血後に神経細胞死が認められるCA1領域で特異的に減少した。さらに、PI4-Kの過剰発現はHEK293細胞における細胞死を抑制した。 軽度の脳虚血を負荷すると、その後の脳虚血に耐性を獲得するが、虚血を加える前に、preconditioning処置を加えておくと、転写因子CREBの活性化が九進していることから、大脳皮質虚血耐性現象はCREBを介したシグナルトランスダクションの増強によって生じる可能性が示唆された。
  • 構造情報を基盤とするヌクレアーゼ抵抗性アンチセンス分子の論理的設計
    日本学術振興会:科学研究費助成事業 基盤研究(B)
    研究期間 : 1999年 -2000年 
    代表者 : 松田 彰, 周東 智, 上野 義仁
     
    2'-デオキシリボヌクレオシド4'位へアミノアルキル基の導入のための新規ラジカル反応を開発した.ヌクレオシド糖部4'位に炭素置換基を導入する方法は幾つか知られているが,4'α位に立体選択的に炭素置換基を導入する方法は,ほとんど知られていなかった.そこで,ラジカル環化反応を利用して立体選択的に炭素置換基を導入する方法を開発中に極めて興味深い反応を見い出した.本反応が,糖部4'ラジカルのビニルシリル基への5-エキソ環化の後,生成するメチルラジカルがさらに6-エンド環化体へ転位することが明らかになり,その生成機構の詳細について解明した.本法を適用して4'α-アミノエチルチミジンを合成した.さらに,アリルシリル基をラジカルアクセプターとして用いて4'α-アミノプロピルチミジンを合成した.既知の方法により4'α-アミノメチルチミジンを合成した.これらのヌクレオシドを含むオリゴデオキシリボヌクレオチド(ODN)を合成し,それらの熱的安定性,エキソヌクレアーゼ,エンドヌクレアーゼに対する抵抗性を調べた.さらに,相補鎖がRNase Hの基質になるかどうかを調べた.その結果,相補鎖がDNAの場合は,アミノアルキル体の数の増加に伴い熱的な安定性を増すことが明らかになったが,RNAの場合は熱的安定性の若干の低下が観察された.しかし,この低下はアンチセンス法への応用を妨げるほどではなかった.一方,これらのアミノアルキル基を導入したODNsは,予想通りエキソヌクレアーゼ(snake venom phosphodiesteraseおよびヒト血清),エンドヌクレアーゼ(DNase I)に対する抵抗性をかなり増すことが確認された.また,相補鎖側のRNAは,RNase H(HIVおよびHeLa細胞核抽出液)の基質になることも確認した.4'α-アミノエチルチミジンを複数個導入したODNsは,熱帯熱マラリア原虫のコハク酸脱水素酵素のアンチセンス分子として働くことを確認した.この実験によって,従来不明であった熱帯熱マラリア原虫のコハク酸脱水素酵素がミトコンドリア中のエネルギー代謝系で機能しており,本酵素が抗マラリア薬の開発のための標的候補として重要であることが明らかになった.
  • 新規ラジカル環拡大反応:反応機構の解明と医薬化学的展開
    日本学術振興会:科学研究費助成事業 基盤研究(C)
    研究期間 : 1999年 -2000年 
    代表者 : 周東 智
     
    ラジカル反応はその合成化学的有用性及び反応自体への有機化学的興味から、近年盛んに研究されている。申請者は、ラジカル反応を用いてハロヒドリンまたはα-ゼレノアルコールの水酸基α-位に立体及び位置選択的にC2ユニットを導入する方法を最近開発し、その研究過程で新規ラジカル環核大反応を見い出した。本研究では、この環核大反応の機構を実験的に明らかにすことを計画した。 平成11年度は、重水素ラベル基質を用いた実験及び反応速度論的解析した。本環拡大反応は3員環型5価ケイ素ラジカルを経る不可逆反応であることが明かとなった。この結果は、5価ケイ素ラジカルの存在を実験的に示した初めての例である。このような5価ケイ素ラジカルを中間体として想定することで、他の類似反応の機構が合理的に説明できる。 平成12年度は、本ラジカル反応を医薬化学へ展開した。先ず、D-グルコースがイノシトールトリスリン酸(IP_3)のイノシトール骨格のmimicとなりうる想定し、代謝的に安定なC-グリコシド型グルコース誘導体を数種類設計し、上記あラジカル反応を鍵反応として合成した。これらの生物活性を検討した結果、IP_3受容体親和性並びに細胞内Ca^<2+>-放出活性を有する新規リガンドを見い出した。さらに、本ラジカル反応をアンチセンス核酸合成用のヌクレオチドユニットとしての利用及び抗ウイルスル活性ができる4'-分枝糖ヌクレオシドの合成に応用した。
  • シクロプロパンの構造特性に基づく新規ヒスタミン受容体拮抗剤の設計と合成
    研究期間 : 2000年
  • Design and synthesis of novel histamine receptor ligands based on the structural feature of cyclopropane ring
    研究期間 : 2000年
  • 新規高次神経変性疾患モデル動物・細胞の開発,神経変性機序の解析と薬効評価法の確立
    日本学術振興会:科学研究費助成事業 基盤研究(A)
    研究期間 : 1997年 -1999年 
    代表者 : 野村 靖幸, 周東 智, 村山 俊彦, 大熊 康修, 服部 征雄, 上原 孝, 松田 彰
     
    老化促進モデルマウス(SAM : senescence accelerated mouse)のP系は促進老化を示し,活動性の低下,脱毛,寿命短縮などの共通の老化所見を示す.SAMP8およびP10は学習記憶障害を示し,痴呆を主とする神経変性疾患の病態モデルとして,また脳の老化機構解析のモデルとして有用である.今回の3年間の研究で以下のような新しい知見を得た. 1)強制水泳実験による行動学的解析からP10が情動障害(うつ症状)を有すると考えられた.SAMP10の情動障害は三環系抗うつ薬デシプラミン投与により改善された. 2)P10脳の中脳領域(視床下部も含む)や大脳皮質では,D2/D3受容体結合量が有意に増加していた.5HT1A受容体結合は,P10海馬においてR1に比較し有意に増加していた. 3)記憶障害を発症するSAMP8(3-6ヶ月齢)にタマネギ水抽出物を2ヶ月間経口投与し(5ml/kg),Morris's water maze法で検討したところ,記憶障害の発症が改善された. 4)4血管閉塞(4VO)ラットの海馬Ca1領域のニューロン死および中大脳動脈結紮による永久全脳虚血(MCAO)ラットの脳梗塞巣のサイズは,dihydropyridine誘導体でありL型Caチャネル遮断作用とカルモジュリン拮抗作用を有するCV-159の経口投与(5-10mg/kg)により抑制された.さらに4VOラットにおいてGDNF(グリア細胞由来栄養因子)の海馬実質内への注入はCA1領域のニューロン死を抑制した.
  • 新規セカンドメッセンジャーCADP−リボースの安定な活性等価体の設計と合成
    日本学術振興会:科学研究費助成事業 基盤研究(C)
    研究期間 : 1997年 -1998年 
    代表者 : 周東 智
     
    最近、細胞内のCa動員を担う新しいセカンドメッセンジャーとしてサイクリックADP-リボース(cADP-リボース)が見いだされたが、酵素的に速やかに代謝されるばかりか、中性水溶液中でさえ容易に加水分解を受ける(半減期40時間)程不安定なために、その機能は十分解明されるに至っていない。 cADP-リボースはADPリボースのリボース部1-位とアデニン環のN1-位が分子内で、β-グリコシド結合した大環状構造を有するが、この分子内N-グルコシド結合がcADP-リボース水解酵素による切断部位であり、また、非酵素的にもこの部位で加水分解されることが知られている。即ちcADP-リボースの不安定性の原因は、このN-グルコシド結合にある。この知見より申請者は、生物学的にも化学的にも安定なcADP-リボースの等価体としてリボース環の酸素原子をメチレンで置き換えたcADPーカーボサイクリックリボースおよびそのイノシンアナログであるcIDPーカーボサイクリックリボースを設計し、合成を計画した。 今年度は、先ずより合成容易と考えられるcIDPーカーボサイクリックリボースの合成を検討した。その結果、シクロペンタジエンを原料に酵素的光学分割を経てカーボサイクリック部を構築し、イノシンユニットと縮合後、数行程を経て目的化合物を合成することに成功した。 現在、この方法を応用して次の目的化合物であるcADPーカーボサイクリックリボースの合成を検討中である。
  • リンパ節転移がんに有効な制がん剤ドラッグデリパリ-システムの開発
    日本学術振興会:科学研究費助成事業 重点領域研究
    研究期間 : 1997年 -1997年 
    代表者 : 周東 智
     
    (1)我々が開発した酵素的リン脂質誘導体の合成法を応用して、DPP-CNDACを大量合成する方法を確立し、活性評価用サンプル(10g)を合成した。リン脂質誘導体の化学合成は一般的には繁雑であり、また、CNDACは、2′-位で異性化しやすいために化学変換が困難であるが、我々が開発したホスフォリパーゼDの触媒するホスファチジル基転移反応を応用したホスファチジン酸エステルの合成法を用いることにより、DPP-CNDACを簡便に合成する方法を見い出すことができた。 (2)合成したDPP-CNDACの制がん活性をin vivoマウス腫瘍を用いて母化合物のDMDCと比較検討した。その結果、疑似リン脂質体に変換することで、CNDACの制がん活性が顕著に増強されることが明かとなった。例えば、皮下移植マウスM5076肉腫系で、DPP-CNDAC投与群(Day1,5,9,100mg/kg/day)は、21日後に93%の腫瘍増殖抑制率を示したが、同量(モル換算すると約1/3量に相当)CNDACを投与した群では、腫瘍増殖抑制率38%であった。また、化合物を経口投与した場合も同様にCNDACを凌ぐ強い制がん効果をDPP-CNDACが有することが明らかになった。 (3)分子設計した当初よりDPP-CNDACは、その構造からリポソーム化に好適であると推定していたが、実際極めて安定なDPP-CNDAC含有リポソームを容易に作製可能であることを確認した。さらに、DPP-CNDAC自身でリポソームを構成できることも判った。 (4)DPP-CNDAC含有の細網内皮系回避型リポソームの制がん効果を制がん活性をin vivoマウス腫瘍系を用いて検討した結果、リポソーム化することでDPP-CNDACの制がん活性が増強されることが判明した。例えば、皮下移植したマウスMethA繊維肉腫系では、DPP-CNDAC量として50/mg/kg(Day6,8,10,12,14)を投与すると、腫瘍の増殖がほぼ完全に抑制された。
  • 遅発性神経細胞死阻止薬の開発
    日本学術振興会:科学研究費助成事業 基盤研究(A)
    研究期間 : 1996年 -1997年 
    代表者 : 松田 彰, 吉井 清哲, 周東 智
     
    〈合成〉容易に入手可能(+)-または(-)-エピクロロヒドリンを出発原料として、多官能性の光学活性シクロプロパン誘導体を高い光学純度で簡便に合成できる新規な方法を開発した。この方法を用いて、目的の様々な立体構造を有するミルナシプラン配座制限誘導体を合成することができた。 〈薬理評価及び作用基序解析〉合成した化合物を以下のようなin vitro系での活性検討を行った。a)ラット海馬NMDA受容体における[^3H]MK-801をリガンドとする結合阻害実験による、同受容体に対する親和性;b)ラット大脳皮質セロトニントランスポーターに対する[^3H]パロキセチンをリガンドとする結合阻害実験によるセロトニン再取り込み阻害活性;c)ラット脳グルタミン酸受容体を発現させたアフリカツメガエル卵母細胞系における、NMDA受容体阻害効果。その結果、(1S,2R,2'S)-1-phenyl-2-(1-aminopropyl)-N,N-diethylcyclopropanecarboxamindes(PPDC)が強力かつ特異的なNMDA受容体阻害作用を有することを見い出した。e)PPDCは、NMDA受容体チャネルブロッカーとして作用する従来にないタイプの拮抗剤であることを確認した。f)培養神経細胞系で、NMDA誘発細胞死をPPDCが顕著に抑制することを確認した。
  • 比較的大きな分子サイズの基質を認識する輸送但体を介したドラッグデリバリーシステム
    日本学術振興会:科学研究費助成事業 基盤研究(A)
    研究期間 : 1995年 -1997年 
    代表者 : 加茂 直樹, 奈良 敏文, 渡辺 徹, 周東 智, 宮内 正二, 松田 彰
     
    比較的大きな分子サイズの基質を認識する輸送担体として、ペプチド輸送担体を取り上げた.ヒトの結腸ガン細胞由来の培養細胞であるCaco-2にはペプチド輸送担体としてPEPTIが発現している.この輸送担体は多様なアミノ酸配列のペプチドを効率よく取り込むための広い基質認識性を有している.そこで、細胞内での加水分解されにくいこと及び修飾に容易な反応基をもつという点を考慮し、Val-Lys-Sarを基本ペプチドとすることにした.細胞への取り込みの測定の容易さを考え、蛍光色素FITC(fluorescein isocyanate)およびcoumarin-3-carboxylic asidを上記のLysに付加することにした. この蛍光レポーター付きPEPTI基質のCaco-2細胞への取り込みを測定した.取り込み初速の濃度依存性を調べたところ、濃度に比例していた.PEPTIはH^+とのシンポーターであるので、脱共役剤であるCCCPによって取り込みは抑制される.実際、Lys-Sarは抑制が見られた.一方、本研究で合成した蛍光基質は、不思議なことに取り込み量が2〜3倍に増大した.文献ではCaco-2細胞には多剤排出輸送体が発現しているとの報告があるので、この排出輸送体によって排出されると考えた.この排出輸送体の基質であると考えられている薬物であるメトキサレートを共存下で蛍光基質の取り込み速度は有意に低下した.この発見を発展させれば、抗ガン剤の排出を止めることのできる薬物を合成できると考えられる.
  • 生体高分子機能を修飾する抗がん化合物の合成と作用解析
    日本学術振興会:科学研究費助成事業 重点領域研究
    研究期間 : 1996年 -1996年 
    代表者 : 松田 彰, 綿矢 祐佑, 堀田 清, 周東 智, 影近 弘之, 佐々木 琢磨
     
    本年度の研究で以下のことを明らかにした.昨年度合成した固形がんに優れた活性を示す3'-C-ethynyluridine (EUrd)および-cytidine (ECyd)の構造-活性相関を調べた。核酸塩基部を変換したエチニル体では活性が、cytosine>uracil>adenine>5-F-cytosine=5-Furacil>>thymine=guanineの順になった.一方、糖部置換基はアセチレン体が最も活性が高く、プロピン、ブチンにするに従い活性は減弱し、ビニル、エチル体はほとんど活性を示さなかった.新規ネオカルジノスタチンの10員環アナログの合成に成功した.本化合物はguanine選択的アルキル化を起こし、DNA切断に必須な構造は、単純な交差共役ジエインであることを明らかにした.タキシニンの化学修飾により分化誘導佐用を市示す化合物を得るとともに、光反応生成物がP糖蛋白質の機能阻害活性を有することを見い出した.抗腫瘍性天然物ハリコンドリンBの合成ルートをほぼ完了し、合成中間体のいくつかにcytotoxicな構造を見い出した.サイクリックADPリボース安定等価体であるカーボサイクリックIDPリボースを合成した.細胞分化の特異的調節因子であるレチノイン酸の作用を制御する化合物として、その拮抗物質、作用増強物質を合成し、核内レセプターレベルでの作用であることを明らかにした.PCNDACをリカンドとしたアフィニティークロマトグラフィーより、ATP存在下dCydをリン酸化する酵素を約2000倍に精製した.CNDAC, DMDCおよびaraCはがん遺伝子を導入した形質転換細胞に対しin vitoroとin vivoで異なる抗腫瘍性を示した.特に、CNDACはin vivoでDMDCやaraCに比して優れた活性を示した.これらの化合物に対する腫瘍細胞側の規定因子はdCyd kinaseの酵素活性と細胞内蓄積量であることを明らかにした.FUdRによるアポトーシスの誘導過程でプロテアーゼが関与することを明らかにした.
  • カルシウム動員細胞内情報伝達系作用分子の設計と合成
    研究期間 : 1996年
  • 新規ラジカル反応の開発と医薬化学への応用
    研究期間 : 1996年
  • Design and synthesis of novel intracellular Ca-mobilizing agents
    研究期間 : 1996年
  • Development of novel radical reactions and their application to medicinal chemical studies
    研究期間 : 1996年
  • 生体高分子機能を修飾する抗がん化合物の合成と作用解析
    日本学術振興会:科学研究費助成事業 重点領域研究
    研究期間 : 1995年 -1995年 
    代表者 : 松田 彰, 綿矢 有佑, 堀田 清, 周東 智, 影近 弘之, 佐々木 琢磨
     
    本年度の研究で以下のことを明らかにした.がん細胞のDNA,RNA合成の両者を阻害するヌクレオシドとして設計した3′-C-ethynyluridine(EUrd)および-cytidine(ECyd)はin vitroのみならずin vivoでも優れた抗がん性を示した.抗がん剤ネオカルチノスタチンの光分解経路の解明に成功し、新しい光缶応型のDNA切断分子を設計した.日本産イチイ葉から得られるタキシニンの化学修飾により分化誘導作用を示す化合物を得た.優れた抗がん性を示すハリコンドリンBの全合成にあと一歩のところまで近づいた.細胞分化の特異的調節因子であるレチノイン酸の作用を制御する化合物として、その拮抗物質、作用増強物質を合成した.サイクリックADPリボース安定等価体と考えられるカーボサイクリックIDPリボースを合成した.固形がんに有効な新規deoxycytidine誘導体KW-2331はがん細胞内で代謝活性化され、cytidine deaminaseにより不活性化されないことを明らかにした.ヒト腫瘍HT1080細胞のCNDAC耐性株はcytidine deaminase活性が親株より強く、deoxycytidine Kinase活性が低下していることを見い出した.アポトーシスを起こす細胞内のpHが酸性になり、新しいendonucleaseが活性化されDNA二本鎖を起こすことが判った.新規抗がん性ヌクレオシドCNDAC,DMDCの作用機序研究により、それらの抗がん性の発現にDNA修復系の関与を示唆する知見を得た.
  • リンパ節転移がんに対する化学療法剤の開発
    日本学術振興会:科学研究費助成事業 重点領域研究
    研究期間 : 1995年 -1995年 
    代表者 : 周東 智, 南川 典昭
     
    制がん性ヌクレオシドDMDC(我々の研究室で開発した制がん性ヌクレオシドで、固形がんを対象にした第一相臨床試験中)を活性本体とする、様々な飽和および不飽和のアシル基を有する制がん性疑似リン脂質である5′-フォスファチジルDMDCを合成した。リン脂質誘導体の化学合成は一般的に繁雑であるが、我々が開発したホスフォリパーゼDの触媒するホスファチジル基転移反応を応用したホスファチジン酸エステルの合成法を用いることにより、5′-フォスファチジルDMDCを簡便に合成することができた。 合成した5′-フォスファチジルDMDCの制がん活性をin vivoマウス腫瘍を用いて母化合物のDMDCと比較検討し、また、グリセロール部アシル基の制がん活性への効果を検討した。その結果、5′-フォスファチジル体に変換することで、DMDCの制がん活性が増強されることが明かとなった。ジパルミトイルタイプの5′-フォスファチジルDMDCが、特に優れた制がん活性を示し、例えば、腹腔移植マウスM5076肉種系では、ジパルミトイルタイプの5′-フォスファチジルDMDC投与群(Day 1-5, 300mg/kg/day)は、全マウスが60生存であったが、等モル量を投与したDMDC群では、1群4匹総てが60日以内に死亡した(平均生存日数45日)。 また、ラットに制がん性疑似リン脂質を経口投与したところ、期待しようにリンパ行性選択的に吸収されることが明かとなった。
  • シクロプロパン環の立体構造特性に基づく分子設計:NMDA受容体特異的拮抗剤の合成
    日本学術振興会:科学研究費助成事業 奨励研究(A)
    研究期間 : 1994年 -1994年 
    代表者 : 周東 智
     
    〈合成〉容易に入手可能(-)-エピクロロヒドリン(1)を出発原料として、鍵中間体であるラクトン体(4)を98%以上の光学純度で簡便に合成できた。このものより種々のアルキル基を有する配座制限誘導体(2aおよび3a)をそれぞれ立体選択的に合成することに成功した。同様にして(+)-エピクロロヒドリンより、2bおよび3bを合成した。 〈薬理評価及び作用基序解析〉合成した化合物をラット海馬NMDA受容体における|^3H|MK-801をリガンドとする結合阻害実験による親和性を検討したところ、2a(R=Me,Et)がIC50値が1μmol以下の顕著な同受容体に対する親和性を有することが判明した。また、ラット脳グルタミン酸受容体発現アフリカツメガエル卵母細胞系において、NMDA受容体拮抗作用を示すことが明かになった。
  • リンパ系への薬物ターゲッティングの合成化学的アプローチ
    日本学術振興会:科学研究費助成事業 奨励研究(A)
    研究期間 : 1993年 -1993年 
    代表者 : 周東 智
     
    リン脂質は、消化管内で酵素的に脱アシルの後、腸管細胞に吸収され、そこで再アシル化されてキロミクロンに取り込まれた後、血中には入らず、リンパ行性に吸収されることが知られている。酵素を利用するホスファチジン酸エステル類の一段階合成法を既に開発したので、種々の薬物のホスファチジル体を合成できる。5-フルオロウリジンが強い制癌活性を持ち、かつその強い紫外吸収によりHPLCを用いた体内動態解析が容易なことから、1,2-ジパルミトイル型の5′-フォスファチオジル-5-フルオロウリジン(1)を合成し、基礎検討を行なった。 1をラットに経口投与後、腸管内液、胸管リンパ液中およ血液をHPLC分析し、1または1由来の化合物を検索した。その結果、グリセロール部2-位が長鎖不飽和脂肪アシル基であるリノレオイル基またはアラキドノイル基で置換した2及び3が血中に比べて約30倍の高濃度でリンパ液中に存在することが確認された。この結果から、当初想定したように、天然リン脂質に特異的な吸収機構によって1が経口吸収されたことが示唆された。
  • リポリームなどDDSの工夫を加えたヌクレオシド系抗寄生原虫剤の開発研究
    日本学術振興会:科学研究費助成事業 試験研究(B)
    研究期間 : 1990年 -1992年 
    代表者 : 石井 明, 朝日 博子, 松田 彰, 保田 立二, 太田 伸生, 綿矢 有佑, 周東 智, 安田 新
     
    カラ・アザールなどリーシュマニア症の病原体であるLeishmania donovaniのin vitro培養を行い、原虫をマウスに接種して薬物の効果を検定してきた。Pentostamを陽性対照として、マウス肝細胞の原虫寄生を示標としてL.D.unitを出した。sulfamoyldapsone(SDDS)についての成績をまとめて報告公表した。SDDS100mg/kg経口投与は感染后13日間で70%抑制率を示し、100mg/kg筋肉注射5回投与で65%抑制を示した。リポソームに封入した5mg/kg静脈内注射では抑制率51%であった。SDDはL.donovaniに治療薬となりうると考えられた。3-deoxyinosineの関連化合物を3種類合成したが、L.donovaniのマウス感染性の低下などの問題が生じ、現在効力検定系の再構築中である。リポソーム封入の条件、改良などについては別途進行中である。Trypanosome cruziについてin vitro培養系のシステムを構築しPentamidineを陽生対照として効力検査のシステムを構築したが、各種抗生部質の中に一二、効力を示すものがあったが、特別のものは未だでていない。熱帯熱マラリアPlasmodium falciparumについてはin vitro培養系をつくり、原虫血症を算定するシステムを構築したが、算定に手数と時間が必要で、未だ充分に活用できていない。Plasmodium bergheiネズミマラリアのin vivoのシステムで生存をみる系をも加えて別の化合物の効果をみた成績が協力研究者により出されたので、将来は各系で調べる事が可能であると考えられる。イノシン系化合物は南米のLeishmania感染患者の皮膚病変に対し軟膏を作り試して貰う機会があったが、濃度の関係か有効な成績は得られていない。
  • NMDA受容体拮抗剤の設計と合成
    研究期間 : 1992年
  • Synthesis of NMDA receptor antagonists
    研究期間 : 1992年
  • 機能性リン脂質の合成研究
    研究期間 : 1990年
  • Synthesis of pseudo-phospholipids of biological activities.

教育活動情報

主要な担当授業

  • 大学院共通授業科目(一般科目):自然科学・応用科学
    開講年度 : 2021年
    課程区分 : 修士課程
    開講学部 : 大学院共通科目
    キーワード : 創薬化学 ドラッグデザイン 配座制限 神経伝達物質 セカンドメッセンジャー 情報伝達 酵素阻害剤 X-線結晶構造解析 ケミカルバイオロジー 標的同定 作用機序 天然生理活性物質 標的志向合成 構造活性相関 がん薬物療法
  • 創薬化学特論
    開講年度 : 2021年
    課程区分 : 修士課程
    開講学部 : 生命科学院
    キーワード : 創薬化学 ドラッグデザイン 配座制限 神経伝達物質 セカンドメッセンジャー 情報伝達 酵素阻害剤 X-線結晶構造解析 ケミカルバイオロジー 標的同定 作用機序 天然生理活性物質 標的志向合成 構造活性相関 がん薬物療法
  • 生命医薬科学概論
    開講年度 : 2021年
    課程区分 : 修士課程
    開講学部 : 生命科学院
    キーワード : (生命医薬科学概論) 有機合成化学,天然物化学,神経,免疫,蛋白質,脂質,遺伝子解析,RNA,バイオイメージング解析,薬剤吸収,薬物送達,痛み,立体構造 (生命融合科学概論/ソフトマター科学概論) 生命融合科学,生命情報分子科学,生命物質科学,細胞機能科学,生命機能制御科学,ソフトマター科学,ソフトマター材料科学,ソフトマター生命分子科学,ソフトマター生体物理学,ソフトマター医科学,SDGs (生命システム科学概論) 細胞増殖,細胞極性,細胞分化,形態形成,遺伝子発現,植物免疫,神経回路,動物行動学,能科学,生殖機構,発生,内分泌,ホルモン,オムニバス,現代生命科学,知的財産
  • 創薬化学
    開講年度 : 2021年
    課程区分 : 学士課程
    開講学部 : 薬学部
    キーワード : 創薬 分子設計 ファーマコフォア 標的分子 構造活性相関
  • 医薬品開発論
    開講年度 : 2021年
    課程区分 : 学士課程
    開講学部 : 薬学部
    キーワード : 非臨床試験 臨床試験 市販後調査 医薬品開発

大学運営

委員歴

  • 2015年04月 - 現在   抗ウイスル療法学会   理事
  • 2016年04月 - 2018年03月   日本薬学会   理事


Copyright © MEDIA FUSION Co.,Ltd. All rights reserved.