研究者データベース

研究者情報

マスター

アカウント(マスター)

  • 氏名

    市川 聡(イチカワ サトシ), イチカワ サトシ

所属(マスター)

  • 薬学研究院 創薬科学研究教育センター

所属(マスター)

  • 薬学研究院 創薬科学研究教育センター

独自項目

syllabus

  • 2020, 創薬化学特論, Medicinal Chemistry, 修士課程, 生命科学院, 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
  • 2020, 化学Ⅱ, Chemistry II, 学士課程, 全学教育, 有機化合物、官能基、分子構造、化学的性質、化学反応、機能性有機物、生体関連有機物質
  • 2020, 有機化学Ⅲ, Organic Chemistry III, 学士課程, 薬学部, ハロゲン化アルキル、アルコール、アミン、エーテル、エポキシド、含硫黄化合物、有機金属化合物、求核置換反応、脱離反応、立体化学、位置選択性、酸化
  • 2020, 健康と社会, Health and Society, 学士課程, 全学教育, 創薬、生命科学、物理化学、有機化学、生化学、薬理学、薬剤学、医療薬学
  • 2020, 薬学英語Ⅱ, Pharmaceutical English Ⅱ, 学士課程, 薬学部

timetable

  • 修士課程, 生命科学院, 2020, 生命科学研究
  • 修士課程, 生命科学院, 2020, 生命科学実習
  • 修士課程, 生命科学院, 2020, 生命科学論文講読Ⅰ
  • 修士課程, 生命科学院, 2020, 生命科学論文講読Ⅱ
  • 博士後期課程, 生命科学院, 2020, 生命科学特別研究
  • 博士後期課程, 生命科学院, 2020, 生命科学文献講読
  • 学士課程, 薬学部, 2020, 卒業研究準備実習Ⅰ
  • 学士課程, 薬学部, 2020, 卒業研究準備実習Ⅱ
  • 学士課程, 薬学部, 2020, 薬学論文講読演習Ⅰ
  • 学士課程, 薬学部, 2020, 薬学論文講読演習Ⅱ
  • 学士課程, 薬学部, 2020, 薬学論文講読演習Ⅲ
  • 学士課程, 薬学部, 2020, 薬学総合演習
  • 学士課程, 薬学部, 2020, 薬学卒業研究
  • 学士課程, 薬学部, 2020, 薬科学演習
  • 学士課程, 薬学部, 2020, 薬科学論文講読演習
  • 学士課程, 薬学部, 2020, 薬科学卒業研究

researchmap

プロフィール情報

学位

  • 博士(薬学)(北海道大学)

プロフィール情報

  • 市川, イチカワ
  • 聡, サトシ
  • ID各種

    200901036483434351

対象リソース

業績リスト

研究キーワード

  • 天然物化学   創薬化学   医薬品化学   有機合成化学   Medicinal Chemistry   Organic Chemistry   

研究分野

  • ライフサイエンス / 薬系化学、創薬科学

経歴

  • 2015年04月 - 現在 北海道大学大学院薬学研究院 教授
  • 2009年04月 - 2015年03月 北海道大学大学院薬学研究院 准教授
  • 2007年04月 - 2009年03月 北海道大学大学院薬学研究院 助教
  • 2001年07月 - 2002年03月 北海道大学大学院薬学研究科 助手
  • 2001年 - 2002年 Graduate School of Pharmaceutical,
  • 1999年04月 - 2001年06月 米国Scripps研究所 博士研究員
  • 1999年 - 2001年 Scripps Research Institute.
  • 北海道大学
  • Postdoctoral Research Associate

学歴

  •         - 1999年   北海道大学   薬学研究科   薬学
  •         - 1999年   北海道大学
  •         - 1994年   北海道大学   薬学部   薬化学
  •         - 1994年   北海道大学

委員歴

  • 2017年04月 - 現在   北見北斗高校スーパーサイエンスハイスクール   研究サポートチーム
  • 2016年10月 - 2017年09月   第59回天然有機化合物討論会   実行委員長

受賞

  • 2012年 日本学術振興会 科研費審査委員表彰
     
    受賞者: 市川 聡
  • 2008年03月 日本薬学会奨励賞
     
    受賞者: 市川 聡
  • 2005年12月 日本薬学会北海道支部奨励賞
     
    受賞者: 市川 聡

論文

  • Yuma Terasawa, Chisato Sataka, Toyotaka Sato, Kazuki Yamamoto, Yukari Fukushima, Chie Nakajima, Yasuhiko Suzuki, Akira Katsuyama, Takanori Matsumaru, Fumika Yakushiji, Shin-Ichi Yokota, Satoshi Ichikawa
    Journal of medicinal chemistry 63 17 9803 - 9827 2020年09月10日 [査読有り][通常論文]
     
    The synthesis and biological evaluation of analogues of uridylpeptide antibiotics were described, and the molecular interaction between the 3'-hydroxy analogue of mureidomycin A (3'-hydroxymureidomycin A) and its target enzyme, phospho-MurNAc-pentapeptide transferase (MraY), was analyzed in detail. The structure-activity relationship (SAR) involving MraY inhibition suggests that the side chain at the urea-dipeptide moiety does not affect the MraY inhibition. However, the anti-Pseudomonas aeruginosa activity is in great contrast and the urea-dipeptide motif is a key contributor. It is also suggested that the nucleoside peptide permease NppA1A2BCD is responsible for the transport of 3'-hydroxymureidomycin A into the cytoplasm. A systematic SAR analysis of the urea-dipeptide moiety of 3'-hydroxymureidomycin A was further conducted and the antibacterial activity was determined. This study provides a guide for the rational design of analogues based on uridylpeptide antibiotics.
  • Jun Hirabayashi, Fumika Yakushiji, Akira Katsuyama, Satoshi Ichikawa
    Organic letters 22 14 5545 - 5549 2020年07月17日 [査読有り][通常論文]
     
    Acaulide and acaulone A, which contain 14-membered macrodiolides, were isolated from a culture of Acaulium sp. H-JQSF. The antiosteoporosis activity of acaulide is expected to contribute to drug discovery research for an aging society. We herein report the first total synthesis of acaulide, acaulone A, and 10-keto-acaudiol A. Acaulide and acaulone A were synthesized via the late stage Michael addition to the 14-membered macrodiolide, which was inspired by plausible biosynthetic pathways. This approach succeeded in the construction of the acaulide skeleton, which revealed the specific conformation of the 14-membered macrodiolide for late stage functionalization.
  • Keita Kojima, Fumika Yakushiji, Akira Katsuyama, Satoshi Ichikawa
    Organic letters 22 11 4217 - 4221 2020年06月05日 [査読有り][通常論文]
     
    The first total synthesis of echinomycin (1) was accomplished by featuring the late-stage construction of the thioacetal moiety via Pummerer rearrangement and simultaneous cyclization, as well as two-directional elongation of the peptide chains to construct a C2-symmetrical bicyclic octadecadepsipeptide bridged with a sulfide linkage. This strategy can be applicable to a variety of echinomycin analogues.
  • Shun Kitahata, Akira Katsuyama, Satoshi Ichikawa
    Organic letters 22 7 2697 - 2701 2020年04月03日 [査読有り][通常論文]
     
    A synthesis strategy for the production of a key synthetic intermediate of gulmirecin A was described. The key reaction in the preparation of the 12-membered macrolactone is the Ni(0)-mediated reductive cyclization reaction of ynal using an N-heterocyclic carbene ligand and silane reductant. In addition, the α-selective glycosylation reaction of the macrolactone was performed to demonstrate the synthesis of gulmirecin and disciformycin precursors.
  • Xiaojun Liu, Yingjun Jiang, Billie Nowak, Satoshi Ichikawa, Masaki Ohtawa, Akira Matsuda, William Plunkett
    Cancer chemotherapy and pharmacology 85 4 661 - 672 2020年04月 [査読有り][通常論文]
     
    PURPOSE: We postulate that the deoxyguanosine analogue CNDAG [9-(2-C-cyano-2-deoxy-1-β-D-arabino-pentofuranosyl)guanine] likely causes a single-strand break after incorporation into DNA, similar to the action of its cytosine congener CNDAC, and that subsequent DNA replication across the unrepaired nick would generate a double-strand break. This study aimed at identifying cellular responses and repair mechanisms for CNDAG prodrugs, 2-amino-9-(2-C-cyano-2-deoxy-1-β-D-arabino-pentofuranosyl)-6-methoxy purine (6-OMe) and 9-(2-C-cyano-2-deoxy-1-β-D-arabino-pentofuranosyl)-2,6-diaminopurine (6-NH2). Each compound is a substrate for adenosine deaminase, the action of which generates CNDAG. METHODS: Growth inhibition assay, clonogenic survival assay, immunoblotting, and cytogenetic analyses (chromosomal aberrations and sister chromatid exchanges) were used to investigate the impact of CNDAG on cell lines. RESULTS: The 6-NH2 derivative was selectively potent in T cell malignant cell lines. Both prodrugs caused increased phosphorylation of ATM and its downstream substrates Chk1, Chk2, SMC1, NBS1, and H2AX, indicating activation of ATM-dependent DNA damage response pathways. In contrast, there was no increase in phosphorylation of DNA-PKcs, which participates in repair of double-strand breaks by non-homologous end-joining. Deficiency in ATM, RAD51D, XRCC3, BRCA2, and XPF, but not DNA-PK or p53, conferred significant clonogenic sensitivity to CNDAG or the prodrugs. Moreover, hamster cells lacking XPF acquired remarkably more chromosomal aberrations after incubation for two cell cycle times with CNDAG 6-NH2, compared to the wild type. Furthermore, CNDAG 6-NH2 induced greater levels of sister chromatid exchanges in wild-type cells exposed for two cycles than those for one cycle, consistent with increased double-strand breaks after a second S phase. CONCLUSION: CNDAG-induced double-strand breaks are repaired mainly through homologous recombination.
  • Fumika Yakushiji, Aoi Ishikawa, Akira Katsuyama, Satoshi Ichikawa
    Bioorganic & medicinal chemistry letters 30 2 126839 - 126839 2020年01月15日 [査読有り][通常論文]
     
    Kaposi's sarcoma-associated herpesvirus (KSHV) is known to be a carcinogenic agent that causes AIDS-associated Kaposi's sarcoma (KS). When KSHV infects host's cells, one of the virus's proteins, latency-associated nuclear antigen 1 (LANA), binds to the host's nucleosomes to retain episomes and create latency circumstances. Although the infectious mechanism of KSHV is partly elucidated, the development of drug candidates for targeting KS is ongoing. In this study, we developed cyclic peptides corresponding to an N-terminal LANA sequence that disrupt the LANA-nucleosome interaction. The cyclic peptides showed a different secondary structure compared to their corresponding linear peptide derivatives, which suggests that our cyclization strategy imitates the N-terminal LANA binding conformation on nucleosomes.
  • Kazuki Yamamoto, Toyotaka Sato, Yuta Hikiji, Akira Katsuyama, Takanori Matsumaru, Fumika Yakushiji, Shin-Ichi Yokota, Satoshi Ichikawa
    Nucleosides, nucleotides & nucleic acids 39 1-3 349 - 364 2020年 [査読有り][通常論文]
     
    Tunicamycins, which are nucleoside natural products, inhibit both bacterial phospho-N-acetylmuraminic acid (MurNAc)-pentapeptide translocase (MraY) and human UDP-N-acetylglucosamine (GlcNAc): polyprenol phosphate translocase (GPT). The improved synthesis and detailed biological evaluation of an MraY-selective inhibitor, 2, where the GlcNAc moiety was modified to a MurNAc amide, has been described.
  • Kazuki Yamamoto, Satoshi Ichikawa
    The Journal of antibiotics 72 12 924 - 933 2019年12月 [査読有り][通常論文]
     
    Tunicamycins are nucleoside natural products and show antibacterial, antiviral and antitumor activities, which are attributed to their inhibition of enzymatic reactions between polyisoprenyl phosphate and UDP-GlcNAc or UDP-MurNAc-pentapeptide. Because of their various intriguing biological activities, tunicamycins have potential as therapeutic agents for infectious diseases or cancers. Structurally, tunicamycins have a unique structure composed of an undecodialdose skeleton, a lipid chain and a GlcNAc fragment linked by a 1,1-β,α-trehalose-type glycosidic bond. In this mini review, we summarize the total chemical syntheses and biosynthetic studies of tunicamycins.
  • Kengo Shigetomi, Albertus Eka Yudistira Sarwono, Satoshi Ichikawa, Makoto Ubukata
    The Journal of antibiotics 72 12 934 - 942 2019年12月 [査読有り][通常論文]
     
    We have found cyclophane-type adenosine derivatives having p-quinone amide moieties (1 and 2) as weak inhibitors of Cryptosporidium parvum inosine 5'-monophosphate dehydrogenase (CpIMPDH) from the Hokkaido University Chemical Library via the luciferase-based high-throughput screening. To obtain more potent inhibitors, we synthesized four new derivatives free from cyclophane rings (3-6). The N-H derivatives 3 and 5 showed more potent activities (24.4 and 11.1 μM, respectively) in the presence of dithiothreitol (DTT), whereas the N-methyl derivative 4 indicated more potent activity (2.1 μM) without DTT. Conformational analysis of compounds 3 and 4 suggested that N-H amide 3 binds to IMP-binding site in the DTT mediated manner.
  • Ellene H Mashalidis, Benjamin Kaeser, Yuma Terasawa, Akira Katsuyama, Do-Yeon Kwon, Kiyoun Lee, Jiyong Hong, Satoshi Ichikawa, Seok-Yong Lee
    Nature communications 10 1 2917 - 2917 2019年07月02日 [査読有り][通常論文]
     
    Novel antibacterial agents are needed to address the emergence of global antibiotic resistance. MraY is a promising candidate for antibiotic development because it is the target of five classes of naturally occurring nucleoside inhibitors with potent antibacterial activity. Although these natural products share a common uridine moiety, their core structures vary substantially and they exhibit different activity profiles. An incomplete understanding of the structural and mechanistic basis of MraY inhibition has hindered the translation of these compounds to the clinic. Here we present crystal structures of MraY in complex with representative members of the liposidomycin/caprazamycin, capuramycin, and mureidomycin classes of nucleoside inhibitors. Our structures reveal cryptic druggable hot spots in the shallow inhibitor binding site of MraY that were not previously appreciated. Structural analyses of nucleoside inhibitor binding provide insights into the chemical logic of MraY inhibition, which can guide novel approaches to MraY-targeted antibiotic design.
  • Yusaku Nomura, Frédéric Thuaud, Daisuke Sekine, Akihiro Ito, Satoko Maeda, Hiroyuki Koshino, Daisuke Hashizume, Atsuya Muranaka, Thomas Cruchter, Masanobu Uchiyama, Satoshi Ichikawa, Akira Matsuda, Minoru Yoshida, Go Hirai, Mikiko Sodeoka
    Chemistry (Weinheim an der Bergstrasse, Germany) 25 35 8387 - 8392 2019年06月21日 [査読有り][通常論文]
     
    A synthetic methodology to access all possible stereoisomers of spectomycin A1 (SMA1) and A2 (SMA2) has been established through late-stage diversification. The key reaction for the construction of all four diastereomers is an intramolecular cyclization based on the umpolung of π-allyl palladium species with bis(pinacolato)diborane (B2 (pin)2 ). Silyl group assisted direct benzylic oxidation of each isomer enabled construction of the fragile β-hydroxytetralone skeleton to provide the SMAs. The relative and absolute stereochemistry of SMA2 was also determined, and the absolute stereochemistry of SMA1 was extrapolated based on the optical rotation of SMA2. The axial chirality of SMAs is discussed based on circular dichroism spectra and DFT calculations, and it is concluded that the M isomer is predominant in solution. Biochemical assessment of all isomers in vitro revealed that the C9 hydroxyl group and dimeric structure were both important for protein SUMOylation-inhibitory activity.
  • Kazuki Yamamoto, Akira Katsuyama, Satoshi Ichikawa
    Bioorganic & medicinal chemistry 27 8 1714 - 1719 2019年04月15日 [査読有り][通常論文]
     
    Elucidating a structure-activity relationship study by evaluating a series of truncated analogues is a simple but important and effective tactic in medicinal chemistry based on natural products with a large and complex chemical structure. In this study, a series of truncated analogues of tunicamycin V were designed and synthesized and their MraY inhibitory activity was investigated in order to gain insight into the effect of these moieties on MraY inhibition.
  • Yukiko Kasai, Kousuke Sato, Shohei Utsumi, Satoshi Ichikawa
    Chembiochem : a European journal of chemical biology 19 17 1866 - 1872 2018年09月04日 [査読有り][通常論文]
     
    DNA cytosine 5-methyltransferase (DNMT) catalyzes methylation at the C5 position of the cytosine residues in the CpG sequence. Aberrant DNA methylation patterns are found in cancer cells. Therefore, inhibition of human DNMT is an effective strategy for treating various cancers. The inhibitors of DNMT have an electron-deficient nucleobase because this group facilitates attack by the catalytic Cys residue in DNMTs. Recently, we reported the synthesis and properties of mechanism-based modified nucleosides, 2-amino-4-halopyridine-C-nucleosides (dX P), as inhibitors of DNMT. To develop a more efficient inhibitor of DNMT for oligonucleotide therapeutics, oligodeoxyribonucleotides (ODNs) containing other nucleoside analogues, which react more quickly with DNMT, are needed. Herein, we describe the design, synthesis, and evaluation of the properties of 2-amino-3-cyano-4-halopyridine-C-nucleosides (dX PCN ) and ODNs containing dX PCN , as more reactive inhibitors of DNMTs. Nucleophilic aromatic substitution (SN Ar) of the designed nucleosides, dX PCN , was faster than that of dX P, and the ODN containing dX PCN effectively formed a complex with DNMTs. This study suggests that the incorporation of an electron-withdrawing group would be an effective method to increase reactivity toward the nucleophile of the DNMTs, while maintaining high specificity.
  • Yuhei Kinoshita, Fumika Yakushiji, Hidehito Matsui, Hideaki Hanaki, Satoshi Ichikawa
    Bioorganic & medicinal chemistry letters 28 16 2713 - 2716 2018年09月01日 [査読有り][通常論文]
     
    A structure-activity relationship study on three classes of polymyxin analogues focusing on hydrophobicity was conducted.
  • Kitahata Shun, Yakushiji Fumika, Ichikawa Satoshi
    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 256 2018年08月19日 [査読有り][通常論文]
  • Katsuyama Akira, Yakushiji Fumika, Ichikawa Satoshi
    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 256 2018年08月19日 [査読有り][通常論文]
  • Katsuyama A, Yakushiji F, Ichikawa S
    The Journal of organic chemistry 83 13 7085 - 7101 2018年07月06日 [査読有り][通常論文]
     
    Full details of our synthetic studies toward plusbacin A3 (1), which is a depsipeptide with antibacterial activity, and its dideoxy derivative are described. To establish an efficient synthetic route of 1, a solvent-dependent diastereodivergent Joullié-Ugi three-component reaction (JU-3CR) was used to construct trans-Pro(3-OH) in a small number of steps. Two strategies were investigated toward the total synthesis. In the first synthetic strategy, the key steps were the trans-selective JU-3CR and a macrolactonization at the final stage of the synthesis. The JU-3CR using alkyl isocyanides in 1,1,1,3,3,3-hexafluoroisopropanol provided the trans products, and the coupling of the fragments to prepare the macrocyclization precursor proceeded smoothly. However, attempts toward the macrolactonization did not provide the desired product. Then, the second strategy that included esterification in an initial stage was investigated. Methods for constructing trans-Pro(3-OH) were examined using a convertible isocyanide, which could be converted to a carboxylic acid required for the following amidation. Ester bond formation was achieved through an intermolecular coupling using a hydroxyl-Asp derivative and the corresponding alcohol, and the amidation afforded a linear depsipeptide. The macrolactamization of the linear peptide gave the cyclic depsipeptide, and then the global deprotection accomplished the total synthesis of 1 and its dideoxy derivative.
  • Shohei Utsumi, Kousuke Sato, Satoshi Ichikawa
    Bioorganic & medicinal chemistry letters 28 12 2189 - 2194 2018年07月01日 [査読有り][通常論文]
     
    DNA cytosine-5 methyltransferase (DNMT) catalyzes methylation at the C5 position of cytosine in the CpG sequence in double stranded DNA to give 5-methylCpG (mCpG) in the epigenetic regulation step in human cells. The entire reaction mechanism of DNMT is divided into six steps, which are scanning, recognition, flipping, loop locking, methylation, and releasing. The methylation and releasing mechanism are well-investigated; however, few reports are known about other reaction steps. To obtain insight into the reaction mechanism, we planned the incorporation of acyclic nucleosides, which make it easy to flip out the target nucleobase, into oligodeoxynucleotides (ODNs) and investigated the interaction between the ODN and DNMT. Here, we describe the design and synthesis of ODNs containing new acyclic 5-fluorocytosine nucleosides and their physiological and biological properties, including their interactions with DNMT. We found that the ODNs containing the acyclic 5-fluorocytosine nucleoside showed higher flexibility than those that contain 5-fluoro-2'-deoxycytidine. The observed flexibility of ODNs is expected to influence the scanning and recognition steps due to the decrease in helicity of the B-form.
  • Paulina D Anindita, Michihito Sasaki, Kazuma Okada, Naoto Ito, Makoto Sugiyama, Noriko Saito-Tarashima, Noriaki Minakawa, Satoshi Shuto, Satoko Otsuguro, Satoshi Ichikawa, Akira Matsuda, Katsumi Maenaka, Yasuko Orba, Hirofumi Sawa
    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.
  • Kousuke Sato, Yuma Kunitomo, Yukiko Kasai, Shohei Utsumi, Isao Suetake, Shoji Tajima, Satoshi Ichikawa, Akira Matsuda
    Chembiochem : a European journal of chemical biology 19 8 865 - 872 2018年04月16日 [査読有り][通常論文]
     
    In chromatin, 5-methylcytosine (mC), which represents the fifth nucleobase in genomic DNA, plays a role as an inducer of epigenetic changes. Tumor cells exhibit aberrant DNA methylation patterns, and inhibition of human DNA cytosine-5 methyltransferase (DNMT), which is responsible for generating mC in CpG sequences, is an effective strategy to treat various cancers. Here, we describe the design, synthesis, and evaluation of the properties of 2-amino-4-halopyridine-C-nucleosides (dX P) and oligodeoxyribonucleotides (ODNs) containing dX P as a novel mechanism-based inhibitor of DNMTs. The designed ODN containing X PpG forms a complex with DNMTs by covalent bonding through a nucleophilic aromatic substitution (SN Ar) reaction, and its cell proliferation activity is investigated. This study suggests that dX P in a CpG sequence of DNA could serve as a potential nucleic acid drug lead in cancer chemotherapy and a useful chemical probe for studies of epigenetics. Our molecular design using a SN Ar reaction would be useful for DNMTs and other protein-DNA interactions.
  • Jiho Yoo, Ellene H Mashalidis, Alvin C Y Kuk, Kazuki Yamamoto, Benjamin Kaeser, Satoshi Ichikawa, Seok-Yong Lee
    Nature structural & molecular biology 25 3 217 - 224 2018年03月 [査読有り][通常論文]
     
    N-linked glycosylation is a predominant post-translational modification of protein in eukaryotes, and its dysregulation is the etiology of several human disorders. The enzyme UDP-N-acetylglucosamine:dolichyl-phosphate N-acetylglucosaminephosphotransferase (GlcNAc-1-P-transferase or GPT) catalyzes the first and committed step of N-linked glycosylation in the endoplasmic reticulum membrane, and it is the target of the natural product tunicamycin. Tunicamycin has potent antibacterial activity, inhibiting the bacterial cell wall synthesis enzyme MraY, but its usefulness as an antibiotic is limited by off-target inhibition of human GPT. Our understanding of how tunicamycin inhibits N-linked glycosylation and efforts to selectively target MraY are hampered by a lack of structural information. Here we present crystal structures of human GPT in complex with tunicamycin. Structural and functional analyses reveal the difference between GPT and MraY in their mechanisms of inhibition by tunicamycin. We demonstrate that this difference could be exploited to design MraY-specific inhibitors as potential antibiotics.
  • Yoshida T, Ri M, Kanamori T, Aoki S, Ashour R, Kinoshita S, Narita T, Totani H, Masaki A, Ito A, Kusumoto S, Ishida T, Komatsu H, Kitahata S, Chiba T, Ichikawa S, Iida S
    Oncotarget 9 11 9975 - 9991 2018年02月09日 [査読有り][通常論文]
     
    Proteasome inhibitors (PI), mainly targeting the β5 subunit of the 20S proteasome, are widely used in the treatment of multiple myeloma (MM). However, PI resistance remains an unresolved problem in the therapy of relapsed and refractory MM. To develop a new PI that targets other proteasome subunits, we examined the anti-MM activity of a novel syringolin analog, syringolog-1, which inhibits the activity of both the β5 and β2 subunits. Syringolog-1 exhibited marked cytotoxicity against various MM cell lines and anti-tumor activity towards bortezomib (Btz)-resistant MM cells through the dual inhibition of chymotrypsin-like (β5 subunit) and trypsin-like (β2 subunit) activities. MM cells, including Btz-resistant cells, showed elevated CHOP and NOXA expression after syringolog-1 treatment, indicating the induction of excessive endoplasmic reticulum stress during syringolog-1 treatment. Similar activities of syringolog-1 were also observed in freshly prepared MM cells derived from patients. To clarify the anti-tumor mechanism of dual inhibition of both the β5 and β2 subunits of the proteasome, PSMB5 and PSMB7 were co-inhibited in MM cells. This resulted in increased apoptosis of MM cells accompanied by accumulation of ubiquitinated proteins compared to inhibition of either PSMB7 or PSMB5 alone, indicating an enhanced effect by double inhibition of β2 and β5 activities. In conclusion, this syringolin analog, a dual inhibitor of proteasome β2 and β5 activities, exhibited potent anti-tumor effects on MM cells and may be useful for overcoming Btz-resistance in the treatment of MM.
  • Kazuki Yamamoto, Fumika Yakushiji, Takanori Matsumaru, Satoshi Ichikawa
    Organic letters 20 1 256 - 259 2018年01月05日 [査読有り][通常論文]
     
    The total synthesis of tunicamycin V is described. This strategy is based on the initial construction of tunicaminyluracil, which is regarded to play an important role in the observed biological activities. The key to the synthesis was a Mukaiyama aldol reaction followed by a furan-oxidation to construct the undecose skeleton, a [3,3] sigmatropic rearrangement of a cyanate, and a highly selective trehalose-type glycosylation.
  • Akira Katsuyama, Kousuke Sato, Fumika Yakushiji, Takanori Matsumaru, Satoshi Ichikawa
    Chemical & pharmaceutical bulletin 66 1 84 - 95 2018年 [査読有り][通常論文]
     
    A solid-phase synthesis of Park nucleotide as well as lipids I and II analogues, which is applicable to the synthesis of a range of analogues, is described in this work. This technique allows highly functionalized macromolecules to be modularly labeled. Multiple steps are used in a short time (4 d) with a single purification step to synthesize the molecules by solid-phase synthesis.
  • Akira Katsuyama, Satoshi Ichikawa
    Chemical & pharmaceutical bulletin 66 2 123 - 131 2018年 [査読有り][通常論文]
     
    Muraymycins, isolated from a culture broth of Streptomyces sp., are members of a class of naturally occurring nucleoside antibiotics. They are strong inhibitors of the phospho-MurNAc-pentapeptide translocase (MraY), which is responsible for the peptidoglycan biosynthesis. Since MraY is an essential enzyme among bacteria, muraymycins are expected to be a novel antibacterial agent. In this review, our efforts to synthesize muraymycin D2, simplify the chemical structure, improve antibacterial spectrum, and solve the X-ray crystal structure of the muraymycin D2/MraY complex are described.
  • Akira Katsuyama, Atmika Paudel, Suresh Panthee, Hiroshi Hamamoto, Toru Kawakami, Hironobu Hojo, Fumika Yakushiji, Satoshi Ichikawa
    Organic letters 19 14 3771 - 3774 2017年07月21日 [査読有り][通常論文]
     
    The total synthesis of plusbacin A3 (1) has been accomplished using a solvent-dependent diastereodivergent Joullié-Ugi three-component reaction (JU-3CR) as a key step. Two trans-3-hydroxy-l-proline residues were constructed by combining the JU-3CR with a convertible isocyanide strategy. Subsequent peptide coupling and macrolactamization afforded plusbacin A3. Investigating the antibacterial activity of 1 compared with that of its dideoxy analogue revealed that the threo-β-hydroxyaspartic acid residues are essential for antibacterial activity. Notably, there is a low potential for the development of resistance in S. aureus against plusbacin A3.
  • 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15日 [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.
  • Kitahata, Shun, Yakushiji, Fumika, Ichikawa, Satoshi
    Chem. Sci. 8 6959 - 6963 2017年 [査読有り][通常論文]
  • Takashi Yoshida, Masaki Ri, Shiori Kinoshita, Tomoko Narita, Haruhito Totani, Reham Ashour, Ayako Masaki, Asahi Ito, Shigeru Kusumoto, Takashi Ishida, Hirokazu Komatsu, Satoshi Ichikawa, Shinsuke Iida
    BLOOD 128 22 2016年12月 [査読有り][通常論文]
     
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  • Kousuke Sato, Kyoji Kawamoto, Shintaro Shimamura, Satoshi Ichikawa, Akira Matsuda
    Bioorganic & medicinal chemistry letters 26 22 5395 - 5398 2016年11月15日 [査読有り][通常論文]
     
    5-Methylcytosine (mC) is known to induce epigenetic changes. Ten-eleven translocation (TET) enzymes produce the further oxidized 5-substituted cytosine derivatives, 5-formylcytosine (fC) and 5-carboxylcytosine (caC). However, their roles are unclear thus far. Here, we synthesized oligodeoxyribonucleotides (ODNs) containing 5-formyl-2'-deoxycytidine and examined their interactions with DNA cytosine-5 methyltransferase (DNMT). We found that the ODN sequence containing fCpG formed a covalent complex with both bacterial and mouse recombinant DNMTs in the absence of any cofactors. The covalent bonding with DNMT suggests that the fCpG sequence in DNA may play a role in epigenetic regulation.
  • Yoshihiro Tsukamoto, Naoki Ohtsu, Smile Echizenya, Satoko Otsuguro, Ryosuke Ogura, Manabu Natsumeda, Mizuho Isogawa, Hiroshi Aoki, Satoshi Ichikawa, Masahiro Sakaitani, Akira Matsuda, Katsumi Maenaka, Yukihiko Fujii, Toru Kondo
    Stem cells (Dayton, Ohio) 34 8 2016 - 25 2016年08月 [査読有り][通常論文]
     
    Glioblastoma (GBM), one of the most malignant human cancers, frequently recurs despite multimodal treatment with surgery and chemo/radiotherapies. GBM-initiating cells (GICs) are the likely cell-of-origin in recurrences, as they proliferate indefinitely, form tumors in vivo, and are resistant to chemo/radiotherapies. It is therefore crucial to find chemicals that specifically kill GICs. We established temozolomide (the standard medicine for GBM)-resistant GICs (GICRs) and used the cells for chemical screening. Here, we identified 1-(3-C-ethynyl-β-d-ribopentofuranosyl) uracil (EUrd) as a selective drug for targeting GICRs. EUrd induced the death in GICRs more effectively than their parental GICs, while it was less toxic to normal neural stem cells. We demonstrate that the cytotoxic effect of EUrd on GICRs partly depended on the increased expression of uridine-cytidine kinase-like 1 (UCKL1) and the decreased one of 5'-nucleotidase cytosolic III (NT5C3), which regulate uridine-monophosphate synthesis positively and negatively respectively. Together, these findings suggest that EUrd can be used as a new therapeutic drug for GBM with the expression of surrogate markers UCKL1 and NT5C3. Stem Cells 2016;34:2016-2025.
  • Katsuyama A, Matsuda A, Ichikawa S
    Organic letters 18 11 2552 - 5 2016年06月03日 [査読有り][通常論文]
     
    The effect of the solvent on the diastereoselectivity of the Joullié-Ugi three-component reaction (JU-3CR) using an α-substituted five-membered cyclic imine is revisited. The cis and trans isomers were generated in toluene and HFIP, respectively. Hammett analysis of the JU-3CR suggests the presence of two reaction mechanisms.
  • Satoshi Ichikawa
    CHEMICAL RECORD 16 3 1106 - 1115 2016年06月 [査読有り][通常論文]
     
    It is important to pursue function-oriented synthesis (FOS), a strategy for the design of less structurally complex targets with comparable or superior activity that can be made in a practical manner, because compared to synthetic drugs, many biologically relevant natural products possess large and complex chemical structures that may restrict chemical modifications in a structure-activity relationship study. In this account, we describe recent efforts to simplify complex nucleoside natural products including caprazamycins. Considering the structure-activity relationship study with several truncated analogues, three types of simplified derivatives, namely, oxazolidine, isoxazolidine, and lactam-fused isoxazolidine-containing uridine derivatives, were designed and efficiently synthesized. These simplified derivatives have exhibited promising antibacterial activities. A significant feature of our studies is the rational and drastic simplification of the molecular architecture of caprazamycins. This study provides a novel strategy for the development of a new type of antibacterial agent effective against drug-resistant bacteria.
  • Ben C Chung, Ellene H Mashalidis, Tetsuya Tanino, Mijung Kim, Akira Matsuda, Jiyong Hong, Satoshi Ichikawa, Seok-Yong Lee
    Nature 533 7604 557 - 560 2016年05月26日 [査読有り][通常論文]
     
    Antibiotic-resistant bacterial infection is a serious threat to public health. Peptidoglycan biosynthesis is a well-established target for antibiotic development. MraY (phospho-MurNAc-pentapeptide translocase) catalyses the first and an essential membrane step of peptidoglycan biosynthesis. It is considered a very promising target for the development of new antibiotics, as many naturally occurring nucleoside inhibitors with antibacterial activity target this enzyme. However, antibiotics targeting MraY have not been developed for clinical use, mainly owing to a lack of structural insight into inhibition of this enzyme. Here we present the crystal structure of MraY from Aquifex aeolicus (MraYAA) in complex with its naturally occurring inhibitor, muraymycin D2 (MD2). We show that after binding MD2, MraYAA undergoes remarkably large conformational rearrangements near the active site, which lead to the formation of a nucleoside-binding pocket and a peptide-binding site. MD2 binds the nucleoside-binding pocket like a two-pronged plug inserting into a socket. Further interactions it makes in the adjacent peptide-binding site anchor MD2 to and enhance its affinity for MraYAA. Surprisingly, MD2 does not interact with three acidic residues or the Mg(2+) cofactor required for catalysis, suggesting that MD2 binds to MraYAA in a manner that overlaps with, but is distinct from, its natural substrate, UDP-MurNAc-pentapeptide. We have determined the principles of MD2 binding to MraYAA, including how it avoids the need for pyrophosphate and sugar moieties, which are essential features for substrate binding. The conformational plasticity of MraY could be the reason that it is the target of many structurally distinct inhibitors. These findings can inform the design of new inhibitors targeting MraY as well as its paralogues, WecA and TarO.
  • Shun Kitahata, Takuya Chiba, Takashi Yoshida, Masaki Ri, Shinsuke Iida, Akira Matsuda, Satoshi Ichikawa
    Organic letters 18 9 2312 - 5 2016年05月06日 [査読有り][通常論文]
     
    Isosyringolin A, which is an isomer of the proteasome-inhibiting natural product syringolin A, was designed and synthesized to develop analogues that are step economical and synthetically accessible in a practical manner. It was revealed that isosyringolin A exhibited proteasome-inhibitory activity comparable to that of syringolin A and that its derivatization leads to great enhancement in its proteasome inhibitory activity as well as its cytotoxicity against human myeloma cells.
  • Takuya Chiba, Shun Kitahata, Akira Matsuda, Satoshi Ichikawa
    Chemical & pharmaceutical bulletin 64 7 811 - 6 2016年 [査読有り][通常論文]
     
    In this study, we designed and synthesized a structurally simplified syringolin A analogue 4, which could have a switched hydrogen bonding interaction with the β5 subunit of 20S proteasome. This analogue exhibits potent β5 proteasome inhibitory activity with an IC50 value of 107 nM. It also shows cytotoxicity against a range of human cancer cells at submicromolar level (109-254 nM). This analogue is expected to be a lead compound as a next generation proteasome inhibitor because of its simple structure.
  • Takuya Chiba, Akira Matsuda, Satoshi Ichikawa
    Bioorganic & medicinal chemistry letters 25 21 4872 - 4877 2015年11月01日 [査読有り][通常論文]
     
    A detailed structure-activity relationship of syringolin A (1), which is a promising antitumor natural product, was described. We previously developed syringolin A analog 2 as a potent proteasome inhibitor by the structure-based drug design of syringolin A. In this Letter, we synthesized a range of analogs of 2, having a different length of the lipophilic chain and substituted aryl group, and their cytotoxicity against human cancer cells was evaluated. It turned out that these modifications greatly affected the cytotoxicity. Further optimization would lead to develop a novel proteasome inhibitor.
  • Takeshi Nakaya, Akira Matsuda, Satoshi Ichikawa
    Organic & biomolecular chemistry 13 28 7720 - 35 2015年07月28日 [査読有り][通常論文]
     
    The discovery of new antibiotics is critical because the emergence of drug-resistant bacteria has posed a serious public health problem. Caprazamycins, which are nucleoside antibiotics, are a promising lead with a novel mode of action, and we have designed simplified analogues containing a piperidine as a scaffold linking the crucial structural units of caprazamycins. These analogues were step-economically synthesized via a sequential aza-Prins-Ritter reaction. Among the tested compounds, the analogue 7 exhibited good MraY inhibitory activity, antibacterial activity against Gram-positive bacterial strains including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci, and metabolic stability. The observed cytotoxicity of 7 against HepG2 cells was overcome by modulating the fatty acyl side chain. The knowledge obtained from our structure-activity relationship studies of the caprazamycins will provide further direction toward the design of potent MraY inhibitors.
  • Satoshi Ichikawa, Mayumi Yamaguchi, Lee Shang Hsuan, Yuta Kato, Akira Matsuda
    ACS infectious diseases 1 4 151 - 6 2015年04月10日 [査読有り][通常論文]
     
    Carbacaprazamycins, which are chemically stable analogues of caprazamycins, were designed and synthesized. These analogues were active against drug-resistant bacterial pathogens such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci, and their activities were comparable to those of the parent caprazamycins. The effect of treatment with carbacaprazamycin on morphological changes in S. aureus indicated that the mode of action was completely different from those of existing peptidoglycan inhibitors.
  • Mayumi Yamaguchi, Akira Matsuda, Satoshi Ichikawa
    Organic & biomolecular chemistry 13 4 1187 - 97 2015年01月28日 [査読有り][通常論文]
     
    Simplification of caprazamycins, which are promising antibacterial nucleoside natural products, was conducted by scaffold-hopping of the structurally complex diazepanone moiety to the isoxazolidine scaffold. The designed isoxazolidine-containing uridine derivatives were synthesized by an intramolecular 1,3-dipolar cycloaddition of alkenyl nitrone as a key step. The lactone-fused isoxazolidine intermediate was easily converted to the target compounds by sequential introduction of key substituents upon ring-opening the lactone moiety by nucleophilic substitution and electrophilic capping of the resulting primary alcohol. Several analogues exhibited good activity against H. influenzae ATCC 10211 (MIC 0.25-0.5 μg mL(-1)) and moderate activity against vancomycin-resistant E. faecalis SR7914 (MIC 4-8 μg mL(-1)).
  • S. Ichikawa, M. Yamaguchi, A. Matsuda
    CURRENT MEDICINAL CHEMISTRY 22 34 3951 - 3979 2015年 [査読有り][通常論文]
     
    The continued emergence of drug-resistance to existing antibacterial agents represents a severe and ongoing public health concern, which demands the discovery of new antibiotics. However the number of novel classes of antibacterial drugs launched in the clinic has been remarkably slow since the 1960s, and it is urgent to develop novel antibacterial agents to fight against drug-resistant bacterial pathogens. Peptidoglycan is a component of the bacterial cell wall, which consists of a repeated N-acetylmuramic acid (MurNAc) and N-acetylglucosamine (GluNAc) polymer cross-linked with polypeptides, and is a good target for antibacterial drug discovery. Among enzymes responsible for its biosynthesis, phospho-MurNAc-pentapeptide translocase (MraY) is a novel and promising target. Many nucleoside natural products, which strongly inhibit MraY, have been found in nature. This review will summarize the synthesis and biological properties of selected MraY inhibitory nucleoside natural products and their analogues synthesized in our laboratory and by others.
  • Mayumi Yamaguchi, Akira Matsuda, Satoshi Ichikawa
    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 248 2014年08月 [査読有り][通常論文]
  • Takuya Chiba, Akira Matsuda, Satoshi Ichikawa
    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 248 2014年08月 [査読有り][通常論文]
  • Takeshi Nakaya, Akira Matsuda, Satoshi Ichikawa
    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 248 2014年08月 [査読有り][通常論文]
  • Yusuke Takeoka, Tetsuya Tanino, Mitsuaki Sekiguchi, Shuji Yonezawa, Masahiro Sakagami, Fumiyo Takahashi, Hiroko Togame, Yoshikazu Tanaka, Hiroshi Takemoto, Satoshi Ichikawa, Akira Matsuda
    ACS medicinal chemistry letters 5 5 556 - 60 2014年05月08日 [査読有り][通常論文]
     
    It is urgent to develop novel anti-Pseudomonas agents that should also be active against multidrug resistant P. aeruginosa. Expanding the antibacterial spectrum of muraymycins toward P. aeruginosa was investigated by the systematic structure-activity relationship study. It was revealed that two functional groups, a lipophilic side chain and a guanidino group, at the accessory moiety of muraymycins were important for the anti-Pseudomonas activity, and analogue 29 exhibited antibacterial activity against a range of P. aeruginosa strains with the minimum inhibitory concentration values of 4-8 μg/mL.
  • Takuya Chiba, Hidetaka Hosono, Koji Nakagawa, Masahiro Asaka, Hiroshi Takeda, Akira Matsuda, Satoshi Ichikawa
    Angewandte Chemie (International ed. in English) 53 19 4836 - 9 2014年05月05日 [査読有り][通常論文]
     
    The development process for syringolin A analogues having improved proteasome inhibitory and antitumor activity is described. The strategy was to first establish a convergent synthesis of syringolin A using a rare intramolecular Ugi three-component reaction in the last stage of the synthesis, so as to gain access toa set of structure-based analogues. The inhibitory activity of chymotrypsin-like activity of 20S proteasome was largely improved by targeting the S3 subsite of the β5 subunit. Cytotoxic activity was also improved by installing the membrane-permeable substituent. These biological properties are comparable to those of bortezomib, a clinically used first-line proteasome inhibitor.
  • Katsushi Katayama, Takuya Okamura, Takuya Sunadome, Koji Nakagawa, Hiroshi Takeda, Motoo Shiro, Akira Matsuda, Satoshi Ichikawa
    The Journal of organic chemistry 79 6 2580 - 90 2014年03月21日 [査読有り][通常論文]
     
    The second-generation total synthesis of quinaldopeptin (1) was established via a Staudinger/aza-Wittig/diastereoselective Ugi three-component reaction sequence and a racemization-free [5 + 5] coupling and macrolactamization. A single-crystal X-ray structure of the chromophore analogue 26 confirmed the structural and stereochemical assignments of the macrocycle. Synthetic 1 successfully unwound supercoiled DNA to form a relaxed DNA in a dose-dependent manner, the binding affinity of 1 to four dsODNs was within a similar range (K(b) = 1.45-2.53 × 10(7) M(-1)), and the sequence selectivity was subtle. It was suggested that 1 possesses biological behaviors similar to those of sandramycin (2) in terms of cytotoxic activity against human cancer cell lines (IC50 = 3.2-12 nM) and HIF-1 inhibitory activity.
  • Tetsuya Tanino, Mayumi Yamaguchi, Akira Matsuda, Satoshi Ichikawa
    EUROPEAN JOURNAL OF ORGANIC CHEMISTRY 2014 9 1836 - 1840 2014年03月 [査読有り][通常論文]
     
    Function-oriented synthesis of a class of liponucleoside antibiotics was investigated through rational simplification guided by previous structure-activity relationship studies of caprazamycins and muraymycins to address the issue associated with their molecular complexity. A lactam-fused isoxazolidine scaffold was designed, and a diverse set of lactam-fused isoxazolidines derivatives were constructed by intramolecular 1,3-dipolar cycloaddition of alkenyl nitrones. Several analogues exhibited moderate activity against a range of Gram-positive drug-resistant bacterial pathogens.
  • Katsushi Katayama, Koji Nakagawa, Hiroshi Takeda, Akira Matsuda, Satoshi Ichikawa
    Organic letters 16 2 428 - 31 2014年01月17日 [査読有り][通常論文]
     
    The total synthesis of sandramycin has been accomplished by using a Staudinger/aza-Wittig/diastereoselective Ugi three-component reaction sequence as a key step to obtain a linear pentadepsipeptide. Subsequent [5 + 5] coupling of the penptapeptide, macrolactamization, and introduction of the quinaldin chromophores afforded sandramycin. Dihydroxy and diacetoxy analogues were also prepared, and the cytotoxic activity of these analogues against a range of human cancer cell lines was evaluated.
  • Satoshi Ichikawa, Takuya Okamura, Akira Matsuda
    The Journal of organic chemistry 78 24 12662 - 70 2013年12月20日 [査読有り][通常論文]
     
    The first total synthesis of quinaldopeptin (1) was accomplished. Our approach to the synthesis of 1 includes the solid-phase peptide synthesis of the linear decapeptide 4 followed by macrocyclization and introduction of the quinoline chromophores 2 at a late stage of the synthesis. As for the preparation of 4, a fragment coupling approach was applied considering the C2 symmetrical structure of 1. Chromophore analogues 22 and 23 and desmethyl analogue 27 were also prepared in a manner similar to the synthesis of 1. Synthetic 1 exhibits a strong cytotoxicity with the IC50 value of 3.2 nM. On the other hand, the activity of 23 and 27 was largely reduced.
  • Satoshi Ichikawa, Nana Tatebayashi, Akira Matsuda
    The Journal of organic chemistry 78 23 12065 - 75 2013年12月06日 [査読有り][通常論文]
     
    Indolocarbazole natural products are known to possess a variety of biological activities that hold promise as cancer chemotherapeutic agents. We newly designed C-glycosyl pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione derivatives 7 and 8, which are natural-product-like scaffolds. Compounds 7 and 8 were stereoselectively and efficiently synthesized using β-selective C-allylation, Heck reaction, and thermal 6π-electron cyclization/oxidative aromatization. Their potential as Chk1 inhibitors was investigated, and 7 and 8 exhibited an inhibitory activity with IC50 values of 0.5-9.5 μM, which is good activity for scaffolds. The key intermediate 23 was obtained by five steps from d-ribose in 33% overall yield by this synthetic route, which would enable us to prepare a range of analogues in order to investigate further structure-activity relationship studies in the optimization process.
  • Satoshi Ichikawa, Hideaki Ueno, Takuya Sunadome, Kousuke Sato, Akira Matsuda
    Organic letters 15 3 694 - 7 2013年02月01日 [査読有り][通常論文]
     
    Triazole-cross-linked oligodeoxynucleotides were synthesized using the Cu(I) catalyzed alkyne-azide cycloaddition with tris(azidoethyl)amine hydrochloride and oligodeoxynucleotides possessing N-3-(propargyl)thymidine at both the 3'- and 5'-termini. Further installation of a functional molecule to the dumbbell oligodeoxynucleotides was achieved by utilizing the remaining azide group.
  • Kazuya Okamoto, Masahiro Sakagami, Fei Feng, Fumiyo Takahashi, Kouichi Uotani, Hiroko Togame, Hiroshi Takemoto, Satoshi Ichikawa, Akira Matsuda
    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 22 14 4810 - 4815 2012年07月 [査読有り][通常論文]
     
    The second-generation synthesis of 3'-hydroxypacidamycin D (2) has been accomplished via an Ugi-four component reaction at a late stage of the synthesis. This approach provided ready access to a range of analogues including diastereomers of the diaminobutylic acid residue and hybrid-type analogues of mureidomycins. Biological evaluations of these analogues indicated that the stereochemistry at the diaminobutylic acid residue has a crucial impact on both the MraY biochemical inhibition and whole-cell anti-bacterial activity. (C) 2012 Elsevier Ltd. All rights reserved.
  • Kazuya Okamoto, Masahiro Sakagami, Fei Feng, Hiroko Togame, Hiroshi Takemoto, Satoshi Ichikawa, Akira Matsuda
    JOURNAL OF ORGANIC CHEMISTRY 77 3 1367 - 1377 2012年02月 [査読有り][通常論文]
     
    Full details of the total synthesis of pacidamycin D (4) and its 3 '-hydroxy analogue 32 are described. The chemically labile Z-oxyacyl enamide moiety is the most challenging chemical structure found in uridylpeptide natural products. Key elements of our approach to the synthesis of 4 include the efficient and stereocontrolled construction of the Z-oxyvinyl halides 6 and 7 and their copper-catalyzed cross-coupling with the tetrapeptide carboxamide 5, a thermally unstable compound containing a number of potentially reactive functional groups. This synthetic route also allowed us to easily prepare 3 '-hydroxy analogue 32. The assemblage by cross-coupling of the Z-oxyvinyl halide 6 and the carboxaimide 5 at a late stage of the synthesis provided ready access to a range of uridylpeptide antibiotics and their analogues, despite their inherent labile nature with potential epimerization, simply by altering the tetrapeptide moiety.
  • Tetsuya Tanino, Bayan Al-Dabbagh, Dominique Mengin-Lecreulx, Ahmed Bouhss, Hiroshi Oyama, Satoshi Ichikawa, Akira Matsuda
    JOURNAL OF MEDICINAL CHEMISTRY 54 24 8421 - 8439 2011年12月 [査読有り][通常論文]
     
    The systematic structure activity relationship (SAX) of the muraymycins (MRYs) using an Ugi four-component reaction (U4CR) was investigated. The impact of the lipophilic substituent on antibacterial activity was significant, and the analogues 8 and 9 having a lipophilic side chain exhibited good activity against a range of Gram-positive bacterial pathogens, including MRSA and VRE. Further investigation of compounds 8 and 9 revealed these analogues to be selective inhibitors of the MraY transferase and nontoxic to HepG2 cells. The SAX of the accessory urea peptide moiety indicated that it could be simplified. Our SAX study of the MRYs suggests a probable mechanism for inhibition of the MraY, where the inner moiety of the urea dipeptide motif interacts with the carbohydrate recognition domain in the cytoplasmic loop S. The predicted binding model would provide further direction toward the design of potent MraY inhibitors. This study has set the stage for the generation of novel antibacterial "lead" compounds based on MRYs.
  • Kazuhiro Muranaka, Satoshi Ichikawa, Akira Matsuda
    JOURNAL OF ORGANIC CHEMISTRY 76 22 9278 - 9293 2011年11月 [査読有り][通常論文]
     
    The new carboxamide protecting group, 4-(tert-butyldimethylsiloxy)-2-methoxybenzyl (SiMB), has been developed. While this SiMB group can be removed using mild basic desilylation methods, it can also be deprotected under strongly acidic or oxidative conditions. An application of this group to simple carboxamide groups, as well as to more complex and acid-sensitive adenosine derivatives containing a cyclophane scaffold, was also demonstrated.
  • Kazuya Okamoto, Masahiro Sakagami, Fei Feng, Hiroko Togame, Hiroshi Takemoto, Satoshi Ichikawa, Akira Matsuda
    ORGANIC LETTERS 13 19 5240 - 5243 2011年10月 [査読有り][通常論文]
     
    The first total synthesis of pacidamycin D, which is expected to be a good candidate as an antibacterial agent against P. aeruginosa, is described. The key elements of our approach feature an efficient and stereocontrolled construction of the Z-oxyvinyl iodide and copper-catalyzed cross-coupling with the tetrapeptide carboxamide.
  • Tetsuya Tanino, Satoshi Ichikawa, Akira Matsuda
    ORGANIC LETTERS 13 15 4028 - 4031 2011年08月 [査読有り][通常論文]
     
    The L-epi-capreomycidine (Cpm) derivatives were efficiently and stereoselectively synthesized via nitrene C-H insertion starling from a readily available D-Tyr. Design of a substrate that takes into account hydrogen bonding is a critical feature in order to achieve high selectivity. Our synthetic strategy could be a new access to epi-Cpm and its derivatives, which are found in several biologically active natural products.
  • Kyoko Furuita, Shunpei Murata, Jun Goo Jee, Satoshi Ichikawa, Akira Matsuda, Chojiro Kojima
    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 133 15 5788 - 5790 2011年04月 [査読有り][通常論文]
     
    High Mobility Group Box 1 (HMGB1) protein, a potential therapeutic target, binds bent DNAs structure-specifically. Here we report on a crucial structural feature of the bent DNA required for strong binding to HMGB1. NMR structures of two bent DNA oligomers, only one of which binds strongly to HMGB1, revealed that the presence of a pocket structure on the minor groove is crucial for strong binding through penetration of a phenylalanine residue.
  • Tetsuya Tanino, Satoshi Ichikawa, Koichi Uotani, Hiroshi Oyama, Akira Matsuda
    YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN 131 3 335 - 346 2011年03月 [査読有り][通常論文]
     
    This review describes the synthesis and structure-activity relationship (SAR) study of muraymycins (MRYs), which are potent antibacterial nucleoside antibiotics. The key elements of our synthetic approach include the preparation of L-epi-capreomycidine via a C-H amination reaction and a convergent assemblage to construct of the framework of MRYs using Ugi four component reaction. With this approach the first total synthesis of MRY D2 and its epimer, epi-MRY D2, which does not have lipophilic substituents, has been accomplished. The fact that MRY D2 and it's epimer did not show any antibacterial activity indicated the lipophilic substituents of MRYs plays an important role in membrane-permeability. Hence, MRY analogues with lipophilic substituents were designed and synthesized simply by altering the aldehyde component in Ugi four-component assemblage. The MRY analogues with lipophilic substituents exhibited improved antibacterial activity against anti drug-resistant bacteria. It was also suggested that the accessory urea-dipeptide motif might contribute to MraY inhibitory and antibacterial activity. Our synthetic approach would effectively provide a variety of MRY analogues and resultant SAR information brings us directions to create further MRY analogues.
  • Yuki Sako, Satoshi Ichikawa, Akiko Osada, Akira Matsuda
    BIOORGANIC & MEDICINAL CHEMISTRY 18 22 7878 - 7889 2010年11月 [査読有り][通常論文]
     
    The structure-activity relationship (SAR) of 5-substituted pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione derivatives 5 was investigated for their potential as Chk1 inhibitors for possible chemo- and radio-potentiators in anticancer chemotherapies. In silico virtual screening helped to optimize the substituent on the phenyl ring, and led to identification of the m-carbamoyl group among the 117 analogues tested. Further optimization studies focusing on the docking model of 15 in the active site of Chk1 revealed that 32b (IC(50) = 2.8 nM) was a more potent inhibitor than UNC-01. (C) 2010 Elsevier Ltd. All rights reserved.
  • Tetsuya Tanino, Satoshi Ichikawa, Bayan Al-Dabbagh, Ahmed Bouhss, Hiroshi Oyama, Akira Matsuda
    ACS MEDICINAL CHEMISTRY LETTERS 1 6 258 - 262 2010年09月 [査読有り][通常論文]
     
    Muraymycin analogues with a lipophilic substituent were synthesized using an Ugi four-component assemblage. This approach provides ready access to a range of analogues simply by altering the aldehyde component. The impact of the lipophilic substituent on the antibacterial activity was very large, and analogues 7b-e and 8b-e exhibited good activity against a range of Gram;positive bacterial pathogens including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. This study also showed that the accessory urea-dipeptide motif contributes to MraY inhibitory and antibacterial activity. The knowledge obtained from our structure activity relationship study of muraymycins provides further direction toward the design of potent MraY inhibitors. This study has set the stage for the generation of novel antibacterial "lead" compounds based on muraymycins.
  • Hironori Sekiguchi, Kazuhiro Muranaka, Akiko Osada, Satoshi Ichikawa, Akira Matsuda
    BIOORGANIC & MEDICINAL CHEMISTRY 18 15 5732 - 5737 2010年08月 [査読有り][通常論文]
     
    The PU-H58-dimers 13a-15b were efficiently synthesized and their biological properties were evaluated. The copper-catalyzed alkyne azide coupling was effective in simultaneously linking three components via a triazole formation to afford the target dimers. These synthesized dimers exhibited binding affinity to the N-terminal domain of Hsp90, cytotoxicity, and client degradation activity although these activities were comparative or weak comparable with that of the parent compound. (C) 2010 Elsevier Ltd. All rights reserved.
  • Kensuke Ii, Satoshi Ichikawa, Bayan Al-Dabbagh, Ahmed Bouhss, Akira Matsuda
    JOURNAL OF MEDICINAL CHEMISTRY 53 9 3793 - 3813 2010年05月 [査読有り][通常論文]
     
    The rational simplification of the caprazamycin (CPZ) class of nucleoside natural products was carried out to address their molecular complexity. First, analogues 6-8, where the diazepanone ring of the CPZ was removed and a lipophilic side chain was attached to either the C-7' or N(6') atom, were used to investigate the conformation activity relationship. On the basis of this relationship, we designed the oxazolidine-containing uridine derivatives 18-21 by restricting the conformation of 6-8. As a result, the 'Bu ester derivatives 20 were found to be the most active against a range of bacterial strains containing VRE with a potency similar to that of the parent CPZs. This study provides a novel strategy for the development of a new type of antibacterial agent effective against drug-resistant bacteria.
  • Leonard Kaysser, Kornelia Eitel, Tetsuya Tanino, Stefanie Siebenberg, Akira Matsuda, Satoshi Ichikawa, Bertolt Gust
    JOURNAL OF BIOLOGICAL CHEMISTRY 285 17 12684 - 12694 2010年04月 [査読有り][通常論文]
     
    Sulfotransferases are involved in a variety of physiological processes and typically use 3'-phosphoadenosine 5'-phosphosulfate (PAPS) as the sulfate donor substrate. In contrast, microbial arylsulfate sulfotransferases (ASSTs) are PAPS-independent and utilize arylsulfates as sulfate donors. Yet, their genuine acceptor substrates are unknown. In this study we demonstrate that Cpz4 from Streptomyces sp. MK730-62F2 is an ASST-type sulfotransferase responsible for the formation of sulfated liponucleoside antibiotics. Gene deletion mutants showed that cpz4 is required for the production of sulfated caprazamycin derivatives. Cloning, overproduction, and purification of Cpz4 resulted in a 58-kDa soluble protein. The enzyme catalyzed the transfer of a sulfate group from p-nitrophenol sulfate (K(m) 48.1 mu M, k(cat) 0.14 s(-1)) and methyl umbelliferone sulfate (K(m) 34.5 mu M, k(cat) 0.15 s(-1)) onto phenol (K(m) 25.9 and 29.7 mM, respectively). The Cpz4 reaction proceeds by a ping pong bi-bi mechanism. Several structural analogs of intermediates of the caprazamycin biosynthetic pathway were synthesized and tested as substrates of Cpz4. Des-N-methyl-acyl-caprazol was converted with highest efficiency 100 times faster than phenol. The fatty acyl side chain and the uridyl moiety seem to be important for substrate recognition by Cpz4. Liponucleosides, partially purified from various mutant strains, were readily sulfated by Cpz4 using p-nitrophenol sulfate. No product formation could be observed with PAPS as the donor substrate. Sequence homology of Cpz4 to the previously examined ASSTs is low. However, numerous orthologs are encoded in microbial genomes and represent interesting subjects for future investigations.
  • Tetsuya Tanino, Satoshi Ichikawa, Motoo Shiro, Akira Matsuda
    JOURNAL OF ORGANIC CHEMISTRY 75 5 1366 - 1377 2010年03月 [査読有り][通常論文]
     
    Full details of the first total synthesis of (-)-muraymycin (MRY) D2 and its epimer, the antibacterial nucleoside natural product, are described. Key strategic elements of the approach Include the preparation of the urea dipeptide moiety found in the muramycins containing an L-epi-capreomycidine via a nitrene C-H insertion of the sulfamate 10 and the fully protected muraymycin skeleton at a late stage by an Ugi four-component reaction. Thus, the nitrene C-H insertion of the sulfamate 10 with 10 mol% of Rh-2(esp)(2) catalyst gave the cyclic sulfamates 11a and 11b in 47% yield (11a: 11b = 1:2.0). Construction 01 the Cyclic guanidine skeleton was effected through the HgBr2-promoted cyclization of 42 followed by desulfonylation upon acetolysis of the oxathiazinane ring to Live 43 111 good yield. The amine obtained by selective removal of the Cbz group of the alcohol 44 was reacted with MeSC(=O)-L-Val-O-t-Bu (38) to provide 45, which was oxidized to the carboxylic Licid 46. Reaction of 46, isonitrile 51, isovaleraldehyde, and 2,4-dimethoxybenzylamine furnished the desired Ugi products, the final deprotection of which successfully afforded (-)-MRY D2 and epi-MRY D2 (53) after HPLC separation of the diastereomers. This approach would afford ready access to a range of analogues simply by altering each component.
  • Kazuhiro Muranaka, Satoshi Ichikawa, Akira Matsuda
    TETRAHEDRON LETTERS 50 36 5102 - 5106 2009年09月 [査読有り][通常論文]
     
    3',5'-Ansa-adenosine derivatives, rationally designed as an Hsp90 inhibitor by extracting and fusing a natural product, geldanamycin, and a natural substrate, ATP, were efficiently synthesized by the ring-closing metathesis assisted by the 2,4-dimethoxybenzyl group. This simpler scaffold design provides a practical synthesis of a set of analogs and demonstrates synthetic innovation. (C) 2009 Elsevier Ltd. All rights reserved.
  • Furuita K, Murata S, Jee J, Ichikawa S, Matsuda A, Kojima C
    Nucleic acids symposium series (2004) 53 89 - 90 2009年 [査読有り][通常論文]
  • Ichikawa S, Otawa M, Teishikata Y, Yamada K, Fujimuro M, Yokosawa H, Matsuda A
    Nucleic acids symposium series (2004) 53 95 - 96 2009年 [査読有り][通常論文]
  • Muranaka K, Ichikawa S, Matsuda A
    Nucleic acids symposium series (2004) 53 5 - 6 2009年 [査読有り][通常論文]
  • Satoshi Ichikawa, Ryoko Hayashi, Shinpei Hirano, Akira Matsuda
    ORGANIC LETTERS 10 22 5107 - 5110 2008年11月 [査読有り][通常論文]
     
    A highly beta-selective C-allylation of 2,3-0-(3-pentylidene)-D-ribofuranosyl fluoride is described. This strategy will provide a new concept for synthesizing beta-C-ribosides by controlling the effect of steric hindrance in the transition state.
  • Satoshi Ichikawa
    CHEMICAL & PHARMACEUTICAL BULLETIN 56 8 1059 - 1072 2008年08月 [査読有り][通常論文]
     
    Synthetic nucleoside chemistry based on nucleoside natural products synthesis were described. First, a samarium diiodide (SmI2)-promoted aldol reaction with the use of alpha-phenylthioketone as an enolate was developed. The characteristics of this reaction are that the enolate can be regioselectively generated and the aldol reaction proceeds under near neutral condition. This reaction is proved to he a powerful reaction for the synthesis of complex nucleoside natural products, and herbicidin B and fully protected tunicaminyluracil, which were undecose nucleoside natural products, were synthesized. Next, the synthetic methodology of the caprazamycins, which are promising antibacterial nucleoside natural products, was also developed by the strategy including beta-selective ribosylation without using a neighboring group participation. Our synthetic route provided a range of key analogues with partial structures to define the pharmacophore. Simplification of the caprazamycins was further pursued to develop diketopiperazine analogs.
  • Kazuhiro Muranaka, Akiko Sano, Satoshi Ichikawa, Akira Matsuda
    BIOORGANIC & MEDICINAL CHEMISTRY 16 11 5862 - 5870 2008年06月 [査読有り][通常論文]
     
    Structure-based drug design was used to systematically synthesize PU3-dimers. The cytotoxicity of PU3 dimers 6 against breast cancer cell lines was evaluated, and their potency increased as the length of the bridging linker increased. Among the compounds tested, 6e with a C-20 linker was the most potent and exhibited a 20- to 30-fold increase in activity compared with that of the parent compound 5. Western blot analyses of the cell lysates treated with 6c revealed that 6c resulted in the concentration-dependent degradation of the Hsp90 client protein Her2, which is consistent with other Hsp90 inhibitors. (C) 2008 Elsevier Ltd. All rights reserved.
  • Shinpei Hirano, Satoshi Ichikawa, Akira Matsuda
    BIOORGANIC & MEDICINAL CHEMISTRY 16 9 5123 - 5133 2008年05月 [査読有り][通常論文]
     
    Systematic structure-activity relationship studies of caprazamycin (CPZ) analogs, including the aminoribose-truncated 5 and the uridine-truncated 6, have been carried out. Both 5 and 6 were synthesized efficiently via diazepanone ring construction by intramolecular reductive alkylation of aminoaldehyde derivatives. The antibacterial activity of a range of analogs, including 5 and 6, against Mycobacteriumosis was evaluated, and it was found that the uridine, the aminoribose, and the fatty acyl side chains are crucial for antibacterial activity. This study would be a guide for designing novel anti-tuberculosis agents based on the 6'-N-alkyl-5'-beta-O-aminoribosyl-glycyluridine class of antibiotics including the CPZs. (C) 2008 Elsevier Ltd. All rights reserved.
  • Masanori Nakane, Satoshi Ichikawa, Akira Matsuda
    JOURNAL OF ORGANIC CHEMISTRY 73 5 1842 - 1851 2008年03月 [査読有り][通常論文]
     
    [Graphics] Triazole-cross-linked oligodeoxynucleotides were synthesized with use of the Cu(I) catalyzed alkyne-azide cycloaddition (CuAAC) with oligodeoxynucleotides possessing N-3-(azidoethyl)thymidine and N-3-(propargyl)thymidine at the 3'- and 5'-termini. The newly synthesized oligodeoxynucleotides were thermally stable and their global structures retained those of non-cross-linked oligodeoxynucleotides. The newly synthesized dumbbell oligodeoxynucleotides showed excellent stability against snake venom phosphodiesterase (3'-exonuclease) and high thermal stability, which are necessary for decoy molecules to achieve biological responses leading to alteration of gene expression. Moreover; dumbbell oligodeoxynucleotides have the ability to bind to NF-kappa B p50 homodimer within a similar range to that of a control double-stranded decoy olicodeoxynucleotide. This strategy allows us to prepare triazole-linked dumbbell oligodeoxynucleotides with a range of loop lengths, and we found that the greater the number of the thymidine residues constituting the loop region, the higher the binding affinity of the dumbbell oligodeoxynucleotides to the nuclear factor kappa B. This means that a protein binding ability of the dumbbell oligodeoxynucleotides could be modulated by altering the loop size. This study clearly shows that cross-linking by the triazole Structure does not prevent the dumbbell oligodeoxynucleotides from binding to the nuclear factor kappa B transcription factor. Therefore, the results obtained conclusively demonstrate that the triazole cross-linked dumbbell oligodeoxynucleotides could be proposed as powerful decoy molecules.
  • Ichikawa S, Matsuda A
    Nucleic acids symposium series (2004) 52 77 - 78 2008年 [査読有り][通常論文]
  • Tanino T, Hirano S, Ichikawa S, Matsuda A
    Nucleic acids symposium series (2004) 52 557 - 558 2008年 [査読有り][通常論文]
  • Shinpei Hirano, Satoshi Ichikawa, Akira Matsuda
    JOURNAL OF ORGANIC CHEMISTRY 73 2 569 - 577 2008年01月 [査読有り][通常論文]
     
    Synthesis of palmitoyl caprazol 7, which possesses a simple fatty acyl side chain at the 3"'-position of the diazepanone moiety, was carried out and their antibacterial activity was evaluated. The key elements of our approach include the improved synthesis of the key 5'-p-0-aminoribosyl-glycyluridine derivative, installation of the palmitoyl side chain to the cyclization precursor, and the construction of the diazepanone by an intramolecular reductive amination. The second generation synthesis of (+)-caprazol was also established. Palmitoyl caprazol 7 exhibited antibacterial activity against Mycobacterium smegmatis ATCC607 (MIC = 6.25 mu g/mL) with potency similar to that of the caprazamycins (CPZs). Palmitoyl caprazol 7 and N-6'-desmethyl palmitoyl caprazol 28 also exhibited antibacterial activity against drug-resistant bacteria including methyciline-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) strains (MIC = 3.13-12.5 mu g/mL).
  • Shinpel Hirano, Satoshi Ichikawa, Akira Matsuda
    BIOORGANIC & MEDICINAL CHEMISTRY 16 1 428 - 436 2008年01月 [査読有り][通常論文]
     
    A systematic simplification methodology of a class of 6'-N-alkyl-5'-O-aminoribosyl-glycyluridine antibiotics was shown to produce potential antibacterial agents having a novel mechanism of action. Diketopiperazines and acyclic analogs of the caprazamycins (CPZs) and liposidomycins (LPMs) were efficiently synthesized, and their antibacterial activity was evaluated. The diketopiperazine analog 11a and the acyclic analogs 12a and 16a having a palmitoyl group as a lipophilic side chain exhibited moderate antibacterial activities with MICs of 12.5-50 mu g/mL. This approach could provide ready access to a range of analogs for the development of potential antibacterial agents. (c) 2007 Elsevier Ltd. All rights reserved.
  • Shinpei Hirano, Satoshi Ichikawa, Akira Matsuda
    JOURNAL OF ORGANIC CHEMISTRY 72 26 9936 - 9946 2007年12月 [査読有り][通常論文]
     
    Full details of the total synthesis of (+)-caprazol are described. The key elements of our approach include the early stage introduction of the aminoribose in a highly beta-selective manner, using the steric hindrance in the transition state and the construction of the diazepanone by a modified intramolecular reductive amination. The 5'-C-glycyluridine derivative 9, which was prepared stereoselectively via Sharpless asymmetric aminohydroxylation, was ribosylated with 2,3-O-alkylidene ribofuranosyl donors. It was revealed that increasing the size of the alkyl substituents of the acetal unit resulted in improving the stereoselectivity of the anomeric position, and the desired ribosides 21b (1 ''-beta) and 22b (1 ''-alpha) were obtained in 80% yield (21b/22b = 24.0/1) when the ribosyl fluoride 16 possessing a more sterically hindered 3-pentylidene group was used. The origin of the stereo selectivity of the ribosylation was also discussed. Construction of the diazepanone system was optimized with the model aldehyde 37, and the desired diazepanone 38 was obtained in 88% yield via two-step reaction sequence including catalytic hydrogenation followed by hydride reduction. Application of this method to the aldehyde 44 successfully afforded the diazepanone derivatives 45 and 46, functional group manipulation of which completed the total synthesis of (+)-caprazol.
  • Shunpei Murata, Youko Mizumura, Kaori Hino, Yoshihito Ueno, Satoshi Ichikawa, Akira Matsuda
    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 129 34 10300 - + 2007年08月 [査読有り][通常論文]
     
    Inspired by the unique bending property of a cisplatin cross-linked DNA with high-mobility group box proteins (such as HMGB1), we designed and synthesized novel oligonucleotides (ODNs) containing a cyclic 2'-deoxyuridylate dimer which possesses an alkylene linkage as a "clasp" with various lengths. The newly synthesized ODNs were revealed to have the deep bending property with HMGB1 A-box protein binding ability. This strategy could provide ready access to systematic preparations of structurally altered ODNs, which would be a useful system for studying structure-specific DNA recognition. Of great significance is this single-point modification of DNA, which results in significant global alteration of the structural features of DNA to acquire new functions.
  • Satoshi Ichikawa, Akira Matsuda
    EXPERT OPINION ON THERAPEUTIC PATENTS 17 5 487 - 498 2007年05月 [査読有り][通常論文]
     
    Nucleoside natural products possess a variety of interesting biological activities, including antibacterial, antiviral and antitumor properties, and are therefore expected to be potential candidates for developing drugs. Complex nucleoside natural products exhibiting antibacterial activity by specific inhibition of bacterial cell wall peptidoglycan biosynthesis are described. In addition to the class of antibacterial nucleoside natural products, the newest members of nucleoside natural products exhibiting interesting antiviral activity are briefly described. In spite of promising properties, no nucleoside natural products and their analogs are presently used in the clinic. A global structure-activity relationship of these classes of nucleoside natural products clearly indicates that it is very important to: i) modulate the cell entry ability; and ii) simplify hydrophilic core structures in order to reduce the size of molecules and stabilize the chemically labile structure.
  • Masaki Ohtawa, Satoshi Ichikawa, Yasuhiro Teishikata, Masahiro Fujimuro, Hideyoshi Yokosawa, Akira Matsuda
    JOURNAL OF MEDICINAL CHEMISTRY 50 9 2007 - 2010 2007年05月 [査読有り][通常論文]
     
    Several 9-(2-C-cyano-2-deoxy-l-beta-D-arabino-pentofuranosyl)purine derivatives were tested against Kaposi's sarcoma-associated herpesvirus (KSHV)-infected primary effusion lymphoma (PEL) cells. The guanine derivative (3, CNDAG), as well as the 2-amino-6-substituted-purine derivatives 4, 5, and 6, exhibited cell growth inhibitory activity against KSHV-infected cells, but showed no cytotoxicity against KSHV-negative cells at > 15 mu M concentrations. Therefore, it was found that compounds 3, 4, 5, and 6 showed selective cytotoxicity against PEL cells infected with KSHV.
  • Seiji Miyauchi, Elangovan Gopal, Santosh V. Thakkar, Satoshi Ichikawa, Puttur D. Prasad, Vadivel Ganapathy
    Journal of Pharmacology and Experimental Therapeutics 321 1 257 - 264 2007年04月 [査読有り][通常論文]
     
    We recently identified a novel opioid peptide transport system in the retinal pigment epithelium that transports opioid peptides by a Na +/Cl--dependent process. Here we describe a similar transport system expressed in SK-N-SH cells (a human neuronal cell line) and show for the first time that the activity of the transport system is modulated differentially by lysine and small nonopioid peptides. The transport process in SK-N-SH cells, monitored with deltorphin II as the substrate, is Na +/Cl--dependent and interacts with several opioid peptides, consisting of 5 to 13 amino acids. The activity of this transport system is markedly stimulated by specific dipeptides and tripeptides, with significant stimulation observable at low micromolar concentrations. The ion dependence, Na+/Cl--activation kinetics, and opioid peptide selectivity of the transport system, however, remain unchanged. The stimulation by the modulatory peptides is associated with an increase in maximal velocity with no change in substrate affinity of the system. Amino acids have no or little effect on the transport system, with the exception of lysine. This cationic amino acid inhibits the transport system, with significant inhibition occurring at physiologic concentrations of the amino acid. The inhibitory effect is primarily associated with a decrease in the maximal velocity of the transport system with little change in substrate affinity. Methyl and ethyl esters of lysine retain the inhibitory potency, but most other structural analogs have no effect. The differential modulation of the transport system by lysine and specific small peptides has important implications in the biology and pharmacology of opioid peptides. Copyright © 2007 by The American Society for Pharmacology and Experimental Therapeutics.
  • Shinpei Hirano, Satoshi Ichikawa, Akira Matsuda
    TETRAHEDRON 63 13 2798 - 2804 2007年03月 [査読有り][通常論文]
     
    The first total synthesis of (+)-FR-900493, an antibacterial nucleoside antibiotic possessing a 6'-N-alkyl-5'-O-aminoribosylglycyluridine structure, is described, and its relative and absolute stereochemistries were established. Key elements of the approach include the early-stage introduction of the aminoribose moiety and two sequential reductive alkylations of an amino group at the 6'-position. This synthetic strategy could be applicable to the synthesis of related nucleoside antibiotics, such as the more potent antibacterial nucleoside antibiotics, muraymycins. (c) 2007 Elsevier Ltd. All rights reserved.
  • Satoshi Ichikawa, Noriaki Minakawa, Satoshi Shuto, Motohiro Tanaka, Takuma Sasaki, Akira Matsuda
    Organic and Biomolecular Chemistry 4 7 1284 - 1296 2006年 [査読有り][通常論文]
     
    3′-β-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. © The Royal Society of Chemistry 2006.
  • S Murata, S Ichikawa, A Matsuda
    TETRAHEDRON 61 24 5837 - 5842 2005年06月 [査読有り][通常論文]
     
    Galactose-linked uridine derivatives without charge or dipole contributions in the linker were designed and synthesized via cross metathesis (CM). This strategy would provide a ready access to a range of hybrid compounds linking uridine and galactose derivatives. (c) 2005 Elsevier Ltd. All rights reserved.
  • S Hirano, S Ichikawa, A Matsuda
    ANGEWANDTE CHEMIE-INTERNATIONAL EDITION 44 12 1854 - 1856 2005年 [査読有り][通常論文]
  • S Ichikawa, A Matsuda
    NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS 24 5-7 319 - 329 2005年 [査読有り][通常論文]
     
    Herbicidin B and fully protected tunicaminyluracil, which were undecose nucleoside antibiotics, were synthesized using a samarium diiodide (SmI2) mediated aldol reaction with the use of alpha-phenylthiokelone as an enolate. The characteristics of the SmI2-mediated aldol reaction are that the enolate can be regioselectively generated and the aldol reaction proceeds under near neutral condition. This reaction is proved to be a powerful reaction for the synthesis of complex nucleoside antibiotics. The synthesis of caprazol, the core structure of caprazamycins, was conducted by the strategy including beta-selective ribosylation without using a neighboring group participation and the construction of a diazepanone by a modified reductive amination. Our synthetic route would provide a range of key analogues with partial structures to define the pharmacophore, which can be a lead for the development Of more effective anti-bacterial agents.
  • 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]
  • Yamamoto Y, Shuto S, Tamura Y, Kodama T, Hoshika S, Ichikawa S, Ueno Y, Ohtsuka E, Komatsu Y, Matsuda A
    Biochemistry 43 27 8690 - 8699 2004年07月 [査読有り][通常論文]
  • S Ichikawa, A Matsuda
    NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS 23 1-2 239 - 253 2004年01月 [査読有り][通常論文]
     
    A tunicaminyluracil derivative, which is a key component of the tunicamycin nucleoside antibiotics, was synthesized using a samarium diiodide (SmI2) mediated aldol reaction and intramolecular Pummerer reaction as the key steps. The alpha-phenylthio ketone 11, the precursor of the samarium enolate, was prepared from D-Galactose. Treatment of 11 with SmI2 at -40degreesC resulted in complete conversion to the corresponding samarium enolate, and subsequent addition of uridine 5'-aldehyde 12 afforded the desired aldol products 13a,b. Compound 13a was converted to the sulfoxide 15 by a sequential diastereoselective reduction of the ketone and an oxidation with mCPBA. Activation of 15 with Tf2O provided the desired cyclized compound 17. In this reaction, the aldol product 13a was also obtained as a consequence of a competitive intramolecular version of DMSO-oxidation via a 7-membered ring intermediate. Compound 18 or 19 are ready for use as a glycosyl donor in glycosylations to provide a range of analogues as potential glycosyltransferase inhibitors as well as related natural products.
  • 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]
  • Sukeda M, Ichikawa S, Matsuda A, Shuto S
    The Journal of organic chemistry 68 9 3465 - 3475 2003年05月 [査読有り][通常論文]
  • Sukeda M, Ichikawa S, Matsuda A, Shuto S
    Angewandte Chemie (International ed. in English) 41 24 4748 - 4750 2002年12月 [査読有り][通常論文]
  • Kodama T, Shuto S, Ichikawa S, Matsuda A
    The Journal of organic chemistry 67 22 7706 - 7715 2002年11月 [査読有り][通常論文]
  • DL Boger, S Ichikawa, HJ Jiang
    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 122 49 12169 - 12173 2000年12月 [査読有り][通常論文]
     
    A total synthesis of the tubrolone aglycon is detailed and is based on two key Diels-Alder reactions. The AB ring system incorporating a tetrasubstituted pyridine was assembled, enlisting the rare 4 pi participation of an O-alkyl alpha,beta -unsaturated oxime in an intramolecular [4 + 2] cycloaddition reaction (70%). The C-ring oxygenated tropolone was introduced through a room-temperature, exo selective [4 + 2] cycloaddition of a cyclopropenone ketal (97%) followed by in situ generation of a norcaradiene and room-temperature electrocyclic rearrangement to a cycloheptatrienone ketal appropriately substituted for hydrolysis directly to a 2,4-dihydroxycycloheptatrienone.
  • S Shuto, Y Yahiro, S Ichikawa, A Matsuda
    JOURNAL OF ORGANIC CHEMISTRY 65 18 5547 - 5557 2000年09月 [査読有り][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.
  • DL Boger, S Ichikawa
    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 122 12 2956 - 2957 2000年03月 [査読有り][通常論文]
  • Satoshi Shuto, Masaru Terauchi, Yumi Yahiro, Hiroshi Abe, Satoshi Ichikawa, Akira Matsuda
    Tetrahedron Letters 41 21 4151 - 4155 2000年 [査読有り][通常論文]
  • S Ichikawa, S Shuto, A Matsuda
    TETRAHEDRON LETTERS 39 25 4525 - 4528 1998年06月 [査読有り][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 Ichikawa, S Shuto, N Minakawa, A Matsuda
    JOURNAL OF ORGANIC CHEMISTRY 62 5 1368 - 1375 1997年03月 [査読有り][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).
  • ヨウ化サマリウムのヌクレオシド化学への展開
    市川 聡
    [査読有り][通常論文]

MISC

  • Development of Positive Modulators of Histone H3K27 Methylation
    Tokodai, Yasuaki, Yakushiji, Fumika, Sengoku, Toru, Katsuyama, Akira, Ichikawa, Satoshi Peptide Science 14 2018年 [査読有り][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]
  • 林健人, 阿部祐希, 前田直良, 前仲勝実, 市川聡, 堺谷政弘 メディシナルケミストリーシンポジウム講演要旨集 34th 103 2016年11月11日 [査読無し][通常論文]
  • 大形悠梨子, 高木朋之, 阿部裕希, 加藤いづみ, 前仲勝実, 市川聡, 堺谷政弘 メディシナルケミストリーシンポジウム講演要旨集 34th 161 2016年11月11日 [査読無し][通常論文]
  • 田所高志, 可野巧, 市川聡, 松田彰, 黒木喜美子, 前仲勝実 日本蛋白質科学会年会プログラム・要旨集 16th 155 2016年05月19日 [査読無し][通常論文]
  • 千葉 拓也, 仲谷 岳志, 片山 勝史, 松田 彰, 市川 聡 有機合成化学協会誌 74 (5) 426 -440 2016年05月 [査読無し][通常論文]
     
    Multicomponent reaction represented by Mannich reaction, Strecker reaction and Biginelli reaction has been applied to several natural product synthesis because a complexed framework of the natural product can be constructed by assembling more than three simple components at one step. It is also attractive from a medicinal chemical point of view because it enables us to supply a range of analogues to investigate a structure-activity relationship simply by changing components in the reaction. Here, we described our recent studies utilizing a multicomponent reaction in natural product-based medicinal chemistry. First topic is about total synthesis of syringolin A class of proteasome inhibitor and its structure-activity relationship study by intramolecular Ugi three-component reaction. We also synthesized cyclic peptide natural products (sandramycin, quinaldopeptin) and analogues and revealed their biological properties. Finally, design and synthesis of simplified caprazamycin analogues using aza-Prins-Ritter reaction was described.
  • 可野巧, 田所高志, 市川聡, 松田彰, 黒木喜美子, 前仲勝実 日本蛋白質科学会年会プログラム・要旨集 15th 115 2015年05月26日 [査読無し][通常論文]
  • 千葉 拓也, 市川 聡, 松田 彰 天然有機化合物討論会講演要旨集 54 (54) 435 -440 2012年09月01日 [査読無し][通常論文]
     
    Syringolin A (1), which was isolated from strains of the plant pathogen Pseudomonas synringae pv Syringae (Pss), possesses a 12-membered dipeptide ring structure containing two (E)-configured double bonds and a urea side chain. In 2008, syringolin A has been identified as a virulence factor which irreversibly inhibits the 20S proteasome. It was showed to selectively inhibit all three catalytic activities of eukaryotic proteasomes by covalent modification of a threonine residue in the active site. The proteasome is essential for protein degradation and has been validated in the clinic as a biological target for the treatment of multiple myeloma. Therefore, we are interested in syringolin A and decided to synthesize 1 and its analogues. Total synthesis of 1 has accomplished by Kaiser's, Stephenson's and Pirrung's groups. We planned to synthesize 1 and its analogues considering to develop more convergent synthetic route, which can be applicable to structure-activity relationship of 1. Our retro-synthetic analysis of 1 is depicted in Scheme 1. The substrate 3 with isonitrile and aldehyde functionalities was reacted with the carboxylic acid 4 and the amine 5 as the Ugi three component reaction. After optimization of Ugi reaction, the macrocycle 30 was obtained 26% yield. This synthesis allows us to construct the 12-membered dipeptide ring and introduce the urea side chain at once. Next, mesylation of the secondary alcohol, β-elimination and deprotection of the tert-butyl ester and the 2,4-dimethoxybenzyl group to afford syringolin A (1).
  • 千葉 拓也, 市川 聡, 松田 彰 天然有機化合物討論会講演要旨集 54 (0) 435 -440 2012年 [査読無し][通常論文]
     
    Syringolin A (1), which was isolated from strains of the plant pathogen Pseudomonas synringae pv Syringae (Pss), possesses a 12-membered dipeptide ring structure containing two (E)-configured double bonds and a urea side chain. In 2008, syringolin A has been identified as a virulence factor which irreversibly inhibits the 20S proteasome. It was showed to selectively inhibit all three catalytic activities of eukaryotic proteasomes by covalent modification of a threonine residue in the active site. The proteasome is essential for protein degradation and has been validated in the clinic as a biological target for the treatment of multiple myeloma. Therefore, we are interested in syringolin A and decided to synthesize 1 and its analogues. Total synthesis of 1 has accomplished by Kaiser's, Stephenson's and Pirrung's groups. We planned to synthesize 1 and its analogues considering to develop more convergent synthetic route, which can be applicable to structure-activity relationship of 1. Our retro-synthetic analysis of 1 is depicted in Scheme 1. The substrate 3 with isonitrile and aldehyde functionalities was reacted with the carboxylic acid 4 and the amine 5 as the Ugi three component reaction. After optimization of Ugi reaction, the macrocycle 30 was obtained 26% yield. This synthesis allows us to construct the 12-membered dipeptide ring and introduce the urea side chain at once. Next, mesylation of the secondary alcohol, β-elimination and deprotection of the tert-butyl ester and the 2,4-dimethoxybenzyl group to afford syringolin A (1).
  • 片山 勝史, 市川 聡, 松田 彰 天然有機化合物討論会講演要旨集 53 (53) 631 -636 2011年09月02日 [査読無し][通常論文]
     
    Sandramycin (1), which was isolated from the culture broth of Norcardioides sp. (ATCC 39419), constitutes one of the members of class of C2-symmetric cyclic decadepsipeptide. It binds to the minor groove of double-strand DNA (dsDNA) with bisintercalation. Sandramycin (1) has exceptionally potent activity against L1210 cell in vitro with IC_<50> values of 0.02 nM. Total synthesis of 1 has accomplished by Boger's group via a sequential peptide coupling approach. The macrocycle moiety of 1 binds to the minor groove of dsDNA and greatly contributes to the sequence selectivity. We planned to synthesize 1 and its analogues of the macrocycle moiety considering to develop more convergent synthesic route, which can be applicable to study the structure-activity relationship of the macrocycle moiety. Our retro-synthetic analysis of sandramycin (1) is depicted in Scheme 1. First, the cyclic imine 6 was obtained by the Staudinger/aza-Wittig reaction sequence, and it was subsequently reacted with the isonitrile 5 and the carboxylic acid 7 in toluene at 70℃ as the Ugi three component reaction. As a result, the desired pentadepsipeptide 4 was obtained in 59% yield in a diastereoselective manner. This synthesis allows us to construct the pentapeptide 4 with simultaneous construction of the unnatural L-Pip residue and its linking to the two dipeptides at both C- and N- terminus. Next, deprotection of either the Boc group or the Tce group of 4 gave the amine 19 and the carboxylic acid 20, respectively. The [5+5] assemblage of 19 and 20 was conducted by the peptide coupling with the formation of the additional N-methylamide moiety to afford the liner decapeptide 21 (DEPBT, NaHCO_3, CH_2C1_2-DMF, 74%). Deprotection of the Boc and the Tce group of 21 with the same conditions used for the preparation of 19 and 20 gave the free liner peptide 3, which was then cyclized by DPPA in CH_2Cl_2-DMF to afford the cyclic decadepsipeptide 2 in 46% yield over three steps from 21. This synthetic approach is advantageous because sarcosine has no substituent at the a-position and the peptide coupling is free from a racemization, which is usually problematic in the peptide coupling chemistry.
  • 市川 聡, 谷野 哲也, 伊井 謙介, 松田 彰 有機合成化学協会誌 69 (9) 1020 -1033 2011年09月 [査読無し][通常論文]
     
    Natural products are a rich source for drug development. However, some biologically relevant natural products possess rather large, complex or labile chemical structures compared to synthetic drugs, which limits chemical modification in a process pursuing a structure-activity relationship. Here we describe the rational simplification of the muraymycins and caprazamycins class of nucleoside natural products to address the issue associated with their molecular complexity. First, the systematic structure-activity relationship (SAR) study of the muraymycins using an Ugi four-component reaction was investigated. Our SAR study of the muraymycins suggests a probable mechanism for inhibition of the MraY. The predicted binding model would provide further direction towards the design of potent MraY inhibitors. Next, function-oriented synthesis (FOS) of caprazamycins was investigated. Based on the conformation-activity relationship study of a series of analogs <b>36</b>-<b>38</b>, we designed the oxazolidine-containing uridine derivatives <b>41</b>-<b>44</b> by restricting the conformation of <b>36</b>-<b>38</b>. As a result, the <i>tert</i>-butyl ester derivatives <b>43</b> were found to be the most active against a range of bacterial strains containing VRE with a similar potency to the parent natural products. These studies provide a novel strategy for the development of a new type of antibacterial agent effective against drug-resistant bacteria.
  • 片山 勝史, 市川 聡, 松田 彰 天然有機化合物討論会講演要旨集 53 (0) 631 -636 2011年 [査読無し][通常論文]
     
    Sandramycin (1), which was isolated from the culture broth of Norcardioides sp. (ATCC 39419), constitutes one of the members of class of C2-symmetric cyclic decadepsipeptide. It binds to the minor groove of double-strand DNA (dsDNA) with bisintercalation. Sandramycin (1) has exceptionally potent activity against L1210 cell in vitro with IC_<50> values of 0.02 nM. Total synthesis of 1 has accomplished by Boger's group via a sequential peptide coupling approach. The macrocycle moiety of 1 binds to the minor groove of dsDNA and greatly contributes to the sequence selectivity. We planned to synthesize 1 and its analogues of the macrocycle moiety considering to develop more convergent synthesic route, which can be applicable to study the structure-activity relationship of the macrocycle moiety. Our retro-synthetic analysis of sandramycin (1) is depicted in Scheme 1. First, the cyclic imine 6 was obtained by the Staudinger/aza-Wittig reaction sequence, and it was subsequently reacted with the isonitrile 5 and the carboxylic acid 7 in toluene at 70℃ as the Ugi three component reaction. As a result, the desired pentadepsipeptide 4 was obtained in 59% yield in a diastereoselective manner. This synthesis allows us to construct the pentapeptide 4 with simultaneous construction of the unnatural L-Pip residue and its linking to the two dipeptides at both C- and N- terminus. Next, deprotection of either the Boc group or the Tce group of 4 gave the amine 19 and the carboxylic acid 20, respectively. The [5+5] assemblage of 19 and 20 was conducted by the peptide coupling with the formation of the additional N-methylamide moiety to afford the liner decapeptide 21 (DEPBT, NaHCO_3, CH_2C1_2-DMF, 74%). Deprotection of the Boc and the Tce group of 21 with the same conditions used for the preparation of 19 and 20 gave the free liner peptide 3, which was then cyclized by DPPA in CH_2Cl_2-DMF to afford the cyclic decadepsipeptide 2 in 46% yield over three steps from 21. This synthetic approach is advantageous because sarcosine has no substituent at the a-position and the peptide coupling is free from a racemization, which is usually problematic in the peptide coupling chemistry.
  • 市川 聡, 松田 彰 化学 65 (2) 30 -34 2010年02月 [査読無し][通常論文]
  • 市川 聡 藥學雜誌 = Journal of the Pharmaceutical Society of Japan 128 (10) 1403 -1430 2008年10月 [査読無し][通常論文]
     
    &nbsp;&nbsp;Nucleosides and nucleotides are one of the most important elements for cells by the fact that they are components of DNAs and RNAs. In addition, they play important roles in most fundamental cellular metabolic pathways such as energy donors, second messengers, and cofactors for various enzymes. Therefore, there exists a rich source in drug discovery targeting nucleosides and nucleotides. In order to utilize nucleosides and nucleic acids on the drug development, it is very important to develop reactions and methods, by which the highly coordinating and labile nucleoside intermediates can be used. With these in mind, we have been working on synthetic nucleoside and nucleic acid chemistry. First, branched sugar nucleoside derivatives, which are potential antitumor agents, have been synthesized utilizing samarium diiodide (SmI<sub>2</sub>) mediated Reformatsky reaction or aldol reaction. 3&prime;-&beta;-Carbamoylmethylcytidine (CAMC) was found to exhibit potent cytotoxicity against various human tumor cell lines. Synthetic methodology of the caprazamycins, which are promising antibacterial nucleoside natural products, was also developed by the strategy including &beta;-selective ribosylation without using a neighboring group participation. Our synthetic route provided a range of key analogues with partial structures to define the pharmacophore. Simplification of the caprazamycins was further pursued to develop diketopiperazine analogs. Medicinal chemistry of oligodeoxynucleotides has been conducted. Thus, novel triazole-linked dumbbell oligodeoxynucleotides and modular bent oligodeoxynucleotides were synthesized. They exhibit excellent binding affinity to NF-&kappa;B or HMGB1 A-box protein, which are important therapeutic targets. Therefore, the results obtained conclusively demonstrated these oligodeoxynucleotides could be proposed as powerful decoy molecules.<br>
  • 周東 智, 市川 聡, 阿部 洋, 松田 彰 有機合成化学協会誌 : JOURNAL OF Synthetic Organic Chemistry JAPAN 66 (1) 50 -60 2008年01月 [査読無し][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 α/β-stereoselectivity 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 α- and β-selective glycosylation can be realized by employing conformationally restricted substrates. We showed that the α/β-stereoselectivity was significantly increased by the conformational restriction and was completely inverted by changing the substrate conformation from the <SUP>4</SUP>C<SUB>1</SUB>-form into the <SUP>1</SUP>C<SUB>4</SUB>-form in radical and nucleophilic C-glycosylation reactions as well as in O-glycosylation reactions. The conformational restriction of substrates also effectively facilitates the α- and β-selective radical cyclization reaction at the anomeric position. Using the method, C-glucoside trisphosphates designed as Ca<SUP>2+</SUP>-mobilizing agents were successfully synthesized.
  • 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]
  • 市川 聡 藥學雜誌 = Journal of the Pharmaceutical Society of Japan 126 (8) 579 -595 2006年08月 [査読無し][通常論文]
     
    Some of nucleoside antibiotics include complex structures as well as sensitive functionality, which are challenging targets for organic chemists. Among complex nucleoside antibiotics, there are also good drug candidates because they possess a variety of interesting biological properties.Herbicidin B and fully protected tunicaminyluracil, which were undecose nucleoside antibiotics, were synthesized using a samarium diiodide (Sml2)mediated aldol reaction with the use of α-phenylthioketones as enolate sources. The characteristics of the Sml2-mediated aldol reaction are that theenolate can be regioselectively generated and the aldol reaction proceeds under near neutral condition. This reaction is proved to be a powerful reactionfor the synthesis of complex nucleoside antibiotics. The synthesis of caprazol, the core structure of caprazamycins, was conducted by the strategy includingβ-selective ribosylation without using a neighboring group participation and the construction of a diazepanone by a modified reductive amination.Our synthetic route would provide a range of key analogues with partial structures to define the pharmacophore, which can be a lead for the development of more effective anti-bacterial agents.
  • DL Boger, S Ichikawa, W Zhong JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 123 (18) 4161 -4167 2001年05月 [査読無し][通常論文]
     
    The first total synthesis of the potent antitumor agent fostriecin (CI-920) is described, confirming the relative and absolute stereochemistry assignments. Fostriecin is a unique phosphate monoester which exhibits weak topoisomerase II inhibition (IC50 40 muM) and more potent and selective protein phosphatase 2A and 4 (PP2A and PP4) inhibition (IC50 = 40-3 nM and 1.5 nM), resulting in mitotic entry checkpoint inhibition. Phase I clinical trials with fostriecin, which were the first to explore the potential of this novel mechanism of action, were halted even before therapeutic concentrations were reached or dose-limiting toxicity established due to problems of drug stability observed during storage of naturally derived material. The synthesis of fostriecin detailed herein is the first stage of efforts that may serve to address these limitations to the clinical examination of this or related promising new antitumor agents.
  • DL Boger, S Ichikawa, W Zhong JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 123 (18) 4161 -4167 2001年05月 [査読無し][通常論文]
     
    The first total synthesis of the potent antitumor agent fostriecin (CI-920) is described, confirming the relative and absolute stereochemistry assignments. Fostriecin is a unique phosphate monoester which exhibits weak topoisomerase II inhibition (IC50 40 muM) and more potent and selective protein phosphatase 2A and 4 (PP2A and PP4) inhibition (IC50 = 40-3 nM and 1.5 nM), resulting in mitotic entry checkpoint inhibition. Phase I clinical trials with fostriecin, which were the first to explore the potential of this novel mechanism of action, were halted even before therapeutic concentrations were reached or dose-limiting toxicity established due to problems of drug stability observed during storage of naturally derived material. The synthesis of fostriecin detailed herein is the first stage of efforts that may serve to address these limitations to the clinical examination of this or related promising new antitumor agents.
  • DL Boger, S Ichikawa, WC Tse, MP Hedrick, Q Jin JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 123 (4) 561 -568 2001年01月 [査読無し][通常論文]
     
    Full derails of the total: syntheses of thiocoraline (1) and BE-22179 (2), C-2 symmetric bicyclic octadepsipeptides: possessing two pendant 3-hydroxyquinoline chromophores, are described in which their relative and absolute stereochemistry were established. Key elements:of the approach include the late-stage introduction of the chromophore, symmetrical; tetrapeptide coupling, macrocyclization of, the 26-membered octadepsipeptide conducted at the single secondary amide site following disulfide formation, and a convergent assemblage:of the tetradepsipeptide with introduction of The labile thiol ester linkage in the final coupling reaction under-near racemization free conditions. By virtue of the late-stage introduction of the chromophore and despite the challenges this imposes on the synthesis, this approach provides ready access to a range of key chromophore analogues. Thiocoraline and BE-22179 were shown to bind to DNA by high-affinity bisintercalation analogous to echinomycin, but with little or no perceptible sequence selectivity. Both 1 and 2 were found to exhibit exceptional cytotoxic activity (IC50 = 200 and 400 pM, respectively, L1210 cell line) comparable to echinomycin and one analogue, which bears the luzopeptin chromophore, was also found to be a potent cytotoxic agent.
  • Journal of the American Chemical Society 123 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 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.
  • 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.
  • The First Synthesis of Herbicidin B. Stereoselective Construction of the Tricyclic Undecose Moiety by a Conformational Restriction Strategy
    Journal of the American Chemical Society 121 1999年 [査読無し][通常論文]
  • 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 (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.
  • 市川 聡 ファルマシア 33 (2) 190 -191 1997年02月01日 [査読無し][通常論文]
  • 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 (0) 373 -378 1997年 [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.
  • 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]

講演・口頭発表等

  • ヌクレオシド系天然物による創薬基盤研究  [通常講演]
    市川 聡
    2014年03月
  • 新規抗菌剤のシードとしてのヌクレオシド系天然物:合成とその生物活性  [通常講演]
    市川 聡
    2013年09月
  • Liponucleoside natural products: synthesis and structure-activity relationship  [通常講演]
    市川 聡
    2013年09月
  • 天然物を用いる創薬化学  [通常講演]
    市川 聡
    2012年09月
  • 新規抗菌剤の開発を指向した天然物の単純化プロセス  [通常講演]
    市川 聡
    2012年03月
  • Chemistry and structure-activity relationship of antibacterial nucleoside natural products  [通常講演]
    市川 聡
    2008年09月
  • 核酸系天然物の合成研究を基軸とした精密ヌクレオシド合成化学  [通常講演]
    市川 聡
    2008年03月
  • The synthesis of complex nucleoside antibiotics  [通常講演]
    市川 聡
    2004年09月

担当経験のある科目(授業)

  • 創薬科学特論北海道大学
  • 薬学英語II北海道大学
  • 基礎有機化学II北海道大学
  • 化学II北海道大学
  • 有機化学III北海道大学
  • 有機化学IV北海道大学

所属学協会

  • 日本薬学会   

共同研究・競争的資金等の研究課題

  • 膵臓がんの頑健性の分子基盤の解明とその破壊による新規治療法の確立
    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 : 園下 将大, 藤井 清永, 市川 聡, 大塩 貴子, 小沼 剛
  • リボフラビン経路を標的とした新規膵臓がん治療法の開発
    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 : 大塩 貴子, 園下 将大, 市川 聡, 藤井 清永
  • MraY阻害天然物による化学コミュニケーションの 制御と創薬シーズの開発
    日本学術振興会:科学研究費助成事業 新学術領域研究(研究領域提案型)
    研究期間 : 2020年04月 -2022年03月 
    代表者 : 市川 聡
  • 天然物創薬を加速するリード創製プラットホーム構築研究
    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 : 2019年04月 -2022年03月 
    代表者 : 市川 聡
     
    天然物を基盤とする創薬研究における、必要な天然物の誘導体を「いかにして迅速かつ網羅的に合成するか?」という至上命題に対して、①パラレルフラグメント連結戦略による迅速かつ網羅的なライブラリー供給と生物活性評価と、発展型である②動的コンビナトリアル合成戦略による活性化合物のテーラーメード合成の2つの柱からなる新たな天然物創薬プラットホームの構築を行う。本年度は、研究項目①パラレルフラグメント連結戦略を検討した。まず、コリスチン・ポリミキシンを対象として、環状ペプチド部を「コア」、アシルペプチド鎖を「アクセサリー」として、それぞれを固相合成した。次に、各フラグメントの連結を96穴プレート上で行い、コリスチン・ポリミキシン誘導体の小規模ライブラリーをパラレル合成した。この際に、最低限必要な量の「コア」と「アクセサリー」の検討や、各ウェル内でヒドラゾン形成反応の進行と収率をLC-MSにて確認した。両フラグメントによる生物活性評価条件でのヒドラゾン形成反応条件、同条件下におけるヒドラゾン体の安定性についても検討した。その結果、SPRやITC等の測定条件下では、化合物は純分安定に存在する事を確認した。一方で、細胞や細菌の培養液中では、24時間で30~40%程度の化合物の分解が起きている事もわかった。ヒドラゾン形成反応条件とその安定性に関する知見を得たため、コリスチン・ポリミキシン誘導体の大規模ライブラリー(600個以上)を一挙にパラレル合成した。また、ヌクレオシド系天然物についても検討を始めた。
  • 「活性配座の増幅と記憶」を鍵概念とする迅速かつ簡便な活性配座の探索法の開発
    日本学術振興会:科学研究費助成事業 挑戦的研究(萌芽)
    研究期間 : 2018年06月 -2021年03月 
    代表者 : 市川 聡, 薬師寺 文華, 勝山 彬
     
    軸不斉を有する化合物(アトロプ異性体)が、ゆっくりともう片方の異性体へと異性化するという性質に着目し、アトロプ異性体と標的分子の結合の活性配座を、片方のエナンチオマーの増幅として検出する、迅速な活性配座探索法の開発に向け、研究を実施した。アトロプ異性体が分離可能なことが報告されているインドメタシン誘導体の構造に基づき、まずは周辺化合物を合成し、小規模なライブラリーの構築を行った。インドメタシンが有するカルボン酸を、アルコールやアミド等の他の極性官能基へと変換した誘導体や、軸不斉をもたらす芳香環上に、置換基導入の足がかりとなるフェノールを導入し、フェノールのアルキル化により、さらに官能基を導入した誘導体等の計15種類程度からなる化合物ライブラリーを合成した。また、合成した誘導体の一部については、元の化合物同様の立体構造を有していることをNMR実験により確認した。合成した誘導体を用いて、モデルタンパク質を用いた活性配座の増幅に関して検討を実施した。モデルタンパク質としては、インドメタシンと結合することが報告されているカタラーゼ、ヒト血清アルブミン等を利用した。これらモデルタンパク質とインドメタシン誘導体を混合し、片方のエナンチオマーの増幅が見られるかについて検討した。37℃の定温条件下、ラセミ体のインドメタシン誘導体をカタラーゼと混合し、24時間後にキラルHPLCで分析したところ、片方のエナンチオマーの若干の増幅が見られた。
  • 線維芽細胞が産生する新規液性因子の肝胆膵癌悪性化の機序解明と革新的治療の開発
    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 : 2018年04月 -2021年03月 
    代表者 : 調 憲, 播本 憲史, 石井 範洋, 久保 憲生, 五十嵐 隆通, 市川 聡, 横堀 武彦, 新木 健一郎, 渡辺 亮, 塚越 真梨子
     
    昨年度までにわれわれはM2BPGi がヒト肝・膵癌細胞株の増殖・浸潤にi n vitroにおいて促進的に働いていることを検証した。また、この作用は癌細胞のGalectin3発現をsiRNAを用いて抑制することでキャンセルされた。したがって、M2BPGiの癌細胞に対する作用はM2BPGiのリガンドとされるgalectin3を介する作用であることが示された。このような成果に基づき、今年度は1)肝・膵癌組織におけるM2BPGiの局在、2)In vivoにおけるM2BPGiの肝・膵癌に対する効果を明らかにした。1)M2BPGiの局在:肝切除された肝細胞癌や膵癌組織におけるM2BPの局在をin situ hybridization法(RNA scope)にて確認したところ、M2BPのmRNAは癌関連線維芽細胞に認められた。多重蛍光免疫組織化学染色において癌細胞にM2BPGiが存在しており、それが癌細胞におけるGalectin 3にmergeすることを証明した。このことから、癌関連線維芽細胞で産生されたM2BPGiが癌細胞において発現するgalectin 3に結合してその作用を発揮していることが示唆された。2)In vivoにおける検討:まず、NOD/SCIDマウスの皮下にヒト肝細胞癌株を接種し、持続注入ポンプを用いてM2BPGiが持続的に吸収されるモデルを作成した。その結果、ヒト肝癌細胞株を用いたマウス皮下腫瘍モデルでもM2BPGi の持続的な投与が腫瘍の増大を促進することを証明した。さらにその機序としてmTORを介したpathwayが重要であることが明らかになった。昨年度と今年度でM2BPGiの癌細胞に対する作用をin vivo、in vitroにおいて世界で初めて明らかにし、その分子機序が明らかになった。
  • 緑膿菌選択的化学コミュニケーション分子の機能解明と創薬シーズへの展開
    日本学術振興会:科学研究費助成事業 新学術領域研究(研究領域提案型)
    研究期間 : 2018年04月 -2020年03月 
    代表者 : 市川 聡
     
    本申請研究では、緑膿菌選択的に抗菌活性を示すウリジルペプチド系化学コミュニケーション分子の取り込み機能解明を行うとともに、積極的に創薬シーズへと展開すべく以下の項目を遂行する。1)ムレイドマイシンの光クロスリンクプローブを用いた化学生物学的手法と、ムレイドマイシン耐性菌の全ゲノムシークエンス解析による遺伝学的手法により、外膜に存在するムレイドマイシンのトランスポーターを同定する。2)ムレイドマイシン誘導体ライブラリーを用いた網羅的解析により、in vivoで緑膿菌にも有効な誘導体を探索する。3)緑膿菌へのムレイドマイシン取り込み機構を利用した「トロイの木馬型」新規抗緑膿菌薬のリード開発を目指す。平成30年度は、まず各種誘導体合成全般を供給可能な固相合成法を確立することで、本申請研究遂行の化合物供給の技術基盤を築いた。以下の各研究項目を並行して遂行した。 1)化学コミュニケーション分子プローブであるムレイドマイシンの光クロスリンクプローブを合成した。さらにこれらの官能基の導入位置を変えたり、ベンゾイルフェニル(ベンゾフェノン)基などの光クロスリンク官能基、アジド基などの他の足掛かりリンカーを導入したプローブも併せて合成した。2)網羅的化学コミュニケーション分子ライブラリー構築の初期段階として、8個程度の新規誘導体を合成した。最も強いMraY阻害活性を有する誘導体とAquifex aeolicus 由来MraYとの複合体のX線結晶構造解析を行った。
  • 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 : 市川 聡, 勝山 彬, 佐藤 豊孝
     
    1)ムライマイシンの制御型誘導体の合成を行った。2)スファエリミシン誘導体の合成とMraY阻害活性評価を行い、高いMraY阻害活性を有する誘導体を見出した。3)ムレイドマイシンA誘導体を合成し、高いMraY阻害活性と抗緑膿菌活性を有する誘導体を見出した。さらにMraYとの複合体のX線結晶構造解析を行った。4)プラスバシンA3誘導体の合成を行った。またプラスバシンA3の作用機構解析も行った。5)コリスチン耐性細菌に有効な誘導体を見出すべく、コリスチン誘導体30個を合成しその抗菌活性を評価した。本研究では、抗薬剤耐性菌薬リードを開発する事が出来たと言える。
  • 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 : 市川 聡
     
    DNAビスインターカレーター能を有する環状ペプチド系天然物を母骨格とした誘導体を合成し、そのDNA結合能とin vitroヒトがん細胞増殖抑制活性を評価した。その中で、天然物と同等の活性を有する誘導体を見出す事ができた。さらに類縁天然物であるトリオスチンAとエチノマイシンの合成にも着手し、6個の誘導体を合成した。各種ヒトがん細胞に対する増殖抑制活性を評価したところ、nMオーダーのIC50値を示す化合物を見出す事ができた。さらに、ヒト腎臓がん細胞皮下移植マウスモデルを用いたin vivo抗がん活性を示す誘導体を見出した。新規抗がん剤のシーズを見出す事が出来たと言える。
  • 創薬を指向した緑膿菌の取り込み機構に関するケミカルバイオロジー
    日本学術振興会:科学研究費助成事業 新学術領域研究(研究領域提案型)
    研究期間 : 2014年04月 -2016年03月 
    代表者 : 市川 聡
     
    1)ムライマイシン・ムレイドマイシンに関して、アルケンスキャンニング法により同定した酵素阻害活性に関与しないアミノ酸残基を、ジアジド含有アミノ酸に置換した光クロスリンクプローブを合成した。これらを用いてMraYとのクロスリンク実験を行ったが、クロスリンク体は得られなかった。2) ムライマイシン誘導体ライブラリーに関しては、固相合成法を用いることで、まずペプチド部変改誘導体29個を合成した。これらはすべて強いMraY阻害活性を保持した。in vivo抗緑膿菌活性評価を行ったところ、脂溶性アミノ酸残基や酸性アミノ酸残基を持つ誘導体は緑膿菌に対して全く無効であったのに対し、リシンやアルギニンなどの塩基性アミノ酸残基を有する誘導体は、抗菌活性を有する事がわかった。また、これらの誘導体は緑膿菌のみならず、広範なグラム陰性菌に対して有効であることもわかった。さらにin vivo黄色ブドウ球菌感染カイコ評価系による治療効果の評価を行ったところ、有意な治療効果を示す事がわかった。これらの誘導体は、細菌細胞膜透過に必要なアシル側鎖として長鎖飽和脂肪酸を有し、ヒト肝がんHepG2細胞に対する細胞毒性を示す事がわかった。そこで、毒性の軽減を目的として、アシル側鎖変換誘導体71個を固相合成し、各種生物活性評価を行った。その結果、分岐脂肪酸をアシル側鎖として有する誘導体が、MraY阻害活性と抗菌活性を保持しつつHepG2細胞に対する細胞毒性が低いことがわかった。
  • 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 : 2013年04月 -2016年03月 
    代表者 : 市川 聡
     
    細菌細胞壁合成阻害膜内作用型の天然物であるムライマイシン・カプラザマイシン類の化学構造の大幅な低減と単純化をはかり、MRSAやVRE等の薬剤耐性菌に対する抗菌活性と十分な代謝安定性を持ち、ヒト細胞に対する毒性が軽減した誘導体を見出した。細菌細胞壁合成阻害膜外作用型の天然物であるプラスバシンの効率的で多彩な誘導体合成に柔軟に対応可能な収束型合成法を確立した。2本鎖DNAに結合する事で、強力な転写阻害活性を示すキナルドペプチンの全合成とその誘導体の合成を行った。これらはグラム陽性菌に対してnMレベルの強力な抗菌活性を示し、天然物の活性を上回る活性を有する誘導体を見出す事ができた。
  • 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 : 市川 聡
     
    タンパク質間相互作用を阻害する低分子化合物(PPI)の分子設計は、創薬化学における最重要課題のひとつである。本申請研究は、薬物設計の段階からタンパク質間相互作用の阻害を考慮した化合物群を設計・合成し、分子進化型薬物変換によるPPIの小分子ライブラリーを構築した。合成した化合物のいくつかは、あるタンパク質間相互作用をμMレベルで阻害することがわかり、さらにライブラリーの拡充を行った。
  • アルケン・アルキンスキャニングによる迅速構造活性相関ストラテジー
    日本学術振興会:科学研究費助成事業 新学術領域研究(研究領域提案型)
    研究期間 : 2012年04月 -2014年03月 
    代表者 : 市川 聡
     
    本年度は、まずムライマイシンのアルケンスキャニング誘導体を合成し、そのMraY阻害活性評価を行った。その結果、ロイシン、エピカプレオミシジン、バリン残基のいずれをアリル基で置換した誘導体も酵素阻害活性を保持し、これらのアミノ酸残基は活性発現に重要ではないことが示唆された。次にアリル基に対する置換基導入に関して、どのような反応が適用できるかを検討し、クロスカップリング・メタセシス反応が適用可能であることがわかった。 また、ムレイドマイシン誘導体の合成についても検討した。ジアステレオ選択的C-Hアミノを利用したジアミノブタン酸の立体選択的・効率的な合成を確立し、さらに銅触媒を用いるカルボキサミドとヨードオレフィンのクロスカップリングと続くペプチドカップリングを用いる事で、ムレイドマイシン誘導体の母骨格の一般的合成法を確立した。本法を用いて、アルケンスキャニング誘導体の合成検討を行った。
  • 天然物を基盤とする包括的な抗薬剤耐性菌薬のリード創出研究
    研究期間 : 2010年04月 -2013年03月 
    代表者 : 市川 聡
  • 日本学術振興会:科学研究費助成事業 若手研究(A)
    研究期間 : 2010年 -2012年 
    代表者 : 市川 聡
     
    本申請研究は、抗菌天然物の抗菌スペクトルの拡大と低分子化による新規抗薬剤耐性菌薬のリードを創出することを目的とする。ムライマイシン、パシダマイシンの全合成を達成するとともに、これらの誘導体の構造活性相関を検討した。またカプラザマイシンの大幅な単純化を論理的に行い、分子量が約半分であるオキサゾリジン誘導体が天然物とほぼ同等の抗菌活性を有し、またメチシリン耐性黄色ブドウ球菌やバンコマイシン耐性腸中菌などの薬剤耐性菌にも広く有効であることもわかった。ムライマイシンについても、分子量が約半分である単純化誘導体を見いだした。これらの研究から、標的酵素MraYとの結合様式を提案することができた。
  • 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 : 2010年 -2011年 
    代表者 : 市川 聡
     
    2本鎖DNAに搭載するキナルドペプチンの全合成研究を行った。ピペコリン酸、ジアミノブタン酸等を用いたペプチド固相合成法により鎖状デカペプチドを合成した。大環状ラクタム化反応を行い、最後に、クロモフォアーを導入してキナルドペプチンの初の全合成を達成した。次に前立腺がん細胞表面に特異的に発現している抗原のリガンドを結合した2本鎖DNAにキナルドペプチンを結合させて、人工低分子核酸抗体を作成した。
  • 日本学術振興会:科学研究費助成事業 新学術領域研究(研究課題提案型)
    研究期間 : 2008年 -2010年 
    代表者 : 藤室 雅弘, 市川 聡
     
    本研究は、カポジ肉腫関連ヘルペスウイルス(KSHV)によって発症するB細胞性リンパ腫(PEL)に対する抗腫瘍化合物とKSHVのウイルス複製を阻害する抗KSHV化合物の開発を目的としている。我々は、KSHV感染特異的にがん細胞に対して殺細胞活性を示す抗腫瘍化合物CNDAGを開発しているが、その作用機序は不明な点が多い。そこで、本研究において、CNDAGの作用機序やヘルペスウイルスに対する複製阻害効を解析し、CNDAGの詳細な作用機序と新しい薬理効果(抗ウイルス効果)を明らかにした。さらに、新規抗PEL化合物と抗KSHV化合物の探索を行い、幾つかの候補化合物を同定すると共にそれらの作用機序も明らかにした。
  • 日本学術振興会:科学研究費助成事業 若手研究(B)
    研究期間 : 2008年 -2009年 
    代表者 : 市川 聡
     
    本研究はタンパク質間相互作用を阻害する小分子有機化合物を設計する方法論の確立を目指して、高立体選択的β-C-リボシル化反応の適用範囲拡大と、本反応を用いて新規タンパク質間相互作用阻害剤を開発するものである。申請者はオキソカルベニウムイオンに対する極めて稀な求核剤のoutside attackを積極的に活用して、高立体選択的なβ-C-リボシル化反応を開発した。得られたアリル-β-C-リボシドから、オキサビシクロ[n.2.1]系化合物を得ることができた。
  • タンパク質間相互作用を調節する小分子有機化合物の論理的開発研究
    研究期間 : 2006年04月 -2008年03月 
    代表者 : 市川 聡
  • Hsp90を分子標的とする多角的抗癌剤開発
    日本学術振興会:科学研究費助成事業 若手研究(B)
    研究期間 : 2006年 -2007年 
    代表者 : 市川 聡
     
    構造に基づいた薬物設計(Structure Based Drug Design, SBDD)を基盤として、複数の癌関連clientの機能発現タンパク質の機能と安定性を調節する分子シャペロンHsp90の阻害剤開発研究を行った。本年度は各種ヒト乳癌細胞(MCF7, Skbr3)に対して増殖抑制活性の増強がみられたN末端結合分子2量体の構造最適化を行った。その結果、C20リンカーで連結した化合物が、各種腫瘍細胞に対して20-30倍の活性増強(IC_<50>=1.2-1.5 μM)を示すことが明らかとした。さらにこれらの化合物で処理した細胞ではHer2の分解が観察されたことから、細胞内に取り込まれた後に確かにHsp90を阻害していることも示唆された。本年度はさらに新規N末端結合型のHsp90の阻害剤の開発研究も行った。すなわち、天然の基質であるATPと、N末端結合型の天然物であるゲルダナマイシンをハイブリッドしたシクロファン含有アデノシン誘導体を設計した。まず予備検証として、非環状型のアデノシン誘導体を合成し、MCF7に対する細胞増殖抑制活性を検討した。その結果、この化合物は中程度の活性(IC_<50>=50 μM)を示すことがわかったため、目的とする化合物の合成を検討した。アミドの回転異性の制御を利用した効率的な閉環メタセシス反応を用いることにより、シクロファン含有アデノシン誘導体の効率的かつ系統的な合成経路を確立することができた。合成した化合物の生物活性評価に関しては、現在検討中である。
  • 糖鎖合成酵素阻害剤の開発
    研究期間 : 2002年 -2006年
  • 核酸系抗生物質の創薬志向型合成研究
    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 : 2005年 -2005年 
    代表者 : 市川 聡
     
    本研究は抗菌・抗真菌・抗ウイルス活性を有する核酸系天然物を高効率的に合成すること、誘導体合成ならびにその構造活性相関を行うことを目的とし、以下の核酸系天然物に関する合成研究を行った。 1.Caprazamycin類:ウリジンから5工程で得られる(S)-6'-(S)-5'-グリシルウリジンに対してペンチリデン基の立体障害を利用したリボシル化反応を行うことで、望みとする5'-O-β-リポシドを高立体選択的に得た。このβ-リポシドを6工程で環化前駆体に変換し、還元的アミノ化反応によりジアゼパノンを構築した。最後に脱保護を行いcaprazolの初の全合成を達成した。さらに抗菌活性を有するFR-900493の全合成も達成し、その全絶対立体配置を決定した。本合成法を創薬研究へと展開すべく、caprazolのコンフォメーション解析を行い、ジアゼパノン部をジケトピペラジン構造へと単純化した新規誘導体を設計・合成した。 2.Tunicamycin類:Tunicamycin類の分子機構とβ-1,4-ガラクトース転移酵素のX線結晶構造を用いたドッキングスタディーの結果を考慮して、11'-置換tunicanminyluracilを設計・合成した。β-1,4-ガラクトース転移酵素の阻害活性を検討した。その結果、11'-フェニルチオ体が中程度の阻害活性を有することを明らかにした。 3.Guanofosfocin類:guanofosfocinは熱・酸化条件に不安定な物質であり、ジリン酸化アセタール構造がその要因と考え、その一つの酸素原子を炭素原子に置換した安定等価体を設計した。マンノースより合成したリチオ体のグアノシン5'-アルデヒド体に対する付加反応により得られた付加体を環化前駆体に変換した。光延反応による環化反応を検討したところ、目的とする8-O-環化体は得られず、7-N-環化体が得られた。
  • 糖供与体2リン酸-2価金属キレート構造に着目した糖転移酵素阻害剤の開発
    日本学術振興会:科学研究費助成事業 若手研究(B)
    研究期間 : 2004年 -2005年 
    代表者 : 市川 聡
     
    本研究は、糖供与体二リン酸-二価金属キレート構造に着目した新規糖転位酵素阻害剤の開発を目的とするものであり、本年度は以下の事柄を行った。 1.昨年度までに確立したTunicaminyluracilの合成法を基盤として、各種Tunicaminyluracil誘導体を合成した。子ウシ由来β1,4-GalT-Iを用いた阻害実験を行った結果、11'-phenylthio tunicaminyluracilにβ1,4-GalT-I阻害活性があることを見出した。 2.糖供与体二リン酸-二価金属キレート構造をガラクトピラノース、ベンゼンジメタノール、アルキル・アルケニルリンカーで模倣し、ガラクトースとウリジンを連結した化合物を設計した。各種誘導体はそれぞれワンポットグリコシル化反応、アルキル化・グリコシル化反応、クロスメタセシス反応を用いることで効率的かつ網羅的に合成することができた。合成した化合物群のβ1,4-GalT-I阻害活性を検討したが、活性は認められなかった。現在は活性を有する化合物を見出すべく、β1,4-GalT-IのX線結晶構造を基にしたin silicoバーチャルスクリーニングを取り入れて、新たな誘導体の設計・合成を継続している。 3.β1,4-GalT-I阻害活性が認められた11'-phenylthio tunicaminyluracilに関しても、β1,4-GalT-Iとのドッキングスタディーを行った結果、undecose内ピラノース環が二リン酸-二価金属キレート構造をうまく模倣しうることが示唆された。本結果をもとにして構造情報に基づいた薬物設計(SBDD)を行い、さらに強いβ1,4-GalT-I阻害活性を有するtunicaminyluracil誘導体の合成を行っている。
  • 優れた抗菌剤の開発を目指したペプチドグリカン生合成阻害物質の創製
    日本学術振興会:科学研究費助成事業 若手研究(B)
    研究期間 : 2002年 -2003年 
    代表者 : 市川 聡
     
    本研究はリポシドマイシンの特異な構造と優れた生物活性を利用する抗菌剤の開発を目的としており、誘導体合成を見据えた全合成研究を行っている。本年度は、昨年度に合成した5'-O-β-アミノリボシル-5'-C-グリシルウリジン1を鍵中間体として各種化学変換後、リポシドマイシンに特徴的な構造である7員環ジアゼパノン構造の構築を検討した。その結果、シッフ塩基形成に続くヒドリド還元によりジアゼパノン環を構築することができ、リポシドマイシンのコア構造の保護体2の合成を完了した。リポシドマイシンが有する長鎖脂肪酸は、抗菌活性の発現に必要とされる細菌細胞壁・細胞膜透過性に重要な役割をはたしていると考えられる。本化合物2は、各種長鎖脂肪酸を容易に導入しうる有用な合成中間体であるうえ、2の各種合成中間体はリポシドマイシンの部分構造欠除誘導体とみなすことができるために、本研究はリポシドマイシンの構造活性相関を検討するうえで有用な合成法を提供しうるものと考えられる。 また本年度はリポシドマイシン誘導体の合成の一環として、類縁化合物の合成研究にも展開した。5'-O-β-アミノリボシル-5'-C-グリシルウリジン1の6'位アミノ基にアルキルアミノ基を導入し、各種官能基を変換することで同じく抗菌活性を有するFR-900493誘導体を合成した。これにより、複雑な構造を有するリポシドマイシンの構造を単純化した化合物の合成が容易となり、リポシドマイシン誘導体合成を効率的・網羅的に行うための合成法を確立することができた。今後は各種化合物の生物活性評価を行う予定である。
  • ヨウ化サマリウムのスクレオシド化学での活用:糖部多環性ヌクレオシドの合成
    日本学術振興会:科学研究費助成事業 特別研究員奨励費
    研究期間 : 1998年 -1999年 
    代表者 : 市川 聡
  • 糖転移酵素に関する研究

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