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

Mar. 2008, 日本薬学会奨励賞　　　　　　　　　　　　　　　
市川 聡

Dec. 2005, 日本薬学会北海道支部奨励賞　　　　　　　　　　　　　　　
市川 聡

Design, Synthesis, and Biological Evaluation of Lipid-Modified Derivatives of Tunicamycins.
Kazuki Yamamoto, Toyotaka Sato, Ellene H Mashalidis, Seok-Yong Lee, Motohiro Horiuchi, Satoshi Ichikawa
Chemistry (Weinheim an der Bergstrasse, Germany), e02296, 15 Sep. 2025, [International Magazine]
English, Scientific journal, Naturally occurring antibiotic tunicamycin targets bacterial peptidoglycan biosynthesis by inhibiting bacterial phospho-N-acetylmuraminic acid (MurNAc)-pentapeptide translocase (MraY), but it also inhibits human UDP-N-acetylglucosamine (GlcNAc): polyprenol phosphate translocase (GPT), leading to cytotoxicity. This study thoroughly investigated the structure-activity relationship of the fatty acyl side chain of tunicamycin to develop MraY-selective inhibitors, based on structural differences between MraY and GPT. Longer alkyl chains and flexible structures were found to favor MraY inhibitory activity, and benzene rings were acceptable for binding. The hybrid analogue containing oleoyl group, which contributed most significantly to MraY inhibitory activity, and the MurNAc moiety, which is important for MraY-selective inhibition, showed enhanced MraY inhibitory activity as well as improved antibacterial activity against S. aureus and E. faecium.

Structure-Activity Relationship of Pseudouridimycin Focusing on the Improvement of Chemical Stability.
Ryotaro Okawa, Irina Artsimovitch, Akira Katsuyama, Toyotaka Sato, Courtney C Aldrich, Satoshi Ichikawa
Journal of medicinal chemistry, 68, 15, 15461, 15482, 14 Aug. 2025, [International Magazine]
English, Scientific journal, In recent years, the spread of drug-resistant bacterial infections has driven a critical demand for new antimicrobial agents with novel mechanisms of action. Pseudouridimycin (PUM) is a nucleoside antibiotic that inhibits bacterial DNA-dependent RNA polymerase (RNAP) by binding in the conserved active site that is distinct from the mutable allosteric sites targeted by the clinically approved rifamycin-class of antibiotics. However, translational development of PUM is compromised by its poor intrinsic chemical stability and competitive modality of inhibition with respect to UTP, which will require further augmentation of binding affinity. We have conducted structure-activity relationship (SAR) studies on PUM by approaching these two problems through the rational design of analogs based on the known PUM·RNAP X-ray cocrystal structure and through elucidation of the decomposition mechanisms.

Concise Total Synthesis of Sandramycin and Its Analogues via Cyclodimerization Using Mitsunobu Reaction.
Radhakrishnam R Ruddarraju, Yuya Komatani, Yasuaki Tokodai, Satoshi Ichikawa
The Journal of organic chemistry, 90, 29, 10550, 10554, 25 Jul. 2025, [International Magazine]
English, Scientific journal, Total synthesis of sandramycin was achieved via a cyclodimerization approach of the precursor pentapeptide by using the Mitsunobu reaction. This strategy allowed us to prepare a range of analogues efficiently. Their DNA binding ability and cytotoxicity against human cancer cell lines were also evaluated.

Structure-guided design and development of cyclic peptide allosteric activators of Polycomb Repressive Complex 2.
Yasuaki Tokodai, Mark Matyas, Azumi Ishigamori, Erin O'Connor, Angel Zhang, Sora Yamazaki, Tsunehide Hiraki, Noah Lohar, Liqi Yao, Ryan Stoner, Luis E Paez-Beltran, Kayoko Kanamitsu, Noriko Nakaya, Satoshi Ichikawa, Justin Brumbaugh, Vignesh Kasinath, Fumika Yakushiji
bioRxiv : the preprint server for biology, 26 Jun. 2025, [International Magazine]
English, Scientific journal, Dysregulation of the histone methyltransferase Polycomb repressive complex 2 (PRC2) results in aberrant silencing of tumor suppressors and activation of oncogenes. Targeting PRC2 with compounds holds significant potential for both basic research and therapeutic applications. Here, we leveraged extensive structural studies of PRC2 to design a cyclic peptide that robustly activates PRC2. Structure-activity relationship studies guided the functional optimization of this cyclic peptide, yielding a Phenylalanine-type (Phe-type) cyclic peptide with approximately eight-fold activation compared to that of the poised state of PRC2. A 3.3Å cryo-electron microscopy structure of the PRC2-peptide complex, combined with biochemical analyses, revealed a shift in the H3K27 methylation from mono- (me1) and dimethylation (me2) to trimethylation (me3). Finally, we demonstrated that the cyclic peptide exhibits improved mouse plasma stability and can also be readily taken up by cells which results in a shift of the H3K27 methylation landscape to trimethylation, similar to the observed effects in vitro. These findings support the utility of such molecules for probing PRC2 activation and targeting dysregulated H3K27 methylation in cancer.

pH-Controlled isomerization kinetics of ortho-disubstituted benzamidines: E/Z isomerism and axial chirality.
Ryota Kimura, Satoshi Ichikawa, Akira Katsuyama
Beilstein journal of organic chemistry, 21, 1568, 1576, 2025, [International Magazine]
English, pH-Responsive molecular switches and motors are a class of organic molecules whose three-dimensional structure can be changed by acid-base stimuli. To date, pH-responsive molecular switches have been developed using various functional groups, but further advances require expanding the range of pH-responsive systems and discovering new molecular architectures. Here, we investigate the pH-responsive behavior of ortho-disubstituted benzamidine, which generates atropisomers and E/Z isomers. The amidine moiety allows modulation of the C-N and C-N/C-C rotational barriers by protonation, providing a novel approach to control the kinetics of isomerization via pH adjustment. The results showed that protonation of the amidine moiety significantly suppresses both C-N bond rotation and C-N/C-C concerted rotation, demonstrating the potential of ortho-disubstituted benzamidine derivatives as a novel pH-responsive molecular switch.

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, 15 Jun. 2024, [International Magazine]
English, Scientific journal, 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, 14 Jun. 2024, [International Magazine]
English, Scientific journal, 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, 04 May 2024, [International Magazine]
English, Scientific journal, 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, May 2024, [International Magazine]
English, Scientific journal, Development of selective or dual proteasome subunit inhibitors based on syringolin B as a scaffold is described. We focused our efforts on a structure-activity relationship study of inhibitors with various substituents at the 3-position of the macrolactam moiety of syringolin B analogue to evaluate whether this would be sufficient to confer subunit selectivity by using sets of analogues with hydrophobic, basic and acidic substituents, which were designed to target Met45, Glu53 and Arg45 embedded in the S1 subsite, respectively. The structure-activity relationship study using systematic analogues provided insight into the origin of the subunit-selective inhibitory activity. This strategy would be sufficient to confer subunit selectivity regarding β5 and β2 subunits.

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, 01 Apr. 2024
Scientific journal, 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, 28 Feb. 2024
Scientific journal

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, [Domestic magazines]
English, Scientific journal, 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, 17 Nov. 2023, [International Magazine]
English, Scientific journal, 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, 12 Oct. 2023, [International Magazine]
English, Scientific journal, 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, 04 Aug. 2023, [International Magazine]
English, Scientific journal, 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), 28 Jan. 2023, [International Magazine]
English, Scientific journal, 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), 27 Jan. 2023
Scientific journal

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, 20 Dec. 2022, [International Magazine]
English, Scientific journal, 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, Dec. 2022, [International Magazine]
English, Scientific journal, 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, 26 Sep. 2022, [International Magazine]
English, Scientific journal, 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, 14 Jul. 2022, [International Magazine]
English, Scientific journal, 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, 20 Apr. 2022, [International Magazine]
English, Scientific journal, 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, 25 Mar. 2022, [International Magazine]
English, Scientific journal, 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, 07 Mar. 2022, [International Magazine]
English

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, Feb. 2022, [International Magazine]
English, Scientific journal, 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, [Domestic magazines]
Japanese, Scientific journal, 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, Dec. 2021
Scientific journal, 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, Apr. 2021
Scientific journal

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, Apr. 2021, [International Magazine]
English, Scientific journal, 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, 10 Sep. 2020, [Peer-reviewed], [Last author, Corresponding author], [International Magazine]
English, Scientific journal

Total Synthesis of Acaulide and Acaulone A.
Jun Hirabayashi, Fumika Yakushiji, Akira Katsuyama, Satoshi Ichikawa
Organic letters, 22, 14, 5545, 5549, 17 Jul. 2020, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, 05 Jun. 2020, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, 03 Apr. 2020, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, Apr. 2020, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, 15 Jan. 2020, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, 2020, [Peer-reviewed], [International Magazine]
English, Scientific journal

Tunicamycin: chemical synthesis and biosynthesis.
Kazuki Yamamoto, Satoshi Ichikawa
The Journal of antibiotics, 72, 12, 924, 933, Dec. 2019, [Peer-reviewed], [Domestic magazines]
English, Scientific journal

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, Dec. 2019, [Peer-reviewed], [Domestic magazines]
English, Scientific journal, 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, 02 Jul. 2019, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, 21 Jun. 2019, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, 15 Apr. 2019, [Peer-reviewed], [International Magazine]
English, Scientific journal

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
Japanese, Scientific journal

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, 04 Sep. 2018, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, 01 Sep. 2018, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, 19 Aug. 2018, [Peer-reviewed]

Total synthesis of plusbacin A3
Katsuyama Akira, Yakushiji Fumika, Ichikawa Satoshi
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 256, 19 Aug. 2018, [Peer-reviewed]

Total Synthesis of Plusbacin A3 and Its Dideoxy Derivative Using a Solvent-Dependent Diastereodivergent Joullié-Ugi Three-Component Reaction.
Akira Katsuyama, Fumika Yakushiji, Satoshi Ichikawa
The Journal of organic chemistry, 83, 13, 7085, 7101, 06 Jul. 2018, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, 01 Jul. 2018, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, Jun. 2018, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, 16 Apr. 2018, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, Mar. 2018, [Peer-reviewed], [International Magazine]
English, Scientific journal

Potent anti-tumor activity of a syringolin analog in multiple myeloma: a dual inhibitor of proteasome activity targeting β2 and β5 subunits.
Takashi Yoshida, Masaki Ri, Takashi Kanamori, Sho Aoki, Reham Ashour, Shiori Kinoshita, Tomoko Narita, Haruhito Totani, Ayako Masaki, Asahi Ito, Shigeru Kusumoto, Takashi Ishida, Hirokazu Komatsu, Shun Kitahata, Takuya Chiba, Satoshi Ichikawa, Shinsuke Iida
Oncotarget, 9, 11, 9975, 9991, Impact Journals LLC, 09 Feb. 2018, [Peer-reviewed], [International Magazine]
English, Scientific journal

Total Synthesis of Tunicamycin V.
Kazuki Yamamoto, Fumika Yakushiji, Takanori Matsumaru, Satoshi Ichikawa
Organic letters, 20, 1, 256, 259, 05 Jan. 2018, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, [Peer-reviewed], [Domestic magazines]
English, Scientific journal

Synthesis and Medicinal Chemistry of Muraymycins, Nucleoside Antibiotics.
Akira Katsuyama, Satoshi Ichikawa
Chemical & pharmaceutical bulletin, 66, 2, 123, 131, 2018, [Peer-reviewed], [Domestic magazines]
English, Scientific journal

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, 21 Jul. 2017, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, 15 May 2017, [Peer-reviewed], [International Magazine]
English, Scientific journal

Impact of Structures of Macrocyclic Michael Acceptors on Covalent Proteasome Inhibition
Kitahata, Shun, Yakushiji, Fumika, Ichikawa, Satoshi
Chem. Sci., 8, 6959, 6963, 2017, [Peer-reviewed]
English, Scientific journal

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, Dec. 2016, [Peer-reviewed]
English

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, 15 Nov. 2016, [Peer-reviewed], [International Magazine]
English, Scientific journal

ChemInform Abstract: Revisited Mechanistic Implications of the Joullie-Ugi Three-Component Reaction.
Akira Katsuyama, Akira Matsuda, Satoshi Ichikawa
ChemInform, 47, 42, Wiley-Blackwell, Sep. 2016
Scientific journal

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, Aug. 2016, [Peer-reviewed], [International Magazine]
English, Scientific journal

ChemInform Abstract: Function-Oriented Synthesis: How to Design Simplified Analogues of Antibacterial Nucleoside Natural Products?
Satoshi Ichikawa
ChemInform, 47, 32, Wiley-Blackwell, Jul. 2016
Scientific journal

Revisited Mechanistic Implications of the Joullié-Ugi Three-Component Reaction.
Akira Katsuyama, Akira Matsuda, Satoshi Ichikawa
Organic letters, 18, 11, 2552, 5, 03 Jun. 2016, [Peer-reviewed], [International Magazine]
English, Scientific journal

Function-Oriented Synthesis: How to Design Simplified Analogues of Antibacterial Nucleoside Natural Products?
Satoshi Ichikawa
CHEMICAL RECORD, 16, 3, 1106, 1115, Jun. 2016, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, 26 May 2016, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, 06 May 2016, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, 2016, [Peer-reviewed], [Domestic magazines]
English, Scientific journal

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, 01 Nov. 2015, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, 28 Jul. 2015, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, 10 Apr. 2015, [Peer-reviewed], [International Magazine]
English, Scientific journal

Synthesis of isoxazolidine-containing uridine derivatives as caprazamycin analogues.
Mayumi Yamaguchi, Akira Matsuda, Satoshi Ichikawa
Organic & biomolecular chemistry, 13, 4, 1187, 97, 28 Jan. 2015, [Peer-reviewed], [International Magazine]
English, Scientific journal

Synthesis of all stereoisomers of spectomycin A1 and their inhibitory activity against protein SUMOylation
Nomura Yusaku, Sodeoka Mikiko, Thuaud F., Sekine Daisuke, Hirai Go, Maeda Satoko, Ito Akihiro, Ichikawa Satoshi, Matsuda Akira, Yoshida Minoru
Symposium on the Chemistry of Natural Products, symposium papers, 57, Oral24, Symposium on the Chemistry of Natural Products Steering Committee, 2015
Japanese,

Spectomycins A1, A2, and B1 (SMA1, A2 and B1) have been isolated in 1994. SMB1 possesses a dimeric structure of SMA2 and shows moderate anti-bacterial activity against Gram-positive microorganism. Recently, it was found that SMB1 remarkably inhibited protein SUMOyltion (Small Ubiquitin related MOdifier) in vitro and in cellulo, through direct interaction with SUMO-conjugating enzyme UBC9. SUMOylation is one of the post-translational modifications and regulates multiple biological systems. Abnormal SUMOylation is proposed to be relevant to several diseases, but molecular mechanisms have not been fully understood. Thus, SMB1 would be candidate as both the tool for biological researches and a lead compound for drug developments. On the other hand, inhibitory activities of monomeric SMA1 and SMA2 against protein SUMOylation as well as their relative and absolute stereochemistry have not been reported yet, although their poor potency as anti-bacterial activity was already reported. To address these issues as a part of SAR studies of SMB1, we envisioned the preparation of all possible stereoisomers of monomeric SMAs. To this end, we aimed to establish the synthetic methodology to access all stereoisomers of SMAs by the late stage diversification from a common intermediate.

Structural features of SMAs are represented as an aromatizable β-hydroxy tetralone moiety and a non-conjugated β-methoxy acrylate with aromatic ring. Palladium-catalyzed reductive cyclization of the common intermediate successfully constructed the all possible stereoisomers at C4 and C5 of the precursors of SMA1 with the β-methoxy acrylate moiety. Finally, synthesis of SMA1 and its all isomers was accomplished by DDQ oxidation.

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, 2015, [Peer-reviewed]
English, Scientific journal

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, Aug. 2014, [Peer-reviewed]
English

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, Aug. 2014, [Peer-reviewed]
English

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, Aug. 2014, [Peer-reviewed]
English

ChemInform Abstract: Total Synthesis of Quinaldopeptin (Ia) and Its Analogues.
Satoshi Ichikawa, Takuya Okamura, Akira Matsuda
ChemInform, 45, 21, no, no, Wiley-Blackwell, 08 May 2014
Scientific journal

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, 08 May 2014, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, 05 May 2014, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, 21 Mar. 2014, [Peer-reviewed], [International Magazine]
English, Scientific journal

Function-Oriented Synthesis of Liponucleoside Antibiotics
Tetsuya Tanino, Mayumi Yamaguchi, Akira Matsuda, Satoshi Ichikawa
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, 2014, 9, 1836, 1840, Mar. 2014, [Peer-reviewed]
English, Scientific journal

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, 17 Jan. 2014, [Peer-reviewed], [International Magazine]
English, Scientific journal

Total synthesis of quinaldopeptin and its analogues.
Satoshi Ichikawa, Takuya Okamura, Akira Matsuda
The Journal of organic chemistry, 78, 24, 12662, 70, 20 Dec. 2013, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, 06 Dec. 2013, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, 01 Feb. 2013, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, Jul. 2012, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, Feb. 2012
Scientific journal

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, Feb. 2012, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, Dec. 2011, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, Nov. 2011, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, Oct. 2011, [Peer-reviewed], [International Magazine]
English, Scientific journal

Synthesis of L-epi-Capreomycidine Derivatives via C-H Amination
Tetsuya Tanino, Satoshi Ichikawa, Akira Matsuda
ORGANIC LETTERS, 13, 15, 4028, 4031, Aug. 2011, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, Apr. 2011, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, Mar. 2011, [Peer-reviewed], [Domestic magazines]
Japanese, Scientific journal

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
Japanese

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, Nov. 2010, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, Sep. 2010, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, Aug. 2010, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, 08 Jun. 2010
Scientific journal

ChemInform Abstract: Total Synthesis of Fostriecin (CI-920).
Dale L. Boger, Satoshi Ichikawa, Wenge Zhong
ChemInform, 32, 36, no, no, Wiley-Blackwell, May 2010
Scientific journal

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, May 2010, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, Apr. 2010, [Peer-reviewed], [International Magazine]
English, Scientific journal

Total Synthesis of (-)-Muraymycin D2 and Its Epimer
Tetsuya Tanino, Satoshi Ichikawa, Motoo Shiro, Akira Matsuda
JOURNAL OF ORGANIC CHEMISTRY, 75, 5, 1366, 1377, Mar. 2010, [Peer-reviewed], [International Magazine]
English, Scientific journal

Design and synthesis of 3 ',5 '-ansa-adenosines as potential Hsp90 inhibitors
Kazuhiro Muranaka, Satoshi Ichikawa, Akira Matsuda
TETRAHEDRON LETTERS, 50, 36, 5102, 5106, Sep. 2009, [Peer-reviewed]
English, Scientific journal

ChemInform Abstract: Medicinal Chemistry Targeting Nucleosides and Nucleic Acids Based on Fine Synthetic Chemistry
Satoshi Ichikawa
ChemInform, 40, 6, Wiley-Blackwell, 10 Feb. 2009
Scientific journal

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, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, Nov. 2008, [Peer-reviewed]
English, Scientific journal

Fine synthetic nucleoside chemistry based on nucleoside natural products synthesis
Satoshi Ichikawa
CHEMICAL & PHARMACEUTICAL BULLETIN, 56, 8, 1059, 1072, Aug. 2008, [Peer-reviewed], [Domestic magazines]
English, Scientific journal

ChemInform Abstract: Stereoselective Glycosylation Based on the Conformational Restriction of Pyranoses
Satoshi Shuto, Satoshi Ichikawa, Hiroshi Abe, Akira Matsuda
ChemInform, 39, 25, Wiley-Blackwell, Jun. 2008
Scientific journal

Synthesis of Hsp90 inhibitor dimers as potential antitumor agents
Kazuhiro Muranaka, Akiko Sano, Satoshi Ichikawa, Akira Matsuda
BIOORGANIC & MEDICINAL CHEMISTRY, 16, 11, 5862, 5870, Jun. 2008, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, May 2008, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, Mar. 2008, [Peer-reviewed], [International Magazine]
English, Scientific journal

ChemInform Abstract: Fine Synthetic Nucleoside Chemistry Based on Nucleoside Natural Products Synthesis
Satoshi Ichikawa
ChemInform, 39, 50, Wiley-Blackwell, 2008
Scientific journal

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, [International Magazine]
English, Scientific journal, 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, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, Jan. 2008, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, Jan. 2008, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, Dec. 2007, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, +, Aug. 2007, [Peer-reviewed], [International Magazine]
English, Scientific journal

Total Synthesis of (+)-FR-900493 (I) and Establishment of Its Absolute Stereochemistry.
Shinpei Hirano, Satoshi Ichikawa, Akira Matsuda
ChemInform, 38, 27, Wiley-Blackwell, 03 Jul. 2007
Scientific journal

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, May 2007, [Peer-reviewed]
English

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, May 2007, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, Apr. 2007, [Peer-reviewed], [International Magazine]
English, Scientific journal

Total synthesis of (+)-FR-900493 and establishment of its absolute stereochemistry
Shinpei Hirano, Satoshi Ichikawa, Akira Matsuda
TETRAHEDRON, 63, 13, 2798, 2804, Mar. 2007, [Peer-reviewed]
English, Scientific journal

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", Symposium on the chemistry of natural products, 23 Jul. 2006
English

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, [International Magazine]
English, Scientific journal, 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, [Peer-reviewed], [International Magazine]
English, Scientific journal

Synthesis of galactose-linked uridine derivatives with simple linkers as potential galactosyltransferase inhibitors
S Murata, S Ichikawa, A Matsuda
TETRAHEDRON, 61, 24, 5837, 5842, Jun. 2005, [Peer-reviewed]
English, Scientific journal

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, 11 Mar. 2005
Scientific journal

Synthesis of cross-linked circular DNAs using Hüisgen reaction.
Masanori Nakane, Satoshi Ichikawa, Akira Matsuda
Nucleic acids symposium series (2004), 49, 189, 90, 2005, [International Magazine]
English, Scientific journal, 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, 2005, [Peer-reviewed], [International Magazine]
English, Scientific journal

Synthesis of complex nucleoside antibiotics
S Ichikawa, A Matsuda
NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS, 24, 5-7, 319, 329, 2005, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, [Peer-reviewed]

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, [International Magazine]
English, Scientific journal, 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, Jul. 2004, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, Jan. 2004, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, [Peer-reviewed]

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, 24 Dec. 2003, [International Magazine]
English, Scientific journal, 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, May 2003, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, Dec. 2002, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, Nov. 2002, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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
In book

Total synthesis of the rubrolone aglycon
DL Boger, S Ichikawa, HJ Jiang
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 122, 49, 12169, 12173, Dec. 2000, [Peer-reviewed]
English, Scientific journal

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, Sep. 2000, [Peer-reviewed]
English, Scientific journal

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, Mar. 2000, [Peer-reviewed]
English, Scientific journal

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, [Peer-reviewed]

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
English, Scientific journal

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, Jun. 1998, [Peer-reviewed]
English, Scientific journal

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, Feb. 1998, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, Aug. 1997, [Peer-reviewed]
English, Scientific journal

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, Mar. 1997, [Peer-reviewed]
English, Scientific journal

ヨウ化サマリウムのヌクレオシド化学への展開　　　　　　　　　　　　　　　
市川 聡
[Peer-reviewed]

新規抗菌薬開発を目指したMraY阻害剤ムレイドマイシン誘導体の創出研究
淺尾健太, 山本一貴, 佐藤豊孝, 堀内基広, 市川聡, 日本蛋白質科学会年会(Web), 24th, 2024

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

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

Probiotic derived Heptelidic acid induces apoptosis through p38 MAPK signal transduction in pancreatic cancer cells.
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

Bacteriophage-resistant variants of MRSA are resensitized to β-lactam antibiotics
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

Nucleoside Antibiotics and Infectious Diseases Caused by Drug-Resistant Bacterial Pathogens
山本一貴, 市川聡, CSJ Current Review, 39, 2021

Efforts to develop new antibacterial drug leads by drug design based on complex structures
山本一貴, 市川聡, 医学のあゆみ, 278, 6, 2021

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

Structure-activity relationship study of anti-P. aeruginosa active uridylpeptide natural products
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

Rapid Construction of a Library of Polymyxin Analogue Using in situ Fragment Linking Strategy
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

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

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

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

Total Synthesis of Tunicamycin V and Conversion to MraY-selective Inhibitor by Structure-Based Design
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

Development of Positive Modulators of Histone H3K27 Methylation　　　　　　　　　　　　　　　
Tokodai, Yasuaki, Yakushiji, Fumika, Sengoku, Toru, Katsuyama, Akira, Ichikawa, Satoshi, Peptide Science 2018, 14, 2018, [Peer-reviewed]
English, Introduction international proceedings

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, Aug. 2017
(公社)日本獣医学会, English

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, Aug. 2017
(公社)日本獣医学会, English

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

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

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

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, 11 Nov. 2016
Japanese

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, 11 Nov. 2016
Japanese

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, 19 May 2016
Japanese

Natural Product Synthesis by Multicomponent Reaction and Structure-activity Relationship Study
Takuya Chiba, Takeshi Nakaya, Katsushi Katayama, Akira Matsuda, Satoshi Ichikawa, JOURNAL OF SYNTHETIC ORGANIC CHEMISTRY JAPAN, 74, 5, 426, 440, May 2016
Japanese, Book review

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, 26 May 2015
Japanese

P-57 Study for Total Synthesis of Syringolin A(Poster Presentation)
Chiba Takuya, Ichikawa Satoshi, Matsuda Akira, 天然有機化合物討論会講演要旨集, 54, 54, 435, 440, 01 Sep. 2012
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, Japanese

P-57 Study for Total Synthesis of Syringolin A(Poster Presentation)
Chiba Takuya, Ichikawa Satoshi, Matsuda Akira, Symposium on the Chemistry of Natural Products, symposium papers, 54, 0, 435, 440, 2012
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)., Symposium on the Chemistry of Natural Products Steering Committee, Japanese

P-50 Synthetic Study of Sandramycin(Poster Presentation)
Katayama K, Ichikawa S, Matsuda A, 天然有機化合物討論会講演要旨集, 53, 53, 631, 636, 02 Sep. 2011
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, Japanese

Development of Antibacterial Agents Active against Drug-resistant Bacterial Pathogens Based on Total Synthesis of Nucleoside Natural Products
Satoshi Ichikawa, Tetsuya Tanino, Kensuke Ii, Akira Matsuda, JOURNAL OF SYNTHETIC ORGANIC CHEMISTRY JAPAN, 69, 9, 1020, 1033, Sep. 2011
Japanese, Book review

NMR structure and thermal stability of bent DNA recognized by HMGB1 protein
FURUITA Kyoko, MURATA Shunpei, JEE JunGoo, ICHIKAWA Satoshi, MATSUDA Akira, KOJIMA Chojiro, KOJIMA Chojiro, Program & Abstracts. International Symposium on Nucleic Acids Chemistry, 38th, 2011

P-50 Synthetic Study of Sandramycin(Poster Presentation)
Katayama K, Ichikawa S, Matsuda A, Symposium on the Chemistry of Natural Products, symposium papers, 53, 0, 631, 636, 2011
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., Symposium on the Chemistry of Natural Products Steering Committee, Japanese

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, Feb. 2010
化学同人, Japanese

Medicinal chemistry targeting nucleosides and nucleic acids based on fine synthetic chemistry
Satoshi Ichikawa, YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, 128, 10, 1403, 1430, Oct. 2008, [Domestic magazines]
Japanese

アルキル架橋ウリジン二量体を含むDNAオリゴマーのNMR構造解析
古板恭子, 村田俊平, JEE JunGoo, JEE JunGoo, 市川聡, 松田彰, 児嶋長次郎, Abstracts. Annual Meeting of the NMR Society of Japan, 47th, 2008

Stereoselective glycosylation based on the conformational restriction of pyranoses
Satoshi Shuto, Satoshi Ichikawa, Hiroshi Abe, Akira Matsuda, JOURNAL OF SYNTHETIC ORGANIC CHEMISTRY JAPAN, 66, 1, 50, 60, Jan. 2008
Japanese, Book review

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, 08 Dec. 2006, [International Magazine]
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., English

Synthetic study of nucleoside antibiotics
Satoshi Ichikawa, YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, 126, 8, 579, 595, Aug. 2006, [Domestic magazines]
Japanese

Total synthesis of fostriecin (CI-920)
DL Boger, S Ichikawa, W Zhong, JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 123, 18, 4161, 4167, May 2001
English

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, Jan. 2001
English

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

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, Dec. 2000
English

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, Nov. 1999
English

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, Jul. 1999
English

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

63(P36) STUDY FOR TOTAL SYNTHESIS OF NUCLEOSIDE ANTIBIOTICS HERBICIDIN B
Ichikawa Satoshi, Shuto Satoshi, Matsuda Akira, 天然有機化合物討論会講演要旨集, 39, 39, 373, 378, 20 Jul. 1997
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, Japanese

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, 01 Feb. 1997
公益社団法人日本薬学会, Japanese

63(P36) STUDY FOR TOTAL SYNTHESIS OF NUCLEOSIDE ANTIBIOTICS HERBICIDIN B
Ichikawa Satoshi, Shuto Satoshi, Matsuda Akira, Symposium on the Chemistry of Natural Products, symposium papers, 39, 0, 373, 378, 1997
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., Symposium on the Chemistry of Natural Products Steering Committee, Japanese

Stereoselective carbon substitution group introduction to a nucleoside 4'-.ALPHA. place by new 6-endo radical cyclization reaction.
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, Mar. 1996
Japanese

ヌクレオシド系天然物による創薬基盤研究　　　　　　　　　　　　　　　
市川 聡
Mar. 2014

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
Sep. 2013

Liponucleoside natural products: synthesis and structure-activity relationship　　　　　　　　　　　　　　　
市川 聡
Sep. 2013

天然物を用いる創薬化学　　　　　　　　　　　　　　　
市川 聡
Sep. 2012

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
Mar. 2012

Chemistry and structure-activity relationship of antibacterial nucleoside natural products　　　　　　　　　　　　　　　
市川 聡
Sep. 2008

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
Mar. 2008

The synthesis of complex nucleoside antibiotics　　　　　　　　　　　　　　　
市川 聡
Sep. 2004

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

構造-レジデンスタイム相関の解明と制御
科学研究費助成事業
01 Apr. 2025 - 31 Mar. 2029
市川 聡, 勝山 彬
日本学術振興会, 基盤研究(A), 北海道大学, 25H01014

活性配座の記憶と固定化に基づく創薬方法論の開発
科学研究費助成事業
27 Jun. 2025 - 31 Mar. 2027
市川 聡
日本学術振興会, 挑戦的研究(萌芽), 北海道大学, 25K22512

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
01 Apr. 2023 - 31 Mar. 2027
園下 将大, 五十嵐 学, 小沼 剛, 市川 聡, 合田 圭介
膵がんは患者予後が最も悪く、その新規治療法の創出は喫緊の福祉課題である。近年遺伝子型に応じた個別化医療の有用性が注目されているが、膵がんに関しては遺伝子型の差異が治療応答性等のがん形質に与える影響や治療標的が個体レベルで十分に解明されておらず、開発が遅れている。本研究ではこれを解決すべく、個体レベルの網羅的解析が可能で代表者らが治療薬シーズ開発の実績を有するショウジョウバエを、哺乳類実験系と相補的に活用する。これにより、膵がん個別化医療創出の研究基盤と治療薬候補の提示を実現し、学術貢献と福祉向上の双方への貢献を目指す。
本年度は、膵がんの遺伝子型の差異が膵がん形質や治療応答性に与える影響の解明に取り組んだ。膵がんにおいては、がん遺伝子KRASの活性化、がん抑制遺伝子群TP53・CDKN2A・SMAD4の不活性化が単独あるいは組み合わせとして頻繁に観察される。そこで代表者らはまず、膵がんの多様な遺伝子型を模倣したモデルショウジョウバエを作出し、これらの間で表現型を比較した。次に、これらのハエを使用して網羅的遺伝学スクリーニングを開始し、それぞれの遺伝子型が異なるシグナル伝達経路を駆動することを見出し、新規治療標的候補を同定した。一方代表者らは近年、膵がん形質を著明に抑制する治療薬シーズを同定することに成功している。代表者らはこのシーズが阻害する標的キナーゼが幅広い遺伝子型のモデルハエにおいて腫瘍形質の抑制を示すことを見出した。
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
01 Apr. 2023 - 31 Mar. 2027
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
01 Apr. 2023 - 31 Mar. 2026
港 雄介, 佐藤 綾人, 御手洗 聡, 土井 洋平, 市川 聡, 美間 健彦
非結核性抗酸菌（Non-tuberculosis Mycobacteria: NTM菌）が引き起こす肺NTM症が先進諸国において急増しており、大きな問題となっている。NTM菌は結核菌に有効な抗結核薬に対して抵抗性を示すため、治療に抗結核薬が使用できず、結核より治療が難しい。そして、そもそもなぜNTM菌に抗結核薬が効かないのか、そのメカニズムはほとんど明らかにされていない。
本研究は、NTM菌が抗結核薬に対して抵抗性を示すメカニズムを明らかにし、抗結核薬のNTM菌に対する効果を増強する薬剤の開発を目的に実施中である。本年度はトランスポゾンを利用した遺伝学的アプローチを用いて、NTM菌の抗結核薬に対する薬剤耐性遺伝子の同定を試みた。そしてNTM菌の、抗結核薬リファンピシンに対する薬剤耐性遺伝子の網羅的同定に成功した。また並行して実施中の化合物スクリーニングによって、NTM菌に対するリファンピシンの効果を増強する化合物を同定した。
同様の手法で抗結核薬ピラジナミドを対象に研究を実施したが、ピラジナミドに対する薬剤耐性遺伝子や、ピラジナミドの効果を増強する化合物は同定されなかった。この事からピラジナミドの標的は、そもそもNTM菌に対して有効で無いことが示唆された。
同定したリファンピシン耐性遺伝子の中から、最もリファンピシンへの自然耐性への寄与が高いと考えられる遺伝子Ｘを欠損した株について解析を進めた結果、遺伝子Ｘ欠損株はリファンピシンに加え、複数の抗菌薬に対する自然耐性に関与することが明らかとなった。
日本学術振興会, 基盤研究(B), 藤田医科大学, 23K27325

Exploring functional roles of osteal macrophages in bone metabolism for the development of osteoporosis therapeutics
Grants-in-Aid for Scientific Research
01 Apr. 2023 - 31 Mar. 2026
照川 アラー, 市川 聡, 清水 智弘, 高橋 大介
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B), Hokkaido University, 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
01 Apr. 2023 - 31 Mar. 2026
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

Functional analysis of bone macrophages that control bone metabolism for the development of therapeutic drugs for osteoporosis.
Grants-in-Aid for Scientific Research
01 Apr. 2023 - 31 Mar. 2026
照川 アラー, 市川 聡, 清水 智弘, 高橋 大介
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B), Hokkaido University, 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
30 Jun. 2023 - 31 Mar. 2025
市川 聡, 勝山 彬
標的に対する結合滞在時間を「レジデンスタイム」と言う。どのような分子・構造単位・要因がレジデンスタイムに影響を与えるのかはよくわかっておらず、論理的に薬物と標的のレジデンスタイムを制御する事はほとんどできていない。本研究は、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を目指す。
本研究では、将来的な創薬展開を見据えて、重要な創薬リード分子である生物活性天然有機化合物を研究対象に設定した。これまで、レジデンスタイムに影響を与える構造単位は全く不明であった。そのため、分子のレジデンスタイムを論理的に制御するためには、まずレジデンスタイム制御構造を同定する必要がある。その方法として、主たる結合を担うコア構造と、これに結合するレジデンスタイムに影響を与えるであろうアクセサリー部からなる天然物誘導体ライブラリーを網羅的かつ系統的に合成し、それらの生物活性評価を通してレジデンスタイムに変化を与える化学構造を包括的に探索する事とした。これまで申請者は、複雑な構造を有する天然有機化合物の迅速かつ網羅的なライブラリー構築法を開発しており、本手法を適用する事で、迅速なレジデンスタイム制御構造の探索と構造活性相関情報の取得を同時に行う。研究の2段階目として、上述の研究により得られる膨大な構造/レジデンスタイム相関データを解析し、レジデンスタイム延長の主要パラメーターを同定する。レジデンスタイム制御構造要素が同定できた際には、分子動力学シミュレーション技術を取り入れる事で、レジデンスタイムが異なる天然物誘導体と標的との複合体の時間変化による配座変化を考慮にいれながら、更なる天然物誘導体を設計し、実際に化学合成した誘導体のレジデンスタイム延長の検証を行う。
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
01 Apr. 2022 - 31 Mar. 2025
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
01 Apr. 2022 - 31 Mar. 2025
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)
01 Apr. 2022 - 31 Mar. 2025
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)
01 Apr. 2022 - 31 Mar. 2025
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

Indentifying the basis for the robustness in pancreatic cancer to develop novel therapeuitics
Grants-in-Aid for Scientific Research
01 Apr. 2020 - 31 Mar. 2023
Sonoshita Masahiro
Pancreatic cancer represents a typical intractable cancer. The number of pancreatic cancer deaths has been rising, therefore the development of new, highly effective therapies is an urgent clinical unmet need. In this study, we generated a novel animal model of pancreatic cancer using Drosophila melanogaster and used it to identify MEK and AURKB as critical factors that determine the robustness of pancreatic cancer against chemical treatment. We further leveraged these findings to identify a candidate compound combination that efficiently inhibits the growth of human pancreatic cancer xenografts in mice. These results reveal key mechanisms of how the robustness of pancreatic cancer develops.
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B), Hokkaido University, 20H03524

Developing a novel therapy for pancreatic cancer targeting the riboflavin pathway
Grants-in-Aid for Scientific Research
01 Apr. 2020 - 31 Mar. 2023
Ooshio Takako
To develop a novel therapy for pancreatic ductal adenocarcinoma (PDAC), we established the first animal model, a 4-hit fly, that mimics the four-gene mutations observed in PDAC. Most of these flies died before reaching adulthood due to the abnormal proliferation of transformed cells. To clarify the signaling pathways involved in their decreased viability, we performed genetic screening with the 4-hit fly. As a result, we revealed that riboflavin (RF) kinase and MEK promote their malignant traits. RF kinase is a rate-limiting enzyme in RF pathway and unclear their roles in PDAC. Therefore, we conducted chemical testing and elucidated that a combination of RF pathway and MEK inhibitors markedly increased the viability of the 4-hit fly. Furthermore, the combination significantly suppressed tumor expansion in mice orthotopically implanted with human PDAC cells. These results indicate that the combination is a novel therapeutic candidate for PDAC.
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Hokkaido University, 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)
01 Apr. 2020 - 31 Mar. 2022
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

Development of lead discovery platform accelerating medicinal chemistry based on natural products
Grants-in-Aid for Scientific Research
01 Apr. 2019 - 31 Mar. 2022
Ichikawa Satoshi
The major skeleton of a natural product was used as the "core" structure and various acylhydrazines as "accessories." Both fragments were reacted on a 96-well plate, and the progress and yield of the hydrazone formation reaction were confirmed in each well by LC-MS. The reaction conditions for hydrazone formation and the stability of the hydrazones under the same conditions were also examined under the conditions of biological activity evaluation using both fragments. Using this method, a library of derivatives of several natural products was synthesized in parallel. As a result, we identified several derivatives that surpassed the activity of the original natural products, including a derivative that is extremely effective against drug-resistant bacteria.


Translated with www.DeepL.com/Translator (free version)
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B), Hokkaido University, 19H03345

Development of a quick and simple search method for active conformations with amplification and memory of active conformations as the key concept
Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Research (Exploratory)
29 Jun. 2018 - 31 Mar. 2021
Ichikawa Satoshi
First, an indomethacin derivative having a substituent at the ortho positions of the benzene ring was synthesized and mixed with various proteins at 37 ° C. for 24 hours. As a result, a slight asymmetric amplification was observed when catalase was used. Next, we focused on the fact that the benzamide structure, which is a structure widely found in drugs, has two axial asymmetry of C-C bond and C-N bond, and investigated the properties of bond rotation. As a result, it was found that the type of substituent at the ortho position of the benzene ring shows the slow interconversion property characteristic of the atropisomer at a wide range of substituents, although the rotational speeds of both axes are slightly changed. Furthermore, this property was applied to enzyme inhibitors such as WDR5 inhibitors and HDAC inhibitors.
Japan Society for the Promotion of Science, Grant-in-Aid for Challenging Research (Exploratory), Hokkaido University, 18K19384

New humoral factor facilitates hepato-biliary and pancreatic cancer progression and development of innovative thrapy
Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)
01 Apr. 2018 - 31 Mar. 2021
Shirabe Ken
M2BPGi and galectin-3 proteins co-localised in HCC cells, while M2BP mRNA was detected in cirrhotic liver stromal cells. mTOR signaling was upregulated in M2BPGi-treated HCC cells. Moreover, M2BPGi treatment induced tumour-promoting effects on HCC in vitro by activated mTOR signaling. In addition, M2BPGi bound to galectin-3 to induce membranous galectin-3 expression in HCC cells. In vivo, M2BPGi enhanced the growth of xenografted HCC. M2BPGi is produced in stromal cells of the cirrhotic liver. Furthermore, M2BPGi enhances the progression of HCC through the galectin-3/mTOR pathway. Therefore, galectin 3 inhibitor would be quite effective in M2BPGi. We have already developed the prototype galectin 3 inhibitor and we are now on the way of new galectin 3 inhibitor production, which has extremely high affinity to galectin 3.
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B), Gunma University, 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)
01 Apr. 2018 - 31 Mar. 2020
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

Development of an innovative evaluation method for superconducting devices due to phase transition on two-dimensional superconductors
Grants-in-Aid for Scientific Research
01 Apr. 2017 - 31 Mar. 2020
ICHIKAWA Fusao
In order to investigate the effects of superconducting fluctuations and superconducting-insulator transition (SIT) phenomena that occur with the reduction of dimension of samples on superconducting devices, these phenomena were investigated for Mo-based superconducting thin films: MoN, MoRu, MoRe, and MoRe-N. For the relationship between superconducting transition temperature and sheet resistance in the normal state of these films with different thickness, the result is consistent with the electron localization model. The relation between sheet resistance and disorder depends on the material. On the other hand, the field-tuned SI transition was observed for MoN thin films, and all the data collapse onto two separate curves as a function of the scaling variable. Peaks were observed in the magnetic field dependence of the Hall resistance. The mechanism may be different between thickness-tuned SIT and magnetic field-tuned SIT.
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Kumamoto University, 17K06390

Significance of immunosurveillance molecules in MYC-positive diffuse large B-cell lymphoma
Grants-in-Aid for Scientific Research
01 Apr. 2017 - 31 Mar. 2019
Satoshi Ichikawa
In analyses of 102 cases of diffuse large B-cell lymphoma (DLBCL), high value of soluble interleukin-2 receptor (sIL-2R) predicted poor clinical outcome. Moreover, most cases of high sIL-2R group with germinal center B-cell (GCB) subtype experienced early relapse. sIL-2R could be a useful prognostic stratification marker of DLBCL, and poor prognosis in high sIL-2R group could be associated with upregulated expression of MYC oncogene.
In analyses utilizing lymphoma cell lines, REL, a subunit of NF-kB, was overexpressed in GCB-derived cell line, and NF-kB signal was activated in REL-overexpressed cell ilnes. It could show the association between overgrowth of lymphoma and upregulation of NF-kB signal pathway mediated by REL.
Japan Society for the Promotion of Science, Grant-in-Aid for Young Scientists (B), Tohoku University, 17K16176

Development of drug leads for drug-resistance bacterial pathogens based on natural products
Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)
01 Apr. 2016 - 31 Mar. 2019
Satoshi Ichikawa, Katsuyama Akira, Sato Toyotaka, Lee Seok-Yong
1)Synthesis and biological evaluation of muraimycin analogues were investigated. 2) Synthesis of the core structure of phaerimycin and its derivatives was achieved and their MraY inhibitory activity was also conducted. As a result, one derivative showed high MraY inhibitory activity. 3) Mureidomycin A analigues were synthesized and it was found that some derivatives exhibited higher MraY inhibitory activity and anti-P. aeruginosa activity than pacidamycin D, which is a conger of mureidomycin A. Furthermore, X-ray crystal structure analysis of the complex of mureidomycin analogue bound to MraY was also established. 4) The synthesis and action mechanism analysis of plasbacin A3 and its derivative were conducted. 5) In order to find an effective derivative against colistin resistant bacteria, 30 colistin derivatives were synthesized and their antibacterial activities were evaluated.
Some drug resistant bacterial drug lead were developed in this study.
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B), Hokkaido University, 16H05097

Control of epigenetics by chemical modulator based on natural products
Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research
01 Apr. 2015 - 31 Mar. 2017
ICHIKAWA Satoshi
Analogues of DNA bisintercalating natural products were designed and synthesized and their DNA binding properties as well as cytotoxicity against human cancer cells were evaluated. Several analogues exhibit a potent cytotoxicity against a panel of human cancer cells with nM level and some of the analogues also show in vivo antitumor activity in the experiments using mouse xenograft model. As a result, we were able to find a promising anticancer lead compound.
Japan Society for the Promotion of Science, Grant-in-Aid for Challenging Exploratory Research, Hokkaido University, 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)
01 Apr. 2014 - 31 Mar. 2016
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

Multifaceted approaches to develop novel antibacterial seeds against drug-resistant bacterial pathogens
Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)
01 Apr. 2013 - 31 Mar. 2016
ICHIKAWA Satoshi
a) Structural simplification of muraymycins and caprazamycins have been investigated to develop analogues possessing antibacterial activity against drug-resistant bacteria such as MRSA and VRE with enough metabolic stability as well as reduced toxicity against human cells. b) Efficient synthetic strategy toward the synthesis of plusbacin A3, which is applicable to the synthesis of a range of analogues, has been developed. c) Total synthesis of quinaldopeptin has been developed via solid-phase synthesis. A range of analogues was synthesized and their antibacterial activity was evaluated to find a potent analogue with superior antibacterial activity than that of natural product.
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B), Hokkaido University, Principal investigator, Competitive research funding, 25293026

Development of Protein-Protein Interaction Inhibitors
Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research
01 Apr. 2013 - 31 Mar. 2015
ICHIKAWA SATOSHI
It is a quite important issue to develop a strategy for rational design of protein-protein interaction inhibitors (PPIs). In this study, a small library of PPIs with diverse structures was first designed and synthesized. We have found that several compounds inhibit a protein-protein interaction with a moderate activity. A larger set of library was further synthesized.
Japan Society for the Promotion of Science, Grant-in-Aid for Challenging Exploratory Research, Hokkaido University, 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)
01 Apr. 2012 - 31 Mar. 2014
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　　　　　　　　　　　　　　　
Apr. 2010 - Mar. 2013
市川 聡
Principal investigator, Competitive research funding

Development of novel antibacterial leads based on natural products
Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (A)
2010 - 2012
ICHIKAWA Satoshi
The caprazamycins (CPZs), muraymycins (MRYs), and mureidomycins (MRDs) which constitute a class of nucleoside natural products, exhibit excellent antimicrobial activity against. This work presents a total synthesis, systematic structure-activity relation-ship (SAR) study, and simplification of CPZs, MRYs, and MRDs. The analogues exhibited good activity against a range of Gram-positive bacterial pathogens, including MRSA and VRE. The oxazolidine analogues were developed through simplification of CPZs, and they exhibited antibacterial activity with a similar potency to the CPZs. Our SAR study of the CPZs and MRYs suggests a probable mechanism for inhibition of the MraY.
Japan Society for the Promotion of Science, Grant-in-Aid for Young Scientists (A), Hokkaido University, 22689004

Development of nucleic acid antibody with ADCC activity
Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research
2010 - 2011
ICHIKAWA Satoshi
First total synthesis of quinaldopeptin has been accomplished via solid-phase peptide synthesis. Namely, the linear decapeptide was sequentially cyclized and attached by chromophores to give quinaldopeptin. It was revealed that quinaldopeptin binds to double-stranded DNA with high affinity. Finally, quinaldopeptin was installed to the double-stranded DNA to afford a nucleic acid antibody with ADCC activity.
Japan Society for the Promotion of Science, Grant-in-Aid for Challenging Exploratory Research, Hokkaido University, 22659020

Studies of the novel chemotherapeutic drugs for herpesvirus infections
Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research on Innovative Areas (Research a proposed research project)
2008 - 2010
FUJIMURO Masahiro, ICHIKAWA Satoshi
Primary effusion lymphoma (PEL) is classified as non-Hodgkin's B-cell lymphoma associated with immunocompromised patients such as AIDS patients. PEL cells are universally infected with Kaposi's sarcoma-associated herpesvirus (KSHV). Previously, we had developed anti-tumor compounds, CNDAG and its derivatives, which induce apoptosis in PEL cells. To establish the effective treatment for PEL and KSHV infection, we have demonstrated the mechanisms of action of CNDAG and novel functions, namely anti-herpesviral activities. We furthermore identified sangivamycin, fullerene analogues and sodium valproate as new anti-PEL compounds.
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research on Innovative Areas (Research a proposed research project), University of Yamanashi, Principal investigator, Competitive research funding, 20200073

Rational Design of Small Molecules Modulating Protein-Protein Interaction
Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)
2008 - 2009
ICHIKAWA Satoshi
This study is to develop a stereoselective C-glycosylation reaction to give C-glycosides, which can be a key intermediate of oxabicyclo[n,2.1]system designed as a scaffold of small molecule protein-protein interaction inhibitors. Reactions of 2,3-O-(3-pentylidene)-D-ribofuranosyl fluoride with various allyltrimethylsilane derivatives exhibited excellent β-selectivity providing a range of β-C-allylribosides (β/α=>98/2). This strategy will provide a new concept to synthesize β-C-allylribosides, which are biologically relevant molecules such as small molecule protein-protein interaction inhibitors, by controlling the effect of steric hindrance in the transition state.
Japan Society for the Promotion of Science, Grant-in-Aid for Young Scientists (B), Hokkaido University, 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　　　　　　　　　　　　　　　
Apr. 2006 - Mar. 2008
市川 聡
Principal investigator, Competitive research funding

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 - 2007
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 - 2006
Competitive research funding

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 - 2005
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 - 2005
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 - 2003
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 - 1999
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　　　　　　　　　　　　　　　
Competitive research funding

核酸抗生物質誘導体
Patent right, 市川 聡, 松田 彰, 岡本 和也, 阪上 昌浩, 国立大学法人北海道大学, 塩野義製薬株式会社
特願2011-146098, 30 Jun. 2011
特開2014-177404, 25 Sep. 2014
201403048239111481

Muraymycin誘導体
Patent right, 市川 聡, 松田 彰, 谷野 哲也, 竹岡 裕輔, 国立大学法人北海道大学, 塩野義製薬株式会社
特願2012-252037, 16 Nov. 2012
特開2014-101276, 05 Jun. 2014
201403086444831127

抗ヘルペスウイルス活性を有するヌクレオシド誘導体
Patent right, 市川 聡, 藤室 雅弘, 松田 彰, 国立大学法人北海道大学
特願2008-510904, 30 Mar. 2007
特許第5070550号
31 Aug. 2012
201303023249510210

ヌクレオシド系抗生物質誘導体
Patent right, 松田 彰, 市川 聡, 国立大学法人北海道大学, 塩野義製薬株式会社
特願2009-049963, 03 Mar. 2009
特開2012-102019, 31 May 2012
201203053334533651

ヌクレオシド系抗生物質
Patent right, 松田 彰, 市川 聡, 国立大学法人北海道大学, 塩野義製薬株式会社
特願2009-043189, 25 Feb. 2009
特開2012-096997, 24 May 2012
201203060112676582

新規ピロロカルバゾールジオン化合物又はその塩
Patent right, 市川 聡, 佐古 友希, 松田 彰, 長田 亜希子, 松田 彰, 大鵬薬品工業株式会社
特願2008-276771, 28 Oct. 2008
特開2010-105920, 13 May 2010
201003038268241519

新規プリンダイマー化合物又はその塩、及びその用途
Patent right, 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, 26 Oct. 2007
特開2009-107939, 21 May 2009
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
Patent right, 市川 聡, 藤室 雅弘, 松田 彰, 国立大学法人 北海道大学
JP2007057206, 30 Mar. 2007
WO2007-119624, 25 Oct. 2007
200903094701573340