2012年, 日本学術振興会, 科研費審査委員表彰　　　　　　　　　　　　　　　
市川 聡

2008年03月, 日本薬学会奨励賞　　　　　　　　　　　　　　　
市川 聡

2005年12月, 日本薬学会北海道支部奨励賞　　　　　　　　　　　　　　　
市川 聡

Development of small molecule-drug conjugates based on derivatives of natural proteasome inhibitors that exhibit selectivity for PSMA-expressing cancer cells.
Takahiro Obara, Nanami Kawano, Kengo Tatsumi, Akira Katsuyama, Kohei Nakajima, Mikako Ogawa, Satoshi Ichikawa
Bioorganic & medicinal chemistry, 108, 117773, 117773, 2024年06月15日, ［国際誌］
英語, 研究論文（学術雑誌）, In this study, we have developedsmall molecule drug conjugates (SMDCs)consisting ofa prostate specific membrane antigen (PSMA) ligandand syringolin derivatives, which are potent proteasome inhibitors, to selectively deliver syringolin derivatives to prostate cancer cells. Two parent compounds were used for syringolin derivatives with different linkage sites. These SMDCs exhibited PSMA-expressing cell-selective cytotoxicity and they could potentially be used for safer treatment of cancer.

Development of a natural product optimization strategy for inhibitors against MraY, a promising antibacterial target.
Kazuki Yamamoto, Toyotaka Sato, Aili Hao, Kenta Asao, Rintaro Kaguchi, Shintaro Kusaka, Radhakrishnam Raju Ruddarraju, Daichi Kazamori, Kiki Seo, Satoshi Takahashi, Motohiro Horiuchi, Shin-Ichi Yokota, Seok-Yong Lee, Satoshi Ichikawa
Nature communications, 15, 1, 5085, 5085, 2024年06月14日, ［国際誌］
英語, 研究論文（学術雑誌）, MraY (phospho-N-acetylmuramoyl-pentapeptide-transferase) inhibitory natural products are attractive molecules as candidates for a new class of antibacterial agents to combat antimicrobial-resistant bacteria. Structural optimization of these natural products is required to improve their drug-like properties for therapeutic use. However, chemical modifications of these natural products are painstaking tasks due to complex synthetic processes, which is a bottleneck in advancing natural products to the clinic. Here, we develop a strategy for a comprehensive in situ evaluation of the build-up library, which enables us to streamline the preparation of the analogue library and directly assess its biological activities. We apply this approach to a series of MraY inhibitory natural products. Through construction and evaluation of the 686-compound library, we identify promising analogues that exhibit potent and broad-spectrum antibacterial activity against highly drug-resistant strains in vitro as well as in vivo in an acute thigh infection model. Structures of the MraY-analogue complexes reveal distinct interaction patterns, suggesting that these analogues represent MraY inhibitors with unique binding modes. We further demonstrate the generality of our strategy by applying it to tubulin-binding natural products to modulate their tubulin polymerization activities.

The MraY Inhibitor Muraymycin D2 and Its Derivatives Induce Enlarged Cells in Obligate Intracellular Chlamydia and Wolbachia and Break the Persistence Phenotype in Chlamydia.
Iris Löckener, Lara Vanessa Behrmann, Jula Reuter, Andrea Schiefer, Anna Klöckner, Sebastian Krannich, Christian Otten, Katja Mölleken, Satoshi Ichikawa, Achim Hoerauf, Tanja Schneider, Kenneth M Pfarr, Beate Henrichfreise
Antibiotics (Basel, Switzerland), 13, 5, 2024年05月04日, ［国際誌］
英語, 研究論文（学術雑誌）, Chlamydial infections and diseases caused by filarial nematodes are global health concerns. However, treatment presents challenges due to treatment failures potentially caused by persisting Chlamydia and long regimens against filarial infections accompanied by low compliance. A new treatment strategy could be the targeting of the reduced peptidoglycan structures involved in cell division in the obligate intracellular bacteria Chlamydia and Wolbachia, the latter being obligate endosymbionts supporting filarial development, growth, and survival. Here, cell culture experiments with C. trachomatis and Wolbachia showed that the nucleoside antibiotics muraymycin and carbacaprazamycin interfere with bacterial cell division and induce enlarged, aberrant cells resembling the penicillin-induced persistence phenotype in Chlamydia. Enzymatic inhibition experiments with purified C. pneumoniae MraY revealed that muraymycin derivatives abolish the synthesis of the peptidoglycan precursor lipid I. Comparative in silico analyses of chlamydial and wolbachial MraY with the corresponding well-characterized enzyme in Aquifex aeolicus revealed a high degree of conservation, providing evidence for a similar mode of inhibition. Muraymycin D2 treatment eradicated persisting non-dividing C. trachomatis cells from an established penicillin-induced persistent infection. This finding indicates that nucleoside antibiotics may have additional properties that can break bacterial persistence.

Modulation of proteasome subunit selectivity of syringolins
Kengo Tatsumi, Shun Kitahata, Yuya Komatani, Akira Katsuyama, Fumika Yakushiji, Satoshi Ichikawa
Bioorganic & Medicinal Chemistry, 106, 117733, 117733, Elsevier BV, 2024年05月
研究論文（学術雑誌）

Synthesis and biological evaluation of echinomycin analogues as potential colon cancer agent
Keita Kojima, Hiroaki Konishi, Kyoka Momosaki, Yuya Komatani, Akira Katsuyama, Koji Nakagawa, Kayoko Kanamitsu, Fumika Yakushiji, Mikihiro Fujiya, Satoshi Ichikawa
Scientific Reports, 14, 1, Springer Science and Business Media LLC, 2024年04月01日
研究論文（学術雑誌）, Abstract

Colorectal cancer is the third most commonly diagnosed cancer and the second leading cause of cancer-related death, thus a novel chemotherapeutic agent for colon cancer therapy is needed. In this study, analogues of echinomycin, a cyclic peptide natural product with potent toxicity to several human cancer cell lines, were synthesized, and their biological activities against human colon cancer cells were investigated. Analogue 3 as well as 1 inhibit HIF-1α-mediated transcription. Notably, transcriptome analysis indicated that the cell cycle and its regulation were involved in the effects on cells treated with 3. Analogue 3 exhibited superior in vivo efficacy to echinomycin without significant toxicity in mouse xenograft model. The low dose of 3 needed to be efficacious in vivo is also noteworthy and our data suggest that 3 is an attractive and potentially novel agent for the treatment of colon cancer.

Photoinduced dual bond rotation of a nitrogen-containing system realized by chalcogen substitution
Shotaro Nagami, Rintaro Kaguchi, Taichi Akahane, Yu Harabuchi, Tohru Taniguchi, Kenji Monde, Satoshi Maeda, Satoshi Ichikawa, Akira Katsuyama
Nature Chemistry, Springer Science and Business Media LLC, 2024年02月28日
研究論文（学術雑誌）

Concise Synthesis of 11-Noriridoids via Pauson-Khand Reaction.
Ryuji Kouda, Kazuki Yamamoto, Akira Katsuyama, Satoshi Ichikawa, Fumika Yakushiji
Chemical & pharmaceutical bulletin, 72, 6, 547, 558, 2024年, ［国内誌］
英語, 研究論文（学術雑誌）, Iridoids, which are a class of monoterpenoids, are attractive synthetic targets due to their diversely substituted cis-fused cyclopenta[c]pyran skeletons. Additionally, various biological activities of iridoids raise the value of synthetic studies on this class of compounds. Here, our synthetic efforts toward 11-noriridoids; (±)-umbellatolide B (6), (±)-10-O-benzoylglobularigenin (9) and 1-O-pentenylaucubigenin (34) are described. For the efficient synthesis of target compounds, common synthetic intermediates (tricyclic enones 17 and 26) were prepared by the Pauson-Khand reaction. The cleavage of the acetal bond on the tricyclic enones and 1,2-reduction introduced the two hydroxy groups on the cyclopentane ring of the core scaffold. Furthermore, the C3-C4 olefin part was constructed by the syn-elimination of a thiocarbonate moiety to obtain 34. The developed synthetic routes for 6, 9, and 34 will be useful for the preparation of iridoid analogs that have a polyfunctionalized core skeleton.

Determining the structure of protein-bound ceramides, essential lipids for skin barrier function.
Yusuke Ohno, Tetsuya Nakamura, Takafumi Iwasaki, Akira Katsuyama, Satoshi Ichikawa, Akio Kihara
iScience, 26, 11, 108248, 108248, 2023年11月17日, ［国際誌］
英語, 研究論文（学術雑誌）, Protein-bound ceramides, specialized ceramides covalently bound to corneocyte surface proteins, are essential for skin permeability barrier function. However, their exact structure and target amino acid residues are unknown. Here, we found that epoxy-enone (EE) ceramides, precursors of protein-bound ceramides, as well as their synthetic analog, formed stable conjugates only with Cys among nucleophilic amino acids. NMR spectroscopy revealed that the β-carbon of the enone was attached by the thiol group of Cys via a Michael addition reaction. We confirmed the presence of Cys-bound EE ceramides in mouse epidermis by mass spectrometry analysis of protease-digested epidermis samples. EE ceramides were reversibly released from protein-bound ceramides via sulfoxide elimination. We found that protein-bound ceramides with reversible release properties accounted for approximately 60% of total protein-bound ceramides, indicating that Cys-bound EE ceramides are the predominant protein-bound ceramides. Our findings provide clues to the molecular mechanism of skin barrier formation by protein-bound ceramides.

Beneficial effects of a new neuroprotective compound in neuronal cells and MPTP-administered mouse model of Parkinson's disease.
Izumi Kato, Yudai Ogawa, Fumika Yakushiji, Jiro Ogura, Masaki Kobayashi, Naoya Shindo, Satoshi Ichikawa, Katsumi Maenaka, Masahiro Sakaitani
Chemical communications (Cambridge, England), 59, 82, 12306, 12309, 2023年10月12日, ［国際誌］
英語, 研究論文（学術雑誌）, A new compound, a derivative of 3,4,5-trimethoxy-N-phenyl benzamide bearing an 8''-methylimidazopyridine moiety, is found to demonstrate neuroprotective effects by preventing cell death caused by oxidative stress. The compound possesses high solubility and metabolic stability, and inhibits MPTP-induced effects in vivo, indicating high potential as a therapeutic drug for Parkinson's disease.

Solid-Phase Synthesis of Nannocystin Ax and Its Analogues.
Daiki Miyakita, Kohei Kawanishi, Akira Katsuyama, Kazuki Yamamoto, Fumika Yakushiji, Satoshi Ichikawa
The Journal of organic chemistry, 88, 15, 11367, 11371, 2023年08月04日, ［国際誌］
英語, 研究論文（学術雑誌）, Solid-phase total synthesis of nannocystin Ax (1) was disclosed. A coupling reaction between a peptide and a polyketide moiety was conducted on a solid support, and macrocyclization was achieved by Mitsunobu cyclization. The established synthetic route was efficient to prepare its analogues, which contain different types of peptide moieties.

Discovery of Biologically Optimized Polymyxin Derivatives Facilitated by Peptide Scanning and In Situ Screening Chemistry
Rintaro Kaguchi, Akira Katsuyama, Toyotaka Sato, Satoshi Takahashi, Motohiro Horiuchi, Shin-ichi Yokota, Satoshi Ichikawa
Journal of the American Chemical Society, 145, 6, 3665, 3681, American Chemical Society (ACS), 2023年01月28日, ［国際誌］
英語, 研究論文（学術雑誌）, Peptides can be converted to highly active compounds by introducing appropriate substituents on the suitable amino acid residue. Although modifiable residues in peptides can be systematically identified by peptide scanning methodologies, there is no practical method for optimization at the "scanned" position. With the purpose of using derivatives not only for scanning but also as a starting point for further chemical functionalization, we herein report the "scanning and direct derivatization" strategy through chemoselective acylation of embedded threonine residues by a serine/threonine ligation (STL) with the help of in situ screening chemistry. We have applied this strategy to the optimization of the polymyxin antibiotics, which were selected as a model system to highlight the power of the rapid derivatization of active scanning derivatives. Using this approach, we explored the structure-activity relationships of the polymyxins and successfully prepared derivatives with activity against polymyxin-resistant bacteria and those with Pseudomonas aeruginosa selective antibacterial activity. This strategy opens up efficient structural exploration and further optimization of peptide sequences.

Solid-Phase Total Synthesis of Sandramycin and Its Analogues
Yuya Komatani, Kyoka Momosaki, Akira Katsuyama, Kazuki Yamamoto, Rintaro Kaguchi, Satoshi Ichikawa
Organic Letters, 25, 3, 543, 548, American Chemical Society (ACS), 2023年01月27日
研究論文（学術雑誌）

Synthesis of macrocyclic nucleoside antibacterials and their interactions with MraY.
Takeshi Nakaya, Miyuki Yabe, Ellene H Mashalidis, Toyotaka Sato, Kazuki Yamamoto, Yuta Hikiji, Akira Katsuyama, Motoko Shinohara, Yusuke Minato, Satoshi Takahashi, Motohiro Horiuchi, Shin-Ichi Yokota, Seok-Yong Lee, Satoshi Ichikawa
Nature communications, 13, 1, 7575, 7575, 2022年12月20日, ［国際誌］
英語, 研究論文（学術雑誌）, The development of new antibacterial drugs with different mechanisms of action is urgently needed to address antimicrobial resistance. MraY is an essential membrane enzyme required for bacterial cell wall synthesis. Sphaerimicins are naturally occurring macrocyclic nucleoside inhibitors of MraY and are considered a promising target in antibacterial discovery. However, developing sphaerimicins as antibacterials has been challenging due to their complex macrocyclic structures. In this study, we construct their characteristic macrocyclic skeleton via two key reactions. Having then determined the structure of a sphaerimicin analogue bound to MraY, we use a structure-guided approach to design simplified sphaerimicin analogues. These analogues retain potency against MraY and exhibit potent antibacterial activity against Gram-positive bacteria, including clinically isolated drug resistant strains of S. aureus and E. faecium. Our study combines synthetic chemistry, structural biology, and microbiology to provide a platform for the development of MraY inhibitors as antibacterials against drug-resistant bacteria.

β-Hydroxylation of α-amino-β-hydroxylbutanoyl-glycyluridine catalyzed by a nonheme hydroxylase ensures the maturation of caprazamycin
Saeid Malek Zadeh, Mei-Hua Chen, Zhe-Chong Wang, Elahe K. Astani, I-Wen Lo, Kuan-Hung Lin, Ning-Shian Hsu, Kamal Adhikari, Syue-Yi Lyu, Hsin-Ying Tsai, Yuma Terasawa, Miyuki Yabe, Kazuki Yamamoto, Satoshi Ichikawa, Tsung-Lin Li
Communications Chemistry, 5, 1, 87, 87, Springer Science and Business Media LLC, 2022年12月, ［国際誌］
英語, 研究論文（学術雑誌）, Abstract

Caprazamycin is a nucleoside antibiotic that inhibits phospho-N-acetylmuramyl-pentapeptide translocase (MraY). The biosynthesis of nucleoside antibiotics has been studied but is still far from completion. The present study characterized enzymes Cpz10, Cpz15, Cpz27, Mur17, Mur23 out of caprazamycin/muraymycin biosynthetic gene cluster, particularly the nonheme αKG-dependent enzyme Cpz10. Cpz15 is a β-hydroxylase converting uridine mono-phosphate to uridine 5′ aldehyde, then incorporating with threonine by Mur17 (Cpz14) to form 5′-C-glycyluridine. Cpz10 hydroxylates synthetic 11 to 12 in vitro. Major product 13 derived from mutant Δcpz10 is phosphorylated by Cpz27. β-Hydroxylation of 11 by Cpz10 permits the maturation of caprazamycin, but decarboxylation of 11 by Mur23 oriented to muraymycin formation. Cpz10 recruits two iron atoms to activate dioxygen with regio-/stereo-specificity and commit electron/charge transfer, respectively. The chemo-physical interrogations should greatly advance our understanding of caprazamycin biosynthesis, which is conducive to pathway/protein engineering for developing more effective nucleoside antibiotics.

Synthesis of capuramycin and its analogues via a Ferrier-type I reaction and their biological evaluation.
Shintaro Kusaka, Kazuki Yamamoto, Motoko Shinohara, Yusuke Minato, Satoshi Ichikawa
Bioorganic & medicinal chemistry, 73, 117011, 117011, 2022年09月26日, ［国際誌］
英語, 研究論文（学術雑誌）, The total synthesis of capuramycin (1), which is a promising anti-tubercular antibiotics, has been accomplished using Ferrier-type I reaction as a key step. This total synthesis is an alternative approach to the synthesis of capuramycin and its analogues. The 3'-O-demethyl analogue (2), which exhibits an equivalent antibacterial activity as capuramycin (1) against Mycobacterium smegmatis and Mycobacterium avium, is suggested to have potential as a lead structure of capuramycin analogues because 2 is more accessible from a synthetic view point.

Total synthesis of pseudouridimycin and its epimer via Ugi-type multicomponent reaction.
Ryotaro Okawa, Courtney C Aldrich, Satoshi Ichikawa
Chemical communications (Cambridge, England), 58, 57, 7956, 7959, 2022年07月14日, ［国際誌］
英語, 研究論文（学術雑誌）, A total synthesis of pseudouridimycin (1) was accomplished featuring an unusual oxime Ugi-type multicomponent condensation to simultaneously construct the dipeptide moiety of this peptidyl nucleoside antibiotic. In this synthetic route 1 is readily accessible via a longest linear sequence of 9 synthetic steps from pseudouridine. This strategy can be applicable to a variety of pseudouridimycin analogues.

Design, synthesis and conformation-activity relationship analysis of LNA/BNA-type 5'-O-aminoribosyluridine as MraY inhibitors.
Shintaro Kusaka, Kazuki Yamamoto, Motoko Shinohara, Yusuke Minato, Satoshi Ichikawa
Bioorganic & medicinal chemistry, 65, 116744, 116744, 2022年04月20日, ［国際誌］
英語, 研究論文（学術雑誌）, It is important to understand and control the biologically active conformation in medicinal chemistry. Muraymycins and caprazamycins, which are strong inhibitors of MraY, are promising antibacterial agents with a novel mode of action. Focusing on a sugar puckering and a dihedral angle ϕ of the uridine moiety of these natural products, LNA/BNA-type 5'-O-aminoribosyluridine analogues, whose puckering of the ribose moiety are completely restricted to the N-type, were designed and synthesized as simplified MraY inhibitors. Their conformation-activity relationship was further investigated in details. The conformation-activity relationship analysis investigated in this study could be a general guideline for simplification and rational drug design of MraY inhibitory nucleoside natural products.

Solid-Phase Total Synthesis of Plusbacin A3.
Kazuki Takashina, Akira Katsuyama, Rintaro Kaguchi, Kazuki Yamamoto, Toyotaka Sato, Satoshi Takahashi, Motohiro Horiuchi, Shin-Ichi Yokota, Satoshi Ichikawa
Organic letters, 24, 11, 2253, 2257, 2022年03月25日, ［国際誌］
英語, 研究論文（学術雑誌）, The total synthesis of the depsipeptide natural product plusbacin A3 (1) utilizing solid-phase peptide synthesis (SPPS) was disclosed. A 3-hydroxy-proline derivative compatible with Fmoc SPPS was prepared by a diastereoselective Joullié-Ugi three-component reaction (JU-3CR)/hydrolysis sequence. After peptide elongation on the solid support, cleavage of the peptide from the resin, followed by macrolactamization and global deprotection, gave plusbacin A3 (1).

Corrigendum to "Design, synthesis and biological evaluation of simplified analogues of MraY inhibitory natural product with rigid scaffold" Bioorganic & Medicinal Chemistry 55 (2021) 116556.
Kazuhiro Okamoto, Aoi Ishikawa, Ryotaro Okawa, Kazuki Yamamoto, Toyotaka Sato, Shin-Ichi Yokota, Kazuhiro Chiba, Satoshi Ichikawa
Bioorganic & medicinal chemistry, 61, 116689, 116689, 2022年03月07日, ［国際誌］
英語

Design, synthesis and biological evaluation of simplified analogues of MraY inhibitory natural product with rigid scaffold
Kazuhiro Okamoto, Aoi Ishikawa, Ryotaro Okawa, Kazuki Yamamoto, Toyotaka Sato, Shin-ichi Yokota, Kazuhiro Chiba, Satoshi Ichikawa
Bioorganic & Medicinal Chemistry, 55, 116556, 116556, Elsevier BV, 2022年02月, ［国際誌］
英語, 研究論文（学術雑誌）, Muraymycins and caprazamycins are strong inhibitors of MraY, which is responsible for peptidoglycan biosynthesis. Although they are promising antibacterial agents with a novel mode of action, their chemical structures are rather complex. This study investigated the simplification of these natural products by structure-based drug design, synthesis, and biological evaluation. We developed a simplified rigid scaffold with an arylalkyne moiety, which shows sub-micromolar MraY inhibitory activity. The scaffold is suitable for further investigating the structure-activity relationship by virtue of our synthetic strategy, where the substituent of interest is installed in the last stage of synthesis. This scaffold shows the potential for further use in optimizing MraY inhibitory and antibacterial activities.

[Bridge between Total Synthesis of Bioactive Natural Products and Development of Drug Leads].
Satoshi Ichikawa
Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan, 142, 4, 355, 363, 2022年, ［国内誌］
日本語, 研究論文（学術雑誌）, Although natural products are rich sources for drug discovery, only a small percentage of natural products themselves have been approved for clinical use, thus it is necessary to modulate various properties, such as efficacy, toxicity, and metabolic stability. A question in natural product drug discovery is how to logically design natural product derivatives with desired biological properties. This review describes our recent studies regarding the medicinal chemistry of tunicamycin. Tunicamycin inhibits bacterial phospho-N-acetylmuramic acid (MurNAc)-pentapeptide translocase (MraY), which is an essential enzyme in bacteria and a good target for antibacterial drug discovery. The usefulness of tunicamycin as antibacterial agents is limited by off-target inhibition of human UDP-N-acetylglucosamine (GlcNAc): polyprenol phosphate translocase (GPT). We positioned the total synthesis of tunicamycin as a starting point for the research and have accomplished the synthesis of tunicamycin V by using the Achmatowicz reaction, [3,3] sigmatropic rearrangement of allyl cyanate, and stereoselective glycosylation as key reactions. Next, the minimum structural requirements for tunicamycin V for MraY inhibition were established by systematic structure-activity relationship studies with truncated analogs of tunicamycin V. Our collaborative study elucidated a crystal structure of human GPT in complex with tunicamycin. This structural information was then exploited to rationally design an MraY-specific inhibitor of tunicamycin V in which the GlcNAc moiety was modified to a MurNAc amide. The analog was identified as a highly selective MraYAA inhibitor.

Probiotic Aspergillus oryzae produces anti-tumor mediator and exerts anti-tumor effects in pancreatic cancer through the p38 MAPK signaling pathway
Hiroaki Konishi, Shotaro Isozaki, Shin Kashima, Kentaro Moriichi, Satoshi Ichikawa, Kazuki Yamamoto, Chikage Yamamura, Katsuyoshi Ando, Nobuhiro Ueno, Hiroaki Akutsu, Naoki Ogawa, Mikihiro Fujiya
Scientific Reports, 11, 1, Springer Science and Business Media LLC, 2021年12月
研究論文（学術雑誌）, Intake of probiotics or fermented food produced by some probiotic bacteria is believed to exert anti-tumor functions in various cancers, including pancreatic cancer, because several studies have demonstrated the anti-tumor effects of probiotic bacteria in vitro and in vivo in animal carcinogenesis models. However, the mechanisms underlying the anticancer effects of probiotics on pancreatic cancer have not been clarified. In this study, we assessed the anti-tumor effects of probiotic bacteria against pancreatic cancer cells. Among the known probiotic bacteria, Aspergillus oryzae exhibited a strong pancreatic tumor suppression effect. The culture supernatant of A. oryzae was separated by HPLC. Heptelidic acid was identified as an anti-tumor molecule derived from A. oryzae by LC–MS and NMR analysis. The anti-tumor effect of heptelidic acid was exhibited in vitro and in vivo in a xenograft model of pancreatic cancer cells. The anti-tumor effect of heptelidic acid was exerted by the p38 MAPK signaling pathway. Heptelidic acid traverses the intestinal mucosa and exerts anti-tumor effects on pancreatic cancer cells. This is a novel anti-tumor mechanism induced by beneficial bacteria against pancreatic cancer in which bacterial molecules pass through the intestinal tract, reach the extra-intestinal organs, and then induce apoptosis via an inducible signaling pathway.

Solid-phase synthesis of fluorescent analogues of Park’s nucleotide, lipid I and lipid II
Akira Katsuyama, Fumika Yakushiji, Satoshi Ichikawa
Tetrahedron Letters, 153101, 153101, Elsevier BV, 2021年04月
研究論文（学術雑誌）

Structure, solubility, and permeability relationships in a diverse middle molecule library
Hiroyuki Miyachi, Kayoko Kanamitsu, Mayumi Ishii, Eri Watanabe, Akira Katsuyama, Satoko Otsuguro, Fumika Yakushiji, Mizuki Watanabe, Kouhei Matsui, Yukina Sato, Satoshi Shuto, Takashi Tadokoro, Shunsuke Kita, Takanori Matsumaru, Akira Matsuda, Tomoyasu Hirose, Masato Iwatsuki, Yasuteru Shigeta, Tetsuo Nagano, Hirotatsu Kojima, Satoshi Ichikawa, Toshiaki Sunazuka, Katsumi Maenaka
Bioorganic & Medicinal Chemistry Letters, 37, 127847, 127847, Elsevier BV, 2021年04月, ［国際誌］
英語, 研究論文（学術雑誌）, To develop methodology to predict the potential druggability of middle molecules, we examined the structure, solubility, and permeability relationships of a diverse library (HKDL ver.1) consisting of 510 molecules (359 natural product derivatives, 76 non-natural products, 46 natural products, and 29 non-natural product derivatives). The library included peptides, depsipeptides, macrolides, and lignans, and 476 of the 510 compounds had a molecular weight in the range of 500-2000 Da. The solubility and passive diffusion velocity of the middle molecules were assessed using the parallel artificial membrane permeability assay (PAMPA). Quantitative values of solubility of 471 molecules and passive diffusion velocity of 287 molecules were obtained, and their correlations with the structural features of the molecules were examined. Based on the results, we propose a method to predict the passive diffusion characteristics of middle molecules from their three-dimensional structural features.

Elucidating the Structural Requirement of Uridylpeptide Antibiotics for Antibacterial Activity.
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, AMER CHEMICAL SOC, 2020年09月10日, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Total Synthesis of Acaulide and Acaulone A.
Jun Hirabayashi, Fumika Yakushiji, Akira Katsuyama, Satoshi Ichikawa
Organic letters, 22, 14, 5545, 5549, 2020年07月17日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Total Synthesis of Echinomycin and Its Analogues.
Keita Kojima, Fumika Yakushiji, Akira Katsuyama, Satoshi Ichikawa
Organic letters, 22, 11, 4217, 4221, 2020年06月05日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

A Synthesis Strategy for the Production of a Macrolactone of Gulmirecin A via a Ni(0)-Mediated Reductive Cyclization Reaction.
Shun Kitahata, Akira Katsuyama, Satoshi Ichikawa
Organic letters, 22, 7, 2697, 2701, 2020年04月03日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Repair of DNA damage induced by the novel nucleoside analogue CNDAG through homologous recombination.
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］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Development of cyclic peptide derivatives from the N-terminal region of LANA for targeting the nucleosome acidic patch.
Fumika Yakushiji, Aoi Ishikawa, Akira Katsuyama, Satoshi Ichikawa
Bioorganic & medicinal chemistry letters, 30, 2, 126839, 126839, PERGAMON-ELSEVIER SCIENCE LTD, 2020年01月15日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Synthesis and biological evaluation of a MraY selective analogue of tunicamycins.
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, TAYLOR & FRANCIS INC, 2020年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Tunicamycin: chemical synthesis and biosynthesis.
Kazuki Yamamoto, Satoshi Ichikawa
The Journal of antibiotics, 72, 12, 924, 933, NATURE PUBLISHING GROUP, 2019年12月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, 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.

Novel adenosine-derived inhibitors of Cryptosporidium parvum inosine 5'-monophosphate dehydrogenase.
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］, ［国内誌］
英語, 研究論文（学術雑誌）, 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.

Chemical logic of MraY inhibition by antibacterial nucleoside natural products.
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］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Synthesis of All Stereoisomers of Monomeric Spectomycin A1/A2 and Evaluation of Their Protein SUMOylation-Inhibitory Activity.
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］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Structural requirement of tunicamycin V for MraY inhibition.
Kazuki Yamamoto, Akira Katsuyama, Satoshi Ichikawa
Bioorganic & medicinal chemistry, 27, 8, 1714, 1719, PERGAMON-ELSEVIER SCIENCE LTD, 2019年04月15日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Total synthesis of plusbacin A3 using a diastereoseletive Joullié-Ugi three component reaction
Akira Katsuyama, Satoshi Ichikawa
Yuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry, 77, 7, 663, 672, Society of Synthetic Organic Chemistry, 2019年
日本語, 研究論文（学術雑誌）, In this manuscript, our synthetic study and antibacterial investigation of plusbacin A 3 (1), which is an antibacterial depsipeptide, and its dideoxy derivative are described. To establish an efficient total synthesis of 1, a solvent-dependent diastereodivergent Joullié-Ugi three-component reaction (JU-3CR) was optimized to construct trans-3-hydroxyl prolines [Pro(3-OH)]. Firstly, the effect of solvent on diastereoselectivity of the J U - 3 C R was investigated by an a-substituted five - membered cyclic imine as a substrate. The cis and trans isomers were selectively generated in toluene and 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), respectively. The Hammett analysis of the JU-3CR suggests the presence of two reaction mechanisms in the JU-3CR. With the diastreose-lective JU-3CR in hand, we applied the reaction to the synthesis of plusbacin A3. Two strategies were investigated toward the total synthesis of 1. In the first synthetic strategy, the key steps were the trans-selective JU-3CR and a late stage macrolactonization. The JU-3CR provided the desired trans products, and the coupling of the fragments to prepare the precursor to the cyclization proceeded smoothly. However, all the attempts toward the macrolactonization were unsuccessful to provide the desired cyclic peptide. Then, the second synthetic strategy that included an esterifi-cation in an initial stage was investigated. Two Pro(3-OH) residues were constructed by the JU - 3CR with a convertible isocyanide strategy. Subsequent peptide coupling and macrolactamization successfully afforded plusbacin A3. Investigating the antibacterial activity of 1 compared with that of its dideoxy analogue revealed that the threo-ß-hydroxyaspartic acid residues are essential for antibacterial activity. Notably, there was a low potential for the development of resistance in S. aureus against plusbacin A3.

Improvement of SN Ar Reaction Rate by an Electron-Withdrawing Group in the Crosslinking of DNA Cytosine-5 Methyltransferase by a Covalent Oligodeoxyribonucleotide Inhibitor.
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］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Study of the structure-activity relationship of polymyxin analogues.
Yuhei Kinoshita, Fumika Yakushiji, Hidehito Matsui, Hideaki Hanaki, Satoshi Ichikawa
Bioorganic & medicinal chemistry letters, 28, 16, 2713, 2716, Elsevier Ltd, 2018年09月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, A structure-activity relationship study on three classes of polymyxin analogues focusing on hydrophobicity was conducted.

Development of a covalent proteasome inhibitor and kinetic analysis of its inhibitory mechanism
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］

Total synthesis of plusbacin A3
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］

Total Synthesis of Plusbacin A₃ and Its Dideoxy Derivative Using a Solvent-Dependent Diastereodivergent Joullié-Ugi Three-Component Reaction.
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］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Insight into the recognition mechanism of DNA cytosine-5 methyltransferases (DNMTs) by incorporation of acyclic 5-fluorocytosine (FC) nucleosides into DNA.
Shohei Utsumi, Kousuke Sato, Satoshi Ichikawa
Bioorganic & medicinal chemistry letters, 28, 12, 2189, 2194, 2018年07月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Ribavirin-related compounds exert in vitro inhibitory effects toward rabies virus.
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］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Mechanism-Based Inhibitor of DNA Cytosine-5 Methyltransferase by a SN Ar Reaction with an Oligodeoxyribonucleotide Containing a 2-Amino-4-Halopyridine-C-Nucleoside.
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］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

GlcNAc-1-P-transferase-tunicamycin complex structure reveals basis for inhibition of N-glycosylation.
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, Nature Publishing Group, 2018年03月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Potent anti-tumor activity of a syringolin analog in multiple myeloma: a dual inhibitor of proteasome activity targeting β2 and β5 subunits.
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, Impact Journals LLC, 2018年02月09日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Total Synthesis of Tunicamycin V.
Kazuki Yamamoto, Fumika Yakushiji, Takanori Matsumaru, Satoshi Ichikawa
Organic letters, 20, 1, 256, 259, American Chemical Society, 2018年01月05日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Solid-Phase Modular Synthesis of Park Nucleotide and Lipids I and II Analogues.
Akira Katsuyama, Kousuke Sato, Fumika Yakushiji, Takanori Matsumaru, Satoshi Ichikawa
Chemical & pharmaceutical bulletin, 66, 1, 84, 95, 2018年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, 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.

Synthesis and Medicinal Chemistry of Muraymycins, Nucleoside Antibiotics.
Akira Katsuyama, Satoshi Ichikawa
Chemical & pharmaceutical bulletin, 66, 2, 123, 131, 2018年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, 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.

Total Synthesis and Antibacterial Investigation of Plusbacin A3.
Akira Katsuyama, Atmika Paudel, Suresh Panthee, Hiroshi Hamamoto, Toru Kawakami, Hironobu Hojo, Fumika Yakushiji, Satoshi Ichikawa
Organic letters, 19, 14, 3771, 3774, AMER CHEMICAL SOC, 2017年07月21日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Divergent synthesis of kinase inhibitor derivatives, leading to discovery of selective Gck inhibitors.
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, PERGAMON-ELSEVIER SCIENCE LTD, 2017年05月15日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Impact of Structures of Macrocyclic Michael Acceptors on Covalent Proteasome Inhibition
Kitahata, Shun, Yakushiji, Fumika, Ichikawa, Satoshi
Chem. Sci., 8, 6959, 6963, 2017年, ［査読有り］
英語, 研究論文（学術雑誌）

Anti-Myeloma Activity of a Syringolin Analog: A Dual 20S Proteasome Inhibitor of Beta 2 and 5 Subunits
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, AMER SOC HEMATOLOGY, 2016年12月, ［査読有り］
英語, 0

An oligodeoxyribonucleotide containing 5-formyl-2'-deoxycytidine (fC) at the CpG site forms a covalent complex with DNA cytosine-5 methyltransferases (DNMTs).
Kousuke Sato, Kyoji Kawamoto, Shintaro Shimamura, Satoshi Ichikawa, Akira Matsuda
Bioorganic & medicinal chemistry letters, 26, 22, 5395, 5398, PERGAMON-ELSEVIER SCIENCE LTD, 2016年11月15日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

ChemInform Abstract: Revisited Mechanistic Implications of the Joullie-Ugi Three-Component Reaction.
Akira Katsuyama, Akira Matsuda, Satoshi Ichikawa
ChemInform, 47, 42, Wiley-Blackwell, 2016年09月
研究論文（学術雑誌）

Chemical Screening Identifies EUrd as a Novel Inhibitor Against Temozolomide-Resistant Glioblastoma-Initiating Cells.
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, WILEY, 2016年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

ChemInform Abstract: Function-Oriented Synthesis: How to Design Simplified Analogues of Antibacterial Nucleoside Natural Products?
Satoshi Ichikawa
ChemInform, 47, 32, Wiley-Blackwell, 2016年07月
研究論文（学術雑誌）

Revisited Mechanistic Implications of the Joullié-Ugi Three-Component Reaction.
Katsuyama A, Matsuda A, Ichikawa S
Organic letters, 18, 11, 2552, 5, AMER CHEMICAL SOC, 2016年06月03日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Function-Oriented Synthesis: How to Design Simplified Analogues of Antibacterial Nucleoside Natural Products?
Satoshi Ichikawa
CHEMICAL RECORD, 16, 3, 1106, 1115, WILEY-V C H VERLAG GMBH, 2016年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Structural insights into inhibition of lipid I production in bacterial cell wall synthesis.
Ben C Chung, Ellene H Mashalidis, Tetsuya Tanino, Mijung Kim, Akira Matsuda, Jiyong Hong, Satoshi Ichikawa, Seok-Yong Lee
Nature, 533, 7604, 557, 560, NATURE PUBLISHING GROUP, 2016年05月26日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Design, Synthesis, and Biological Activity of Isosyringolin A.
Shun Kitahata, Takuya Chiba, Takashi Yoshida, Masaki Ri, Shinsuke Iida, Akira Matsuda, Satoshi Ichikawa
Organic letters, 18, 9, 2312, 5, AMER CHEMICAL SOC, 2016年05月06日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Design, Synthesis and Biological Evaluation of a Structurally Simplified Syringolin A Analogues.
Takuya Chiba, Shun Kitahata, Akira Matsuda, Satoshi Ichikawa
Chemical & pharmaceutical bulletin, 64, 7, 811, 6, PHARMACEUTICAL SOC JAPAN, 2016年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, 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.

Structure-activity relationship study of syringolin A as a potential anticancer agent.
Takuya Chiba, Akira Matsuda, Satoshi Ichikawa
Bioorganic & medicinal chemistry letters, 25, 21, 4872, 4877, PERGAMON-ELSEVIER SCIENCE LTD, 2015年11月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Design, synthesis and biological evaluation of 5'-C-piperidinyl-5'-O-aminoribosyluridines as potential antibacterial agents.
Takeshi Nakaya, Akira Matsuda, Satoshi Ichikawa
Organic & biomolecular chemistry, 13, 28, 7720, 35, ROYAL SOC CHEMISTRY, 2015年07月28日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Carbacaprazamycins: Chemically Stable Analogues of the Caprazamycin Nucleoside Antibiotics.
Satoshi Ichikawa, Mayumi Yamaguchi, Lee Shang Hsuan, Yuta Kato, Akira Matsuda
ACS infectious diseases, 1, 4, 151, 6, AMER CHEMICAL SOC, 2015年04月10日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Synthesis of isoxazolidine-containing uridine derivatives as caprazamycin analogues.
Mayumi Yamaguchi, Akira Matsuda, Satoshi Ichikawa
Organic & biomolecular chemistry, 13, 4, 1187, 97, ROYAL SOC CHEMISTRY, 2015年01月28日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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)).

Spectomycin A1 全立体異性体の合成とSUMO化阻害活性
野村 勇作, 袖岡 幹子, Frederic Thuaud, 関根 大介, 平井 剛, 前田 里子, 伊藤 昭博, 市川 聡, 松田 彰, 吉田 稔
天然有機化合物討論会講演要旨集, 57, Oral24, 天然有機化合物討論会実行委員会, 2015年
日本語,

【研究背景】

タンパク質SUMO（Small Ubiquitin-like MOdifier）化は、細胞周期調節などの多様な細胞現象に関与するタンパク質翻訳後修飾である。近年、SUMO化と様々な疾病との関連が示唆されているが、その詳細は明らかになっていない。このことからSUMO化阻害剤は、有用なSUMO化研究ツールとなるだけでなく、創薬研究のリード化合物としても利用可能と期待される。このような背景の中、ごく最近2量体構造を有するspectomycin B1（SMB1、Figure 1A）が、SUMO活性化酵素E2に結合しSUMO化を阻害することが見出された¹⁾。SMB1は、1994年に抗菌物質として単離された天然物であり、この時単量体型のSMA1、SMA2も同定されている²⁾。これら単量体は抗菌活性を示さないが、SUMO化阻害活性の有無については明らかになっていない。そこで今回我々は、SMB1の構造活性相関研究の一環として、SMA1の合成法を確立し、そのSUMO化阻害能を明らかにすることを計画した。この際、4、5位の可能な立体異性体全てを合成し、それらの阻害活性と未決定であった天然物の相対・絶対立体化学も明らかにしようと考えた。合成上のポイントは、芳香環化しやすいC環β-ヒドロキシテトラロン構造と、4位に存在し芳香環と共役していないβ-メトキシアクリレート構造を如何に構築するかにある。また、我々は3-4位結合間に軸不斉があり、H-4とOMe基の2面角が180 °になるP体と0 °になるM体が存在すると予想した（Figure 1B）。DFT計算によってP体が安定と見積もられたが、合成中間体では異性化し、回転異性体間で異なる反応性を示す可能性が考えられた。

Figure 1. A）Spectomycin類の構造；B）(4S5S)-SMA1の3-4位間の軸不斉

【合成戦略】

今回我々は、全ての立体異性体を効率的に得るため、1つの共通中間体からlate-stageでそれぞれの異性体に導ける合成法を立案した。SMA1に必要な全炭素と置換基を有する1を共通中間体として設定し、これを4-5位間の結合形成反応によって環化し、2のすべての立体異性体を得ようと考えた。環化反応は、π-アリルパラジウム種の極性転換反応を利用することを考え、この時同時にE体のβ-メトキシアクリレート構造を構築することを計画した。7位には5位ケトンが存在しても脱離しにくいシリル基を導入し、環化後に短工程でβ-ヒドロキシケトンに導くとした。

Scheme 1. SMA1全立体異性体の合成計画

【共通中間体の合成】

m-アニスアルデヒド（3）から、Snyderらの報告³⁾に従って調製したナフタレン誘導体4のエステルを還元した後、塩基性条件下、フェノール性水酸基のオルト位選択的にヨウ素化⁴⁾して5に導いた。2つの水酸基をMOM基で保護した6をDDQ酸化し、アルデヒド7を合成した。これをDBU存在下、ホスホニウム塩8 ⁵⁾と処理し、Z選択的にα-メトキシ不飽和エステル9へ変換した。生じたエステルを還元した後、MVKとのMizoroki-Heck反応により3炭素増炭し、エノン体10を得た。これとヘキサメチルジシラン、MeLi、およびCuIより調製した(Me₃Si)₂CuLiを処理すると、7位へシリル基導入が円滑に進行し11を得た⁶⁾。アリルアルコールを酸化し、12に変換した後、M

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Antibacterial Nucleoside Natural Products Inhibiting Phospho-MurNAc-Pentapeptide Translocase; Chemistry and Structure-Activity Relationship
S. Ichikawa, M. Yamaguchi, A. Matsuda
CURRENT MEDICINAL CHEMISTRY, 22, 34, 3951, 3979, BENTHAM SCIENCE PUBL LTD, 2015年, ［査読有り］
英語, 研究論文（学術雑誌）, 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.

Design and synthesis of isoxazolidine-containing uridine derivatives as antibacterial agents
Mayumi Yamaguchi, Akira Matsuda, Satoshi Ichikawa
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 248, AMER CHEMICAL SOC, 2014年08月, ［査読有り］
英語

Total synthesis of syringolin A and its structure-activity relationship study
Takuya Chiba, Akira Matsuda, Satoshi Ichikawa
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 248, AMER CHEMICAL SOC, 2014年08月, ［査読有り］
英語

Synthesis of piperidine analogs of caprazamycins by aza-Prins-Ritter reaction
Takeshi Nakaya, Akira Matsuda, Satoshi Ichikawa
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 248, AMER CHEMICAL SOC, 2014年08月, ［査読有り］
英語

ChemInform Abstract: Total Synthesis of Quinaldopeptin (Ia) and Its Analogues.
Satoshi Ichikawa, Takuya Okamura, Akira Matsuda
ChemInform, 45, 21, no, no, Wiley-Blackwell, 2014年05月08日
研究論文（学術雑誌）

Expansion of Antibacterial Spectrum of Muraymycins toward Pseudomonas aeruginosa.
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, AMER CHEMICAL SOC, 2014年05月08日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Total synthesis of syringolin A and improvement of its biological activity.
Takuya Chiba, Hidetaka Hosono, Koji Nakagawa, Masahiro Asaka, Hiroshi Takeda, Akira Matsuda, Satoshi Ichikawa
Angewandte Chemie (International ed. in English), 53, 19, 4836, 9, WILEY-V C H VERLAG GMBH, 2014年05月05日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Synthesis and biological evaluation of quinaldopeptin.
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, AMER CHEMICAL SOC, 2014年03月21日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Function-Oriented Synthesis of Liponucleoside Antibiotics
Tetsuya Tanino, Mayumi Yamaguchi, Akira Matsuda, Satoshi Ichikawa
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, 2014, 9, 1836, 1840, WILEY-V C H VERLAG GMBH, 2014年03月, ［査読有り］
英語, 研究論文（学術雑誌）, 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.

Total synthesis of sandramycin and its analogues via a multicomponent assemblage.
Katsushi Katayama, Koji Nakagawa, Hiroshi Takeda, Akira Matsuda, Satoshi Ichikawa
Organic letters, 16, 2, 428, 31, AMER CHEMICAL SOC, 2014年01月17日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Total synthesis of quinaldopeptin and its analogues.
Satoshi Ichikawa, Takuya Okamura, Akira Matsuda
The Journal of organic chemistry, 78, 24, 12662, 70, AMER CHEMICAL SOC, 2013年12月20日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Synthesis of C-glycosyl pyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones as a scaffold for check point kinase 1 inhibitors.
Satoshi Ichikawa, Nana Tatebayashi, Akira Matsuda
The Journal of organic chemistry, 78, 23, 12065, 75, AMER CHEMICAL SOC, 2013年12月06日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Tris(azidoethyl)amine hydrochloride; a versatile reagent for synthesis of functionalized dumbbell oligodeoxynucleotides.
Satoshi Ichikawa, Hideaki Ueno, Takuya Sunadome, Kousuke Sato, Akira Matsuda
Organic letters, 15, 3, 694, 7, AMER CHEMICAL SOC, 2013年02月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Synthesis of pacidamycin analogues via an Ugi-multicomponent reaction
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, PERGAMON-ELSEVIER SCIENCE LTD, 2012年07月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

ChemInform Abstract: Development of the Carboxamide Protecting Group, 4-(tert-Butyldimethylsiloxy)-2-methoxybenzyl.
Kazuhiro Muranaka, Satoshi Ichikawa, Akira Matsuda
ChemInform, 43, 12, no, no, Wiley-Blackwell, 2012年02月
研究論文（学術雑誌）

Total Synthesis and Biological Evaluation of Pacidamycin D and Its 3 '-Hydroxy Analogue
Kazuya Okamoto, Masahiro Sakagami, Fei Feng, Hiroko Togame, Hiroshi Takemoto, Satoshi Ichikawa, Akira Matsuda
JOURNAL OF ORGANIC CHEMISTRY, 77, 3, 1367, 1377, AMER CHEMICAL SOC, 2012年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Mechanistic Analysis of Muraymycin Analogues: A Guide to the Design of MraY Inhibitors
Tetsuya Tanino, Bayan Al-Dabbagh, Dominique Mengin-Lecreulx, Ahmed Bouhss, Hiroshi Oyama, Satoshi Ichikawa, Akira Matsuda
JOURNAL OF MEDICINAL CHEMISTRY, 54, 24, 8421, 8439, AMER CHEMICAL SOC, 2011年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Development of the Carboxamide Protecting Group, 4-(tert-Butyldimethylsiloxy)-2-methoxybenzyl
Kazuhiro Muranaka, Satoshi Ichikawa, Akira Matsuda
JOURNAL OF ORGANIC CHEMISTRY, 76, 22, 9278, 9293, AMER CHEMICAL SOC, 2011年11月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Total Synthesis of Pacidamycin D by Cu(I)-Catalyzed Oxy Enamide Formation
Kazuya Okamoto, Masahiro Sakagami, Fei Feng, Hiroko Togame, Hiroshi Takemoto, Satoshi Ichikawa, Akira Matsuda
ORGANIC LETTERS, 13, 19, 5240, 5243, AMER CHEMICAL SOC, 2011年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Synthesis of L-epi-Capreomycidine Derivatives via C-H Amination
Tetsuya Tanino, Satoshi Ichikawa, Akira Matsuda
ORGANIC LETTERS, 13, 15, 4028, 4031, AMER CHEMICAL SOC, 2011年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Structural Feature of Bent DNA Recognized by HMGB1
Kyoko Furuita, Shunpei Murata, Jun Goo Jee, Satoshi Ichikawa, Akira Matsuda, Chojiro Kojima
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 133, 15, 5788, 5790, AMER CHEMICAL SOC, 2011年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Comprehensive Synthetic Study of Muraymycins toward the Development of Novel Antibacterial Agents
Tetsuya Tanino, Satoshi Ichikawa, Koichi Uotani, Hiroshi Oyama, Akira Matsuda
YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, 131, 3, 335, 346, PHARMACEUTICAL SOC JAPAN, 2011年03月, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, 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.

後周期遷移金属エノラート 非ビアリール型アトロプ異性化合物 FOS（function oriented synthesis） SAR（structure-activity relationship）
袖岡 幹子, 北川 理, 市川 聡
有機合成化学協会誌, 69, 9, 1046, 1046, The Society of Synthetic Organic Chemistry, Japan, 2011年
日本語

Synthesis and evaluation of 5-substituted 9-hydroxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones as check point 1 kinase inhibitors
Yuki Sako, Satoshi Ichikawa, Akiko Osada, Akira Matsuda
BIOORGANIC & MEDICINAL CHEMISTRY, 18, 22, 7878, 7889, PERGAMON-ELSEVIER SCIENCE LTD, 2010年11月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Synthesis and Biological Evaluation of Muraymycin Analogues Active against Anti-Drug-Resistant Bacteria
Tetsuya Tanino, Satoshi Ichikawa, Bayan Al-Dabbagh, Ahmed Bouhss, Hiroshi Oyama, Akira Matsuda
ACS MEDICINAL CHEMISTRY LETTERS, 1, 6, 258, 262, AMER CHEMICAL SOC, 2010年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Efficient synthesis of Hsp90 inhibitor dimers as potential antitumor agents
Hironori Sekiguchi, Kazuhiro Muranaka, Akiko Osada, Satoshi Ichikawa, Akira Matsuda
BIOORGANIC & MEDICINAL CHEMISTRY, 18, 15, 5732, 5737, PERGAMON-ELSEVIER SCIENCE LTD, 2010年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

ChemInform Abstract: Total Syntheses of Thiocoraline and BE-22179: Establishment of Relative and Absolute Stereochemistry.
Dale L. Boger, Satoshi Ichikawa
ChemInform, 31, 25, no, no, Wiley-Blackwell, 2010年06月08日
研究論文（学術雑誌）

ChemInform Abstract: Total Synthesis of Fostriecin (CI-920).
Dale L. Boger, Satoshi Ichikawa, Wenge Zhong
ChemInform, 32, 36, no, no, Wiley-Blackwell, 2010年05月
研究論文（学術雑誌）

Function-Oriented Synthesis of Simplified Caprazamycins: Discovery of Oxazolidine-Containing Uridine Derivatives as Antibacterial Agents against Drug-Resistant Bacteria
Kensuke Ii, Satoshi Ichikawa, Bayan Al-Dabbagh, Ahmed Bouhss, Akira Matsuda
JOURNAL OF MEDICINAL CHEMISTRY, 53, 9, 3793, 3813, AMER CHEMICAL SOC, 2010年05月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

A New Arylsulfate Sulfotransferase Involved in Liponucleoside Antibiotic Biosynthesis in Streptomycetes
Leonard Kaysser, Kornelia Eitel, Tetsuya Tanino, Stefanie Siebenberg, Akira Matsuda, Satoshi Ichikawa, Bertolt Gust
JOURNAL OF BIOLOGICAL CHEMISTRY, 285, 17, 12684, 12694, AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2010年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Total Synthesis of (-)-Muraymycin D2 and Its Epimer
Tetsuya Tanino, Satoshi Ichikawa, Motoo Shiro, Akira Matsuda
JOURNAL OF ORGANIC CHEMISTRY, 75, 5, 1366, 1377, AMER CHEMICAL SOC, 2010年03月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Design and synthesis of 3 ',5 '-ansa-adenosines as potential Hsp90 inhibitors
Kazuhiro Muranaka, Satoshi Ichikawa, Akira Matsuda
TETRAHEDRON LETTERS, 50, 36, 5102, 5106, PERGAMON-ELSEVIER SCIENCE LTD, 2009年09月, ［査読有り］
英語, 研究論文（学術雑誌）, 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.

ChemInform Abstract: Medicinal Chemistry Targeting Nucleosides and Nucleic Acids Based on Fine Synthetic Chemistry
Satoshi Ichikawa
ChemInform, 40, 6, Wiley-Blackwell, 2009年02月10日
研究論文（学術雑誌）

NMR studies of DNA recognition mechanism of HMGB1 protein.
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］, ［国際誌］
英語, 研究論文（学術雑誌）, A 2'-deoxyuridylate dimer cyclized via cross-linkage by an ethylene (U(et)(p)U) or a propylene (U(pr)(p)U) linker at the 5-position was incorporated into DNA oligomers. Fluorescence resonance energy transfer (FRET) experiments showed that they bent at approximately 90 degrees . We investigated binding abilities of U(et)(p)U and U(pr)(p)U DNA oligomers to HMGB1 A-box protein, which specifically binds to bent DNA, using nuclear magnetic resonance (NMR) spectroscopy. Both DNA oligomers bind to HMGB1 A-box protein, however, the U(et)(p)U DNA oligomer has higher affinity than the U(pr)(p)U DNA oligomer. In order to explain this difference, we studied the solution structures of the U(et)(p)U and U(pr)(p)U DNA oligomers using NMR. Most (1)H signals except for 4', 5' and 5'' were assigned. Cross-peak patterns of (1)H-(1)H NOESY spectra indicate that both oligomers have right-handed B-form like structures and the cyclization in 2'-deoxyuridylates does not break Watson-Crick base pairs. Chemical shift differences between these two DNA oligomers suggest the presence of the local structural differences in the region of 2'-deoxyuridylate dimer and its 3' side between the U(et)(p)U and U(pr)(p)U DNA oligomers.

9-(2-C-Cyano-2-deoxy-beta-D-arabino-pentofuranosyl)guanine, a potential antitumor agent against B-lymphoma infected with Kaposi's sarcoma-associated herpesvirus.
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］, ［国際誌］
英語, 研究論文（学術雑誌）, 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 (2, CNDAG) as well as the 2-amino-6-substituted-purine derivatives 3, 4 and 5 inhibited KSHV-positive cell growth but showed no cytotoxicity against KSHV-negative cells at >15 muM concentrations. Therefore, it was found that compounds 2, 3, 4 and 5 showed selective cytotoxicity against PEL cells infected with KSHV.

Rational design and synthesis of ansa-adenosines as potential antitumor agents.
Muranaka K, Ichikawa S, Matsuda A
Nucleic acids symposium series (2004), 53, 5, 6, 2009年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Synthesis of benzoquinone ansa-adenosines, which are rationally designed as Hsp90 inhibitors by extracting and fusing a natural substrate, ATP, and a natural product, geldanamycin, was described. This simpler scaffold design provides practical synthesis of a set of analogs and demonstrates synthetic innovation.

Highly beta-Selective C-Allylation of a Ribofuranoside Controlling Steric Hindrance in the Transition State
Satoshi Ichikawa, Ryoko Hayashi, Shinpei Hirano, Akira Matsuda
ORGANIC LETTERS, 10, 22, 5107, 5110, AMER CHEMICAL SOC, 2008年11月, ［査読有り］
英語, 研究論文（学術雑誌）, 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.

Fine synthetic nucleoside chemistry based on nucleoside natural products synthesis
Satoshi Ichikawa
CHEMICAL & PHARMACEUTICAL BULLETIN, 56, 8, 1059, 1072, PHARMACEUTICAL SOC JAPAN, 2008年08月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, 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.

ChemInform Abstract: Stereoselective Glycosylation Based on the Conformational Restriction of Pyranoses
Satoshi Shuto, Satoshi Ichikawa, Hiroshi Abe, Akira Matsuda
ChemInform, 39, 25, Wiley-Blackwell, 2008年06月
研究論文（学術雑誌）

Synthesis of Hsp90 inhibitor dimers as potential antitumor agents
Kazuhiro Muranaka, Akiko Sano, Satoshi Ichikawa, Akira Matsuda
BIOORGANIC & MEDICINAL CHEMISTRY, 16, 11, 5862, 5870, PERGAMON-ELSEVIER SCIENCE LTD, 2008年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Structure-activity relationship of truncated analogs of caprazamycins as potential anti-tuberculosis agents
Shinpei Hirano, Satoshi Ichikawa, Akira Matsuda
BIOORGANIC & MEDICINAL CHEMISTRY, 16, 9, 5123, 5133, PERGAMON-ELSEVIER SCIENCE LTD, 2008年05月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Triazole-linked dumbbell oligodeoxynucleotides with NF-kappa B binding ability as potential decoy molecules
Masanori Nakane, Satoshi Ichikawa, Akira Matsuda
JOURNAL OF ORGANIC CHEMISTRY, 73, 5, 1842, 1851, AMER CHEMICAL SOC, 2008年03月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, [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.

ChemInform Abstract: Fine Synthetic Nucleoside Chemistry Based on Nucleoside Natural Products Synthesis
Satoshi Ichikawa
ChemInform, 39, 50, Wiley-Blackwell, 2008年
研究論文（学術雑誌）

NMR structural study of DNA oligomers containing alkylene crosslinked cyclic 2'-deoxyuridylate dimers.
Kyoko Furuita, Shunpei Murata, JunGoo Jee, Satoshi Ichikawa, Akira Matsuda, Chojiro Kojima
Nucleic acids symposium series (2004), 52, 181, 2, 2008年, ［国際誌］
英語, 研究論文（学術雑誌）, A 2'-deoxyuridylate dimer cyclized via cross-linkage by ethylene (U(et)(p)U) or propylene (U(pr)(p)U) linker was incorporated in DNA oligomer. Fluorescence resonance energy transfer (FRET) experiment showed that they bent at a sharp angle of approximately 90 degree. HMGB1 A-box protein, which selectively binds to bent DNA, binds to the U(et)(p)U DNA oligomer with high affinity, but not to the U(pr)(p)U. In order to explain this difference, we have studied the solution structures of the U(et)(p)U and U(pr)(p)U DNA oligomers using NMR. Most (1)H signals except for 4', 5' and 5'' were assigned by (1)H-(1)H two-dimensional NMR spectra and natural abundance (1)H-(13)C HSQC spectra. Cross-peak patterns of (1)H-(1)H NOESY spectra indicate that both oligomers have right-handed B-form DNA like structures and the cyclization in 2'-deoxyuridylates by alkylene crosslinking does not break Watson-Crick base pairs. Chemical shift differences between these two DNA oligomers are localized to the region of 2'-deoxyuridylate dimer and its 3' side. These chemical shift differences and some characteristic NOE crosspeaks suggest the presence of the local structural differences in these regions between the U(et)(p)U and U(pr)(p)U DNA oligomers.

Chemistry and structure-activity relationship of antibacterial nucleoside natural products.
Ichikawa S, Matsuda A
Nucleic acids symposium series (2004), 52, 77, 78, 2008年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Synthetic methodology of the caprazamycins, which are promising antibacterial nucleoside natural products, was developed. Palmitoylcaprazol, which possesses a simple fatty acyl side chain at the diazepanone moiety of caprazamycins, has been synthesized and exhibited antibacterial activity against pathogens threatening a public health. Simplification of the caprazamycins was further pursued to develop diketopiperazine analogs.

Synthetic study of muraymycins using Ugi-four component reaction.
Tanino T, Hirano S, Ichikawa S, Matsuda A
Nucleic acids symposium series (2004), 52, 557, 558, 2008年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, The synthetic study of muraymycins (MRYs), which have potent antibacterial activity, is described. The key elements of our approach include the synthesis of L-epicapreomycidine via a C-H amination reaction and a conversient assemblage to construct of the framework of muraymycins using Ugi-four component reaction. First, isonitrile 4 was prepared from uridine in 14 steps. The precursor of carboxylic acid component 15 was synthesised via the C-H amination reaction, formation of cyclic guanidine structure. Muraymycin D2 analogs were synthesized by a model Ugi-four component reaction.

Synthesis of caprazamycin analogues and their structure - Activity relationship for antibacterial activity
Shinpei Hirano, Satoshi Ichikawa, Akira Matsuda
JOURNAL OF ORGANIC CHEMISTRY, 73, 2, 569, 577, AMER CHEMICAL SOC, 2008年01月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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).

Design and synthesis of diketopiperazine and acyclic analogs related to the caprazamycins and liposidomycins as potential antibacterial agents
Shinpel Hirano, Satoshi Ichikawa, Akira Matsuda
BIOORGANIC & MEDICINAL CHEMISTRY, 16, 1, 428, 436, PERGAMON-ELSEVIER SCIENCE LTD, 2008年01月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Development of a highly beta-selective ribosylation reaction without using neighboring group participation: Total synthesis of (+)-caprazol, a core structure of caprazamycins
Shinpei Hirano, Satoshi Ichikawa, Akira Matsuda
JOURNAL OF ORGANIC CHEMISTRY, 72, 26, 9936, 9946, AMER CHEMICAL SOC, 2007年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Modular bent DNAs: A new class of artificial DNAs with a protein binding ability
Shunpei Murata, Youko Mizumura, Kaori Hino, Yoshihito Ueno, Satoshi Ichikawa, Akira Matsuda
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 129, 34, 10300, +, AMER CHEMICAL SOC, 2007年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Total Synthesis of (+)-FR-900493 (I) and Establishment of Its Absolute Stereochemistry.
Shinpei Hirano, Satoshi Ichikawa, Akira Matsuda
ChemInform, 38, 27, Wiley-Blackwell, 2007年07月03日
研究論文（学術雑誌）

Nucleoside natural products and related analogs with potential therapeutic properties as antibacterial and antiviral agents
Satoshi Ichikawa, Akira Matsuda
EXPERT OPINION ON THERAPEUTIC PATENTS, 17, 5, 487, 498, INFORMA HEALTHCARE, 2007年05月, ［査読有り］
英語, 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.

9-(2-C-cyano-2-deoxy-beta-(D)-arabino-pentofuranosyl)guanine, a potential antitumor agent against B-lymphoma infected with Kaposi's sarcoma-associated herpesvirus
Masaki Ohtawa, Satoshi Ichikawa, Yasuhiro Teishikata, Masahiro Fujimuro, Hideyoshi Yokosawa, Akira Matsuda
JOURNAL OF MEDICINAL CHEMISTRY, 50, 9, 2007, 2010, AMER CHEMICAL SOC, 2007年05月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Differential modulation of sodium- and chloride-dependent opioid peptide transport system by small nonopioid peptides and free amino acids
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］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Total synthesis of (+)-FR-900493 and establishment of its absolute stereochemistry
Shinpei Hirano, Satoshi Ichikawa, Akira Matsuda
TETRAHEDRON, 63, 13, 2798, 2804, PERGAMON-ELSEVIER SCIENCE LTD, 2007年03月, ［査読有り］
英語, 研究論文（学術雑誌）, 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.

P-530 Synthetic Study of the Stable Analog of Chitin Synthase Inhibitors, Guanofosfosins
Ichikawa Satoshi, Kitamuki Makoto, Yamamoto Yuji, Matsuda Akira
International Symposium on the Chemistry of Natural Products, 2006, "P, 530", 天然有機化合物討論会, 2006年07月23日
英語

Design, synthesis and structural analysis of novel bent DNAs containing cyclic uridylate dimer analogues.
Shunpei Murata, Yoko Mizumura, Satoshi Ichikawa, Akira Matsuda
Nucleic acids symposium series (2004), 50, 63, 4, 2006年, ［国際誌］
英語, 研究論文（学術雑誌）, We developed novel bent DNAs containing cyclic uridylate dimmer analogues (Figure 1, 1a-c), which possess an alkylene linkage with various length. These structural properties were revealed by fluorescence energy transfer (FRET) experiments, and their bending angles were found to be quite deep. This result suggests that our strategy can be applicable to highly refined studies to analyze various structure-specific DNA recognitions.

Synthesis of 3′-β-carbamoylmethylcytidine (CAMC) and its derivatives as potential antitumor agents
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］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Synthesis of galactose-linked uridine derivatives with simple linkers as potential galactosyltransferase inhibitors
S Murata, S Ichikawa, A Matsuda
TETRAHEDRON, 61, 24, 5837, 5842, PERGAMON-ELSEVIER SCIENCE LTD, 2005年06月, ［査読有り］
英語, 研究論文（学術雑誌）, 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.

Total Synthesis of Caprazol, a Core Structure of the Caprazamycin Antituberculosis Antibiotics
Shinpei Hirano, Satoshi Ichikawa, Akira Matsuda
Angewandte Chemie, 117, 12, 1888, 1890, Wiley-Blackwell, 2005年03月11日
研究論文（学術雑誌）

Synthesis of cross-linked circular DNAs using Hüisgen reaction.
Masanori Nakane, Satoshi Ichikawa, Akira Matsuda
Nucleic acids symposium series (2004), 49, 189, 90, 2005年, ［国際誌］
英語, 研究論文（学術雑誌）, Triazole-cross-linked ODNs were synthesized using Hüisgen reaction with 21 mer hairpin DNA possessing N-3 azidoethylthymidine and N-3 propargylthymidine at the 3' and 5'-terminals. Newly synthesized ODNs revealed thermally stable and their structures nearly retained those of non-cross-liked ODNs. This strategy is quite effective to prepare cross-linked circular ODNs.

Total synthesis of caprazol, a core structure of the caprazamycin antituberculosis antibiotics
S Hirano, S Ichikawa, A Matsuda
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 44, 12, 1854, 1856, WILEY-V C H VERLAG GMBH, 2005年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）

Synthesis of complex nucleoside antibiotics
S Ichikawa, A Matsuda
NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS, 24, 5-7, 319, 329, TAYLOR & FRANCIS INC, 2005年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Synthesis of 4,8-anhydro-D-glycero-D-ido-nonanitol 1,6,7-trisphosphate as a novel IP3 receptor ligand using a stereoselective radical cyclization reaction based on a conformational restriction strategy
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］

Synthesis of stable and cell-type selective analogues of cyclic ADP-ribose, a Ca(2+)-mobilizing second messenger. Structure--activity relationship of the N1-ribose moiety.
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, ［国際誌］
英語, 研究論文（学術雑誌）, We previously developed cyclic ADP-carbocyclic ribose (cADPcR, 2) as a stable mimic of cyclic ADP-ribose (cADPR, 1), a Ca(2+)-mobilizing second messenger. A series of the N1-ribose modified cADPcR analogues, designed as novel stable mimics of cADPR, which were the 2"-deoxy analogue 3, the 3"-deoxy analogue 4, the 3"-deoxy-2"-O-(methoxymethyl) analogue 5, the 3"-O-methyl analogue 6, the 2",3"-dideoxy analogue 7, and the 2",3"-dideoxydidehydro analogue 8, were successfully synthesized using the key intramolecular condensation reaction with phenylthiophosphate-type substrates. We investigated the conformations of these analogues and of cADPR and found that steric repulsion between both the adenine and N9-ribose moieties and between the adenine and N1-ribose moieties was a determinant of the conformation. The Ca(2+)-mobilizing effects were evaluated systematically using three different biological systems, i.e., sea urchin eggs, NG108-15 neuronal cells, and Jurkat T-lymphocytes. The relative potency of Ca(2+)-mobilization by these cADPR analogues varies depending on the cell-type used: e.g., 3"-deoxy-cADPcR (4) > cADPcR (2) > cADPR (1) in sea urchin eggs; cADPR (1) >> cADPcR (2) approximately 3"-deoxy-cADPcR (4) in T-cells; and cADPcR (2) > cADPR (1) > 3"-deoxy-cADPcR (4) in neuronal cells, respectively. These indicated that the target proteins and/or the mechanism of action of cADPR in sea urchin eggs, T-cells, and neuronal cells are different. Thus, this study represents an entry to cell-type selective cADPR analogues, which can be used as biological tools and/or novel drug leads.

Oligodeoxynucleotides having a loop consisting of 3'-deoxy-4'-C-(2-hydroxyethyl)thymidines form stable hairpins.
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］, ［国際誌］
英語, 研究論文（学術雑誌）, Components that form stable hairpin loops are highly useful for the development of functional DNA and RNA molecules. We have designed and synthesized a sugar-modified thymidine analogue, 3'-deoxy-4'-C-(2-hydroxyethyl)thymidine (X), as a nucleosidic loop component stabilizing the hairpin structure. The ODNs I-1-4, 5'-d[CGAACG-X(n)-CGTTCG]-3' (I-1, n = 1; I-2, n = 2; I-3, n = 3; I-4, n = 4), forming the hairpin loop structures, of which the loop moiety consisted of the analogue X, and also the corresponding unmodified ODNs II-1-4, 5'-d[CGAACG-T(n)-CGTTCG]-3' (II-1, n = 1; II-2, n = 2;II-3, n = 3; II-4, n = 4), having a thymidine loop, were synthesized by the phosphoramidite method. The melting temperatures (T(m)) of the ODNs I-1-4 containing X in the loop moiety at 5 microM were 67.1, 68.1, 73.0, and 69.3 degrees C, respectively, and those of the control natural ODNs II-1-4 were 65.3, 67.0, 69.2, and 68.8 degrees C, respectively. Thus, the ODNs I-1-4 formed a more thermally stable hairpin than the corresponding unmodified ODNs II-1-4 having an equal number of loop residues. The hairpin structures of the modified ODNs I-1-4 and the unmodified ODNs II-1-4 were investigated by CD spectroscopy and molecular mechanics calculations. These results showed that the 4'-branched nucleoside X can stabilize hairpin structures when it is present in the loop moiety, probably due to the flexibility of the one-carbon-elongated 4'-branched structure.

Nucleosides and nucleotides: Part 225. Synthesis of tunicaminyluracil derivatives
S Ichikawa, A Matsuda
NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS, 23, 1-2, 239, 253, MARCEL DEKKER INC, 2004年01月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Stereoselective synthesis of α- and β-C-glucosides via radical cyclization with an allylsilyl tether. Control of the stereoselectivity by changing the conformation of the pyranose ring.
Satoshi Shuto, Masaru Terauchi, YumiYahiro, Hiroshi Abe, Satoshi Ichikawa, Akira Matsuda
Tetrahedron Letters, 45, 6819, 2004年, ［査読有り］

Fundamental role of the fostriecin unsaturated lactone and implications for selective protein phosphatase inhibition.
Suzanne B Buck, Christophe Hardouin, Satoshi Ichikawa, Danielle R Soenen, C-M Gauss, Inkyu Hwang, Mark R Swingle, Kathy M Bonness, Richard E Honkanen, Dale L Boger
Journal of the American Chemical Society, 125, 51, 15694, 5, 2003年12月24日, ［国際誌］
英語, 研究論文（学術雑誌）, Key derivatives and analogues of fostriecin were prepared and examined that revealed a fundamental role for the unsaturated lactone and confirmed the essential nature of the phosphate monoester. Thus, an identical 200-fold reduction in protein phosphatase 2A (PP2A) inhibition is observed with either the saturated lactone (7) or with an analogue that lacks the entire lactone (15). This 200-fold increase in PP2A inhibition attributable to the unsaturated lactone potentially may be due to reversible C269 alkylation within the PP beta12-beta13 active site loop accounting for PP2A/4 potency and selectivity.

The first radical method for the introduction of an ethynyl group using a silicon tether and its application to the synthesis of 2'-deoxy-2'-C-ethynylnucleosides.
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］, ［国際誌］
英語, 研究論文（学術雑誌）, A novel radical method for the stereoselective introduction of an ethynyl group has been developed. When a solution of ethynyldimethylsilyl (EDMS) or [2-(trimethylsilyl)ethynyl]dimethylsilyl (TEDMS) ethers of trans-2-iodoindanol was treated with Et(3)B followed by tetrabutylammonium fluoride in toluene, atom transfer 5-exo-cyclization and subsequent elimination occurred to give cis-2-ethynylindanol in high yield. The method was shown to be useful in the introduction of an ethynyl group in various five- and six-membered-ring iodohydrins. Furthermore, 2'-deoxy-2'-C-ethynyluridine (6) and -cytidine (7), which were designed as novel antimetabolites, were readily synthesized by using this method as the key step. This would be the first example in which a radical reaction was used for introducing an ethynyl group.

A new entry to the stereoselective introduction of an ethynyl group by a radical reaction: synthesis of the potential antimetabolite 2'-deoxy-2'-C-ethynyluridine.
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］, ［国際誌］
英語, 研究論文（学術雑誌）

A highly stereoselective samarium diiodide-promoted aldol reaction with 1'-phenylseleno-2'-keto nucleosides. Synthesis of 1'alpha-branched uridine derivatives.
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］, ［国際誌］
英語, 研究論文（学術雑誌）, Since 1'-branched nucleosides are biologically important targets in medicinal chemistry, more efficient methods for preparing them are required. The 1'alpha-branched uridine derivatives were successfully synthesized via a samarium diiodide (SmI(2))-promoted aldol reaction. Treatment of the 1'alpha-phenylseleno-2'-ketouridine derivative 6, readily prepared from uridine, with SmI(2) at -78 degrees C in THF reductively cleaved the anomeric Se-C bond to generate the corresponding samarium enolate, which was highly stereoselectively condensed with aldehydes, such as PhCHO, MeCHO, i-PrCHO, or (CH(2)O)(n)(), to give the corresponding 1'alpha-1' 'S-branched products 12a-d. This is the first time an enolate has been generated by reductively cleaving a C-Se bond. The highly selective stereochemical results suggest that the aldol reaction proceeds via a chelation-controlled transition state. When an excess of aldehyde was used and the reaction mixture was gradually warmed, the tandem aldol-Tishchenko reaction proceeded to give the "arabino-type" nucleosides 14a-c, having a 2'-"up" hydroxyl and 1'alpha-1' 'S-branched chain. 1'alpha-Hydroxymethyluridine (21), which is the uracil version of the antitumor antibiotic angustmycin C, was synthesized from the aldol reaction product 10.

Development of New Radical Reactions with a Vinylsilyl Group and Their Application to the Synthesis of Branched-Chain Sugar Nucleosides
Satoshi Shuto, Makiko Kanazaki, Isamu Sugimoto, Satoshi Ichikawa, Yuki Nagasawa, Yoshihito Ueno, Hiroshi Abe, Noriaki Minakawa, Makoto Sukeda, Tetsuya Kodama, Makoto Nomura, Akira Matsuda
Recent Advances in Nucleosides: Chemistry and Chemotherapy, 21, 55, Elsevier, 2002年
論文集(書籍)内論文

Total synthesis of the rubrolone aglycon
DL Boger, S Ichikawa, HJ Jiang
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 122, 49, 12169, 12173, AMER CHEMICAL SOC, 2000年12月, ［査読有り］
英語, 研究論文（学術雑誌）, 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.

Synthesis of 3,7-anhydro-D-glycero-D-ido-octitol 1,5,6-trisphosphate as an IP3 receptor ligand using a radical cyclization reaction with a vinylsilyl tether as the key step. Conformational restriction strategy using steric repulsion between adjacent bulky protecting groups on a pyranose ring
S Shuto, Y Yahiro, S Ichikawa, A Matsuda
JOURNAL OF ORGANIC CHEMISTRY, 65, 18, 5547, 5557, AMER CHEMICAL SOC, 2000年09月, ［査読有り］
英語, 研究論文（学術雑誌）, 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.

Total syntheses of thiocoraline and BE-22179: Establishment of relative and absolute stereochemistry
DL Boger, S Ichikawa
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 122, 12, 2956, 2957, AMER CHEMICAL SOC, 2000年03月, ［査読有り］
英語, 研究論文（学術雑誌）

Stereoselective synthesis of alpha- and beta-C-glucosides via radical cyclization with an allylsilyl tether. Control of the stereoselectivity by changing the conformation of the pyranose ring.
Satoshi Shuto, Masaru Terauchi, Yumi Yahiro, Hiroshi Abe, Satoshi Ichikawa, Akira Matsuda
Tetrahedron Letters, 41, 21, 4151, 4155, 2000年, ［査読有り］

The first synthesis of herbicidin B, a tricyclic-sugar adenine nucleoside antibiotic, using samarium diiodide-promoted aldol-type C-glycosidation reaction as a key-step.
S. Shuto, S. Ichikawa, A. Matsuda
Nucleic acids symposium series, 42, 21, 22, 1999年
英語, 研究論文（学術雑誌）, A first total synthesis of the nucleoside antibiotic herbicidin B (1) was achieved in which a novel aldol-type C-glycosidation reaction promoted by samarium diiodide (SmI2) was used as a key step. Construction of the desired stereochemistry of the tricyclic-sugar moiety was successfully achieved by conformational restriction strategy based on repulsion between adjacent bulky protecting groups on the pyranose ring.

A novel aldol-type C-glycosidation reaction promoted by samarium diiodide. Regioselective generation of a ulose-1-enolate from phenyl 3,4,6-tri-O-benzyl-1-thio-beta-D-arabino-hexopyranosid-2-ulose.
S Ichikawa, S Shuto, A Matsuda
TETRAHEDRON LETTERS, 39, 25, 4525, 4528, PERGAMON-ELSEVIER SCIENCE LTD, 1998年06月, ［査読有り］
英語, 研究論文（学術雑誌）, 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.

Stereo- and Regioselective Introduction of 1- or 2-Hydroxyethyl Group via Intramolecular Radical Cyclization Reaction with a Novel Silicon-Containing Tether. An Efficient Synthesis of 4'alpha-Branched 2'-Deoxyadenosines(1).
Shuto S, Kanazaki M, Ichikawa S, Minakawa N, Matsuda A
The Journal of organic chemistry, 63, 3, 746, 754, 1998年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, An efficient method for the synthesis of 4'alpha-branched 2'-deoxyadenosines starting from 2'-deoxyadenosine has been developed utilizing a novel radical cyclization reaction with a silicon tether. The radical reaction of 4'beta-(phenylseleno)-3'-O-diphenylvinylsilyl adeninenucleoside derivative 17 with Bu(3)SnH and AIBN, followed by Tamao oxidation, gave selectively either the 4'alpha-(2-hydroxyethyl) derivative 21 or 4'alpha-(1-hydroxyethyl) derivative 19, depending on the reaction conditions. With a lower Bu(3)SnH concentration, the reaction gave the 4'alpha-(2-hydroxyethyl) derivative 21, via a 6-endo-radical cyclized product 20, as the sole product in 72% yield. The reaction of 17 in the presence of excess Bu(3)SnH gave 19 quantitatively, via a 5-exo-cyclized product 18, as a diastereomeric mixture. The reaction mechanism was examined using Bu(3)SnD. The results demonstrated that the 5-exo cyclized (3-oxa-2-silacyclopentyl)methyl radical (C) was formed initially which was trapped when the concentration of Bu(3)SnH(D) was high enough. With lower concentrations of Bu(3)SnH(D), radical C rearranged into the ring-enlarged 4-oxa-3-silacyclohexyl radical (D) which was then trapped with Bu(3)SnH(D) to give endo-cyclized product F.

A novel ring-enlargement reaction of (3-oxa-2-silacyclopentyl)methyl radicals into 4-oxa-3-silacyclohexyl radicals. Stereoselective introduction of a hydroxyethyl group via unusual 6-endo-cyclization products derived from 3-oxa-4-silahexenyl radicals and its application to the synthesis of a 4'-alpha-branched nucleoside
S Shuto, M Kanazaki, S Ichikawa, A Matsuda
JOURNAL OF ORGANIC CHEMISTRY, 62, 17, 5676, 5677, AMER CHEMICAL SOC, 1997年08月, ［査読有り］
英語, 研究論文（学術雑誌）

Nucleosides and nucleotides .163. Synthesis of 3'-beta-branched uridine derivatives via intramolecular Reformatsky-type reaction promoted by samarium diiodide
S Ichikawa, S Shuto, N Minakawa, A Matsuda
JOURNAL OF ORGANIC CHEMISTRY, 62, 5, 1368, 1375, AMER CHEMICAL SOC, 1997年03月, ［査読有り］
英語, 研究論文（学術雑誌）, 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］

ジペプチドを用いたスキャニングによる新規ポリミキシン誘導体の創製研究
家口凜太郎, 勝山彬, 勝山彬, 佐藤豊孝, 堀内基広, 横田伸一, 市川聡, 市川聡, 創薬懇話会講演要旨集, 2022, 2022年

迅速ライブラリー構築とin situスクリーニングによるムレイドマイシンの構造活性相関研究
淺尾健太, 山本一貴, 佐藤豊孝, 堀内基広, 横田伸一, 市川聡, 市川聡, 反応と合成の進歩シンポジウム講演要旨集, 48th, 2022年

麹菌由来Heptelidic acidはp38MAPKシグナルカスケードを介して膵癌細胞にアポトーシスを誘導する
小西弘晃, 山村千景, 磯崎翔太郎, 盛一健太郎, 山本一貴, 市川聡, 藤谷幹浩, 日本薬学会年会要旨集(Web), 142nd, 2022年

MRSAのファージ耐性獲得によるβラクタム系抗菌薬の再感受性化
中村暢宏, 西田啓汰, 藤木純平, 村田亮, 山本一貴, 市川聡, 岩野英知, 日本細菌学雑誌(Web), 77, 1, 2022年

ヌクレオシド系天然物と薬剤耐性菌感染症
山本一貴, 市川聡, CSJ Current Review, 39, 2021年

構造解析から創薬へ 複合体構造に基づく薬物設計による新規抗菌薬リード開発への取り組み
山本一貴, 市川聡, 医学のあゆみ, 278, 6, 2021年

黄色ブドウ球菌におけるファージ耐性化機構の解明
西田啓汰, 中村暢宏, 藤木純平, 村田亮, 山本一貴, 市川聡, 岩野英知, 日本獣医学会学術集会講演要旨集, 164th (CD-ROM), 2021年

抗緑膿菌活性を有するウリジルペプチド系天然物の構造活性相関研究
寺澤侑馬, 佐高千里, 佐藤豊孝, 山本一貴, 勝山彬, 松丸尊紀, 松丸尊紀, 薬師寺文華, 横田伸一, 市川聡, 市川聡, 日本薬学会年会要旨集(Web), 141st, 2021年

フラグメント連結戦略を用いたポリミキシン類誘導体ライブラリーの簡便かつ迅速な構築
家口凜太郎, 勝山彬, 佐藤豊孝, 横田伸一, 市川聡, 万有札幌シンポジウム, 32nd, 2020年

ウリジルペプチド系天然物の構造活性相関研究
寺澤侑馬, 佐高千里, 佐藤豊孝, 山本一貴, 勝山彬, 松丸尊紀, 松丸尊紀, 薬師寺文華, 横田伸一, 市川聡, 市川聡, 反応と合成の進歩シンポジウム講演要旨集, 2020年

ツニカマイシンVの全合成と低毒性誘導体の創製
山本一貴, 勝山彬, 薬師寺文華, 市川聡, 日本薬学会年会要旨集(CD-ROM), 139th, 2019年

ツニカマイシンVの全合成と構造に基づく低毒性誘導体の創製
山本一貴, 勝山彬, 薬師寺文華, 松丸尊紀, 市川聡, 次世代を担う有機化学シンポジウム講演要旨集, 17th, 2019年

Tunicamycin Vの全合成と構造に基づいたMraY選択的阻害剤への変換
山本一貴, 市川聡, 天然有機化合物討論会講演要旨集(Web), 60th, 2018年

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］
英語, 記事・総説・解説・論説等（国際会議プロシーディングズ）

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
(公社)日本獣医学会, 英語

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
(公社)日本獣医学会, 英語

Tunicamycin類の全合成研究
山本一貴, 薬師寺文華, 市川聡, 万有札幌シンポジウム, 29th, 2017年

Tunicamycin類の全合成研究
山本一貴, 市川聡, 日本薬学会年会要旨集(CD-ROM), 137th, 2017年

ヒストンメチル化酵素複合体構成因子EZH2-EED相互作用阻害剤の創製研究
塩田勇介, 薬師寺文華, 加藤いづみ, 岡田ゆかり, 堀内正隆, 児玉耕太, 松田彰, 前仲勝実, 市川聡, メディシナルケミストリーシンポジウム講演要旨集, 35th, 2017年

悪性脳腫瘍治療を指向した新規ベンゾオキサゾール誘導体の合成と活性評価
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
日本語

緑膿菌のレクチンLecA・LecB阻害剤リード化合物の創製研究
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
日本語

可溶性HLA‐Gの製剤化に向けて
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
日本語

多成分反応を用いた天然物合成と構造活性相関研究
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
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., 社団法人 有機合成化学協会, 日本語, 書評論文,書評,文献紹介等

可溶性HLA‐G分子の効率的生産に向けてのアプローチ
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
日本語

P-57 シリンゴリンAの全合成研究(ポスター発表の部)
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
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)., 天然有機化合物討論会, 日本語

P-57 シリンゴリンAの全合成研究(ポスター発表の部)
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
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)., 天然有機化合物討論会実行委員会, 日本語

P-50 抗腫瘍活性環状ペプチドサンドラマイシンの合成研究(ポスター発表の部)
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
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., 天然有機化合物討論会, 日本語

ヌクレオシド系天然物の全合成を基盤とした抗薬剤耐性菌薬シーズの創製研究
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
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., The Society of Synthetic Organic Chemistry, Japan, 日本語, 書評論文,書評,文献紹介等

P-50 抗腫瘍活性環状ペプチドサンドラマイシンの合成研究(ポスター発表の部)
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
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., 天然有機化合物討論会実行委員会, 日本語

化学レビュー(第18回)創薬化学 新たな切り口で結核菌と戦う!
市川 聡, 松田 彰, 化学, 65, 2, 30, 34, 2010年02月
化学同人, 日本語

精密有機合成化学に基づいたヌクレオシドと核酸の創薬研究
市川 聡, 藥學雜誌 = Journal of the Pharmaceutical Society of Japan, 128, 10, 1403, 1430, 2008年10月, ［国内誌］
&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 (SmI₂) 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>, 公益社団法人日本薬学会, 日本語

ピラノースの配座制御に基づく立体選択的グリコシル化反応
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
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., The Society of Synthetic Organic Chemistry, Japan, 日本語, 書評論文,書評,文献紹介等

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, 48, 67-68, 8, 2006年12月08日, ［国際誌］
A novel sugar-modified thymidine analogue, 3'-deoxy-4'-C-(2-hydroxyethyl)thymidine (X), was designed and synthesized to show that it can stabilize hairpin structures when it is present in the loop moiety, probably due to the flexibility of the one-carbon-elongated 4'-branched structure., 英語

核酸系抗生物質の合成研究
市川 聡, 藥學雜誌 = Journal of the Pharmaceutical Society of Japan, 126, 8, 579, 595, 2006年08月, ［国内誌］
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., 日本薬学会（The Pharmaceutical Society of Japan）, 日本語

Total synthesis of fostriecin (CI-920)
DL Boger, S Ichikawa, W Zhong, JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 123, 18, 4161, 4167, 2001年05月
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., AMER CHEMICAL SOC, 英語

Total synthesis of fostriecin (CI-920)
DL Boger, S Ichikawa, W Zhong, JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 123, 18, 4161, 4167, 2001年05月
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., AMER CHEMICAL SOC, 英語

Total syntheses of thiocoraline and BE-22179 and assessment of their DNA binding and biological properties
DL Boger, S Ichikawa, WC Tse, MP Hedrick, Q Jin, JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 123, 4, 561, 568, 2001年01月
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., AMER CHEMICAL SOC, 英語

Total Synthesis of Thiocoraline and BE22179 and Assessment of their DNA Binding and Biological Property
Journal of the American Chemical Society, 123, 2001年

Synthesis of pyrimidine 2 '-deoxy ribonucleosides branched at the 2 '-position via radical atom-transfer cyclization reaction with a vinylsilyl group as a radical-acceptor tether
M Sukeda, S Shuto, Sugimoto, I, S Ichikawa, A Matsuda, JOURNAL OF ORGANIC CHEMISTRY, 65, 26, 8988, 8996, 2000年12月
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., AMER CHEMICAL SOC, 英語

The first synthesis of herbicidin B. Stereoselective construction of the tricyclic undecose moiety by a conformational restriction strategy using steric repulsion between adjacent bulky silyl protecting groups on a pyranose ring
S Ichikawa, S Shuto, A Matsuda, JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 121, 44, 10270, 10280, 1999年11月
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., AMER CHEMICAL SOC, 英語

Synthesis of C-glycosides via radical cyclization reactions with a vinylsilyl tether. Control of the reaction course by a change in the conformation of the pyranose ring due to steric repulsion between adjacent bulky protecting groups
Y Yahiro, S Ichikawa, S Shuto, A Matsuda, TETRAHEDRON LETTERS, 40, 30, 5527, 5531, 1999年07月
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., PERGAMON-ELSEVIER SCIENCE LTD, 英語

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

63(P36) 核酸系抗生物質Herbicidin Bの合成研究(ポスター発表の部)
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
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., 天然有機化合物討論会, 日本語

光学活性デュオカルマイシンAの全合成
市川 聡, ファルマシア, 33, 2, 190, 191, 1997年02月01日
公益社団法人日本薬学会, 日本語

63(P36) 核酸系抗生物質Herbicidin Bの合成研究(ポスター発表の部)
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
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., 天然有機化合物討論会実行委員会, 日本語

新規6‐endoラジカル環化反応によるヌクレオシド4′‐α位への立体選択的な炭素置換基導入
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
日本語

ヌクレオシド系天然物による創薬基盤研究　　　　　　　　　　　　　　　
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　　　　　　　　　　　　　　　
市川 聡
2013年09月

Liponucleoside natural products: synthesis and structure-activity relationship　　　　　　　　　　　　　　　
市川 聡
2013年09月

天然物を用いる創薬化学　　　　　　　　　　　　　　　
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　　　　　　　　　　　　　　　
市川 聡
2012年03月

Chemistry and structure-activity relationship of antibacterial nucleoside natural products　　　　　　　　　　　　　　　
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　　　　　　　　　　　　　　　
市川 聡
2008年03月

The synthesis of complex nucleoside antibiotics　　　　　　　　　　　　　　　
市川 聡
2004年09月

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

遺伝子型に立脚した膵がん個別化医療開発基盤の創出
科学研究費助成事業
2023年04月01日 - 2027年03月31日
園下 将大, 五十嵐 学, 小沼 剛, 市川 聡, 合田 圭介
日本学術振興会, 基盤研究(B), 北海道大学, 23K27450

遺伝子型に立脚した膵がん個別化医療開発基盤の創出
科学研究費助成事業
2023年04月01日 - 2027年03月31日
園下 将大, 市川 聡, 五十嵐 学, 小沼 剛
日本学術振興会, 基盤研究(B), 北海道大学, 23H02759

非結核性抗酸菌が抗結核薬に耐性を示すメカニズムの解明と新規治療法開発への応用
科学研究費助成事業
2023年04月01日 - 2026年03月31日
港 雄介, 佐藤 綾人, 御手洗 聡, 土井 洋平, 市川 聡, 美間 健彦
日本学術振興会, 基盤研究(B), 藤田医科大学, 23K27325

骨粗鬆症治療薬開発のための骨代謝制御を担う骨マクロファージの機能解析
科学研究費助成事業
2023年04月01日 - 2026年03月31日
照川 アラー, 市川 聡, 清水 智弘, 高橋 大介
日本学術振興会, 基盤研究(B), 北海道大学, 23K27716

非結核性抗酸菌が抗結核薬に耐性を示すメカニズムの解明と新規治療法開発への応用
科学研究費助成事業
2023年04月01日 - 2026年03月31日
港 雄介, 佐藤 綾人, 御手洗 聡, 土井 洋平, 市川 聡
日本学術振興会, 基盤研究(B), 藤田医科大学, 23H02634

骨粗鬆症治療薬開発のための骨代謝制御を担う骨マクロファージの機能解析
科学研究費助成事業
2023年04月01日 - 2026年03月31日
照川 アラー, 市川 聡, 清水 智弘, 高橋 大介
日本学術振興会, 基盤研究(B), 北海道大学, 23H03025

レジデンスタイム制御構造要素探索とその制御による薬物設計理論の提唱
科学研究費助成事業
2023年06月30日 - 2025年03月31日
市川 聡, 勝山 彬
日本学術振興会, 挑戦的研究(萌芽), 北海道大学, 23K18171

ビルドアップライブラリー構築法を用いた薬剤耐性菌リードの創出研究
科学研究費助成事業
2022年04月01日 - 2025年03月31日
市川 聡, 勝山 彬
天然物は人智を超えた活性・構造を有する重要な創薬シード分子である。中分子天然物を創薬リードへと昇華させるためには、包括的な天然物誘導体から構成されるライブラリーの構築は極めて大きな意義を持つ。申請者はこれまで、迅速かつ網羅的な中分子天然物ライブラリーの合成を可能とする「ビルドアップライブラリー構築」とその直接生物活性評価スキームを開発してきた。本申請研究では、本法を更に創薬リード創出に資する強力な中分子天然物創薬プラットホームとすべく、さらに①標的とする天然物とアクセサリーの拡充と、②様々な生物学的等価体に変換と構造最適化を行う事で、創薬リード創出を図る。令和4年度は、コリスチン、リファンピシン、ツニカマイシン、ムレイドマイシン等のビル負度アップライブラリーを作製した。更にその直接の生物活性評価を迅速に行う事により、コリスチン、ツニカマイシン、ムレイドマイシンの３つについては、もとの天然物の生物活性を凌駕する誘導体を同定する事が出来た。また、ムライマイシンについては、連結部であるヒドラゾン構造を、化学的・生物学的により安定な結合に変換した誘導体も合成し、in vitroでの生物活性の向上と、in vivoで薬理活性を発現する誘導体の同定に至っている。コリスチンに関する論文は、既にJ. Am. Chem. Soc.にて公表されている。ムライマイシンに関する研究については、論文投稿中である。
日本学術振興会, 基盤研究(B), 北海道大学, 23K24001

Galectin 3阻害剤創薬による難治疾患の病態解明と治療応用を目指した研究
科学研究費助成事業
2022年04月01日 - 2025年03月31日
調 憲, 矢島 俊樹, 佐藤 賢, 高橋 昭久, 市川 聡, 横堀 武彦, 佐伯 浩司
本年度はまずGalectin 3(gal 3)結合性を評価するアッセイ系の確立を行った。化合物のgal3結合能については、サーマルシフトアッセイ、表面プラズモン共鳴アッセイ、等温滴定カロリメトリーの複数のアッセイ系が確立した。このアッセイ系の確立により、新規薬剤のgal3親和性を高い精度で検討することが可能となり、さらに薬剤の作成・絞り込み・構造改変などが飛躍的なスピードで可能となった。新規gal3阻害剤については、アッセイ直前にフラグメントを連結する「ビルドアップ法」により、54種類の化合物を合成・評価した。各化合物のgal3結合能については、サーマルシフトアッセイ、表面プラズモン共鳴アッセイ、等温滴定カロリメトリーにより多角的に評価し、5種類程度の高親和性誘導体を獲得した。さらに、フラグメント同士の連結に用いた化学結合を、生体内でも安定な結合を有するものに変更したところ、ヒドロキシルアミンリンカーを導入した誘導体において、結合能が10倍程度向上することが明らかとなった。
これらの候補薬剤に対してGal3発現の程度の異なる複数の膵がん細胞株に対するin vitroのアッセイを繰り返してきた。現在、確立されたGal3親和性アッセイ系に基づき、見出されたGal3高親和性低分子化合物のin vitroにおける効果の評価を行うところである。さらに現在高親和性Gal3化合物に抗がん剤やセリンプロテアーゼを結合した化合物を生成中である。前者は全く新たな抗がん剤、後者は臓器線維化に対する治療薬としてのみならず、癌線維芽細胞に対する新たな薬剤としての可能性を有している。
日本学術振興会, 基盤研究(B), 群馬大学, 23K24402

ビルドアップライブラリー構築法を用いた薬剤耐性菌リードの創出研究
科学研究費助成事業 基盤研究(B)
2022年04月01日 - 2025年03月31日
市川 聡, 勝山 彬
日本学術振興会, 基盤研究(B), 北海道大学, 22H02738

Galectin 3阻害剤創薬による難治疾患の病態解明と治療応用を目指した研究
科学研究費助成事業 基盤研究(B)
2022年04月01日 - 2025年03月31日
調 憲, 矢島 俊樹, 佐藤 賢, 高橋 昭久, 市川 聡, 横堀 武彦, 佐伯 浩司
日本学術振興会, 基盤研究(B), 群馬大学, 22H03143

悪性リンパ腫の自然退縮メカニズムの解明
科学研究費助成事業 若手研究
2021年04月01日 - 2023年03月31日
市川 聡
免疫不全関連リンパ増殖性疾患(OIIA-LPD)として発症する悪性リンパ腫の自然退縮に関わる遺伝子異常を明らかにするため，まず自己免疫疾患に対して免疫抑制療法を行われ，かつ悪性リンパ腫を発症し当科にて診断・治療が行われた当院の症例を抽出した．その結果解析が可能であったのは10例で，原疾患の内訳は，関節リウマチ(RA)が8例，皮膚筋炎が1例，overlap症候群が1例，組織型の内訳はびまん性大細胞型B細胞リンパ腫(DLBCL)が3例，ろ胞性リンパ腫(FL) grade 3Bが2例，FL grade 1-2が1例，古典的ホジキンリンパ腫(CHL)が4例であった．さらに，固形臓器移植後のリンパ増殖性疾患(PTLD)として発症した悪性リンパ腫症例のうち，上記と同様に解析が可能であった症例2例を対象に加えた(いずれも腎移植後，組織型はDLBCL)．上記計12例について，それぞれの症例のホルマリン固定パラフィン包埋組織から核酸を抽出し，デジタルオミックスアナライザー(nCounterシステム)を用いて，網羅的にmRNAレベルでの遺伝子発現の増減を解析した．上記12例全てで解析に成功し，全遺伝子でクラスタリングを行ったところ，肝臓原発と腸管原発の2例はプロファイルが明らかに異なったため除外し，そのほかの10例(FL・DLBCL 5例，CHL 5例)をID群として，解析に使用することとした．次に，別の研究で同様の解析を行った高腫瘍量FL(HT-FL群)12例とのデータとの比較で，ID群における発現が有意に上昇および低下している遺伝子群を抽出した．その結果，67遺伝子を抽出することができ，そのうち，ID群の中での組織型の別で有意差を認めない47遺伝子が，OIIA-LPDの発症に関連する遺伝子群である可能性が考えられた．
日本学術振興会, 若手研究, 東北大学, 21K16260

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
科学研究費助成事業 基盤研究(B)
2020年04月01日 - 2023年03月31日
園下 将大, 藤井 清永, 市川 聡, 大塩 貴子, 小沼 剛
がんは日本人の死因の第一位で、対策が急務となっている。種々のがんの中でも特に治療の選択肢が少なく、患者の予後が最も悪いものが膵がんである。哺乳類実験系で膵がんの本態の解明や治療標的候補の同定が進められてきたものの、それらの知識はいまだ断片的で、詳細な発生機序や、他のがん種に比べて治療に対する頑健性が極めて高い理由は解明されていない。
そこで本研究では、治療に対する膵がんの頑健性の成立機序を解明し、その知見に基づいて新規膵がん治療戦略を創出する。特に本研究は、脆弱性を人為的に誘導する新しい方法論の提唱を目指す。本研究の遂行により、膵がんの治療応答性の詳細な分子機序を明らかにして新規膵がん治療法を確立し、膵がんの本態解明と福祉向上の両面に貢献することを目指す。
初年度はまず、膵がん遺伝子型モデルハエの作出ならびに表現型解析実施した。膵がん患者の中で最も予後不良の患者群が有する４遺伝子変異（がん遺伝子KRASの活性化、がん抑制遺伝子群TP53やCDKN2A、SMAD4の不活性化）を模倣した4-hitハエは、細胞の過剰な増殖や運動能の亢進、そして致死表現型を呈した。これらは、RAS活性化のみ模倣した1-hitハエやRAS活性化とTP53不活性化を模倣した2-hitハエと比較して著明な腫瘍表現型であった。
次に、これらの表現型の発現に関与するシグナル伝達経路を同定すべく、これらのハエを使用してキナーゼの網羅的遺伝学解析を実施した。その結果、4-hit表現型を促進する新規治療標的キナーゼ群を同定することに成功した。並行して新規膵がん治療薬候補も見出したが、臨床と同様、効果は限定的だった。次年度以降、この頑健性の詳細な分子機序の解明に取り組む。
日本学術振興会, 基盤研究(B), 北海道大学, 20H03524

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
科学研究費助成事業 基盤研究(C)
2020年04月01日 - 2023年03月31日
大塩 貴子, 園下 将大, 市川 聡, 藤井 清永
日本学術振興会, 基盤研究(C), 北海道大学, 20K07558

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
科学研究費助成事業 新学術領域研究(研究領域提案型)
2020年04月01日 - 2022年03月31日
市川 聡
研究目的：緑膿菌（P. aeruginosa）は、他の細菌に比べて、一般に物質透過制限が極めて高い外膜で覆われているために薬が効きにくいうえに、最近、従来の抗生物質などに幅広く耐性を獲得した「多剤耐性緑膿菌」の出現が世界規模の問題となっている。我々はこれまでに、緑膿菌に対して選択的な抗菌活性を示すヌクレオシド系MraY阻害天然物であるムレイドマイシン1)に関する研究を行ってきており、ムレイドマイシン誘導体を含むヌクレオシド系天然物群と、その標的分子であるMraYとの複合体の網羅的なX線結晶構造解析に成功した2)。これらの成果を基盤として、本研究では、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を利用し、MraY阻害活性を有するヌクレオシド系天然物を積極的に創薬シーズへと展開すべく、トランスポーター認識能の拡張を行うともに、グラム陽性菌にのみ有効な他のMraY阻害天然物の抗菌スペクトルの拡張を行い、緑膿菌を中心とした薬剤耐性菌に対する創薬シーズを開発する事を目的とする。
研究結果：MraY阻害とMraYの複合体X線結晶構造解析から、ウレアジペプチド部の2つのアミノ酸残基はMraYとの結合に関与しない事が示唆された。ムレイドマイシン誘導体を合成して構造活性相関を検討したところ、予想通りアミノ酸残基の種類によらず強力なMraY阻害活性が見られた。一方で、抗緑膿菌活性はアミノ酸残基の種類により大きく変化する事がわかった。そこで、ムレイドマイシン誘導体の耐性菌を作製し、本耐性菌の全ゲノムシークエンス解析を行う事で、オリゴペプチドトランスポーターとして知られているNppA1A2BCDがムレイドマイシン選択的なトランスポーターである事を同定した。抗緑膿菌活性の変化は、NppA1A2BCDによる分子認識に依存すると予想される。その他、ツニカマイシンのMraY阻害活性増強や、スファエリミシンの合成研究も行っている。
日本学術振興会, 新学術領域研究(研究領域提案型), 北海道大学, 20H04757

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
科学研究費助成事業 基盤研究(B)
2019年04月01日 - 2022年03月31日
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。
日本学術振興会, 基盤研究(B), 北海道大学, 19H03345

「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
科学研究費助成事業 挑戦的研究(萌芽)
2018年06月29日 - 2021年03月31日
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。
日本学術振興会, 挑戦的研究(萌芽), 北海道大学, 18K19384

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
科学研究費助成事業 基盤研究(B)
2018年04月01日 - 2021年03月31日
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。
日本学術振興会, 基盤研究(B), 群馬大学, 18H02877

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
科学研究費助成事業 新学術領域研究(研究領域提案型)
2018年04月01日 - 2020年03月31日
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, 新学術領域研究(研究領域提案型), 北海道大学, 18H04599

薬剤耐性菌制圧に向けた天然物から創薬リードへの変換研究
科学研究費助成事業 基盤研究(B)
2016年04月01日 - 2019年03月31日
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, 基盤研究(B), 北海道大学, 16H05097

天然物を利用したヒストン化学修飾剤によるエピジェネティックス制御
科学研究費助成事業 挑戦的萌芽研究
2015年04月01日 - 2017年03月31日
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。
日本学術振興会, 挑戦的萌芽研究, 北海道大学, 15K14974

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
科学研究費助成事業 新学術領域研究(研究領域提案型)
2014年04月01日 - 2016年03月31日
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, 新学術領域研究(研究領域提案型), 北海道大学, 26102701

新規抗多剤耐性菌薬シード開発の多角的戦略
科学研究費助成事業 基盤研究(B)
2013年04月01日 - 2016年03月31日
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, 基盤研究(B), 北海道大学, 研究代表者, 競争的資金, 25293026

タンパク質間相互作用阻害剤の分子進化型開発研究
科学研究費助成事業 挑戦的萌芽研究
2013年04月01日 - 2015年03月31日
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。
日本学術振興会, 挑戦的萌芽研究, 北海道大学, 25670050

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
科学研究費助成事業 新学術領域研究(研究領域提案型)
2012年04月01日 - 2014年03月31日
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。
日本学術振興会, 新学術領域研究(研究領域提案型), 北海道大学, 24102502

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　　　　　　　　　　　　　　　
2010年04月 - 2013年03月
市川 聡
研究代表者, 競争的資金

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
科学研究費助成事業 若手研究(A)
2010年 - 2012年
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, 若手研究(A), 北海道大学, 22689004

ADCC様活性を有する人工低分子核酸抗体の開発研究
科学研究費助成事業 挑戦的萌芽研究
2010年 - 2011年
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, 挑戦的萌芽研究, 北海道大学, 22659020

次世代型抗ヘルペスウイルス薬開発のための創薬研究
科学研究費助成事業 新学術領域研究(研究課題提案型)
2008年 - 2010年
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, 新学術領域研究(研究課題提案型), 山梨大学, 研究代表者, 競争的資金, 20200073

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
科学研究費助成事業 若手研究(B)
2008年 - 2009年
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。
日本学術振興会, 若手研究(B), 北海道大学, 20790097

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　　　　　　　　　　　　　　　
2006年04月 - 2008年03月
市川 聡
研究代表者, 競争的資金

Hsp90を分子標的とする多角的抗癌剤開発
科学研究費助成事業 若手研究(B)
2006年 - 2007年
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。
日本学術振興会, 若手研究(B), 北海道大学, 18790083

糖鎖合成酵素阻害剤の開発　　　　　　　　　　　　　　　
2002年 - 2006年
競争的資金

核酸系抗生物質の創薬志向型合成研究
科学研究費助成事業 特定領域研究
2005年 - 2005年
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。
日本学術振興会, 特定領域研究, 北海道大学, 17035001

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
科学研究費助成事業 若手研究(B)
2004年 - 2005年
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。
日本学術振興会, 若手研究(B), 北海道大学, 16790002

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
科学研究費助成事業 若手研究(B)
2002年 - 2003年
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。
日本学術振興会, 若手研究(B), 北海道大学, 14771237

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
科学研究費助成事業 特別研究員奨励費
1998年 - 1999年
市川 聡
日本学術振興会, 特別研究員奨励費, 北海道大学, 98J02573

糖転移酵素に関する研究　　　　　　　　　　　　　　　
競争的資金

核酸抗生物質誘導体
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特許第5070550号
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特願2009-049963, 2009年03月03日
特開2012-102019, 2012年05月31日
201203053334533651

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特許権, 村中 一大, 市川 聡, 松田 彰, 佐野 亜希子, 国立大学法人 北海道大学, 大鵬薬品工業株式会社
特願2007-279056, 2007年10月26日
特開2009-107939, 2009年05月21日
200903073287392500

抗ヘルペスウイルス活性を有するヌクレオシド誘導体
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WO2007-119624, 2007年10月25日
200903094701573340

学士課程, 薬学部

修士課程, 生命科学院

博士課程, 生命科学院