田邉 元三 (タナベ ゲンゾウ)

  • 薬学部 医療薬学科 教授
Last Updated :2024/03/01

コミュニケーション情報 byコメンテータガイド

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    インド、スリランカにおけるアーユルヴェーダ医学における糖尿病の特効天然薬物から単離された新奇チオ糖スルホニウム硫酸分子内塩、サラシノールの構造活性相関について研究しています。

研究者情報

学位

  • 薬学博士
  • 博士(薬学)(大阪大学)

ホームページURL

J-Global ID

研究キーワード

  • salacia   kotalanol   salacinol   α-glucosidase   salacia   kotalanol   salacinol   

現在の研究分野(キーワード)

    インド、スリランカにおけるアーユルヴェーダ医学における糖尿病の特効天然薬物から単離された新奇チオ糖スルホニウム硫酸分子内塩、サラシノールの構造活性相関について研究しています。

研究分野

  • ライフサイエンス / 薬系化学、創薬科学

所属学協会

  • 日本油化学会   日本薬学会   

研究活動情報

論文

  • Katsuki Takashima; Shinya Nakamura; Maiko Nagayama; Shinsuke Marumoto; Fumihiro Ishikawa; Weijia Xie; Isao Nakanishi; Osamu Muraoka; Toshio Morikawa; Genzoh Tanabe
    RSC Advances 14 7 4471 - 4481 2024年 
    In contrast to previous SAR studies of aza-compounds (23vs.24 and 25), the present study using analogues (26a–26c, 27c, and 28a–28c) of salacinol (1) revealed an essential role of the thiosugar ring in effectively inhibiting α-glucosidase.
  • Katsuki Takashima; Akane Asai; Mina Ashidate; Riko Suzuki; Shinsuke Marumoto; Fumihiro Ishikawa; Toshio Morikawa; Genzoh Tanabe
    Journal of Natural Products 86 12 2672 - 2684 2023年11月
  • Fumihiro Ishikawa*; Natsumi Tsukumo; Erika Morishita; Shumpei Asamizu; Shinsuke Marumoto; Katsuki Takashima; Hiroyasu Onaka; Genzoh Tanabe*
    Chem. Commun. DOI: 10.1039/D3CC02633G 59 62 9473 - 9476 2023年07月 
    We describe activity-based protein profiling for analyzing the adenylation domains of non-ribosomal peptide synthetases (ABPP-NRPS) in bacterial proteomes. Using a range of non-proteoinogenic amino acid sulfamoyladenosines, the competitive format of ABPP-NRPS provided substrate tolerance toward non-proteinogenic amino acids. When coupled with precursor-directed biosynthesis, a non-proteinogenic amino acid (O-allyl-L-serine) was successfully incorporated into gramicidin S.
  • Golam Iftakhar Khandakar; Yoichi Miyamoto; Ryosuke Satoh; Kenta Kishimoto; Mingzuo Xie; Mengyu Shih; Teruaki Takasaki; Genzoh Tanabe; Masahiro Oka; Reiko Sugiura
    Genes to cells : devoted to molecular & cellular mechanisms 2023年03月 [査読有り]
     
    The extracellular-signal-regulated-kinase (ERK) signaling pathway is essential for cell proliferation and is frequently deregulated in human tumors such as pancreatic cancers. ACAGT-007a (GT-7), an anti-cancer compound, stimulates ERK phosphorylation, thereby inducing growth inhibition and apoptosis in T3M4 pancreatic cancer cells. However, how GT-7 stimulates ERK phosphorylation and induces apoptosis in ERK-active T3M4 cells remains unclear. To look into the mechanism, we performed a spatiotemporal analysis of ERK phosphorylation mediated by GT-7 in T3M4 cells. The immunoblotting showed that GT-7 stimulates ERK phosphorylation within 1 hr, which was more remarkable after 2 hr. Importantly, apoptosis induction as evaluated by the cleaved Caspase-3 was observed only after 2 hr incubation with GT-7. The immunofluorescence staining revealed the enrichment of phosphorylated ERK (phospho-ERK) in the nucleus upon 1 hr incubation with GT-7. Fractionation experiments showed that GT-7 increases phospho-ERK levels in the cytoplasm within 1 hr, whereas nuclear phospho-ERK accumulation is observed after 2 hr incubation with GT-7. MEK inhibition by U0126 significantly diminishes nuclear phospho-ERK distribution and apoptosis induction stimulated by GT-7. Thus, GT-7 may initiate the induction of ERK phosphorylation in the cytoplasm, which leads to phospho-ERK enrichment in the nucleus. This nuclear phospho-ERK accumulation by GT-7 precedes and may underlie apoptosis induction in T3M4.
  • Exploring a chemical scaffold for rapid and selective photoaffinity labelling of non-ribosomal peptide synthetases in living bacterial cells
    Fumihiro Ishikawa; Sho Konno; Yuko Uchiyama; Hideaki Kakeya; Genzoh Tanabe
    Philos Trans R Soc Lond B Biol Sci 378 20220026  2023年02月 [査読有り]
  • Lu Lu; Jingyi Chen; Wenxiang Tao; Zhimei Wang; Dan Liu; Jiahui Zhou; Xiaoxing Wu; Haopeng Sun; Wei Li; Genzoh Tanabe; Osamu Muraoka; Bo Zhao; Liang Wu; Weijia Xie
    Journal of Medicinal Chemistry 66 5 3484 - 3498 2023年02月 [査読有り]
  • Fumiko Sekiguchi; Nene Koike; Yasuhiro Shimada; Kaho Sugimoto; Hiroshi Masuda; Takashi Nakamura; Hiroaki Yamaguchi; Genzoh Tanabe; Shinsuke Marumoto; Yoshihito Kasanami; Maho Tsubota; Tsuyako Ohkubo; Shigeru Yoshida; Atsufumi Kawabata
    Redox biology 59 102579 - 102579 2023年02月 [査読有り]
     
    Poly-trans-[(2-carboxyethyl)germasesquioxane] (Ge-132), an organogermanium, is hydrolyzed to 3-(trihydroxygermyl)propanoic acid (THGP) in aqueous solutions, and reduces inflammation, pain and cancer, whereas the underlying mechanisms remain unknown. Sulfides including H2S, a gasotransmitter, generated from l-cysteine by some enzymes including cystathionine-γ-lyase (CSE), are pro-nociceptive, since they enhance Cav3.2 T-type Ca2+ channel activity expressed in the primary afferents, most probably by canceling the channel inhibition by Zn2+ linked via coordinate bonding to His191 of Cav3.2. Given that germanium is reactive to sulfur, we tested whether THGP would directly trap sulfide, and inhibit sulfide-induced enhancement of Cav3.2 activity and sulfide-dependent pain in mice. Using mass spectrometry and 1H NMR techniques, we demonstrated that THGP directly reacted with sulfides including Na2S and NaSH, and formed a sulfur-containing reaction product, which decreased in the presence of ZnCl2. In Cav3.2-transfected HEK293 cells, THGP inhibited the sulfide-induced enhancement of T-type Ca2+ channel-dependent membrane currents. In mice, THGP, administered systemically or locally, inhibited the mechanical allodynia caused by intraplantar Na2S. In the mice with cyclophosphamide-induced cystitis and cerulein-induced pancreatitis, which exhibited upregulation of CSE in the bladder and pancreas, respectively, systemic administration of THGP as well as a selective T-type Ca2+ channel inhibitor suppressed the cystitis-related and pancreatitis-related visceral pain. These data suggest that THGP traps sulfide and inhibits sulfide-induced enhancement of Cav3.2 activity, leading to suppression of Cav3.2-dependent pain caused by sulfide applied exogenously and generated endogenously.
  • Katsuki Takashima; Miyu Teramachi; Shinsuke Marumoto; Fumihiro Ishikawa; Yoshiaki Manse; Toshio Morikawa; Genzoh Tanabe
    Bioorganic & Medicinal Chemistry Letters 78 129034 - 129034 2022年12月 [査読有り]
     
    Although 4,5-didehydroguadiscine (12a), an alkaloid with potent melanogenesis-inhibitory activity isolated from Hornschuchia obliqua (Annonaceae), consists of an aporphine nucleus with an aromatized B-ring, to date, it has not been utilized as a template for structure-activity relationship (SAR) studies of pharmacological activities because of its exceptional structure. Accordingly, herein, five analogs (12b-12f) of 12a and five benzylisoquinoline analogs (13b-13f) lacking the C11a-C11b bond of 12b-12f were prepared. The inhibitory effects of 12b-12f and 13b-13f on melanogenesis in theophylline-stimulated B16 melanoma 4A5 cells were examined and compared with those of 12a. Melanogenesis-inhibitory activities of 12b-12f were the same as that of 12a, whereas the melanogenesis-inhibitory activities of 13b-13f were significantly inferior to those of 12a and 12b-12f. These results suggest that the C11a-C11b bond plays an essential role in the melanogenesis-inhibitory activities of 12a-12e.
  • Fumihiro Ishikawa; Rina Ohnishi; Chiharu Uchida; Genzoh Tanabe
    STAR Protocols 3 3 101462 - 101462 2022年09月 [査読有り]
  • Ying Ding; Jingyi Chen; Dan Liu; Jiahui Zhou; Wenxiang Tao; Zhizhong Yang; Genzoh Tanabe; Osamu Muraoka; Weijia Xie
    Journal of Carbohydrate Chemistry 41 5 287 - 313 2022年06月 [査読有り]
  • Golam Iftakhar Khandakar; Ryosuke Satoh; Teruaki Takasaki; Kana Fujitani; Genzoh Tanabe; Kazuko Sakai; Kazuto Nishio; Reiko Sugiura
    Cells 11 4 702  2022年02月 [査読有り]
     
    The mitogen-activated protein kinase (MAPK)/ERK and phosphatidylinositol-3 kinase (PI3K)/AKT pathways are dysregulated in various human cancers, including pancreatic ductal adenocarcinoma (PDAC), which has a very poor prognosis due to its lack of efficient therapies. We have previously identified ACAGT-007a (GT-7), an anti-cancer compound that kills ERK-active melanoma cells by inducing ERK-dependent apoptosis. Here, we investigated the apoptosis-inducing effect of GT-7 on three PDAC cell lines and its relevance with the MAPK/ERK and PI3K/AKT signaling pathways. GT-7 induced apoptosis in PDAC cells with different KRAS mutations (MIA-Pa-Ca-2 (KRAS G12C), T3M4 (KRAS Q61H), and PANC-1 (KRAS G12D)), being T3M4 most susceptible, followed by MIA-Pa-Ca-2, and PANC-1 was most resistant to apoptosis induction by GT-7. GT-7 stimulated ERK phosphorylation in the three PDAC cells, but only T3M4 displayed ERK-activation-dependent apoptosis. Furthermore, GT-7 induced a marked down-regulation of AKT phosphorylation after a transient peak in T3M4, whereas PANC-1 displayed the strongest and most sustained AKT activation, followed by MIA-Pa-Ca-2, suggesting that sustained AKT phosphorylation as a determinant for the resistance to GT-7-mediated apoptosis. Consistently, a PI3K inhibitor, Wortmannin, abolished AKT phosphorylation and enhanced GT-7-mediated apoptosis in T3M4 and MIA-Pa-Ca-2, but not in PANC-1, which showed residual AKT phosphorylation. This is the first report that ERK stimulation alone or in combination with AKT signaling inhibition can effectively induce apoptosis in PDAC and provides a rationale for a novel concurrent targeting of the PI3K/AKT and ERK pathways.
  • Katsuki Takashima; Takuya Okada; Atsushi Kato; Yuhei Yamasaki; Takeshi Sugouchi; Shin‐ichi Akanuma; Yoshiyuki Kubo; Ken‐ichi Hosoya; Hiroyuki Morita; Takuya Ito; Takeshi Kodama; Genzoh Tanabe; Naoki Toyooka
    ChemistrySelect 7 5 e202104533  2022年02月 [査読有り]
     
    The divergent synthesis of cis-, 4a-epi-cis-, 2-epi-cis-, and trans-decahydroquinoline-type poison-frog alkaloids was achieved from the known chiral acetate 5 using a stereoselective Michael-type conjugate addition reaction and an intramolecular aldol-type cyclization with epimerization. The conformational control was achieved on the basis of the A1,3 strain in the starting material and the stereoelectronic effect. More specifically, the synthesis of cis-251 A, cis-209 J-1, cis-223F-1, 4a-epi-cis-251 A, 2-epi-cis-251 A, and trans-251 A bearing a seven-carbon chain at the α-position of the nitrogen atom on the piperidine nucleus was also realized. These compounds are expected to show selective and potent inhibitory activities toward nicotinic acetylcholine receptors.
  • Yu‐Ang Cui; Guang‐Yu Zhang; Yun‐Zhi Li; Wei Li; Genzoh Tanabe; Muraoka Osamu; Wei‐Jia Xie
    Asian Journal of Organic Chemistry 11 2 2022年02月 [査読有り]
  • Woojoo E. Kim; Fumihiro Ishikawa; Rebecca N. Re; Takehiro Suzuki; Naoshi Dohmae; Hideaki Kakeya; Genzoh Tanabe; Michael D. Burkart
    RSC Chemical Biology 3 3 312 - 319 2022年 [査読有り]
     
    Epimerization (E) domain mechanism in initiaion modules of NRPSs studied using pantetheine analog crosslinking probes containing sulfonyl warheads that target domain's catalytic residues (His and Glu).
  • Fumihiro Ishikawa; Sho Konno; Chiharu Uchida; Takehiro Suzuki; Katsuki Takashima; Naoshi Dohmae; Hideaki Kakeya; Genzoh Tanabe
    Cell Chemical Biology 29 1 145 - 156.e8 2022年01月 [査読有り]
     
    Much of our current knowledge on nonribosomal peptide synthetases (NRPSs) is based on studies in which the full NRPS system or each protein domain is expressed in heterologous hosts. Consequently, methods to detect the endogenous activity of NRPSs, under natural cellular conditions, are needed for the study of NRPS cell biology. Here, we describe the in vivo activity-based protein profiling (ABPP) for endogenous NRPSs and its applications to the study of their activities in bacteria. Remarkably, in vitro and in vivo ABPP in the context of the surfactin producer Bacillus subtilis enabled the visualization, tracking, and imaging of an endogenous SrfAB-NRPS with remarkable selectivity and sensitivity. Furthermore, in vivo, ABPP allowed the discovery of the degradation processes of the endogenous SrfAB-NRPS in the context of its native producer bacteria. Overall, this study deepens our understanding of the properties of NRPSs that cannot be addressed by conventional methods.
  • Fumihiro Ishikawa; Sho Konno; Katsuki Takashima; Hideaki Kakeya; Genzoh Tanabe
    Organic & biomolecular chemistry 19 41 8906 - 8911 2021年10月 [査読有り]
     
    A major challenge in fluorescence imaging experiments, which are essential to determine protein activity, expression, and localization, is the penetration of small-molecule probes through the outer membrane permeability barrier of bacteria. Here, we describe a novel strategy for small-molecule probe-based fluorescence protein labeling and imaging in the Gram-negative bacterium Escherichia coli. We targeted a siderophore enterobactin biosynthetic enzyme EntE in E. coli. When coupled with an efflux pump inhibitor carbonyl cyanide m-chlorophenylhydrazone, small-molecule probes were able to efficiently enter the cells, leading to the fluorescence labeling and imaging of overproduced EntE in E. coli. This study demonstrates that the combination of small-molecule probes with appropriate efflux pump inhibitors may substantially enhance their interaction with the target proteins in live bacteria.
  • Toshio Morikawa; Kiyofumi Ninomiya; Genzoh Tanabe; Hisashi Matsuda; Masayuki Yoshikawa; Osamu Muraoka
    Journal of natural medicines 75 3 449 - 466 2021年04月 [査読有り]
     
    During our studies characterizing functional substances from food resources for the prevention and treatment of lifestyle-related diseases, we isolated the active constituents, salacinol (1) and neokotalanol (4), and related thiosugar sulfoniums, from the roots and stems of the genus Salacia plants [Celastraceae (Hippocrateaceae)] such as Salacia reticulata Wight, S. oblonga Wall., and S. chinensis L., and observed their antidiabetic effects. These plant materials have been used traditionally in Ayurvedic medicine as a specific remedy at the early stage of diabetes, and have been extensively consumed in Japan, the United States, and other countries as a food supplement for the prevention of obesity and diabetes. Here, we review our studies on the antidiabetic effects of plants from the genus Salacia, from basic chemical and pharmacological research to their application and development as new functional food ingredients.
  • Fumitaka Kudo; Sotaro Takahashi; Akimasa Miyanaga; Yuichiro Nakazawa; Kota Nishino; Yuki Hayakawa; Koichi Kawamura; Fumihiro Ishikawa; Genzoh Tanabe; Naeko Iwai; Yoko Nagumo; Takeo Usui; Tadashi Eguchi
    ACS chemical biology 16 3 539 - 547 2021年03月 [査読有り]
     
    Hitachimycin is a macrolactam antibiotic with an (S)-β-phenylalanine (β-Phe) at the starter position of its polyketide skeleton. (S)-β-Phe is formed from l-α-phenylalanine by the phenylananine-2,3-aminomutase HitA in the hitachimycin biosynthetic pathway. In this study, we produced new hitachimycin analogs via mutasynthesis by feeding various (S)-β-Phe analogs to a ΔhitA strain. We obtained six hitachimycin analogs with F at the ortho, meta, or para position and Cl, Br, or a CH3 group at the meta position of the phenyl moiety, as well as two hitachimycin analogs with thienyl substitutions. Furthermore, we carried out a biochemical and structural analysis of HitB, a β-amino acid-selective adenylation enzyme that introduces (S)-β-Phe into the hitachimycin biosynthetic pathway. The KM values of the incorporated (S)-β-Phe analogs and natural (S)-β-Phe were similar. However, the KM values of unincorporated (S)-β-Phe analogs with Br and a CH3 group at the ortho or para position of the phenyl moiety were high, indicating that HitB functions as a gatekeeper to select macrolactam starter units during mutasynthesis. The crystal structure of HitB in complex with (S)-β-3-Br-phenylalanine sulfamoyladenosine (β-m-Br-Phe-SA) revealed that the bulky meta-Br group is accommodated by the conformational flexibility around Phe328, whose side chain is close to the meta position. The aromatic group of β-m-Br-Phe-SA is surrounded by hydrophobic and aromatic residues, which appears to confer the conformational flexibility that enables HitB to accommodate the meta-substituted (S)-β-Phe. The new hitachimycin analogs exhibited different levels of biological activity in HeLa cells and multidrug-sensitive budding yeast, suggesting that they may target different molecules.
  • Ryoya Iioka; Kohei Yorozu; Yoko Sakai; Rika Kawai; Noriyuki Hatae; Katsuki Takashima; Genzoh Tanabe; Hiroaki Wasada; Mitsuhiro Yoshimatsu
    EUROPEAN JOURNAL OF ORGANIC CHEMISTRY 2021 10 1553 - 1558 2021年03月 [査読有り]
     
    Lewis acid-catalyzed [6+1] annulation reactions of 2-cyano-1-propargyl- and 2-alkynyl-1-cyanomethyl-indoles with Reformatsky reagent are described. 8-Aryl, 8-alkyl-, 8-hetaryl-, 9-aryl, and 9-alkyl-azepino[1,2-a]indole amines were obtained through a 7-endo-mode cyclization of the beta-aminoacrylate intermediates. The antiproliferative activity of the azepino[1,2-a]indoles analogs against the HCT-116 cells were also examined.
  • Katsuki Takashima; Mika Sakano; Eri Kinouchi; Shinya Nakamura; Shinsuke Marumoto; Fumihiro Ishikawa; Kiyofumi Ninomiya; Isao Nakanishi; Toshio Morikawa; Genzoh Tanabe
    Bioorganic & medicinal chemistry letters 33 127751 - 127751 2021年02月 [査読有り]
     
    Four chain-extended analogs (12a-12d) and two related de-O-sulfonated analogs (13a and 13c) by introducing alkyl groups (a: R = C3H7, b R = C6H13, c: R = C8H17, d: R = C10H21) to the side chains of salacinol (1), a natural α-glucosidase inhibitor from Ayurvedic traditional medicine "Salacia", were synthesized. The α-glucosidase inhibitory activities of all the synthesized analogs were evaluated in vitro. Against human intestinal maltase, the inhibitory activities of 12a and 13a with seven-carbon side chain were equal to that of 1. In contrast, analogs (12b-12d, and 13c) exhibited higher level of inhibitory activity against the same enzyme than 1 and had equal or higher potency than those of the clinically used anti-diabetics, voglibose, acarbose, and miglitol. Thus, elongation of the side chains of 1 was effective for specifically increasing the inhibitory activity against human intestinal maltase.
  • Ligand compatibility of salacinol-type -glucosidase inhibitors toward family GH31.
    Fumihiro Ishikawa; Aiko Hirano; Yuuto Yoshimori; Kana Nishida; Shinya Nakamura; Katsuki Takashima; Shinsuke Marumoto; Kiyofumi Ninomiya; Isao Nakanishi; Weijia Xie; Toshio Morikawa; Osamu Muraoka; Genzoh Tanabe
    RSC Adv. 11 3221 - 3225 2021年01月 [査読有り]
  • Fumihiro Ishikawa; Hinano Kitayama; Shinya Nakamura; Katsuki Takashima; Isao Nakanishi; Genzoh Tanabe
    Chemical & pharmaceutical bulletin 69 2 222 - 225 2021年 [査読有り]
     
    The gatekeeping adenylation (A) domain of the non-ribosomal peptide synthetase (NRPS) selectively incorporates specific proteinogenic/non-proteinogenic amino acid into a growing peptide chain. The EntE of the enterobactin NRPS is a discrete aryl acid A-domain with 2,3-dihydroxybenzoic acid (DHB) substrate specificity. Reprogrammed EntE N235G variant possesses an enlarged substrate recognition site, and is capable of accepting non-native aryl acids. Biochemical characterization of this unique substrate recognition site should provide a better understanding of activi-site microenvironments. Here, we synthesized a non-hydrolysable adenylate analogue with 2-aminobenzoic acid (2-ABA), 3-aminobenzoic acid (3-ABA), and 4-aminobenzoic acid (4-ABA) and used them to calculate the apparent inhibition constants (Kiapp.). Dose-response experiments using 3-ABA-sulfamoyladenosine (AMS) provided Kiapp. values of 596 nM for wild-type EntE and 2.4 nM for the N235G variants. These results suggest that 3-amino group of benzoic acid plays an important role in substrate recognition by the N235G variant. These findings would help designing aryl acid substrates with substituents at the 2- and 3-positions.
  • Yuki Kanda; Ayami Mizuno; Teruaki Takasaki; Ryosuke Satoh; Kanako Hagihara; Takashi Masuko; Yuichi Endo; Genzoh Tanabe; Reiko Sugiura
    Genes to Cells 26 2 109 - 116 2020年11月 [査読有り]
  • Ryosuke Satoh; Naoya Hamada; Ami Yamada; Yuki Kanda; Fumihiro Ishikawa; Teruaki Takasaki; Genzoh Tanabe; Reiko Sugiura
    Bioorganic chemistry 103 104137 - 104137 2020年07月 [査読有り]
     
    The recent discovery that an ERK signaling modulator [ACA-28 (2a)] preferentially kills human melanoma cell lines by inducing ERK-dependent apoptosis has generated significant interest in the field of anti-cancer therapy. In the first SAR study on 2a, here, we successfully developed candidates (2b, 2c) both of which induce more potent and selective apoptosis towards ERK-active melanoma cells than 2a, thus revealing the structural basis for inducing the ERK-dependent apoptosis and proposing the therapeutic prospect of these candidates against ERK-dependent cancers represented by melanoma.
  • Probing the compatibility of an enzyme-linked immunosorbent assay toward the reprogramming of nonribosomal peptide synthetase adenylation domains
    Fumihiro Ishikawa; Maya Nohara; Katsuki Takashima; Genzoh Tanabe
    ChemBioChem, DOI: 10.1002/cbic.2000206 2020年06月 [査読有り]
  • Fumihiro Ishikawa; Maya Nohara; Shinya Nakamura; Isao Nakanishi; Genzoh Tanabe
    Biochemistry DOI: 10.1021/acs.biochem.9b00748 59 4 351 - 363 2020年01月 [査読有り]
     
    Aryl acids are most commonly found in iron-scavenging siderophores but are not limited to them. The nonribosomal peptide synthetase (NRPS) codes of aryl acids remain poorly elucidated relative to those of amino acids. Here, we defined more precisely the role of active-site residues in aryl acid adenylation domains (A-domains) by gradually grafting the NRPS codes used for salicylic acid (Sal) into an archetypal aryl acid A-domain, EntE [specific for the substrate 2,3-dihydroxybenzoic acid (DHB)]. Enzyme kinetics and modeling studies of these EntE variants demonstrated that the NRPS code residues at positions 236, 240, and 339 collectively regulate the substrate specificity toward DHB and Sal. Furthermore, the EntE variants exhibited the ability to activate the non-native aryl acids 3-hydroxybenzoic acid, 3-aminobenzoic acid, 3-fluorobenzoic acid, and 3-chlorobenzoic acid. These studies enhance our knowledge of the NRPS codes of aryl acids and could be exploited to reprogram aryl acid A-domains for non-native aryl acids.
  • Chemical strategies for visualizing and analyzing endogenous non ribosomal peptide synthetase (NRPS) megasynthetases
    Fumihiro Ishikawa; Genzoh Tanabe
    ChemBioChem DOI: 10.1002/cbic.201900186 2019年05月 [査読有り]
  • Synthesis of thiazinoimidazoles by lewis acid-catalyzed [3+3] cycloaddition reactions of propargyl alcohols with 2-mercaptoimidazoles
    N. Mishima; T. Ogawa; G. Tanabe; O. Muraoka; H. Wasada; N. Hatae; M. Yoshimatsu
    Eur. J. Org. Chem. 3117 - 3121 2019年05月 [査読有り]
  • F. Ishikawa; A. Miyanaga; H. Kitayama; S. Nakamura; I. Nakanishi; F. Kudo; T. Eguchi; G. Tanabe
    Angew. Chem. Int. Ed. 58 21 6906 - 6910 2019年05月 [査読有り]
     
    Adenylation (A) domains act as the gatekeepers of non-ribosomal peptide synthetases (NRPSs), ensuring the activation and thioesterification of the correct amino acid/aryl acid building blocks. Aryl acid building blocks are most commonly observed in iron-chelating siderophores, but are not limited to them. Very little is known about the reprogramming of aryl acid A-domains. We show that a single asparagine-to-glycine mutation in an aryl acid A-domain leads to an enzyme that tolerates a wide range of non-native aryl acids. The engineered catalyst is capable of activating non-native aryl acids functionalized with nitro, cyano, bromo, and iodo groups, even though no enzymatic activity of wild-type enzyme was observed toward these substrates. Co-crystal structures with non-hydrolysable aryl-AMP analogues revealed the origins of this expansion of substrate promiscuity, highlighting an enlargement of the substrate binding pocket of the enzyme. Our findings may be exploited to produce diversified aryl acid containing natural products and serve as a template for further directed evolution in combinatorial biosynthesis.
  • Ishikawa F; Miyanaga A; Kitayama H; Nakamura S; Nakanishi I; Kudo F; Eguchi T; Tanabe G
    Angewandte Chemie (International ed. in English) 58 21 6906 - 6910 2019年04月 [査読有り]
     
    Adenylation (A) domains act as the gatekeepers of non-ribosomal peptide synthetases (NRPSs), ensuring the activation and thioesterification of the correct amino acid/aryl acid building blocks. Aryl acid building blocks are most commonly observed in iron-chelating siderophores, but are not limited to them. Very little is known about the reprogramming of aryl acid A-domains. We show that a single asparagine-to-glycine mutation in an aryl acid A-domain leads to an enzyme that tolerates a wide range of non-native aryl acids. The engineered catalyst is capable of activating non-native aryl acids functionalized with nitro, cyano, bromo, and iodo groups, even though no enzymatic activity of wild-type enzyme was observed toward these substrates. Co-crystal structures with non-hydrolysable aryl-AMP analogues revealed the origins of this expansion of substrate promiscuity, highlighting an enlargement of the substrate binding pocket of the enzyme. Our findings may be exploited to produce diversified aryl acid containing natural products and serve as a template for further directed evolution in combinatorial biosynthesis.
  • Facile synthesis of neokotalanol, a potent α-glycosidase inhibitor isolated from the Ayurvedic traditional medicine “Salacia”.
    G. Tanabe; S. Ueda; K. Kurimoto; N. Sonoda; S. Marumoto; F. Ishikawa; W. Xie; O. Muraoka
    ACS Omega 4 7533 - 7533 2019年04月 [査読有り]
  • Design, synthesis and biological evaluation of nitrate derivatives of sauropunol A and B as potent vasodilatory agents
    L. Lu; X. Rao; R. Cong; C. Zhang; Z. Wang; J. Xu; G. Tanabe; O. Muraoka; X. Wu; W. Xie
    Molecules 24 583  2019年02月 [査読有り]
  • Practical route to neokotalanol and its natural analogues: sulfonium sugars with antidiabetic activities.
    Y. Huang; Y. Gao; W. He; Z. Wang; W. Li; Z. Wang; W. Li; A. Lin; G. Tanabe; O. Muraoka; X. Wu; W. Xie
    Angew. Chem. Int. Ed. 58 6400 - 6404 2019年02月 [査読有り]
  • T. Go; A. Morimatsu; H. Wasada; G. Tanabe; O. Muraoka; Y. Sawada; M. Yoshimatsu
    Beilstein J. Org. Chem. 14 2722 - 2729 2018年10月 [査読有り]
     
    A unique 1,7-S- and Se-shift reaction under Pummerer reaction conditions of 4-alkenyl-3-sulfinyl- and seleninylpyrroles was described. The usual Pummerer reaction of 4-(alkenylaminomethyl)-3-phenylsulfinylpyrroles and a successive reaction with tetrabutylammonium hydroxide (TBAH) yielded either pyrrolo[3,2-c]azepines or N-pyrrol-3-ylmethyl-N-(4-hydroxy-3-sulfanylpropyl)-p-toluenesulfonamides (diols). Seleno-Pummerer reactions of 3-selanylmethylpyrroles also proceeded via in situ generation of selenoxides, followed by a treatment with TBAH.
  • Synthesis of salacinol-d4 as an internal standard for mass-spectrometric quantitation of salacinol, a potent a-glucosidase inhibitor found in a traditional Ayurvedic medicine “Salacia”
    G. Tanabe; S. Teramae; Y.e Kunikata; S. Marumoto; S. Okugawa; F. Ishikawa; W. Xie; T. Morikawa; O. Muraoka
    Heterocycles 97 314 - 332 2018年09月 [査読有り]
  • タイ天然薬物Melodorum fruticosum花部含有butenolideの一酸化窒素産生抑制活性
    二宮 清文; 坂本 裕介; 田邉 元三; 村岡 修; 森川 敏生
    日本生薬学会年会講演要旨集 65回 244 - 244 (一社)日本生薬学会 2018年08月 [査読有り]
  • Expanding the Scope of Functionalized Small Nonprotein Components for Holoabzyme 27C1
    F. Ishikawa; M. Shirahashi; H. Hayakawa; G. Tanabe; T. Tsumuraya; I. Fujii
    ChemistrySelect 3 9313 - 9317 2018年08月 [査読有り]
  • A. Miyanaga; R. Ouchi; F. Ishikawa; E. Goto; G. Tanabe; F. Kudo; T. Eguchi
    J. Am. Chem. Soc. 140 25 7970 - 7978 2018年06月 [査読有り]
     
    Acyltransferases (ATs) are responsible for the selection and incorporation of acyl building blocks in the biosynthesis of various polyketide natural products. The trans-AT modular polyketide synthases have a discrete trans-acting AT for the loading of an acyl unit onto the acyl carrier protein (ACP) located within each module. Despite the importance of protein-protein interactions between ATs and ACPs in trans-AT assembly lines, the dynamic actions of ACPs and trans-acting ATs remain largely uncharacterized because of the inherently transient nature of ACP-enzyme interactions. Herein, we report the crystal structure of the AT-ACP complex of disorazole trans-AT polyketide synthase. We used a bromoacetamide pantetheine cross-linking probe in combination with a Cys mutation to trap the transient AT-ACP complex, allowing the determination of the crystal structure of the disorazole AT-ACP complex at 2.03 Å resolution. On the basis of the cross-linked AT-ACP complex structure, ACP residues recognized by trans-acting AT were identified and validated by mutational studies, which demonstrated that the disorazole AT recognizes the loop 1 and helix III′ residues of disorazole ACP. The disorazole AT-ACP complex structure presents a foundation for defining the dynamic processes associated with trans-acting ATs and provides detailed mechanistic insights into their ability to recognize ACPs.
  • Qi Miao; Yunzhi Li; Jinyi Xu; Aijun Lin; Genzoh Tanabe; Osamu Muraoka; Xiaoming Wu; Weijia Xie
    European Journal of Organic Chemistry 2018 12 1443 - 1448 2018年03月 [査読有り]
     
    Syntheses of amorfrutin C, a natural product with potent antitumor activity, as well as pseudo-amorfrutin A were accomplished. Protected 2,4-dihydroxybenzoic acid derivative 5 was used as a common synthetic intermediate. The introduction of a prenyl moiety to 5 was achieved through bromination followed by a CuCN-meditated alkylation reaction. Interestingly, N-bromosuccinimide promoted monobromination at the 6-position, leading to pseudo-amorfrutin A 1,3-dibromo-5,5-dimethylhydantoin triggered bromination at both the 6- and 8-positions, leading to naturally occurring amorfrutin C.
  • 4,5-ジデヒドロアポルフィン型アルカロイドの合成およびメラニン形成抑制活性評価
    白戸 美希; 萬瀬 貴昭; 二宮 清文; 丸本 真輔; 石川 文洋; 村岡 修; 森川 敏生; 田邉 元三
    日本薬学会年会要旨集 138年会 2 186 - 186 (公社)日本薬学会 2018年03月 [査読有り]
  • Wang Zihao; Huang Yuhao; Liu Dan; Xu Jinyi; Tanabe Genzoh; Muraoka Osamu; Wu Xiaoming; Xie Weijia
    Current Organic Chemistry 22 9 930 - 935 2018年 [査読有り]
     
    Background: Neoponkoranol is one of de-O-sulfonated sulfonium salts isolated from Genus Salacia showing potent inhibitory activities against α-glucosidases. In previously reported synthetic strategies, the two key coupling partners should be firstly constructed from different starting materials and the following coupling reaction is usually time-consuming. Thus, a more efficient and scalable synthetic protocol would be necessary for further SAR studies of this bioactive natural product. Objective: Based on our previous synthetic studies on this series of natural products, the aim of the present study is to develop a novel total synthesis of neoponkoranol in a divergent and efficient way starting from inexpensive commercially available D-glucose. This is the first report of gram-scale synthesis of neoponkoranol. Method and Results: Unlike all other reported strategies, the two coupling partners epoxide (14) and thiosugar (19) were firstly synthesized from an identical intermediate diol (12) which could be easily obtained in 3 steps from D-glucose. Notably, the construction of 14 and 19 could be achieved without any purification process. The subsequent acid mediated coupling reaction between resulted coupling partners was accomplished in only 4 hours while previous strategies usually took several days to complete the process. A gram-scale quantity of coupling reaction was then conducted under the same reacting condition and the desired sulfonium salt was isolated without any loss of the yield. Conclusion: The newly developed scalable synthesis of neoponkoranol provided a good opportunity for further pharmaceutical studies on this bioactive natural product.
  • Activity-based protein profiling of non-ribosomal peptide synthetases
    Fumihiro Ishikawa; Genzoh Tanabe; Hideaki Kakeya
    Curr. Top. Microbiol. Immunol. DOI: 10.1007/82_2018_133 2018年 [査読有り]
  • F. Ishikawa; K. Jinno; E. Kinouchi; K. Ninomiya; S. Marumoto; W. Xie; O. Muraoka; T. Morikawa; G. Tanabe
    J. Org. Chem. 83 1 185 - 193 2018年 [査読有り]
  • G. Tanabe; Y. Manse; T. Ogawa; N. Sonoda; S. Marumoto; F. Ishikawa; K. Ninomiya; S. Chaipech; Y. Pongpiriyadacha; O. Muraoka; T. Morikawa
    J. Org. Chem. 83 15 8250 - 8261 2018年 [査読有り]
  • D. Fu; X. Rao; J. Xu; G. Tanabe; O. Muraoka; X. Wu; W Xie
    Tetrahedron Lett. 59 2876 - 2879 2018年 [査読有り]
     
    The first total syntheses of naturally occurring cyclodepsipeptides Hikiamides A–C are described. The key linear pentapeptide precursors, prepared efficiently via Fmoc-solid-phase synthesis, were cyclized in dilute solution to provide the target Hikiamides A–C. The structures of the synthetic Hikiamides A–C were characterized by NMR and HRMS spectroscopy which were in agreement with those of natural products.
  • Fumihiro Ishikawa; Shota Kasai; Hideaki Kakeya; Genzoh Tanabe
    CHEMBIOCHEM 18 22 2199 - 2204 2017年11月 [査読有り]
     
    Structural and activity studies have revealed the dynamic and transient actions of carrier protein (CP) activity in primary and secondary metabolic pathways. CP-mediated interactions play a central role in nonribosomal peptide biosynthesis, as they serve as covalent tethers for amino acid and aryl acid substrates and enable the growth of peptide intermediates. Strategies are therefore required to study protein-protein interactions efficiently. Herein, we describe activity-based probes used to demonstrate the protein-protein interactions between aryl CP (ArCP) and aryl acid adenylation (A) domains as well as the substrate specificities of the aryl acid Adomains. If coupled with in-gel fluorescence imaging, this strategy allows visualization of the protein-protein interactions required to recognize and transfer the substrate to the partner ArCP. This technique has potential for the analysis of protein-protein interactions within these biosynthetic enzymes at the molecular level and for use in the combinatorial biosynthesis of new nonribosomal peptides.
  • Sho Konno; Fumihiro Ishikawa; Takehiro Suzuki; Naoshi Dohmae; Hideaki Kakeya; Genzoh Tanabe
    CHEMBIOCHEM 18 18 1855 - 1862 2017年09月 [査読有り]
     
    Phosphopantetheinylation is an essential post-translational protein modification to primary and secondary metabolic pathways that ensures bacterial cell viability and virulence, and it is used in the production of many pharmaceuticals. Traditional methods have not provided a comprehensive understanding of these modifications. By using chemical proteomic probes for adenylation and thiolation domains in nonribosomal peptide synthetases (NRPSs), chemoproteomics has been applied to survey and validate the cellular activity of 4-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-N-(4-methoxypyridin-2-yl)piperazine-1-carbothioamide (ML267), which is a potent and selective small-molecule 4-phosphopantetheinyl transferase (PPTase) inhibitor that attenuates secondary metabolism and viability of bacterial cells. ML267 inhibited Sfp-type PPTase and antagonized phosphopantetheinylation in cells, which resulted in a decrease in phosphopantetheinylated NRPSs and the attenuation of Sfp-PPTase-dependent metabolite production. These results indicate that this chemoproteomics platform should enable a precise interpretation of the cellular activities of Sfp-type PPTase inhibitors.
  • アーユルベーダ天然薬物 ”サラシア” 由来スルホニウム塩類のジアステレオ選択的合成及びin vivo α-グルコシダーゼ阻害活性評価
    石川 文洋; 神農 佳澄; 薗田 直樹; 木内 恵里; 赤木 淳二; 二宮 清文; 村岡 修; 吉川 雅之; 森川 敏生; 田邉 元三
    第59回天然有機化合物討論会講演要旨集 363 - 368 2017年08月 [査読有り]
  • Satoh Ryosuke; Hagihara Kanako; Matsuura Kazuki; Manse Yoshiaki; Kita Ayako; Kunoh Tatsuki; Masuko Takashi; Moriyama Mariko; Moriyama Hiroyuki; Tanabe Genzoh; Muraoka Osamu; Sugiura Reiko
    Genes to cells : devoted to molecular & cellular mechanisms 22 7 608-618  2017年07月 [査読有り]
     
    Here, we carried out a chemical genetic screen using a fission yeast phenotypic assay and showed that ACA-28, a synthetic derivative of 1'-acetoxychavicol acetate (ACA), which is a natural ginger compound, effectively inhibited the growth of melanoma cancer cells wherein ERK MAPK signaling is hyperactivated due to mutations in the upstream activating regulators. ACA-28 more potently inhibited the growth of melanoma cells than did the parental compound ACA. Importantly, the growth of normal human epidermal melanocytes (NHEM) was less affected by ACA-28 at the same 50% inhibitory concentration. In addition, ACA-28 specifically induced apoptosis in NIH/3T3 cells which were oncogenically transformed with human epidermal growth factor receptor-2 (HER2/ErbB2), but not in the parental cells. ACA-28 might serve as a promising seed compound for melanoma treatment.
  • Genzoh Tanabe; Nozomi Tsutsui; Kanae Shibatani; Shinsuke Marumoto; Fumihiro Ishikawa; Kiyofumi Ninomiya; Osamu Muraoka; Toshio Morikawa
    TETRAHEDRON 73 30 4481 - 4486 2017年07月 [査読有り]
     
    The first total syntheses of the geranylated pyranocoumarins, mameasins C (1) and D (2), aromatase inhibitors isolated from the flowers of Mammea siamensis, were accomplished in five steps, starting from phloroglucinol 3. In this strategy, the characteristic pyran ring-fused coumarin core of 1 and 2 was effectively constructed by Friedel-Crafts acylation of 3, followed by Reformatsky reaction of the resultant ketone to give a key coumarin intermediate 9. Compound 9 was converted to targets 1 and 2 in a stepwise manner by successive C-acylation and O-geranylation, followed by a [1,3]-sigmatropic geranyl shift. Furthermore, screening of intermediates obtained in the synthetic pathway to 1 and 2 revealed that de-geranylated pyranocoumarins (10 and 11) show superior aromatase inhibitory activity as compared to the natural products 1 and 2. (C) 2017 Elsevier Ltd. All rights reserved.
  • Ryosuke Satoh; Kanako Hagihara; Kazuki Matsuura; Yoshiaki Manse; Ayako Kita; Tatsuki Kunoh; Takashi Masuko; Mariko Moriyama; Hiroyuki Moriyama; Genzoh Tanabe; Osamu Muraoka; Reiko Sugiura
    GENES TO CELLS 22 7 608 - 618 2017年07月 [査読有り]
     
    The extracellular signal-regulated kinase (ERK) signaling pathway is essential for cell proliferation and is frequently deregulated in human tumors such as melanoma. Melanoma remains incurable despite the use of conventional chemotherapy; consequently, development of new therapeutic agents for melanoma is highly desirable. Here, we carried out a chemical genetic screen using a fission yeast phenotypic assay and showed that ACA-28, a synthetic derivative of 10-acetoxychavicol acetate (ACA), which is a natural ginger compound, effectively inhibited the growth of melanoma cancer cells wherein ERK MAPK signaling is hyperactivated due to mutations in the upstream activating regulators. ACA-28 more potently inhibited the growth of melanoma cells than did the parental compound ACA. Importantly, the growth of normal human epidermal melanocytes (NHEM) was less affected by ACA-28 at the same 50% inhibitory concentration. In addition, ACA-28 specifically induced apoptosis in NIH/3T3 cells which were oncogenically transformed with human epidermal growth factor receptor-2 (HER2/ErbB2), but not in the parental cells. Notably, the ACA-28-induced apoptosis in melanoma and HER2-transformed cells was abrogated when ERK activation was blocked with a specific MEK inhibitor U0126. Consistently, ACA-28 more strongly stimulated ERK phosphorylation in melanoma cells, as compared in NHEM. ACA-28 might serve as a promising seed compound for melanoma treatment.
  • Computational study on the comparative differences in the activity of inhibitors of human versus rat alpha-glucosidase
    Shinya Nakamura; Kazuko Shimada; Genzoh Tanabe; Osamu Muraoka; Isao Nakanishi
    Open Journal of Medicinal Chemistry 7 2 19 - 28 2017年06月 [査読有り]
  • S. Marumoto; R. Shimizu; G. Tanabe; Y. Okuno; M. Miyazawa
    Planta Med. 83 3-4 292 - 299 2017年02月 [査読有り]
     
    The metabolism of the norisoprenoid beta-ionone was investigated in vitro using human liver microsomes and 11 different recombinant cytochrome P450 enzymes expressed in Trichoplusia ni cells. beta-Ionone was found to be oxidized via 4S-hydroxylation by CYP2B6 in human liver microsomes. CYP1A2 also regioselectively catalyzed the hydroxylation of beta-ionone to yield 4-hydroxylation; this conversion was not stereoselective. Further kinetic analysis revealed that CYP2B6 exhibited the highest activity for beta-ionone 4-hydroxylation. Kinetic analysis showed that K-m and V-max for oxidation of beta-ionone by CYP1A2 and CYP2B6 was 107.9 +/- 36.0 mu M and 3200.3 +/- 323.0 nmol/min/nmol P450 and 5.6 +/- 1.2 mu M and 572.8 +/- 29.8 nmol/min/nmol P450, respectively. The reaction rates observed using human liver microsomes and recombinant CYP2B6 were very high compared with those of other CYP2B6 substrates reported thus far. These results suggest that beta-ionone, a norisoprenoid present in nature, is one of the effective substrates for CYP2B enzymes in human liver microsomes. To the best of our knowledge, this is the first time that 4-hydroxy beta-ionone has been described as a human metabolite of beta-ionone.
  • N. Tsutsui; G. Tanabe; N. Ikeda; S. Okamura; M. Ogawa; K. Miyazaki; A. Kita; R. Sugiura; O. Muraoka
    Eur. J. Med. Chem. 121 250 - 271 2016年10月 [査読有り]
     
    As part of an ongoing study on the structure-activity relationship of acremomannolipin A (1)-the novel glycolipid isolated from Acremonium strictum possessing potent calcium signal-modulating activity-the role of acyl substituents on the D-mannose moiety was examined. Three partially deacylated homologs (2a-2c) and 20 homologs (2d-2w) bearing different acyloxy side chains were synthesized via the stereoselective beta-mannosylation of appropriately protected mannosyl sulfoxides (3) with D-mannitol derivatives (4), and their calcium signal-modulating activities were examined. The activities of 2a-2c were completely lost. Homologs bearing relatively short acyloxy groups at C-3, C-4, and C-6 positions (2t-2v) exhibited less activity than 1, whereas a heptanoyl homolog (2w: C-7) maintained activity nearly equal to that of 1. When the acyl groups at these three positions were substituted by an octanoyl group (2i: C-8), the activity was completely lost. On the other hand, of the 10 homologs in which the octanoyl at C-2 was substituted by other acyloxy moieties (2j-2s), three (2m: C-7, 2n: C-9, 2o: C-10) maintained potent activity. These results suggested that peracylated mannose structure is critical for calcium signal modulating activity, and this activity is precisely dependent on the length of four acyl side chains on D-mannose. (C) 2016 Published by Elsevier Masson SAS.
  • Tomoya Takeda; Masanobu Tsubaki; Kotaro Sakamoto; Eri Ichimura; Aya Enomoto; Yuri Suzuki; Tatsuki Itoh; Motohiro Imano; Genzoh Tanabe; Osamu Muraoka; Hideaki Matsuda; Takao Satou; Shozo Nishida
    Toxicology and applied pharmacology 306 105 - 12 2016年09月 [査読有り]
     
    Advanced metastatic melanoma, one of the most aggressive malignancies, is currently without reliable therapy. Therefore, new therapies are urgently needed. Mangiferin is a naturally occurring glucosylxanthone and exerts many beneficial biological activities. However, the effect of mangiferin on metastasis and tumor growth of metastatic melanoma remains unclear. In this study, we evaluated the effect of mangiferin on metastasis and tumor growth in a mouse metastatic melanoma model. We found that mangiferin inhibited spontaneous metastasis and tumor growth. Furthermore, mangiferin suppressed the nuclear translocation of nuclear factor kappa B (NF-κB) and expression of phosphorylated NF-κB-inducing kinase (NIK), inhibitor of kappa B kinase (IKK), and inhibitor of kappa B (IκB) and increases the expression of IκB protein in vivo. In addition, we found that mangiferin inhibited the expression of matrix metalloproteinases (MMPs) and very late antigens (VLAs) in vivo. Mangiferin treatment also increased the expression of cleaved caspase-3, cleaved Poly ADP ribose polymerase-1 (PARP-1), p53 upregulated modulator of apoptosis (PUMA), p53, and phosphorylated p53 proteins, and decreased the expression of Survivin and Bcl-associated X (Bcl-xL) proteins in vivo. These results indicate that mangiferin selectivity suppresses the NF-κB pathway via inhibition of NIK activation, thereby inhibiting metastasis and tumor growth. Importantly, the number of reported NIK selective inhibitors is limited. Taken together, our data suggest that mangiferin may be a potential therapeutic agent with a new mechanism of targeting NIK for the treatment of metastatic melanoma.
  • G. Tanabe; W. Xie; G. Balakishan; M. F. A. Amer; N. Tsutsui; H. Takemura; S. Nakamura; J. Akaki; K. Ninomiya; T. Morikawa; I. Nakanishi; O. Muraoka
    Bioorg. Med. Chem. 24 16 3705 - 3715 2016年08月 [査読有り]
     
    Using an in silico method, seven analogs bearing hydrophobic substituents (8a: Me, 8b: Et, 8c: n-Pent, 8d: n-Hept, 8e: n-Tridec, 8f: isoBu and 8g: neoPent) at the 3'-O-position in salacinol (1), a highly potent natural alpha-glucosidase inhibitor from Ayurvedic traditional medicine 'Salacia', were designed and synthesized. In order to verify the computational SAR assessments, their alpha-glucosidase inhibitory activities were evaluated in vitro. All analogs (8a-8g) exhibited an equal or considerably higher level of inhibitory activity against rat small intestinal alpha-glucosidases compared with the original sulfonate (1), and were as potent as or higher in potency than the clinically used anti-diabetics, voglibose, acarbose or miglitol. Their activities against human maltase exhibited good relationships to the results obtained with enzymes of rat origin. Among the designed compounds, the one with a 3'-O-neopentyl moiety (8g) was most potent, with an approximately ten fold increase in activity against human maltase compared to 1. (C) 2016 Elsevier Ltd. All rights reserved.
  • Toshio Morikawa; Niichiro Kitagawa; Genzoh Tanabe; Kiyofumi Ninomiya; Shuhei Okugawa; Chiaki Motai; Iyori Kamei; Masayuki Yoshikawa; I-Jung Lee; Osamu Muraoka
    MOLECULES 21 7 931  2016年07月 [査読有り]
     
    A quantitative analytical method for five aporphine alkaloids, nuciferine (1), nornuciferine (2), N-methylasimilobine (3), asimilobine (4), and pronuciferine (5), and five benzylisoquinoline alkaloids, armepavine (6), norarmepavine (7), N-methylcoclaurine (8), coclaurine (9), and norjuziphine (10), identified as the constituents responsible for the melanogenesis inhibitory activity of the extracts of lotus flowers (the flower buds of Nelumbo nucifera), has been developed using liquid chromatography-mass spectrometry. The optimum conditions for separation and detection of these 10 alkaloids were achieved on a NAP column, a reversed-phase column with naphthylethyl group-bonded silica packing material, with CH3CN-0.2% aqueous acetic acid as the mobile phase and using mass spectrometry equipped with a positive-mode electrospray ionization source. According to the protocol established, distributions of these 10 alkaloids in the petal, receptacle, and stamen parts, which were separated from the whole flower, were examined. As expected, excellent correlations were observed between the total alkaloid content and melanogenesis inhibitory activity. Among the active alkaloids, nornuciferine (2) was found to give a carbamate salt (2) via formation of an unstable carbamic acid (2) by absorption of carbon dioxide from the air.
  • T. Takeda; M. Tsubaki; T. Kino; M. Yamagishi; M. Iida; T. Itoh; M. Imano; G. Tanabe; O. Muraoka; T. Satou; S. Nishida
    Int. J. Oncol. 48 6 2704 - 12 2016年06月 [査読有り]
     
    Multiple myeloma (MM) is still an incurable hematological malignancy with a 5-year survival rate of ~35%, despite the use of various treatment options. The nuclear factor κB (NF-κB) pathway plays a crucial role in the pathogenesis of MM. Thus, inhibition of the NF-κB pathway is a potential target for the treatment of MM. In a previous study, we showed that mangiferin suppressed the nuclear translocation of NF-κB. However, the treatment of MM involves a combination of two or three drugs. In this study, we examined the effect of the combination of mangiferin and conventional anticancer drugs in an MM cell line. We showed that the combination of mangiferin and an anticancer drug decreased the viability of MM cell lines in comparison with each drug used separately. The decrease in the combination of mangiferin and an anticancer drug induced cell viability was attributed to increase the expression of p53 and Noxa and decreases the expression of XIAP, survivin, and Bcl-xL proteins via inhibition of NF-κB pathway. In addition, the combination treatment caused the induction of apoptosis, activation of caspase-3 and the accumulation of the cells in the sub-G1 phase of the cell cycle. Our findings suggest that the combination of mangiferin and an anticancer drug could be used as a new regime for the treatment of MM.
  • Tomoya Takeda; Masanobu Tsubaki; Toshiki Kino; Misa Yamagishi; Megumi Iida; Tatsuki Itoh; Motohiro Imano; Genzoh Tanabe; Osamu Muraoka; Takao Satou; Shozo Nishida
    Chemico-biological interactions 251 26 - 33 2016年05月 [査読有り]
     
    Mangiferin is a naturally occurring glucosyl xanthone, which induces apoptosis in various cancer cells. However, the molecular mechanism underlying mangiferin-induced apoptosis has not been clarified thus far. Therefore, we examined the molecular mechanism underlying mangiferin-induced apoptosis in multiple myeloma (MM) cell lines. We found that mangiferin decreased the viability of MM cell lines in a concentration-dependent manner. We also observed an increased number of apoptotic cells, caspase-3 activation, and a decrease in the mitochondrial membrane potential. In addition, mangiferin inhibited the nuclear translocation of nuclear factor kappa B (NF-κB) and expression of phosphorylated inhibitor kappa B (IκB) and increased the expression of IκB protein, whereas no changes were observed in the phosphorylation levels of extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal protein kinase 1/2 (JNK1/2), and mammalian target of rapamycin (mTOR). The molecular mechanism responsible for mangiferin-induced inhibition of nuclear translocation of NF-κB was a decrease in the expression of phosphorylated NF-κB-inducing kinase (NIK). Moreover, mangiferin decreased the expression of X-linked inhibitor of apoptosis protein (XIAP), survivin, and Bcl-xL proteins. Knockdown of NIK expression showed results similar to those observed with mangiferin treatment. Our results suggest that mangiferin induces apoptosis through the inhibition of nuclear translocation of NF-κB by suppressing NIK activation in MM cell lines. Our results provide a new insight into the molecular mechanism of mangiferin-induced apoptosis. Importantly, since the number of reported NIK inhibitors is limited, mangiferin, which targets NIK, may be a potential anticancer agent for the treatment of MM.
  • G. Tanabe; Y. Matsuda; M. Oka; Y. Kunikata; N. Tsutsui; W. Xie; G. Balakishan; M. F. A. Amer; S. Marumoto; O. Muraoka
    J. Org. Chem. 81 8 3407 - 3415 2016年04月 [査読有り]
     
    A facile and highly diastereoselective route to potent natural a-glucosidase inhibitors, i.e., neosalacinol (4) and neoponkoranol (6), isolated from the traditional Ayurvedic medicine "Salacia" was developed by intramolecular cyclization of appropriately substituted sulfides (9 and 12).
  • D. Liu; W. He; Z. Wang; L. Liu; C. Wang; C. Zhang; C. Wang; Y. Wang; G. Tanabe; O. Muraoka; X. Wu; L. Wu; W. Xie
    Eur. J. Med. Chem 110 224 - 236 2016年03月 [査読有り]
     
    A group of 3'-epi-neoponkoranol analogs with different hydrophobic substituents attached at 3'-position of side chain moiety were designed and synthesized in order to further improve the inhibitory activities against alpha-glucosidases. Biological evaluation of these compounds revealed that sulfonium salts attached with ortho-substituted benzyl groups showed best alpha-glucosidase inhibitory activities. The most potent compound 10i showed greater inhibitory activities than all natural products. Moreover, docking studies on 10i with ntMGAM presented a new binding mode, indicating that amino residue Asp542 should be the key interacting point for strong inhibitory activity of small molecules against alpha-glucosidase enzymes. The strongest alpha-glucosidase inhibitory activity of 10i could be rationalized by van der Waals interactions between the 3'-attached substituent and particularly the ortho-substituted trifluoromethyl on benzyl group with the adjacent hydrophobic amino residues. Cytotoxicity evaluation assay demonstrated a high level of safety profile of the synthesized sulfonium salts against normal cell line. The enzyme kinetic studies showed a fully competitive inhibition of these sulfonium salts on each alpha-glucosidase. (C) 2016 Elsevier Masson SAS. All rights reserved.
  • Yoshimatsu Mitsuhiro; Tanaka Miki; Fujimura Yu; Ito Yukiteru; Goto Yusuke; Kobayashi Yuka; Wasada Hiroaki; Hatae Noriyuki; Tanabe Genzoh; Muraoka Osamu
    The Journal of organic chemistry 80 19 9480 - 9494 2015年10月 [査読有り]
     
    A protocol for the direct synthesis of azepines using a hafnium(III)-catalyzed [6 + 1]annulation of N-tetheredynenitriles with Reformatsky reagents is reported. A broad range of 3-amino-2,7-dihydro-1H-azepine-4-carboxylates 4aa-4he were obtained in high yields and with excellent functional group tolerance. The copper-mediated reactions of isolable Blaise intermediates (enamino esters 3), uniquely underwent 5-endo cyclization to afford the β-2,5-dihydropyrrolyl α,β-unsaturated esters 5aa-5fc, which exhibit anticancer activity.
  • Mitsuhiro Yoshimatsu; Miki Tanaka; Yu Fujimura; Yukiteru Ito; Yusuke Goto; Yuka Kobayashi; Hiroaki Wasada; Noriyuki Hatae; Genzoh Tanabe; Osamu Muraoka
    JOURNAL OF ORGANIC CHEMISTRY 80 19 9480 - 9494 2015年10月 [査読有り]
     
    A protocol for the direct synthesis of azepines using a hafnium(III)-catalyzed [6 + 1] annulation of N-tethered ynenitriles with Reformatsky reagents is reported. A broad range of 3-amino-2,7-dihydro-1H-azepine-4-carboxylates 4aa-4he were obtained in high yields and with excellent functional group tolerance. The copper-mediated reactions of isolable Blaise intermediates (enamino esters 3), uniquely underwent beta-endo cydization to afford the beta-2,5-dihydropyrrolyl alpha,beta-unsaturated esters 5aa-5fc, which exhibit anticancer activity.
  • Nozomi Tsutsui; Genzoh Tanabe; Nao Morita; Yoshitomo Okayama; Ayako Kita; Reiko Sugiura; Osamu Muraoka
    BIOORGANIC & MEDICINAL CHEMISTRY 23 13 3761 - 3773 2015年07月 [査読有り]
     
    Five homologs of a novel glycolipid acremomannolipin A (1a), the potential Ca2+ signal modulator isolated from Acremonium strictum, bearing alditols of different length (1g-1k) were synthesized by a stereoselective beta-mannosylation of appropriately protected mannosyl sulfoxide (2) with five alditols (1g: C2, 1h: C3, 1i: C4, 1j: C5 and 1k: C7 units), and their potential in modulating Ca2+ signaling were evaluated. Homologs with alditols of more than 4 carbons (1i, 1j and 1k) were equally or more potent than the parent compound (1a) regardless of the length of the alditol chain. Whereas activities of two homologs with shorter chains (1g and 1h) decreased to a considerable extent. The results indicated that the length of the alditol side chain was a crucial determinant for the potent calcium signal modulating activity. (C) 2015 Elsevier Ltd. All rights reserved.
  • Genzoh Tanabe; Youta Sugano; Miki Shirato; Naoki Sonoda; Nozomi Tsutsui; Toshio Morikawa; Kiyofumi Ninomiya; Masayuki Yoshikawa; Osamu Muraoka
    JOURNAL OF NATURAL PRODUCTS 78 7 1536 - 1542 2015年07月 [査読有り]
     
    The first total Synthesis of the 7,7-dimethylaporphinoid, 4,5-didehydroguadiscine (6), originally isolated from the stems and roots of Hornschuchia oblique (Annonaceae), was achieved by the condensation of homopiperonylamine (7) with an alpha,alpha-dimethylphenylacetic acid derivative (8) and subsequent Pschorr reaction of the resulting benzylisoquinoline intermediate (22). The reported C-13 NMR data were partially revised on the basis of the analysis of HMBC spectra measured under different conditions. The melanogenesis inhibitory activity (IC50 = 4.7 mu M) of 6 was 40 times stronger than that of arbutin (174 mu M), which was used as reference standard. Furthermore, 6 was the most potent natural melanogenesis inhibitor Within this class of compounds.
  • Toshio Morikawa; Junji Akaki; Kiyofumi Ninomiya; Eri Kinouchi; Genzoh Tanabe; Yutana Pongpiriyadacha; Masayuki Yoshikawa; Osamu Muraoka
    NUTRIENTS 7 3 1480 - 1493 2015年03月 [査読有り]
     
    The antidiabetic effect of a hot water extract of stems of Salacia chinensis (SCE) was evaluated in vivo in KK-A(y) mice, a typical type 2 diabetes mellitus mice model. Administration of CE-2 dietary feed containing 0.25 and/or 0.50% of SCE for three weeks to KK-A(y) mice significantly suppressed the elevation of both blood glucose and HbA1c levels without significant changes in body weight or food intake. Glucose tolerance was improved by administration to KK-A(y) mice for 27 days of AIN93M purified dietary feed containing 0.12% of SCE. No suppressive effect with respect to HbA1c level was observed when AIN93M/Glc dietary feed in which all digestible glucides were replaced with glucose was administered with SCE. Thus, alpha-glucosidase inhibitory activity approved as the mechanism of action of the antidiabetic effect of SCE by in vitro investigation was reconfirmed also in in vivo studies. Evaluation of the alpha-glucosidase inhibitory activity of the active constituents, salacinol (1), kotalanol (3), and neokotalanol (4), by employing human alpha-glucosidases revealed that these compounds inhibited them as potently (IC50 = 3.9-4.9 mu M for maltase) as they inhibited rat small intestinal alpha-glucosidase. The principal sulfonium constituents (1-4) were highly stable in an artificial gastric juice. In addition, 1-4 were hardly absorbed from the intestine in an experiment using the in situ rat ligated intestinal loop model. The results indicate that these sulfoniums are promising leads for a new type of anti-diabetic agents.
  • M. Tsubaki; T. Takeda; T. Kino; T. Itoh; M. Imano; G. Tanabe; O. Muraoka; T. Satou; S. Nishida
    Am. J. Transl. Res. 7 8 1371 - 81 2015年 [査読有り]
     
    Rheumatoid arthritis is a systemic autoimmune disease characterized by chronic inflammation of synovial joints, ultimately leading to a progressive and irreversible joint destruction. Activation of nuclear factor-kappa B (NF-κB) promotes production of proinflammatory cytokines in various inflammatory diseases including rheumatoid arthritis. Mangiferin, 1,3,6,7-tetrahydroxyxanthone-C2-β-D-glucoside (C-glucosyl xanthone), is a naturally occurring polyphenol. Our previous results showed that mangiferin suppressed NF-κB activation. However, it is unclear, whether mangiferin can prevent rheumatoid arthritis through suppression of NF-κB activation and expression of various cytokines, such as tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6), which play a critical role in the pathogenesis of rheumatoid arthritis. In the present study, we found that mangiferin suppressed the progression and incidence of CIA in DBA1/J mice. In CIA mice, mangiferin inhibited the mRNA expression of cytokine genes in thymus and spleen of CIA mie and led to decreased serum levels of IL-1β, IL-6, TNF-α, and receptor activator NF-κB ligand (RANKL) via inhibition of NF-κB and activation of extracellular signal-regulated kinase 1/2 (ERK1/2). In addition, mangiferin markedly inhibited not only developing but also clinically evident CIA. These findings suggest that mangiferin has potential clinical applications for the treatment of rheumatoid arthritis.
  • Akaki J; Morikawa T; Miyake S; Ninomiya K; Okada M; Tanabe G; Pongpiriyadacha Y; Yoshikawa M; Muraoka O
    Phytochemical analysis : PCA 25 6 544 - 550 2014年11月 [査読有り]
     
    IntroductionStems and roots of Salacia genus plants have been used in Ayurveda as a specific remedy for early stage diabetes. Previous investigations identified four sulphonium sulphates, that is, salacinol (1), kotalanol (3), ponkoranol (5) and salaprinol (7), as the compounds responsible for the anti-diabetic activity. Their desulphonates (2, 4, 6 and 8) were also isolated as active constituents. Two separate quantitative analytical protocols, that is, for 1 and 3 and for 2 and 4, have been developed recently. ObjectiveTo: validate the two analytical protocols with respect to all eight sulphoniums; evaluate the quality of a variety of Salacia samples collected in different geographical regions, that is, Thailand, Sri Lanka and India; and determine their distribution in each part of the plant, that is, stems/roots, leaves and fruits. MethodsAnalyses of four sulphonium sulphates in 32 Salacia extracts were carried out on an Asahipak NH2P-50 column, and those of the corresponding desulphonates were conducted on an Inertsil ODS-3 column. ResultsNeokotalanol (4) was the major constituent in Salacia samples from Thailand, whereas 1 was the primary constituent in extracts of the stems/roots of plants from Sri Lanka and India. These sulphoniums were only present in trace amounts in leaves and fruits of the plants. ConclusionTwo analytical protocols were successfully applied to analyse 32 Salacia samples, and revealed that sulphoniums (1-8) had characteristic distributions due to the plant part and/or due to geographical region. Copyright (c) 2014 John Wiley & Sons, Ltd. Using the recently developed two analytical protocols, the distributions of eight sulphoniums (1-8) responsible for the anti-diabetic activity of Salacia, a specific remedy for the treatment of early stage diabetes in Ayurveda, were examined in 32 extracts of Salacia samples collected in Thailand, Sri Lanka and India. The distribution of these sulphoniums in the different plant parts was also examined. Each constituent had characteristic distributions in the different plant parts and different geographical regions.
  • Long Liu; Cheng-Qian Wang; Dan Liu; Wei-Gang He; Jin-Yi Xu; Ai-Jun Lin; He-Quan Yao; Genzoh Tanabe; Osamu Muraoka; Wei-Jia Xie; Xiao-Ming Wu
    ORGANIC LETTERS 16 19 5004 - 5007 2014年10月 [査読有り]
     
    A novel synthetic approach to construct various 3,6-anhydrohexosides via an intramolecular cyclization of corresponding triflates is described. The nucleophilic attack from C3 p-methoxybenzylated hydroxyl to C6 trifluoromethanesulfonate on triflate structures triggered the cyclization reaction to provide 3,6-anhydrohexosides in excellent yields, making the strategy more efficient with respect to the reported protocols. By applying this methodology, a concise first total synthesis of natural product isolated from leaves of Sauropus rostratus was accomplished.
  • Nozomi Tsutsui; Genzoh Tanabe; Genki Gotoh; Nao Morita; Naohisa Nomura; Ayako Kita; Reiko Sugiura; Osamu Muraoka
    BIOORGANIC & MEDICINAL CHEMISTRY 22 3 945 - 959 2014年02月 [査読有り]
     
    Five alditol analogs 1b-1f of a novel glycolipid acremomannolipin A (1a), the potential Ca2+ signal modulator isolated from Acremonium strictum, were synthesized by employing a stereoselective beta-mannosylation of appropriately protected mannose with five hexitols with different stereochemistry, and their potential on modulating Ca2+ signaling were evaluated. All these analogs were more potent compared to the original compound 1a, and proved that mannitol stereochemistry of 1a was not critical for the potent calcium signal modulating. (C) 2014 Elsevier Ltd. All rights reserved.
  • Dan Liu; Weijia Xie; Long Liu; Jinyi Xu; Hequan Yao; Genzoh Tanabe; Osamu Muraoka; Xiaoming Wu
    JOURNAL OF CHEMICAL RESEARCH 12 715 - 719 2013年12月 [査読有り]
     
    A practical synthesis of neoponkoranol and its related sulfonium salt as potent a-glucosidase inhibitors has been developed in which the key step of coupling reaction was optimised by using isopropylidene as an effective protecting group. The characteristic intramolecular cyclisation of the coupling precursor previously encountered as a side reaction has not been detected and coupling yields were dramatically improved in the present study.
  • Xie Wei-Jia; Tanabe Genzoh; Tsutsui Nozomi; Wu Xiao-Ming; Muraoka Osamu
    CHINESE JOURNAL OF NATURAL MEDICINES 11 6 676 - 683 2013年11月 [査読有り]
     
    Neokotalanol, a potent alpha-glucosidase inhibitor isolated from Salacia reticulata, was synthesized through a key coupling reaction between a perbenzylated thiosugar and an appropriately protected perseitol triflate derived from D-mannose. This key step was found to be quite temperature dependent, and a simultaneous cyclization of the triflate leading to a characteristic 2,4,7-trioxabicyclo[4.2.1]nonane system was detected.
  • D. Liu; W. Xie; L. Liu; H. Yao; J. Xu; G. Tanabe; O. Muraoka; X. Wu
    Tetrahedron Lett. 54 47 6333 - 6336 2013年11月 [査読有り]
     
    Coupling reaction between thiosugar and triflate as the key protocol to synthesize neoponkoranol, a naturally occurring potent alpha-glucosidase inhibitor, and its related sulfonium salts was optimized by applying different esters as protecting group, with the yields of desired products being greatly improved. Our proposed mechanism of the coupling reaction indicated that the nucleophilicity of C3-hydroxyl moiety on monosaccharide structure is closely related to the reaction mode. (C) 2013 Elsevier Ltd. All rights reserved.
  • Xie WJ; Tanabe G; Tsutsui N; Wu XM; Muraoka O
    Chinese journal of natural medicines 11 6 676 - 683 2013年11月 [査読有り]
  • Nozomi Tsutsui; Genzoh Tanabe; Genki Gotoh; Ayako Kita; Reiko Sugiura; Osamu Muraoka
    TETRAHEDRON 69 47 9917 - 9930 2013年11月 
    A full account of stereoselective total synthesis of a novel glycolipid, acremomannolipin A (1), the potent calcium signal modulator isolated from Acremonium strictum, by employing the stereoselective beta-mannosylation of 4,6-O-benzylidene-protected mannosyl sulfoxide with D-mannitol as the key reaction is described. The alpha-anomer (epi-1) of 1 was also synthesized selectively. The calcium modulating activity was reduced upon inversion of the configuration at the anomeric center, indicating that the beta-configuration of the mannose moiety is preferable for the activity. (C) 2013 Elsevier Ltd. All rights reserved.
  • Jason M. Ridlon; Shigeo Ikegawa; Joao M. P. Alves; Biao Zhou; Akiko Kobayashi; Takashi Iida; Kuniko Mitamura; Genzoh Tanabe; Myrna Serrano; Ainee De Guzman; Patsy Cooper; Gregory A. Buck; Phillip B. Hylemon
    JOURNAL OF LIPID RESEARCH 54 9 2437 - 2449 2013年09月 [査読有り]
     
    Clostridium scindens American Type Culture Collection 35704 is capable of converting primary bile acids to toxic secondary bile acids, as well as converting glucocorticoids to androgens by side-chain cleavage. The molecular structure of the side-chain cleavage product of cortisol produced by C. scindens was determined to be 11 beta-hydroxyandrost-4-ene-3,17-dione (11 beta-OHA) by high-resolution mass spectrometry, H-1 and C-13 NMR spectroscopy, and X-ray crystallography. Using RNA-Seq technology, we identified a cortisol-inducible (similar to 1,000-fold) operon (des ABCD) encoding at least one enzyme involved in anaerobic side-chain cleavage. The des C gene was cloned, overexpressed, purified, and found to encode a 20 alpha-hydroxysteroid dehydrogenase (HSDH). This operon also encodes a putative "transketolase" (des AB) hypothesized to have steroid-17,20-desmolase/oxidase activity, and a possible corticosteroid transporter (des D). RNA-Seq data suggests that the two-carbon side chain of glucocorticords may feed into the pentose-phosphate pathway and are used as a carbon source. The 20 alpha-HSDH is hypothesized to function as a metabolic "rheostat" controlling rates of side-chain cleavage. Phylogenetic analysis suggests this operon is rare in nature and the des C gene evolved from a gene encoding threonine dehydrogenase.jlr The physiological effect of 11 beta-OHAD on the host or other gut microbes is currently unknown.
  • Seikou Nakamura; Souichi Nakashima; Genzo Tanabe; Yoshimi Oda; Nami Yokota; Katsuyoshi Fujimoto; Takahiro Matsumoto; Rika Sakuma; Tomoe Ohta; Keiko Ogawa; Shino Nishida; Hisako Miki; Hisashi Matsuda; Osamu Muraoka; Masayuki Yoshikawa
    BIOORGANIC & MEDICINAL CHEMISTRY 21 3 779 - 787 2013年02月 [査読有り]
     
    Methanolic extracts from the flower buds and leaves of sacred lotus (Nelumbo nucifera, Nymphaeaceae) were found to show inhibitory effects on melanogenesis in theophylline-stimulated murine B16 melanoma 4A5 cells. From the methanolic extracts, a new alkaloid, N-methylasimilobine N-oxide, was isolated together with eleven benzylisoquinoline alkaloids. The absolute stereostructure of the new alkaloid was determined from chemical and physicochemical evidence. Among the constituents isolated, nuciferine, N-methylasimilobine, (-)-lirinidine, and 2-hydroxy-1-methoxy-6a, 7-dehydroaporphine showed potent inhibition of melanogenesis. Comparison of the inhibitory activities of synthetic related alkaloids facilitated characterization of the structure-activity relationships of aporphine-and benzylisoquinoline-type alkaloids. In addition, 3-30 mu M nuciferine and N-methylasimilobine inhibited the expression of tyrosinase mRNA, 3-30 mu M N-methylasimilobine inhibited the expression of TRP-1 mRNA, and 10-30 mu M nuciferine inhibited the expression of TRP-2 mRNA. (C) 2012 Elsevier Ltd. All rights reserved.
  • Nozomi Tsutsui; Genzoh Tanabe; Ayako Kita; Reiko Sugiura; Osamu Muraoka
    TETRAHEDRON LETTERS 54 6 451 - 453 2013年02月 
    The first total synthesis of acremomannolipin A, the potential Ca2+ signal modulator isolated from Acremonium strictum, was achieved by employing the characteristic stereoselective beta-mannosylation of 4,6-O-benzylidene-protected mannosyl sulfoxide with a D-mannitol derivative in the presence of trifluoromethanesulfonic anhydride as the key reaction. (C) 2012 Elsevier Ltd. All rights reserved.
  • Wei-Jia Xie; Genzoh Tanabe; Nozomi Tsutsui; Xiao-Ming Wu; Osamu Muraoka
    Chinese Journal of Natural Medicines 11 6 676 - 683 2013年 [査読有り]
     
    Neokotalanol, a potent α-glucosidase inhibitor isolated from Salacia reticulata, was synthesized through a key coupling reaction between a perbenzylated thiosugar and an appropriately protected perseitol triflate derived from D-mannose. This key step was found to be quite temperature dependent, and a simultaneous cyclization of the triflate leading to a characteristic 2,4,7-trioxabicyclo[4.2.1]nonane system was detected. © 2013 China Pharmaceutical University.
  • M. Yoshimatsu; G. Tanabe; O. Muraoka
    Yuki Gousei Kagaku kyokai shi 71 12 1282 - 1293 2013年 [査読有り]
     
    In this paper, molecular activation of sulfur functional groups, including the 7-sulfur-stabilization effect on propargyl cations generated from the corresponding alcohols and sulfur-activated cyclizations of oxygen- and nitrogen-tethered 1,6-diynes triggered by some useful transformations, is described. With respect to propargylation, Lewis acid-catalyzed C-C, C-O and C-N bond formations in nitromethane or nitromethane - H2O have been developed. Moreover, C-N bond formation for the synthesis of pyrazoles via intra- and intermolecular cyclizations is investigated. Thioamides underwent cycloaddition with allenyl cation intermediates, while this reaction did not occur with propargyl cations. In sulfur-activated cyclizations, nucleophile-triggered cyclization provided alkoxymethyl-, aryloxymethylfurans and tanshinon derivatives. Furthermore, the alkynylation- and amination-triggered cyclizations of 1,6-diynes are also described.
  • 田邉 元三
    Mini-Rev. Org. Chem. 10 2 141 - 159 2013年 [査読有り]
     
    Salacinol was isolated as the first naturally occurring sulfonium type α-glucosidase inhibitor from Salacia reticulata, a large woody, climbing plant widely distributed in Sri Lanka and South India, in 1997. This compound presents a quite unique zwitterionic sulfonium sulfate structure and its α-glucosidase inhibitory activity (in vitro) was revealed to be as potent as those of anti-diabetics used in clinic. Since then, great efforts have been made to discover other bioactive ingredients as potent α-glucosidase inhibitors from the same genus of plants, which directly led to the identification of several side chain analogs of salacinol such as kotalanol, salaprinol and ponkoranol together with their de-Osulfonated analogs. In the mean time, much attention has been focused on the total syntheses, structure activity relationship (SAR) studies on this group of natural products in order to design molecules with improved activities. Thus, as a possible result of present findings, this class of natural products has the potential to become lead compounds with potent α- glucosidase inhibitory activities, which could be further developed to a new class of hypoglycemic drug candidates. The present review was developed as a summary of the recent researches of total synthesis and SAR of this series of natural products. In addition, several important structural determinants including the most recent discoveries on SAR are summarized, which may provide new insights into the development of novel anti-diabetic agents. © 2013 Bentham Science Publishers.
  • Tanabe G; Matsuoka K; Yoshinaga M; Xie W; Tsutsui N; A Amer MF; Nakamura S; Nakanishi I; Wu X; Yoshikawa M; Muraoka O
    Bioorganic & medicinal chemistry 20 21 6321 - 6334 2012年11月 [査読有り]
     
    To examine the role of the side chain of kotalanol (2), a potent natural alpha-glucosidase inhibitor isolated from Salacia reticulata, on inhibitory activity, four diastereomers (11a-11d) with reversed configuration (S) at the C-4' position in the side chain were synthesized and evaluated. Two of the four (11b and 11d) significantly lost their inhibitory activity against both maltase and sucrase, while the other two (11a and 11c) sustained the inhibitory activity to a considerable extent, showing distinct activity in response to the change of stereochemistry of the hydroxyls at the 5' and 6' positions. Different activities were rationalized with reference to in silico docking studies on these inhibitors with hNtMGAM. Against isomaltase, all four analogs showed potent inhibitory activity as well as 2, and 11b and 11d exhibited enzyme selectivity. (C) 2012 Elsevier Ltd. All rights reserved.
  • Homology modeling of human alpha-glucosidase catalytic domains and SAR study of salacinol derivatives
    S. Nakamura; K. Takahira; G. Tanabe; O. Muraoka; I. Nakanishi
    Open J. Med. Chem. 2 50 - 60 2012年09月 [査読有り]
  • Mitsuhiro Yoshimatsu; Hitomi Sasaki; Yuko Sugimoto; Yuya Nagase; Genzoh Tanabe; Osamu Muraoka
    ORGANIC LETTERS 14 12 3190 - 3193 2012年06月 [査読有り]
     
    Copper(I)-catalyzed alkynylation-cyclization of 4-oxahepta-1,6-diynes 1 with a wide variety of terminal alkynes proceeded to give (3E,4Z)-3-(phenylsulfanylmethylene)-4-(2-propynylidene)tetrahydrofuran-2-yl]benzenes 2aa-he in high yields with complete regio- and stereoselectivity.
  • Nami Takahashi; Yuya Nagase; Genzoh Tanabe; Osamu Muraoka; Mitsuhiro Yoshimatsu
    TETRAHEDRON 68 5 1566 - 1580 2012年02月 [査読有り]
     
    We have reported sodium alkoxide- or aryloxide-mediated cyclization of 4-oxahepta-1,6-diynes bearing the phenylsulfanyl group 1a-d. The reactions with diverse sodium alkoxides and aryloxide produced 4-alkoxymethyl- and 4-aryloxymethylfurans 2aa-2db in good to high yields. Although reactions with sodium benzenethiolate yielded 3,4-bis(phenylsulfanylmethyl)furans 5a-g, they readily desulfanylated in the presence of tributyltin hydride/AIBN to give the 3-methyl- and 3,4-dimethylfuran derivatives 6a-g. This method's utility was demonstrated by the synthesis of tetrahydronaphthalenyl furan derivatives bearing alkoxy- and aryloxymethyl substituents. (C) 2011 Elsevier Ltd. All rights reserved.
  • 田邉 元三; 吉川 雅之; 村岡 修; 中村 真也; 吉長 正絋; 筒井 望; Balakishan Gorre; 赤木 淳二; 森川 敏生; 二宮 清文; 仲西 功
    天然有機化合物討論会講演要旨集 54 0 285 - 290 天然有機化合物討論会実行委員会 2012年 
    To develop more potent α-glucosidase inhibitors whose seed-compound is salacinol (1), a potent natural α-glucosidase inhibitor isolated from Salacia reticulata of Ayurvedic traditional medicine, a series of 3'-O-benzylated analogs of 1 were designed with the aid of in silico method. Intensive docking studies proposed several promising compounds. To verify the computational SAR assessments, designed derivatives were synthesized and evaluated in vitro. Their α-glucosidase inhibitory activities against rat intestinal α-glucosidases were so potent as were expected by the docking studies, and all the compounds showed superior inhibitory activities to the original sulfonium sulfate (1). Among the sulfonium salts designed, one with 3'-O-(ortho-nitrobenzyl) moiety (8k) was found to be the most potent, and ca. forty times as potent as 1, the compound being the strongest inhibitor among the sulfonium type inhibitors synthesized so far. [chemical formula]
  • G. Tanabe; S. Nakamura; N. Tsutsui; G. Balakishan; W. Xie; S.i Tsuchiya; J. Akaki; T. Morikawa; K. Ninomiya; I. Nakanishi; M. Yoshikawa; O. Muraoka
    Chem. Commun. 48 69 8646 - 8648 2012年 [査読有り]
     
    With the aid of an in silico method, alpha-glucosidase inhibitors with far more potent activities than salacinol (1), a potent natural alpha-glucosidase inhibitor isolated from an Ayurvedic traditional medicine Salacia reticulata, have been developed.
  • G. Tanabe; T. Otani; W. Cong; T. Minematsu; K. Ninomiya; M. Yoshikawa; O. Muraoka
    Bioorg. Med. Chem. Lett. 21 10 3159 - 3162 2011年05月 [査読有り]
     
    Four analogs with 3'-O-alkyl groups (9a: CH(3), 9b: C(2)H(5), 9c: C(13)H(27) or 9d: CH(2)Ph) instead of the 3'-O-sulfate anion in salacinol (1), a naturally occurring potent alpha-glucosidase inhibitor, were synthesized by the coupling reaction of 1,4-dideoxy-1,4-epithio-D-arabinitols (18a and 18b) with appropriate epoxides (10a-10d). These analogs showed equal or considerably higher inhibitory activity against rat small intestinal alpha-glucosidases than the original sulfate (1), and one of them (9d) was found more potent than currently used alpha-glucosidase inhibitors as antidiabetics. Thus, introduction of a hydrophobic moiety at the C3' position of this new class of inhibitor was found beneficial for onset of stronger inhibition against these enzymes. (C) 2011 Elsevier Ltd. All rights reserved.
  • G. Tanabe; K. Matsuoka; M. Yoshinaga; W. Xie; N. Tsutsui; M. F. A. Amer; S. Nakamura; I. Nakanishi; X. Wu; M. Yoshikawa; O. Muraoka
    Bioorg. Med. Chem. 19 7 2252 - 2262 2011年04月 [査読有り]
     
    Synthesis and evaluation of four diastereomers (9a, 9b, 9c and 9d) of kotalanol, a potent alpha-glucosidase inhibitor isolated from an Ayurvedic medicinal plant Salacia species, are described. Stereo-inversion at C-3' and C-4' of kotalanol (2) caused significant decrease of the inhibitory activities against maltase and sucrase, whereas inhibitory activity against isomaltase sustained, thus resulted in exerting selectivity against isomaltase. (C) 2011 Elsevier Ltd. All rights reserved.
  • W. Xie; G. Tanabe; J. Akaki; T. Morikawa; K. Ninomiya; T. Minematsu; M. Yoshikawa; X. Wu; O. Muraoka
    Bioorg. Med Chem. 19 6 2015 - 2022 2011年03月 [査読有り]
     
    Two hitherto missing members of sulfonium salts family in Salacia genus plants as a new class of a-glucosidase inhibitors, neoponkoranol (7) and neosalaprinol (8), were isolated from the water extracts, and their structures were unambiguously identified. For further SAR studies on this series of sulfonium salts, several epimers of 7 and 8 were synthesized, and their inhibitory activities against rat small intestinal alpha-glucosidases were evaluated. Among them, 3'-epimer of 7 was found most potent in this class of molecules, and revealed as potent as currently used antidiabetics, voglibose and acarbose. (C) 2011 Elsevier Ltd. All rights reserved.
  • Weijia Xie; Genzoh Tanabe; Hiroyuki Morimoto; Takanori Hatanaka; Toshie Minematsu; Xiaoming Wu; Osamu Muraoka
    TETRAHEDRON 66 38 7487 - 7491 2010年09月 [査読有り]
     
    Reexamination of heterocyclization of an enantiopure C-2-symmetric bis-epoxide (7) with sodium sulfide is described. In addition to the reported processes leading to thiane (4a) and thiepane (6), another mode of cyclization was found to occur to a considerable extent, affording a symmetric dialkyl sulfide (5), and the structure of the main product reported (4a) has been revised. Conditions for the chemoselective formation of 6 were established, and effective transformation of 6 into 4 was accomplished by the modification of the processes. (C) 2010 Elsevier Ltd. All rights reserved.
  • Katsuki Ohta; Taira Kobayashi; Genzoh Tanabe; Osamu Muraoka; Mitsuhiro Yoshimatsu
    CHEMICAL & PHARMACEUTICAL BULLETIN 58 9 1180 - 1186 2010年09月 [査読有り]
     
    Propargylations of 1,3-diketones using 3-sulfanyl and 3-selanylpropargyl alcohols 1 in MeNO2-H2O gave alkynyl ketones 2a-m, 2o-v and 6,7-dihydro-5H-cyclohexa[b]pyran-5-ones 3k-n. With some bases, the useful propargylated 1,3-diketones underwent intramolecular cyclization to give 6,7-dihydro-5H-benzofuran-4-ones 4a-i or 4,5,6,7-tetrahydrobenzofurans 5p, 6p-v.
  • S. Nakamura; K. Takahira; G. Tanabe; T. Morikawa; M. Sakano; K. Ninomiya; M. Yoshikawa; O. Muraoka; I. Nakanishi
    Bioorg. Med. Chem. Lett. 20 15 4420 - 4423 2010年08月 [査読有り]
     
    Salacinol is a potent alpha-glucosidase inhibitor isolated from Salacia reticulata, and a good lead compound for an antidiabetic drug. It is essential to clarify the binding state of salacinol to alpha-glucosidase for efficient optimization study using structure-based drug design. Redocking simulations of two inhibitors, acarbose and casuarine whose complex structures are known, were performed to assure the appropriate docking pose prediction. The simulation reproduced both experimental binding states with accuracy. Then, using the same simulation protocol, the binding mode of salacinol and its derivatives has been predicted. Salacinol bound to the protein with a similar binding mode as casuarine, and the predicted structures could explain most of the structure-activity relationships of salacinol derivatives. (C) 2010 Elsevier Ltd. All rights reserved.
  • Osamu Muraoka; Weijia Xie; Satomi Osaki; Ayumi Kagawa; Genzoh Tanabe; Mumen F. A. Amer; Toshie Minematsu; Toshio Morikawa; Masayuki Yoshikawa
    TETRAHEDRON 66 21 3717 - 3722 2010年05月 [査読有り]
     
    Stereochemical structure of kotalanol (2), a highly potent a-glucosidase inhibitor isolated from an Ayurvedic traditional medicine Salacia reticulata, was proved by alkaline catalyzed degradation of natural kotalanol (2), in which characteristic stereospecific cyclization of the degradative side chain leading to anhydroheptitols (10 and 11) was involved. (C) 2010 Elsevier Ltd. All rights reserved.
  • M. Yoshimatsu; T. Yamamoto; A. Sawa; T. Kato; G. Tanabe; O. Muraoka
    Organic Lett. 11 13 2952 - 2955 2009年07月 [査読有り]
     
    alpha-Sultanyl and alpha-selanyl propadienyl cations were easily generated by the catalytic system, scandium triflate-nitromethane-H2O in the presence of Bu4NHSO4, to regioselectively afford the multifunctionalized thiazoles and selenazoles in high yields.
  • G. Tanabe; W. Xie; A. Ogawa; T. Minematsu; M. Yoshikawa; O. Muraoka
    Bioorg. Med. Chem. Lett. 19 8 2195 - 2198 2009年04月 [査読有り]
     
    Facile synthesis of de-O-sulfated salacinols (3) was developed by employing the coupling reaction of an epoxide, 1,2-anhydro-3,4-di-O-benzyl-D-erythritol (9) with 2,3,5-tri-O-benzyl-1,4-dideoxy-1,4-epithio-D-arabinitol (10) as the key reaction. The reported structure of a potent alpha-glucosidase inhibitor named neosalacinol (8), isolated recently from Ayurvedic medicine Salacia oblonga, was proved incorrect, and revised to be de-O-sulfated salacinol formate (3c) by comparison of the spectroscopic properties with those of the authentic specimen synthesized. Discrepancies and confusion in the literature concerning the NMR spectroscopic properties of salacinol (1) have also been clarified. (C) 2009 Elsevier Ltd. All rights reserved.
  • G. Tanabe; T. Hatanaka; T. Minematsu; H. Matsuda; M. Yoshikawa; O. Muraoka
    Heterocycles 79 1093 - 1100 2009年04月 [査読有り]
     
    N-Alkylated deoxynojirimycin (10) bearing the same alkyl chain as salacinol (1), a potent alpha-glucosidase inhibitor isolated from Ayurvedic traditional medicine, Salacia reticulata, was found to inhibit both rat intestinal maltase and sucrase as strong as 1, while 10 has been reported to be inactive against glucoamylase G2 from Aspergillus niger. Its O-desulfate (12) was also found active against these enzymes, and characteristic sulfate anion moiety of I was found not essential for the alpha-glucosidase inhibitory activity.
  • Osamu Muraoka; Weijia Xie; Genzoh Tanabe; Mumen F. A. Amer; Toshie Minematsu; Masayuki Yoshikawa
    TETRAHEDRON LETTERS 49 51 7315 - 7317 2008年12月 [査読有り]
     
    The reported structure of a potent a-glucosidase inhibitor 7 isolated recently from ayurvedic medicine Salacia reticulata was found incorrect, and the compound was proved to be de-O-sulfated kotalanol 4. Discussion and detailed analysis of the spectral data leading to the revised structure are presented. (C) 2008 Elsevier Ltd. All rights reserved.
  • Genzoh Tanabe; Mika Sakano; Toshie Minematsu; Hisashi Matusda; Masayuki Yoshikawa; Osamu Muraoka
    TETRAHEDRON 64 43 10080 - 10086 2008年10月 [査読有り]
     
    Synthesis and elucidation of absolute stereochemistry of salaprinol (3) isolated from the root and sterns of Salacia prinoides, which has been used for the treatment of diabetes in India, Sri Lanka, and Southeast Asia countries, is described. Compound 3 and its 2'-epimer, epi-salaprinol (epi-3) were synthesized via the coupling reaction of a cyclic sulfate, 2-O-benzylglycerol 1,3-cyclic sulfate (S), with a thiosugar, 1,4-dideoxy-1,4-epithio-D-arabinitol (6), as the key reaction, and S configuration of the asymmetric center in the side chain of 3 was elucidated by the X-ray crystallographic analysis. (C) 2008 Published by Elsevier Ltd.
  • M. Yoshikawa; F. Xu; S. Nakamura; T. Wang; H. Matsuda; G. Tanabe; O. Muraoka
    Heterocycles 75 6 1397 - 1405 2008年06月 [査読有り]
     
    The methanolic extract from the roots and stems of Indian Salacia prinoides and its water-eluted fraction of Diaion HP-20 column were found to exhibit inhibitory activities against α-glucosidase. From the water-eluted fraction, two new unique constituents with thiosugar sulfonium sulfate, salaprinol (1) and ponkoranol (2), were isolated together with 10 known constituents including salacinol and kotalanol. The structures of 1 and 2 were elucidated on the basis of chemical and physicochemical evidence. Furthermore, ponkoranol (2) and kotalanol desulfate (14) were found to show potent inhibitory activities against α- glucosidase. © 2008 The Japan Institute of Heterocyclic Chemistry.
  • T. Taniguchi; G. Tanabe; O. Muraoka; H. Ishibashi
    Org. Lett. 10 2 197 - 199 2008年01月 [査読有り]
     
    Total synthesis of stemonamide and isostemonamide is described. The concise construction of the tricyclic core of these alkaloids was achieved by radical cascade involving 7-endo and 5-endo cyclizations.
  • G. Tanabe; K. Yoshikai; T. Hatanaka; M. Yamamoto; Y. Shao; T. Minematsu; O. Muraoka; T. Wang; H. Matsuda; M.Yoshikawa
    Bioorg. Med. Chem. 15 11 3926 - 3937 2007年06月 [査読有り]
     
    De-O-sulfonated analogs (10a, Y- = CH(3)QSO(3) and 10b, Y- = Cl) of salacinol, a naturally occurring glycosidase inhibitor, and its diastereomer (12a, Y- = CH3OSO3) With L-thiosugar moiety (1,4-dideoxy- 1,4-epithio-L-arabinitol) were prepared. Their inhibitory activities against intestinal maltase and sucrase were examined and compared with those of the parent alpha-glycosidase inhibitor, salacinol (1a). Compounds 10a and 10b showed a potent inhibitory activity equal to that of la against both enzymes, although 12a was a weak inhibitor against sucrase and maltase. These results indicated that the O-sulfonate anion moiety of 1a is not essential for the inhibitory activity. (C) 2007 Published by Elsevier Ltd.
  • Genzoh Tanabe; Kanjyun Matsuoka; Toshie Minematsu; Toshio Morikawa; Kiyofumi Ninomiya; Hisashi Matsuda; Masayuki Yoshikawa; Hideaki Murata; Osamu Muraoka
    J. Pharm. Soc. Jpn. 127 129 - 130 2007年 [査読有り]
     
    Kotalanol (1) and salacinol (2) are potent alpha-glucosidase inhibitors isolated from methanol extract of an antidiabetic Ayurvedic traditional medicine, Salacia reticulata. Although 1 is more active against certain glycosidase enzymes than 2, no synthetic trial of 1 has been reported because of the unidentified absolute stereochemistry of the heptitol unit. Herein reported are synthetic study on 1 and evaluation of the inhibitory activities of four synthesized diastereomers 1a-1d, which maintained 2'S and 3'S configuration of 2 in addition to 4'S configuration as common side chain feature. All the analogs showed less inhibitory activity against sucrase and maltase compared to 1, and the results indicated that the 4'S configuration was essential for the inhibitory activity. Newly developed quantitative analytical method of 1 and 2 in the extract of several Salacia species by LC-MS to evaluate the quality of the Salacia extract is also presented.
  • Keiji Nishiwaki; Takashi Ogawa; Ken-ichi Tagami; Genzoh Tanabe; Osamu Muraoka; Keizo Matsuo
    TETRAHEDRON 62 47 10854 - 10858 2006年11月 [査読有り]
     
    We are reporting on a new method of constructing dearomatized compounds from alpha-substituted aryltriazenes. Deprotonation occurs at C atom alpha to N3. Nucleophilic attack of generated anion at the ortho-position of aryl group forms a new carbon-carbon bond. A stereoselective reaction was observed when the substituents on the C alpha to N3 are tied together in either a pyrrolidine or a piperidine. The product of this reaction possessed an interesting dearomatized tetrahydrobenzotriazine framework. (c) 2006 Elsevier Ltd. All rights reserved.
  • 村岡修; 田邉元三; 畑中上憲; 松田久司; 吉川雅之
    薬学雑誌 126 Suppl.3 112 - 113 2006年10月
  • Tanabe Genzoh; Hatanaka Takanori; Yoshikai Kazuya; Minematsu Toshie; Wang Tao; Matsuda Hisashi; Yoshikawa Masayuki; Muraoka Osamu
    International Symposium on the Chemistry of Natural Products 2006 "P - 298" 天然有機化合物討論会 2006年07月
  • H. Kinoshita; T. Osamura; K. Mizuno; K. Kazumi; S. Kinoshita; T. Iwamura; S. Watanabe; T. Kataoka; O. Muraoka; G. Tanabe
    Acta Pharm. Sinica 41 7 647 - 653 2006年07月 [査読有り]
     
    Aim: To investigate more efficient synthetic method of the nitrogen analogue 4 of salacinol (1) for searching new antidiabetic agents. Methods: The synthesis of the key intermediate 2,4-O-isopropylidene-L-erythritol 1,3-cyclic sulfate (2a) was accomplished by modification of reports from D-glucose via seven steps in much more less expensive. Using this method, an efficient synthesis of 4 was carried out. The glycosidase inhibitory activity of 4 was tested for the intestinal α-glucosidase in vitro and compared with that of salacinol. Results: A nitrogen analogue 4 of salacinol (1) was synthesized by the coupling reaction between the cyclic sulfate 2a and an azasugar 3b. Conclusion: Substitution of the sulfur atom in 1 with a nitrogen reduced the activity considerably.
  • Hironori Kinoshita; Takashi Osamura; Kazumi Mizuno; Sayaka Kinoshita; Tatsunori Iwamura; Shin-ichi Watanabe; Tadashi Kataoka; Osamu Muraoka; Genzoh Tanabe
    CHEMISTRY-A EUROPEAN JOURNAL 12 14 3896 - 3904 2006年05月 
    Reactions between chiral 3-cinnamoyl-4-methyl-5-phenyl-1,3-oxazolidine-2-thiones and aromatic aldehydes in the presence of BF3 center dot Et2O diastereoselectively produced tricyclic compounds incorporating a bridgehead carbon bound to four heteroatoms in high yields. Four stereocenters were induced during the reaction. The tricyclic products were transformed into propane-1,3-diols bearing three consecutive stereocenters by acid hydrolysis, S-methylation, and reductive removal of the chiral auxiliary.
  • O. Muraoka; K. Yoshikai; H. Takahashi; T. Minematsu; G.Lu; G. Tanabe; T. Wang; H. Matsuda; M. Yoshikawa
    Bioorg. Med. Chem. 14 2 500 - 509 2006年01月 [査読有り]
     
    Three analogs (5, 6, and 7) lacking polar substituents in the side chain of a naturally occurring a-glucosidase inhibitor, salacinol (la), were synthesized by the coupling reaction of a thiosugar, 1,4-dideoxy-1,4-epithio-D-arabinitol (3), with cyclic sulfates (8, 9, and 10), and their a-glucosidase inhibitory activities were examined. All these simpler analogs (5, 6, and 7) showed less inhibitory activity compared to la, and proved the importance of cooperative role of the polar substituents for the a-glucosidase inhibitory activity. A practical synthetic route to 3 starting from D-xylose is also described. (c) 2005 Elsevier Ltd. All rights reserved.
  • Design and synthesis of a simplified analogue of salacinol
    Muraoka O; Tanabe G; Shao Y
    Daxue Zhongguo Yaoke Daxue Xuebao 37 403 - 406 2006年 [査読有り]
  • H Kinoshita; N Takahashi; T Iwamura; S Watanabe; T Kataoka; O Muraoka; G Tanabe
    TETRAHEDRON LETTERS 46 42 7155 - 7158 2005年10月 [査読有り]
     
    (2S,3S,1'R)-2-(alpha-Methoxybenzyl)-3-phenyl-3-sulfanylpropionamides were diastereoselectively prepared by the reactions of N-cinnamoyl-4S-isopropyl-5,5-dimethyloxazolidinethione with acetals in the presence of SnCl4. The absolute configuration of the three newly created contiguous stereocenters was determined by the X-ray analysis of the disulfide. The amides were transformed into propanols by the reductive removal of the oxazolidinone moiety. (c) 2005 Elsevier Ltd. All rights reserved.
  • M. Yoshimatsu; Y. Murase; A. Itoh; G. Tanabe; O. Muraoka
    Chem. Lett. 34 7 998 - 999 2005年07月 [査読有り]
     
    The Z-sclective formation of alpha-fluoro-alpha,beta-unsaturated esters was achieved using the deselenenic acid of the synand/or anti-3-aryl-2-fluoro-3-hydroxy-2-organoselanylacetates 3 and 4 with trifluoromethanesuffonic acid. In contrast, the 3-alkyl-substituted propanoates 3f and 4b stereospecifically underwent alkenylation to give the (E)- or (Z)-alpha-fluoro-alpha,beta-unstaurated esters 5f. We were also successful in the one-pot alkenylation reactions.
  • H. Matsuda; M. Yoshikawa; T. Morikawa; G.Tanabe; O. Muraoka
    J.T rad. Med. 22(Suppl. 1) 1 145 - 153 和漢医薬学会 2005年06月 [査読有り]
     
    In the course of our studies on antidiabetogenic compounds from natural medicines and medicinal foodstuffs, we found that the extracts from the roots and stems of Salacia reticulata, S. oblonga, and S. chinensis showed substantial inhibitory effects on increase in serum glucose levels in oral sucrose- and maltose-loaded rats and inhibitory effects on intestinal α-glucosidase. Through bioassay-guided separation using α-glucosidase inhibitory activities, we isolated α-glucosidase inhibitors named salacinol and kotalanol with unique chemical structures from the active fractions together with several known phenolic compounds, new sesquiterpenes (salasols A and B) and triterpenes (kotalagenin 16-acetate, salasones A-E, salaquinones A and B). Furthermore, S. reticulata and its phenolic constituents were found to exhibit pancreatic lipase inhibitory and anti-obese effects. This paper summarizes our recent studies including the synthetic and structure-activity relationships on antidiabetogenic principles of Salacia species. In addition, clinical studies and safety evaluations of the extracts from S. reticulata and S. oblonga are summarized.
  • T Taniguchi; O Tamura; M Uchiyama; O Muraoka; G Tanabe; H Ishibashi
    SYNLETT 70(5) 7 1179 - 1181 2005年05月 [査読有り]
     
    On treatment with Bu3SnH and azobis(cyclohexanecarbonitrile) (ACN), enamide 19 underwent a 6-endo-trig/5-endo-trig radical cascade to afford perhydropyrrolo[2.1-j]quinoline derivative 21, a cylindricine skeleton.
  • T Taniguchi; A Ishita; M Uchiyama; O Tamura; O Muraoka; G Tanabe; H Ishibashi
    JOURNAL OF ORGANIC CHEMISTRY 70 5 1922 - 1925 2005年03月 [査読有り]
     
    Bu3SnH-mediated radical cyclizations of 2-(2-bromophenyl)N-ethenylacetamide gave 6-exo cyclization product 15 as the major product, whereas N-[2-(2-bromophenyl)ethyl]-N-ethenylamides gave almost exclusively 7-endo cyclization products. These results indicated that the position of the carbonyl group on enamide played an important role in deciding the course of the cyclization. The 7-endo selective cyclization was applied to concise construction of a cephalotaxine skeleton.
  • 村岡修; 吉海和哉; 高橋秀雄; 峯松敏江; 田辺元三; 松田久司; 吉川雅之
    近畿大学薬学総合研究所紀要 12 117 - 132 2004年03月
  • H. Kinoshita; T. Osamura; S. Kinoshita; T. Iwamura; S. Watanabe; T. Kataoka; G. Tanabe; O. Muraoka
    J. Org. Chem. 68 19 7532 - 7534 2003年09月 [査読有り]
     
    1-[2-(Methylsulfanyl)phenyl]prop-2-en-1-one (1) and the seleno congener (2) reacted with acetals 3 and 21 in the presence of (BF3Et2O)-Et-. to give alpha-alkoxyalkyl enones 4, 5 and 22, 23 in good yields. When the reaction mixtures were worked up with a saturated NaHCO3 solution instead of Et3N, onium salts 6 and 7 were obtained together with 4 and 5. Reactions with cyclic acetal 14 gave alpha-(beta-hydroxy-ethoxy) enones 15 and 16 accompanied by dimeric products 17 and 18.
  • A. Imamura; H. Ando; S. Korogi; G. Tanabe; O. Muraoka; H. Ishida; M. Kiso
    Tetrahedron Lett. 44 35 6725 - 6728 2003年08月 [査読有り]
     
    We have discovered an unusual alpha-galactosylation using phenylthioglycoside of 4,6-O-di-tert-butylsilylene (DTBS)-protected galactose derivatives as a glycosyl donor, which was not hampered by the neighboring participation of C-2 acyl functionality such as NTroc and OBz. The power of the DTBS effect has been exemplified by the coupling reaction with various glycosyl acceptors. (C) 2003 Elsevier Ltd. All rights reserved.
  • S Watanabe; T Ikeda; T Kataoka; G Tanabe; O Muraoka
    ORGANIC LETTERS 5 4 565 - 567 2003年02月 [査読有り]
     
    [GRAPHICS] A novel alkenylation of enolates using alkenylselenonium salts is described. A reaction of lithium enolates, which were prepared in situ by the reaction of LiHMDS and carbonyl compounds, with alkenylselenonium salts gave the ethenylation products of carbonyl compounds in high yield. Diastereoselective alkenylation was also accomplished by the reaction of the enolates derived from N-acyl-1,3-oxazolidin-2-ones with the alkenylselenonium salt to afford good results (up to 92% yield and up to 95% de).
  • T Kataoka; H Kinoshita; S Kinoshita; T Osamura; S Watanabe; T Iwamura; O Muraoka; G Tanabe
    ANGEWANDTE CHEMIE-INTERNATIONAL EDITION 42 25 2889 - 2891 2003年 [査読有り]
  • T Minami; S Wada; H Tokuda; G Tanabe; O Muraoka; R Tanaka
    JOURNAL OF NATURAL PRODUCTS 65 12 1921 - 1923 2002年12月 [査読有り]
     
    A new nor-labdane-type diterpene, 15-nor-labda-8(17),12E-dien-13,19-dienoic acid (1), along with five known diterpenes, 15-nor-14-oxolabda-8(17),12E-dien-19-oic acid (2), trans-communic acid (3), sandaracopimaric acid (4), dehydroabietic acid (5), and abieta-8,11,13-triene-15,18-diol (6), was isolated from the cones of Pinus luchuensis. The structure of 1 was established by chemical and spectroscopic methods. Among these isolates, compounds 2, 4, and 6 showed potent inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol 13-acetate.
  • M Yoshimatsu; M Hibino; M Ishida; G Tanabe; O Muraoka
    CHEMICAL & PHARMACEUTICAL BULLETIN 50 11 1520 - 1524 2002年11月 [査読有り]
     
    5-(Phenylselenenyl)- and 5-(phenylsulfenyl)-4-ethoxy-1-phenyl-2,4-pentadien-1-ones (2) and (3) underwent [4+2] cycloaddition with N-methyl and N-phenylmaleimides and successive isomerization to give the 7-benzoyl-3a,4,5,7a-tetrahydro-1H-isoindole-1,3(2H)-diones 5, 8 and 9 in good yields. The 4-ethoxy group on the 2,4-pentadien-1-one was found to be effective to facilitate the cycloaddition with dienophiles. We also performed other [4+2] cycloadditions of 2,4-pentadien-1-ones with DMAD or naphthoquinone.
  • M. Yoshikawa; T. Morikawa; H. Matsuda; G. Tanabe; O. Muraoka
    Bioorg. Med. Chem. 10 5 1547 - 1554 2002年05月 [査読有り]
     
    A most potent alpha-glucosidase inhibitor named salacinol has been isolated from an antidiabetic Ayurvedic traditional medicine. Salacia reticulata WIGHT, through bioassay-guided separation. The absolute stereostructure of salacinol was determined on the basis of chemical and physicochemical evidence, which included the alkaline degradation of salacinol to 1-deoxy-4-thio-D-arabinofuranose and the X-ray crystallographic analysis, to be the unique spiro-like configuration of the inner salt comprised of 1-deoxy-4-thio-D-arabinofuranosyl sulfonium cation and 1'-deoxy-D-erythrosyl-3'-sulfate anion. Salacinol showed potent inhibitory activities on several alpha-glucosidases, such as maltase, sucrase, and isomaltase, and the inhibitory effects on serum glucose levels in maltose- and sucrose-loaded rats (in vivo) were found to be more potent than that of acarbose, a commercial alpha-glucosidase inhibitor. (C) 2002 Elsevier Science Ltd. All rights reserved.
  • M Yoshimatsu; K Oh-Ishi; G Tanabe; O Muraoka
    JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1 1413-1416 12 1413 - 1416 2002年 [査読有り]
     
    We have isolated the sulfonylbuta-1,3-diynes 3 and 5 as colorless prisms, which demonstrate unprecedented dimerization. Furthermore, the reactions of 3 and 5 with alkoxides or buta-1,3-dienes were examined and the products obtained were either sulfonyl-beta-alkoxybut-1-en-3-ynes 16a-e, beta-alkoxybut-3-en-1-ynes 17a-d or the cycloadducts 23 and 24a, b.
  • O. Muraoka; S. Ying; K. Yoshikai; Y. Matsuura; E. Yanada; T. Minematsu; G. Tanabe; H. Matsuda; M. Yoshikawa
    Chem. Pharm. Bull. 49 11 1503 - 1505 2001年11月 [査読有り]
     
    A nitrogen analogue 4 of the naturally occurring sulfonium ion salacinol (1), a potent alpha -glucosidase inhibitor isolated from the Ayruvedic medicine Salacia reticulata, was synthesized and its inhibitory activity against alpha -glucosidase tested. Substitution of the sulfur atom in I with a nitrogen reduced the activity considerably. The solid-state stereostructure of the related compound (5) was determined on the basis of single crystal X-ray measurement.
  • O Muraoka; M Fujimoto; G Tanabe; M Kubo; T Minematsu; H Matsuda; T Morikawa; Toguchida, I; M Yoshikawa
    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 11 16 2217 - 2220 2001年08月 [査読有り]
     
    Novel 14- norcadinane-type sesquiterpenes. oxyphyllenodiols A and B, and 11,12,13-trinoreudesmane-type sesquiterpenes. oxyphyllenones A and B, were isolated from the methanolic extract of kernels of Alpinia oxiphylla. The absolute stereostructures of these norsesquiterpenes were determined on the basis of physicochemical and chemical evidence. In addition, oxyphyllenodiol A and oxyphyllenone A were found to inhibit the NO production in lipopolysuccharide-activated macrophages. (C) 2001 Elsevier Science Ltd. All rights reserved.
  • A. Toyao; S. Chikaoka; Y. Takeda; O. Tamura; O. Muraoka; G. Tanabe; H. Ishibashi
    TETRAHEDRON LETTERS 42 9 1729 - 1732 2001年02月 [査読有り]
     
    Oxidative radical cyclizations of enamide 3 with Mn(OAc)(3) in the presence of Cu(II) were examined. When Cu(OAc)(2) was used as an additive, 4-acetoxyerythrinane derivative 5 was formed, whereas the use of Cu(OTf)(2) afforded simple erythrinane 6. (C) 2001 Elsevier Science Ltd. All rights reserved.
  • S. Watanabe; K. Yamamoto; Y. Itagali; T. Iwamura; T. Iwama; T. Kataoka; G. Tanabe; O. Muraoka
    J. Chem. Soc., Perkin Trans. 1 3 239 - 247 2001年 [査読有り]
     
    The treatment of alkynylselenonium salt with benzenesulfinic acid in (PrOH)-Pr-i gives (Z)-beta -sulfonylvinylselenonium salts in good yields. The alkenylselenonium salts thus prepared react with nucleophiles such as alkoxides, halides, and acetylides to produce beta -functionalized (Z)-vinyl sulfones in high yields. Furthermore, we succeeded in the simple stereoselective one-step synthesis of various chiral (Z)-beta -alkoxyvinyl sulfones by the use of chiral alcohols.
  • E. Ho E. Honda; T. Iwamura; S. Watanabe; T. Kataoka; O. Muraoka; G. Tanabenda; T. Iwamura; S. Watanabe; T. Kataoka; O. Muraoka; G. Tanabe
    J. Chem. Soc., Perkin Trans. 1 5 529 - 536 2001年 [査読有り]
     
    Selenabenzenes 12a-c with two electron-withdrawing groups (EWGs) at the 2- and 6-positions were synthesized from dihalides 1a, 1b and 1c' via seven steps and isolated as stable compounds at room temperature. According to X-ray structural analysis of the dibenzoyl derivative 12c, the six-membered ring containing a selenium atom is almost planar and the structure of the selenium atom is tetrahedral with four sp(3) hybridized orbitals.
  • T Ogiso; K Koike; M Iwaki; T Tanino; G Tanabe; O Muraoka
    BIOLOGICAL & PHARMACEUTICAL BULLETIN 23 7 844 - 849 2000年07月 [査読有り]
     
    The effects of a series of fatty acids on the percutaneous penetration of ozagrel (OZ), a selective thromboxane A(2) synthetase inhibitor, through rat skin and the mechanism by which fatty acids enhance the skin penetration of OZ were examined in vitro. Lauric acid, at the fatty acid:OZ molar ratio of 2:1, was the most potent agent as far as increasing the skin penetration was concerned,,vith a flux 24-fold higher than that without fatty acid. A molar ratio of 3:1 also produced a large enhancing effect, comparable with that of a molar ratio of 2:1, When the gel formulation with lauric acid (molar ratio of 2: 1) was applied to the skin for 6 h, the amount of drug penetrating into the skin was significantly increased compared with that after the formulations without lauric acid and with capric and palmitic acids. However Lauric acid did not change the apparent partition coefficient of OZ between n-heptane and phosphate buffer (pH 7.4), The C-13-NMR spectra of OZ was also unaffected by the addition of lauric acid, indicating that a complex or ion pair with lauric acid was not formed, A possible mechanism for the enhancing effect is the increased incorporation of lauric acid with OZ into the bulk lipid phase of the stratum corneum, where the fatty acid would act as a co-penetrant enhancing passage through the stratum corneum.
  • Tadashi Kataoka; Hironori Kinoshita; Tetsuo Iwama; Shin-Ichiro Tsujiyama; Tatsunori Iwamura; Shin-Ichi Watanabe; Osamu Muraoka; Genzoh Tanabe
    Tetrahedron 56 27 4725 - 4731 2000年06月 [査読有り]
     
    Reactions of p-nitrobenzaldehyde (4) with methyl vinyl ketone (5) were conducted in the presence of TiCl4 and dimethyl sulfide (3) or selenopyranone 6. When the raw product was purified by column chromatography on silica gel, α-chloromethyl aldol 8 was obtained as a mixture of diastereoisomers 8a and 8b. In contrast, purification of the raw product by preparative TLC on silica gel gave α-methylene aldol 7. The mechanism for the formation of α-chloromethyl aldol 8 and diasteroselection for the syn- isomer 8a and anti-isomer 8b are discussed. (C) 2000 Elsevier Science Ltd.
  • H Shimizu; N Araki; O Muraoka; G Tanabe
    TETRAHEDRON LETTERS 41 13 2161 - 2164 2000年03月 [査読有り]
     
    Treatment of 2-benzothiopyrylium salt with alkenes such as styrene, p-methylstyrene, p-methoxystyrene, alpha-methylstyrene, and trans-anethole afforded the corresponding [4(+)+2]-type polar cycloaddition products, respectively. The structures of the cycloadducts were confirmed by X-ray crystal structure determination of the corresponding sulfone derivative. (C) 2000 Elsevier Science Ltd. All rights reserved.
  • K. Hirota; R. Hattori; H. Sajiki; Y. Monguchi; O. Muraoka; G. Tanabe
    Nucleic acids symposium series 113 - 114 2000年01月 
    A novel reductive method for the chemical modification of nucleosides is described. Reaction of inosine derivatives with boran-THF resulted in the regioselective reduction of purine ring to afford the corresponding 2,3-dihydroinosine derivatives in moderate yields.
  • Mitsuhiro Yoshimatsu; Satoshi Gotoh; Genzoh Tanabe; Osamu Muraoka
    Chemical Communications 10 909 - 910 1999年05月 [査読有り]
     
    The photo-reactions of 2,4,6-tris(phenylthio)hepta-2,4,6-trienal 1 and its 2,4-dinitrophenylhydrazone 5 gave the 2-oxa- or 2-azabicyclo[3.3.0]octa-3,7-dienes 2 and 9, respectively, via a photo-induced intramolecular tandem cyclization reaction.
  • T. Iwama; T. Kataoka; O. Muraoka; G. Tanabe
    J. Org. Chem. 63 23 8355 - 8360 1998年11月 [査読有り]
     
    alpha-Amino acid thioesters were synthesized by the Pummerer reaction of 3-substituted-4-sulfinyl-beta-sultams with TFAA. The 3-substituted-4-sulfinyl-beta-sultams were prepared from the corresponding beta-sultams by sulfenylation with diphenyl disulfide followed by m-CPBA oxidation. Diastereoselective synthesis of beta-sultams by 1,3-asymmetric induction in [2 + 2] cycloaddition of a sulfene intermediate and chiral imines in solution-phase was studied, and it was found that N-alkylimines gave better diastereoselectivities than N-aralkylimines. The use of imines derived from (R)- and (S)-alpha-methylbenzylamine followed by separation of the major and minor diastereomers gave enantiopure 3-substituted-N-methylbenzyl-beta-sultams. These beta-sultams were then converted to N-methylbenzyl-alpha-amino acid thioesters via sulfenylation and Pummerer rearrangement with high or complete retention of configuration.
  • T Ogiso; T Tanino; D Kawaratani; M Iwaki; G Tanabe; O Muraoka
    BIOLOGICAL & PHARMACEUTICAL BULLETIN 21 10 1084 - 1089 1998年10月 [査読有り]
     
    To improve the absorbability of phenytoin (DPH), a prodrug, N-acetyl-DPH (EDPH), was synthesized, and the absorptive characteristics and pharmacokinetics of the prodrug were evaluated in rats. EDPH was rapidly hydrolyzed to DPH in the intestinal fluid and the mucosa (rate constant, 0.055 and 0.169 min(-1), respectively). The plasma concentrations of DPH after intravenous dosing of EDPH declined in a biexponential manner, although two different elimination patterns were observed in these rats. When dosed orally (25 mg/kg, DPH equivalent), the plasma levels of DPH converted from the prodrug were significantly higher and more sustained than those after DPH alone, giving bioavailability 11.4 (rapid decay) and 9.1 times (slow decay) as high, respectively, as that after DPH alone. The concentrations of DPH distributed into the mucosa of the duodenum and jejunum 1 and 5 h after oral dosing of EDPH were significantly higher than those after DPH alone. The prodrug and DPH converted from the prodrug dissolved 2-4 fold more than DPH alone in bile salt solution and bile salt-oleic acid mixed micelles, indicating the increased solubility of the prodrug in the intestinal fluid. It is concluded from the data that such high solubility of EDPH enhanced the intestinal absorption of the prodrug, part of which would be absorbed in the amide form, and thus gave the high bioavailability.
  • T Kataoka; S Watanabe; K Yamamoto; M Yoshimatsu; G Tanabe; O Muraoka
    JOURNAL OF ORGANIC CHEMISTRY 63 18 6382 - 6386 1998年09月 [査読有り]
     
    The reaction of the diphenyl(phenylethynyl)selenonium triflate 1a with active methylene compounds 5 and t-BuOK in THF gave furan derivatives 6. The [10-Se-4(C3O)] selenuranes 8a and 8b could be isolated from the reactions with benzoylacetonitrile 5f and with 1,3-indandione 5g, respectively, as reaction intermediates. The structures of the selenuranes 8 were elucidated by X-ray crystallography and Se-77 high-resolution solid-state NMR spectroscopy. The selenuranes 8 underwent ligand coupling on standing at room temperature or refluxing in chloroform and gave the furan derivatives 6 and the ring-opened product 9. Similarly, the reaction of 1a with benzamide 13a and pivalamide 13d in the presence of NaH in THF afforded oxazole derivatives 14.
  • T. Iwama; M. Ogawa; T. Kataoka; O. Muraoka; G. Tanabe
    Tetrahedron 54 31 8941 - 8974 1998年07月 [査読有り]
     
    Selective C-S bond cleavage of a beta-sultam ring was achieved by the reactions with Lewis acids. Aryl ketones or aldehyde were provided from 3-aryl-beta-sultams whereas beta-sultams bearing a poorly migratory substituent at C-3 gave trans-1,2,3-oxathiazolidine 2-oxides and/or cis-aziridines. These reactions were influenced by the cation-stabilizing capability of C-4 substituents and by the configuration of the substituents at C-3 and C-4. Some 4-alkenyl-3-aryl-beta-sultams underwent tandem intramolecular cyclization to give bicyclo[3.2.1]- and [2.2.1]-gamma-sultams via the processes of C-S bond cleavage, 1,2-aryl shift, cation-olefin cyclization and recombination of the sulfonyl anion. (C) 1998 Elsevier Science Ltd. All rights reserved.
  • T Iwama; H Matsumoto; H Shimizu; T Kataoka; O Muraoka; G Tanabe
    JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1 9 1569 - 1576 1998年05月 [査読有り]
     
    Generation of butadienylthionium ions in the Pummerer reactions of 2-vinylcyclopropyl sulfoxides has been investigated. Although the Pummerer reactions of 2-vinylcyclopropyl sulfoxides 1 are complicated, benzothiazinone derivatives 10 smoothly react with trifluoroacetic anhydride to give 1,3-dienes in good yields, The reactions proceed via butadienylthionium ions by proton abstraction from the 2'-methyl group or the cyclopropane ring, Reactions of disubstituted benzothiazinones 10e-h provided cyclic dienes while treatment of mono-or un-substituted derivatives gave acyclic conjugated dienes 11a-d. 2-Vinylcyclopropyl sulfoxides 1 and 10 were prepared by MCPBA oxidation of the corresponding 2-vinylcyclopropyl sulfides 19 and 23, respectively, which were obtained by cyclopropanation of a-chloro sulfides with 1,3-dienes via the 5,6-dihydro-2H-thiopyranium intermediate 22.
  • T. Iwama; T. Kataoka; O. Muraoka; G. Tanabe
    Tetrahedron 54 21 5507 - 5522 1998年05月 [査読有り]
     
    Reactions of 4-nonsubstituted beta-sultams 1 with methyllithium gave only (E)-vinylsulfonamides 2, whereas 2-aminoethyl sulfones 3 were obtained as minor products by use of methylmagnesium bromide. Reactions of 4-monosubstituted beta-sultams 6 with organolithiums gave (E)-vinylsulfonamides 7 stereoselectively regardless of the configuration of 3- and 4-substituents. Treatment of 4,4-dimethyl-beta-sultam 8a with methylmagnesium bromide and methyllithium provided 2-aminoethyl sulfone 9 and bis-sulfone 10, respectively, and isopropyl phenyl sulfone 11 was obtained by use of phenyllithium or phenylmagnesium bromide. (C) 1998 Elsevier Science Ltd. All rights reserved.
  • M. Miyazawa; M. Nobata; S. Okamura; O. Muraoka; G. Tanabe; H. Kameoka
    J. Chem. Technol. 71 4 281 - 284 1998年04月 [査読有り]
     
    The biotransformation of (+/-)-bicyclo[3.3.1]nonane-2,6-dione by Aspergillus niger and Glomerella cingulara was investigated. The diketone was reduced to the ketoalcohol 2-endo-hydroxy-bicyclo[3.3.1]nonane-6-one and the diol endo,endo-bicyclo[3.3.1]nonane-2,6-diol respectively. Endo,endo-bicyclo[3.3.1]nonane-2,6-diol and ketoalcohols produced by G. cingulata had high optical purity, on the other hand, reduction by A. niger yielded optically active (-)-(1R, 2S, 5R, 6S)-bicyclo[3.3.1]nonane-2,6-diol(99.9% e.e.). (C) 1998 SCI.
  • T Tanino; T Ogiso; M Iwaki; G Tanabe; O Muraoka
    INTERNATIONAL JOURNAL OF PHARMACEUTICS 163 1-2 91 - 102 1998年03月 [査読有り]
     
    To improve the oral absorbability of phenytoin (DPH), prodrugs of DPH with a small acyl substituent, N-carboethoxy- and N-carboisopropoxy-DPH (PT-1 and PT-2, respectively), were synthesized and bioavailabilities of them were evaluated after oral administration in rats, compared to that of DPH dosed. The prodrugs were rapidly hydrolyzed in the intestinal fluid, intestinal mucosa, liver homogenates and plasma of rats, the plasma giving the highest hydrolytic activity. Two different eliminations of DPH, slow and rapid, were observed after intravenous and oral administrations of prodrugs. The bioavailabilities of DPH after oral administration at a dose of 25 mg/kg of PT-1 and PT-2 (DPH equivalent), increased to approximately 8.5- and 6.0-fold for PT-1 and PT-2 (rapid elimination group) or 3.0- and 3.0-fold (slow elimination group), respectively, compared to those after dosing of DPH. The plasma levels of DPH converted from PT-2 dosed were lower, but more sustained in slow elimination groups than those from PT-1. The normalized AUC values after oral dosing of prodrugs at a dose of 50 mg/kg were increased dramatically, compared to those at a dose of 25 mg/kg, suggesting non-linear clearance at a high dose. In order to clarify the mechanism for preponderance of intestinal absorption of the prodrugs, concentrations of parent drug and prodrug were measured in intestinal mucosa after a single oral dosing of 50 mg/kg (DPH equivalent). Upon the administration of PT-I and PT-2, greater amounts of DPH, in comparison with those after dosing of DPH, and small amounts of intact prodrugs were detected in the duodenal and jejunal mucosa. These data indicated that these prodrugs was subjected to the extensive intestinal absorption compared to DPH, giving comparatively high plasma levels. Therefore, PT-1 and PT-2 will be useful prodrugs as an orally applicable form. In particular, PT-2 seems to serve as a benign prodrug with the intention of improving the absorption of DPH. (C) 1998 Elsevier Science B.V. All rights reserved.
  • M Yoshimatsu; K Konishi; G Tanabe; O Muraoka
    TETRAHEDRON LETTERS 39 13 1781 - 1782 1998年03月 [査読有り]
     
    A 1,2-sulfonyl shift reaction on cyclopropane proceeded during the reactions of 2-alkynyl-1a-e, 2-aryl-1,1-bis(sulfonyl)cyclopropanes 1f,1j-k and Bu4NF to give trans-1,2-bis(sulfonyl)cyclopropanes 2a-e, 2f, 2J-k. (C) 1998 Elsevier Science Ltd. All rights reserved.
  • M Yoshikawa; T Murakami; H Shimada; H Matsuda; J Yamahara; G Tanabe; O Muraoka
    TETRAHEDRON LETTERS 38 48 8367 - 8370 1997年12月 [査読有り]
     
    A most potent natural alpha-glucosidase inhibitor named salacinol has been isolated from an antidiabetic Ayurvedic traditional medicine, Salacia reticulata WIGHT, through bioassay-guided separation. The stereostructure of salacinol was determined on the basis of chemical and physicochemical evidence, which included the X-ray crystallographic analysis, and the molecular conformation showed the unique spiro-like configuration of the inner salt comprised of 1-deoxy-4-thioarabinofuranosyl cation and 1'-deoxyerythrosyl-3'-sulfate anion. (C) 1997 Elsevier Science Ltd.
  • O. Muraoka; G. Tanabe; E. Yamamoto; M. Ono; T. Minematsu; T. Kimura
    J. Chem. Soc, Perkin Trans. 1 19 2879 - 2890 1997年10月 [査読有り]
     
    Photoirradiation of cis-and trans-4,7-diphenyl-1,3,4,7-tetrahydroisobenzofuran-1-one cis-and trans-14 and its 4-methyl analogues cis-and trans-15 afford the corresponding di-pi-methane rearrangement products 27, 28 and 24 in moderate yields. MM2 calculations for the cis-and trans-4,7-diphenyl substrates cis-and trans-14 showed that the planar structure is most stable for both compounds and that the molecular energy difference between the planar structure and the boat conformation is small enough for a boat-planar-boat conversion. On the basis of the calculations, the di-pi-methane rearrangement of the compounds 14 and 15 is supposed to proceed via the boat conformation with a pseudoaxial phenyl substituent. An X-ray structure determination of the two diphenyl substrates cis-and trans-14 provides strong support for the validity of the calculations in predicting optimum structures for cis-and trans-disubstituted tetrahydroisobenzofuranone.
  • M. Yoshimatsu; S. Gotoh; E. Gotoh; G. Tanabe; O. Muraoka
    J. Chem. Soc, Perkin Trans.1 20 3035 - 3041 1997年10月 [査読有り]
     
    Addition of nucleophiles such as dimethylsulfoxonium methylide and (BuOOLi)-O-t to the conjugate enyne sulfones 4-7, 11-14, 27-28 and 31 occurs at the beta-position to the phenylsulfonyl group to give the corresponding cyclopropanes 15-17 and 19-22 and the oxiranes 33-38 in high yields. The thermal reactions of vinyloxirane 36 show an oxy-Cope rearrangement to give 2-phenylsulfonylphenol 39.
  • O Muraoka; G Tanabe; Y Igaki
    JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1 11 1669 - 1679 1997年06月 [査読有り]
     
    The photoreactivity of two variations of the di-pi-methane system involving the tetrahydro- and hexahydro-isobenzofuran structures 10 and 11 have been examined and compared with those of beta-apolignans 1. The former, 9-phenyl-1,3,4,5,6,7,8,9-octahydronaphtho[2,3-c]furan-1-one 10a and 7-phenyl-1,3,4,7-tetrahydroisobenzofuran-1-one 10b, gave primarily the di-pi-methane rearrangement products 18a and 18b, respectively, while the hexahydro substrate, 7-phenyl-1, 3,4,5,6,7-hexahydroisobenzofuran-1-one 11, afforded mainly the photoreduced products 21-24. This difference in chemoselectivity is explained in terms of the variant configuration of the phenyl group, an axially orientated one migrating most effectively. A new pathway for the reaction leading to the cyclopropano product 18a or 18b, by way of another cyclopropano derivative 19a or 19b, respectively, is described.
  • T Kataoka; Y Nakamura; H Matsumoto; T Iwama; H Kondo; H Shimizu; O Muraoka; G Tanabe
    JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1 3 309 - 316 1997年02月 [査読有り]
     
    Tricyclic benzothiazinium salts 3 are prepared by [2(+)+4] polar cycloaddition of thionium intermediates 2A, generated from the corresponding alpha-chloro sulfides 2, and dienes in the presence of silver perchlorate. Ring transformation of benzothiazinium salts 3 with a reducing agent such as Mg, NaBH4 and Zn-AcOH or with a base, furnishes spiro-vinylcyclopropane derivatives 4 in moderate to high yields. Electrolysis of 3a at -1.4 V vs. SCE in acetonitrile also affords vinylcyclopropane 4a (60%). These results indicate that both ionic and radical mechanisms may account for the vinylcyclopropane formation, although it is unclear as to the nature of the radical intermediate. The stereochemistry of 4a was determined by X-ray analysis showing that sulfur and the vinyl group are cis-orientated. Ten-membered lactam sulfides 6 are obtained as the major product of SmI2 reduction of 3.
  • T Kataoka; Y Nakamura; H Matsumoto; T Iwama; H Shimizu; O Muraoka; G Tanabe
    CHEMICAL & PHARMACEUTICAL BULLETIN 45 2 265 - 271 1997年02月 [査読有り]
     
    Tricyclic benzothiazepinium salts (5) were prepared by [2(+) + 4] polar cycloaddition of thionium intermediates (4A), generated from corresponding alpha-chloro sulfides (4) and dienes in the presence of silver perchlorate, X-Ray analysis of 5a revealed that the configuration of the thiazepinone skeleton and the dihydrothiopyran ring is cis-fused, Reactions of benzothiazepinium salts (5) with NaBH4 or NaH afforded 3,6-epithiobenzazocinone derivatives (9) in high yields by [2,3]-sigmatropic rearrangement of an ylide intermediate (11), The stereochemistry of epithiobenzazocinone (9a) was determined by the nuclear Overhauser enhancement (NOE) technique and finally by X-ray analysis of the sulfoxide (10) derived from epithiobenzazocinone (9a) by m-chloroperbenzoic acid (MCPBA) oxidation, Alkylation of epithiobenzazocinone (9a) afforded 3-alkyl-3,6-epithiobenzazocinones (12) with retention of the configuration at C-3. Dihydrothiopyran derivatives (13) were obtained in good yields by SmI2 reduction of benzothiazepinium salts (5).
  • O. Muraoka; B.-Z. Zheng; K. Okumura; E. Tabata; G. Tanabe; M. Kubo
    J. Chem. Soc, Perkin Trans.1 2 113 - 119 1997年01月 [査読有り]
     
    The second mode of the Huisgen-White rearrangement of the bicyclic lactam, (-)-2-ethyl-4-oxo-3,10-diazabicyclo[4.3.1]decane (-)-13, leading to cis-[6-(prop-1-enyl)piperidin-2-yl]acetic acid (-)-9a under alkaline conditions is described. A reasonable reaction mechanism accounting for the preferable formation of the (E)-propenyl isomer (E)-9a is presented. Conversions of the olefinic acid 9a into two piperidine alkaloids (+)-pinidine (+)-10 and (-)-dihydropinidine (-)-21, and (-)-cis-2-formyl-6-methylpiperidine (-)-22, a key synthetic intermediate for an ants' trail pheromone (+)-monomorine I (+)-11, are also described.
  • M Yoshimatsu; M Naito; H Shimizu; O Muraoka; G Tanabe; T Kataoka
    JOURNAL OF ORGANIC CHEMISTRY 61 23 8200 - 8206 1996年11月 [査読有り]
     
    2-Ethoxy-4-(phenylchalcogeno)but-3-ynyl ketones 1-10 were reduced with LiBH4 in Et(2)O diastereoselectively to give 5-(phenylchalcogeno)pent-4-yn-1-ols 11-20. Treatment of the phenylchalcogen-substituted alkynyl alcohols 11-20 with t-BuOK in t-BuOH provided useful (Z)-2-((phenylchalcogeno)methylene)tetrahydrofurans 21-31 stereoselectively.
  • T Ogiso; M Iwaki; T Tanino; T Nagai; Y Ueda; O Muraoka; G Tanabe
    BIOLOGICAL & PHARMACEUTICAL BULLETIN 19 9 1178 - 1183 1996年09月 [査読有り]
     
    In order to develop a potential prodrug of indomethacin (IM) which causes less irritation to the gastrointestinal mucosa, the ester prodrugs [butyl ester (IM-BE) and octyl ester (IM-OE)] of IM were synthesized and evaluated for their ulcerogenic activity and hepatic injury after oral administration in rats. Additionally, the kinetics of hydrolysis of the prodrugs,were examined to characterize the tissues or organs capable of hydrolyzing the ester bonds. The plasma levels of IM after the oral administration of IM-OE and IM-BE were comparatively low compared with those after IM, with a small bioavailability (2.1 and 15.0%, respectively). Ulcerogenic activity and hepatic injury, expressed by decreased hepatic microsomal enzyme activities, were hardly seen after repeated oral administration of the prodrugs, in contrast with the severely irritating effects of IM alone. Hydrolysis of the prodrugs was adequately described by first-order kinetics. IM-BE was relatively rapidly hydrolyzed in plasma, skin and whole blood, but the hydrolysis in the intestinal mucosa and liver was very slow. The hydrolytic rates for IM-OE were exceedingly small or negligible. These results indicate that the main part of IM-BE and IM-OE administered orally might not be hydrolyzed to IM in the gastrointestinal tract, and that the ester prodrugs themselves were absorbed through the mucosa; also, that the hydrolysis of ester bonds would be carried out mainly in the circulatory system. Consequently, IM-BE seems to be an ideal prodrug of IM.
  • H Shimizu; N Araki; O Muraoka; G Tanabe
    CHEMICAL COMMUNICATIONS 18 2185 - 2186 1996年09月 [査読有り]
     
    2-Benzothiopyrylium salt 1 reacted via a [4(+) + 2]-type polar cycloaddition with dienes 2 in the presence of methanol to afford benzo-fused bicyclo[2.2.2] compounds 5, while in the absence of methanol cycloaddition of 1 with 2,3-dimethylbuta-1,3-diene 2a afforded a novel benzo-fused tricyclic compound 4a, whose structure has been confirmed by X-ray crystallography.
  • Photochemical behavior of ω-thiabicyclo[3.n.1]alkan-3-one: a mechanistic and exploratory study
    O. Muraoka; B.-Z. Zheng; M. Nishimura; G. Tanabe
    J. Chem. Soc. , Perkin Trans. 1 1996 2265 - 2270 1996年08月 [査読有り]
  • O. Muraoka; B.-Z. Zheng; K. Okumura; G. Tanabe; T. Momose; C. H. Eugster
    J. Chem. Soc. , Perkin Trans. 1 13 1567 - 1575 1996年07月 [査読有り]
     
    The transformation of the 'fork head ketone' 3b into the corresponding bicyclic lactone 13 via the Beckmann followed by the Huisgen-White rearrangement is described. Application of the method to a homochiral 2-ethyl-substituted bicyclic ketone(+)-3da gave efficiently(-)-dihydropalustramic acid (-)-2a, a degradation product from the alkaloid palustrine 1, in good optical yield.
  • M Yoshimatsu; M Hayashi; G Tanabe; O Muraoka
    TETRAHEDRON LETTERS 37 24 4161 - 4164 1996年06月 [査読有り]
     
    p-Tolyl benzeneselenosulfonate regioselectively added to the conjugate enynesulfones 1-9 gave (1E, 3E)-1,4-bis(arylsulfonyl)-1,3-butadienes 10-17, which were converted to the 4-hetero atom-substituted-1-phenylsulfonyl-1,3-butadienes 18, 21 and 22. (C) 1996 Elsevier Science Ltd
  • O. Muraoka; B.-Z. Zheng; N. Fujiwara; G. Tanabe
    J. Chem. Soc. , Rerkin Trans. 1 1996 5 405 - 411 1996年03月 [査読有り]
     
    Facile enantioselective syntheses of the di-O-methyl ethers of the norlignans, (-)-agatharesinol (-)-1a, (+)-hinokiresinol (+)-2a and (-)-sugiresinol (-)-3a are described. Grignard addition of vinylmagnesium bromide to an aldimine (-)-13, prepared from the tert-butyl ester 11 and 4-methoxycinnamaldehyde 12, afforded a homochiral vinyl aldehyde, (-)-3-(4-methoxyphenyl)pent-4-enal (-)-14 in >95% ee, which was converted into a diastereoisomeric mixture of 1,3-bis(4-methoxyphenyl)pent-4-enal-ols (3R)-6 by a second Grignard reaction with 4-methoxyphenylmagnesium bromide. Sharpless' asymmetric dihydroxylation of the vinyl alcohols (3R)-6 proceeded diastereoselectively to give the triol of desired relative stereochemistry (2S,3S)-7. This, upon dehydration, afforded (-)-di-O-methylsugiresinol (-)-3b, the subsequent acid-catalysed cyclization of which gave (-)-di-O-methyl agatharesinol (-)-1b, (+)-Di-O-methylhinokiresinol (+)-2b was readily obtained by the dehydration of the vinyl alcohols (3R)-6.
  • O Muraoka; YL Wang; M Okumura; S Nishiura; G Tanabe; T Momose
    SYNTHETIC COMMUNICATIONS 26 8 1555 - 1562 1996年 [査読有り]
     
    A practical synthesis of 7-methylenebicyclo[3.3.1]nonan-3-one 2 by the fragmentation of 1,3-adamantanediol 8, which was prepared effectively by the ruthenium-catalized oxyfunctionalization of 1-adamantanol 7, is described. Characteristic transannular cyclization of 2 leading to a novel tricyclic system, 1-hydroxy-4-protoadamantanone 9, via the corresponding exo-epoxide 10 is also presented.
  • O. Muraoka; G. Tanabe; M. Higashiura; T. Minematsu; T. Momose
    J. Chem. Soc., Perkin Trans. 1 11 1437 - 1443 1995年06月 [査読有り]
     
    The effect of the 'central methane' substitution on the di-pi-methane rearrangement in 4-benzyl-2,5-dihydrofuran-2-ones 8a-d was investigated. Significant enhancement of efficiency in the rearrangement leading in high combined yields to two isomeric products, endo-12, is discussed in terms of both the substituent effects at the benzylic carbon and the restrained features of the ring-enrolled pi-system. The origin of the difference in chemoselectivity compared with that of the 3-benzyl counterpart 5 where a photoarylated product 6 resulted upon photoirradiation was also investigated, and was rationalized by postulating a higher reactivity at the beta-position of the enone system.
  • O. Muraoka; M. Okumura; T. Maeda; L. Wang; G. Tanabe
    Chem. Pharm. Bull. 43 3 517 - 519 1995年03月 [査読有り]
     
    The photo-reaction of 9-oxabicyclo[3.3.1]nonan-3-one (2) was investigated. Upon irradiation in methanol, the ketone (2) predominantly gave the methanol adduct, 3-hydroxymethyl-9-oxabicyclo[3.3.1]nonan-3-ol (3), accompanied with photo-reduced products, exo- and endo-9-oxabicyclo[3.3.1]nonan-3-ol (4 and 5). Irradiation in water resulted in Norrish type I cleavage to give directly (cis-6-methyltetrahydropyran-2-yl)acetic acid (1), a constituent of civet, in moderate yield.
  • Osamu Muraoka; Genzoh Tanabe; Mié Higashiura; Toshie Minematsu; Takefumi Momose
    Journal of the Chemical Society, Perkin Transactions 1 1437 - 1443 1995年 [査読有り]
     
    The effect of the ‘central methane’ substitution on the di-π-methane rearrangement in 4-benzyl-2,5-dihydrofuran-2-ones 8a-d was investigated. Significant enhancement of efficiency in the rearrangement leading in high combined yields to two isomeric products, endo-12 and exo-12, is discussed in terms of both the substituent effects at the benzylic carbon and the restrained features of the ring-enrolled π-system. The origin of the difference in chemoselectivity compared with that of the 3-benzyl counterpart 5 where a photoarylated product 6 resulted upon photoirradiation was also investigated, and was rationalized by postulating a higher reactivity at the β-position of the enone system. © 1995 by the Royal Society of Chemistry. All Rights Reserved.
  • T OGISO; T TANINO; M IWAKI; O MURAOKA; G TANABE
    BIOLOGICAL & PHARMACEUTICAL BULLETIN 17 10 1425 - 1429 1994年10月 [査読有り]
     
    To further clarify the pharmacokinetic characteristics of phenytoin (DPH) and its derivatives, DPH-1-methylnicotininate (MNDPH), valeroyl DPH (VADPH) and valproyl DPH (VPDPH), in plasma and brain, we have investigated their physicochemical properties and protein binding characteristics. Additionally, the hydrolytic conversion of these derivatives to DPH was also studied using small intestine, liver and brain tissues, as well as rat plasma. The log partition coefficient (PC) values of all derivatives were much higher than that of DPH. Judging from their pK(a) values (5.68 and 5.91 for VADPH and VPDPH, respectively) and pH-solubilities, VADPH and VPDPH were acidic compounds, while MNDPH was basic. These data indicated that most fractions of VADPH and VPDPH existed as an ionized form (these fractions existed in an ionized form, 0.98 and 0.97, respectively) at physiological pH, whereas MNDPH existed as a unionized form under the same conditions. Rosenthal or Scatchard plots of the binding data of DPH and its derivatives to both rat plasma protein and bovine serum albumin (BSA) exhibited straight lines over their concentration ranges used, indicating that DPH and its derivatives have a single binding site on the protein. The binding potencies (K or n.P-1 value) of the derivatives to both proteins were much greater than that of DPH. No DPH produced from VADPH and VPDPH was found in the biological fluids over a period of 24h. However, the hydrolysis of MNDPH to DPH was observed in plasma and the tissues used, with the most rapid hydrolysis in the small intestine, and the hydrolysis rate constant in plasma was ca. 20-fold greater than that in the brain. The present results lead us to propose that the low uptake of VADPH and VPDPH into the brain, as well as their rapid elimination from plasma is mainly ascribed to both the high protein binding and the large dissociation of derivatives in the plasma, compared with that of DPH.
  • O MURAOKA; G TANABE; K SANO; T MINEMATSU; T MOMOSE
    JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1 13 1833 - 1845 1994年07月 [査読有り]
     
    The effect of substitution at the 'central methane' on the photoreactivity of 3-benzylfuran-2(5H)ones 5a-g was investigated. Despite its di-pi-methane structure, photochemical arylation was effected to give substituted indenofuranones 6 in good yields. Only the substitution by phenyl caused the di-pi-methane rearrangement to give a cyclopropanofuranone 18g in moderate yield.
  • O. Muraoka; K. Okumura; T. Maeda; G. Tanabe; T. Momose
    Tetrahedron Asymmetry 5 3 317 - 320 1994年03月 [査読有り]
     
    The enantioselective alkylation of the ''fork head ketone'' (1) followed by the Norrish Type I photo-cleavage provided the short enantioselective synthesis of (-)-indolizidine 223AB (4).
  • Osamu Muraoka; Genzoh Tanabe; Kyohko Sano; Toshie Minematsu; Takefumi Momose
    Journal of the Chemical Society, Perkin Transactions 1 1833 - 1845 1994年 [査読有り]
     
    The effect of substitution at the "central methane" on the photoreactivity of 3-benzylfuran-2(5H)ones 5a-g was investigated. Despite its di-π-methane structure, photochemical arylation was effected to give substituted indenofuranones 6 in good yields. Only the substitution by phenyl caused the di-π-methane rearrangement to give a cyclopropanofuranone 18g in moderate yield. © 1994 by the Royal Society of Chemistry. All Rights Reserved.
  • T OGISO; M IWAKI; T TANINO; O MURAOKA; G TANABE
    BIOLOGICAL & PHARMACEUTICAL BULLETIN 16 10 1025 - 1030 1993年10月 [査読有り]
     
    The derivatives of phenytoin (DPH) were synthesized by the reaction at 3 position of hydantoin ring with valproic acid and valeric acid, producing valproyl DPH (VPDPH) and valeroyl DPH (VADPH), respectively. These derivatives showed much higher lipid solubilities than that of DPH. Their distribution and elimination were compared to those of DPH. Additionally, the concentration profiles of the drugs in brain and plasma were analyzed with a modified 2-compartment model. DPH and its derivatives, without hydrolysis to DPH in blood, were found rapidly distributed into brain, although the distribution of derivatives was much less, probably due to the high protein binding capacities. The distribution of DPH and its derivatives into brain regions was similar to that into the cortex cerebri. VPDPH and VADPH were more rapidly eliminated from plasma and brain than DPH, giving smaller mean residence time (MRT) values (0.92 and 0.85 h) and much smaller cortex/plasma concentration ratio than those of DPH. The VPDPH and VADPH concentrations in the cerebrospinal fluid (CSF) were also much lower than that of DPH. The time course of plasma and brain concentrations of DPH and its derivatives after i.v. administration was successfully described by the modified 2-compartment models presented.
  • T. Momose; K. Okumura; H. Tsujimori; K. Inokawa; G. Tanabe; Osamu Muraoka; Y. Sasaki; C. H. Eugster
    Heterocycles 36 1 7 - 11 1993年01月 [査読有り]
     
    The transformation of the ''fork head ketone'' (1) into the corresponding bicyclic lactone (4) via the Beckmann followed by the Huisgen-White Rearrangement is described. An alpha-ethyl-substituted bicyclic ketone (5) was converted efficiently to dihydropalustramic acid (6), a degradation product from the alkaloid palustrine.
  • O. Muraoka; T. Sawada; E. Morimoto; G. Tanabe
    Chem. Pharm. Bull. 41 4 772 - 774 1993年 [査読有り]
     
    A facile synthetic route was developed to (+)-magnosalicin (1), a new type of neolignan with antiallergy activity isolated from Magnolia salicifolia, starting from a chalcone, (3). © 1993, The Pharmaceutical Society of Japan. All rights reserved.
  • T MOMOSE; G TANABE; H TSUJIMORI; O MURAOKA
    CHEMICAL & PHARMACEUTICAL BULLETIN 40 9 2525 - 2530 1992年09月 [査読有り]
     
    The photo-irradiation of 3,4-bis(phenylmethyl)-2(5H)-furanone (5) in acetone or in methanol resulted in selective rearrangement of the 4-phenylmethyl moiety and gave 5-phenyl-1-(phenylmethyl)-3-oxabicyclo[3.1.0]hexan-2-one (9) along with cis- and trans-3,4-bis(phenylmethyl)dihydro-2(3H)-furanone (10a and 10b). The difference in photochemical behavior from that of beta-apolignan (1) is discussed.
  • A breakthrough for the photochemical arylation in the 3-(phenylmethyl)-2(5H)-furanone system leading to the tetrahydroindenofuranone system
    O. Muraoka; G. Tanabe; K. Sano; T. Momose
    Heterocycles 34 1093 - 1096 1992年05月 [査読有り]
  • O. Muraoka; B.-Z. Zheng; N. Fujiwara; G. Tanabe
    Tetrahedron : Asymmetry 2 5 357 - 358 1991年 [査読有り]
     
    Efficient enantioselective synthesis of (-)-sugiresinol dimethyl ether was accomplished based upon two asymmetric induction processes: asymmetric beta-alkylation of alpha,beta-unsaturated aldimines and enantioselective dihydroxylation of olefins.
  • O. Muraoka; G. Tanabe; T. Momose
    Heterocycles 31 9 1589 - 1592 1990年09月 [査読有り]
  • T. Momose; G. Tanabe; H. Tsujimori; M. Higashiura
    Heterocycles 29 2 257 - 262 1989年02月 [査読有り]

書籍

  • 大地からの贈り物サラシア
    田邉 元三 (担当:共著範囲:第四章 合成研究)サラシア属植物普及協会 2018年02月
  • 構造解析プラクティス
    田邉 元三 (担当:共著範囲:)京都廣川書店 2010年09月
  • 医歯薬系学生のためのillustrated基礎化学
    掛樋 一晃; 田邉 元三; 久保 兼信; 岡部 亘雄; 多賀 淳; 桑島 博 (担当:共著範囲:)京都廣川書店 2008年10月
  • 生命科学のための無機化学・錯体化学
    (担当:共著範囲:)廣川書店 2005年 ISBN: 9784567211604 
    平成17年
  • 医歯薬系学生のために illustrated 基礎化学
    (担当:共著範囲:)京都廣川書店 ISBN: 9784901789066 
    平成20年

講演・口頭発表等

  • アーユルヴェーダ植物“サラシア”由来, -グルコシダーゼ阻害剤, ネオコタラノールの合成  [通常講演]
    林 紗也子; 石川文洋; 田邉元三
    第69回日本薬学会関西支部大会 2019年10月
  • タイ天然薬物 Melodorum fruticosum 由来, メラニン産生抑制活性ブテノリド類の合成およびその活性評価  [通常講演]
    塩谷友梨; 石川文洋; 田邉元三
    第69回日本薬学会関西支部大会 2019年10月
  • 拡張型基質結合部位をもつアデニル化酵素の機能解析  [通常講演]
    野原麻耶; 石川文洋; 田邉元三
    第69回日本薬学会関西支部大会 2019年10月
  • Facile Synthesis of Neokotalanol, a Potent α-Glycosidase Inhibitor Isolated from the Ayurvedic Traditional Medicine “Salacia”  [通常講演]
    G. Tanabe; S. Ueda; K. Kurimoto; N. Sonoda; S. Marumoto; F. Ishikawa; O. Muraoka
    27th International Society of Heterocyclic Chemistry Congress (27 ISHC) 2019年09月
  • アデニル化酵素のエンジニアリングによる基質許容性の拡張および構造的基盤  [通常講演]
    石川文洋; 宮永 顕正; 北山陽菜乃; 工藤史貴; 江口正; 田邉 元三
    第13回バイオ関連化学シンポジウム 2019年09月
  • アデニル化酵素の基質特異性の拡張および構造的基盤  [通常講演]
    石川文洋; 宮永顕正; 北山陽菜乃; 工藤史貴; 江口正; 田邉 元三
    第61回天然物討論会 2019年09月
  • Reprogramming aryl acid adenylation domains for non-native building block  [通常講演]
    F. Ishikawa; A. Miyanaga; H. Kitayama; F. Kudo; T. Eguchi; G. Tanabe
    ACS Fall 2019 National Meeting & Exposition 2019年08月
  • 覚醒剤メタンフェタミンにより誘起されるマウスの行動量増加と脳内cFos発現におけるT型カルシウムチャネルの役割  [通常講演]
    小池寧々; 安井洋樹; 関口富美子; 田邉元三; 川畑篤史
    生体機能と創薬シンポジウム2019 2019年08月
  • Repagermanium水解物3-(trihydroxygermyl)propanoic acid (THGP)はH2Sに直接作用し外因性および内因性H2Sによるアロディニアを抑制する  [通常講演]
    杉本果歩; 小池寧々; 島田康弘; 佐藤克行; 中村宣司; 山口浩明; 田邉元三; 関口富美子; 川畑篤史
    生体機能と創薬シンポジウム2019 2019年08月
  • 有機ゲルマニウム化合物repagermanium水解物は気体メディエーターH2Sを捕捉することでアロディニアを抑制する  [通常講演]
    小池寧々; 杉本果歩; 島田康弘; 佐藤克行; 中村宣司; 山口浩明; 田邉元三; 関口富美子; 川畑篤史
    次世代を担う創薬・医療薬理シンポジウム2019 2019年08月
  • アデニル化酵素の基質特性拡張および構造的基盤  [通常講演]
    石川文洋; 宮永顕正; 北山陽菜乃; 工藤史貴; 江口正; 田邉元三
    日本ケミカルバイオロジー学会第14回年会 2019年06月
  • 4,5-ジデヒドロアアリルメルカプタン供与剤としてのチアジノ[3,2-a]ベンズイミダゾール  [通常講演]
    三島 尚也; 田邊 元三; 吉松 三博
    日本化学会第99春季年会 2019年03月
  • チオ糖とエポキシドとのS-アルキル化を鍵反応に用いる“サラシア”由来α-グルコシダーゼ阻害剤, ネオコタラノールの高ジアステレオ選択的合成  [通常講演]
    上田 哲志; 小林 祐喜; 石川 文洋; 村岡 修; 田邉 元三
    日本薬学会第 139 年会 2019年03月
  • T型カルシウムチャネルはマウスにおいてメタンフェタミンにより誘起される行動量増加および脳内特定部位におけるcFos発現に関与する  [通常講演]
    小池 寧々; 安井 洋樹; 関口 富美子; 田邉 元三; 川畑 篤史
    第134回日本薬理学会近畿部会 2019年03月
  • Reprogramming aryl acid adenylating enzymes for non-native building blocks  [通常講演]
    Fumihiro Ishikawa; Hinano Kitayama; Genzoh Tanabe
    10th International Peptide Symposium (10th IPS) 2018年12月
  • タイ天然薬物 Mammea siamensis 花部クマリン 成分の CYP 19 阻害活性  [通常講演]
    二宮清文; ○羅 鳳琳; 柴谷華苗; C. Saowanee; P. Yutana; 村岡 修; 石川文洋; 田邉元三; 森川敏生
    第22回天然薬物の開発と応用シンポジウム 2018年10月
  • ジケトピペラジン生成反応を利用した NRPS プロテオミクス機能解析法の妥当性評価  [通常講演]
    九十九 菜摘; 田邉 元三; 石川 文洋
    第68回日本薬学会近畿支部大会 2018年10月
  • アデニル化酵素 EntE 変異体の精密機能解析を指向した特異的リガンドの設計, 合成および機能評価  [通常講演]
    北山 陽菜乃; 田邉; 元三; 石川 文洋
    第68回日本薬学会近畿支部大会 2018年10月
  • マウスにおいて覚醒剤メタンフェタミンにより誘起される行動量増加と脳内cFos 発現に及ぼすT型カルシウムチャネル阻害薬の効果  [通常講演]
    小池 寧々; 安井 洋樹; 関口 富美子; 田邉 元三; 川畑 篤史
    第68回日本薬学会近畿支部大会 2018年10月
  • 非リボソームペプチド生合成におけるプロテオミクス機能解析法の妥当性評価  [通常講演]
    九十九 菜摘; 石川 文洋; 田邊 元三
    第12回バイオ関連化学シンポジウム 2018年09月
  • アデニル化酵素EntE 変異体の精密機能解析を指向した分子リガンドの合成および機能解析  [通常講演]
    北山 陽菜乃; 石川 文洋; 田邉 元三
    第12回バイオ関連化学シンポジウム 2018年09月
  • Melodorum fruticosum から単離したButenolide 類の全合成とメラニン産生抑制活性  [通常講演]
    田邉 元三
    第60回天然有機化合物討論会 2018年09月
  • Antidiabetic Effects of Naturally Occurring Thiosugar Sulfoniums, Neokotalanol and Salacinol, from Salacia Genus Plants  [通常講演]
    T. Morikawa; M. Kobayashi; J. Akaki; K. Ninomiya; O. Muraoka; G. Tanabe
    28th International Symposium on the Organic Chemistry of Sulfur (ISOCS-28) 2018年08月
  • Highly Diastereoselective Synthesis of Salacinol-type α-Glucosidase Inhibitors and Evaluation of Their in vivo α-Glucosidase Inhibitory Activity  [通常講演]
    田邉 元三
    28th International Symposium on the Organic Chemistry of Sulfur (ISOCS-28) 2018年08月
  • ポリケチド生合成におけるアシル基転移酵素とアシルキャリアタンパク質のクロスリンク反応の検討  [通常講演]
    大内 理紗子; 石川 文洋; 後藤 絵菜; 木村 真希; 宮永 顕正; 田邉 元三; 工藤 史貴; 江口 正
    日本化学会第98春季年会 2018年03月
  • 4,5-ジデヒドロアポルフィン型アルカロイドの合成およびメラニン形成抑制活性評価  [通常講演]
    白戸 美希; 萬瀬 貴昭; 二宮 清文; 丸本 真輔; 石川 文洋; 村岡 修; 森川 敏生; 田邉 元三
    日本薬学会第 138 年会 2018年03月
  • チオ糖とエポキシドとのS-アルキル化を鍵反応に用いる“サラシア”由来,サラシノール型α-グルコシダーゼ阻害剤の高ジアステレオ選択的合成  [通常講演]
    石川文洋; 神農佳澄; 薗田直樹; 村岡修; 田邉元三
    第43回反応と合成の進歩シンポジウム 2017年11月
  • Salacinol, a Potent α-Glucosidase Inhibitor from Ayurvedic Traditional Medicine “Salacia” as a Lead for anti-Diabetic Agents  [招待講演]
    Osamu Muraoka; Genzoh Tanabe; Toshio Morikawa; Shinya Nakamura; Isao Nakanishi; Masayuki Yoshikawa
    第15回和漢研国際伝統薬物シンポジウム 2017年11月
  • タイ天然薬物 Mammea siamensis 由来クマリン成分のアロマターゼ阻害活性  [通常講演]
    森川敏生; 二宮清文; 柴谷華苗; 田邉元三; 筒井 望; Chaipech Saowanee; Pongpiriyadacha Yutana; 村岡 修
    第 60 回香料・テルペンおよび精油化学に関する討論会 2017年10月
  • キャビコール誘導体 ACA-28 は, がん細胞特異的に ERK 依存的細胞死を誘導する革新的抗がん剤シーズである  [通常講演]
    杉浦 麗子; 佐藤 亮介; 松浦 一貴; 萩原 加奈子; 神田 勇輝; 石川 文洋; 田邉 元三; 村岡 修; 高崎 輝恒
    第35回メディシナルケミストリーシンポジウム 2017年09月
  • アーユルベーダ天然薬物“サラシア” 由来スルホニウム塩類のジアステレオ選択的合成及びin vivo α-グルコシダーゼ阻害活性評価  [通常講演]
    石川文洋; 神農佳澄; 薗田直樹; 木内恵里; 赤木淳二; 二宮清文; 村岡修; 吉川雅之; 森川敏生; 田邉元三
    第59回天然有機化合物討論会 2017年09月
  • タイ天然薬物 Melodorum fruticosum含有butenolide類のメラニン産生抑制活性  [通常講演]
    萬瀬貴昭; 田邉元三; 二宮清文; 今川貴仁; 安藤恵里; 福田梨沙; 福田友紀; 石川文洋; 村岡 修; 森川敏生
    日本生薬学会第64回年会 2017年09月
  • アデニレーションドメインの活性部位制御と機能開拓  [通常講演]
    石川 文洋; 田邉 元三
    第11回バイオ関連化学シンポジウム 2017年09月
  • タイ天然薬物 Mammea siamensis 花部のアロマターゼ阻害活性  [通常講演]
    二宮清文; 柴谷華苗; 田邉元三; 筒井 望; Chaipech Saowanee; Pongpiriyadacha Yutana; 村岡 修; 森川敏生
    日本農芸化学会 2017 年度大会 2017年03月
  • 蓮花 (Nelumbo nucifera,花部) 含有メラニン産生抑制アルカロイド成分を指標とした品質評価  [通常講演]
    奥川修平; 北川仁一朗; 甕 千明; 田邉元三; 亀井惟頼; 二宮清文; 吉川雅之; 村岡 修; 森川敏生
    日本農芸化学会 2017 年度大会 2017年03月
  • タイ天然薬物 Melodorum fruticosum 由来成分の NO 産生抑制活性および全合成  [通常講演]
    萬瀬貴昭; 安藤恵里; 田邉元三; 福田梨沙; 福田友紀; 筒井 望; 三宅史織; 中屋友紀子; 山添晶子; 松本朋子; 松田久司; 二宮清文; 村岡 修; 森川敏生
    日本農芸化学会 2017 年度大会 2017年03月
  • タイ天然薬物Melodorum fruticosum由来NO産生抑制活性Butenolide 類の合成およびその活性評価  [通常講演]
    田邉元三; 森川敏生; 福田梨沙; 福田友紀; 萬瀬貴昭; 二宮清文; 松本朋子; 眞野みのり; 松田久司; 村岡 修
    日本薬学会第 137 年会 2017年03月
  • タイ天然薬物 Melodorum fruticosum 由来 butenolide 類の全合成および NO 産生抑制活性評価  [通常講演]
    萬瀬貴昭; 田邉元三; 福田梨沙; 福田友紀; 筒井 望; 三宅史織; 中屋友紀子; 山添晶子; 松本朋子; 松田久司; 二宮清文; 村岡 修; 森川敏生
    第21回天然薬物の開発と応用シンポジウム 2016年10月
  • Anti-cancer drug discovery using fission yeast genetics identified a novel analog of 1’-Acetoxychavicol Acetate (ACA) with a potent anti-tumor activity against human melanoma cells  [通常講演]
    Kazuki Matsuura; Ryosuke Satoh; Kanako Hagihara; Nozomu Tsuchimoto; Yoshimasa Hyodo; Ayako Kita; Genzoh Tanabe; Osamu Muraoka; Reiko Sugiura
    The 12th International Conference on Protein Phosphatase (ICPP12) 2016年10月
  • Anticancer-drug screening utilizing fission yeast genetics identified Acremomannolipin A, a Calcium signalling modulator with anti-tumor activity  [通常講演]
    Ryosuke Satoh; Kazuki Matsuura; Kanako Hagihara; Nozomu Tsuchimoto; Yoshimasa Hyodo; Ayako Kita; Osamu Muraoka; Genzoh Tanabe; Reiko Sugiura
    The 12th International Conference on Protein Phosphatase (ICPP12) 2016年10月
  • タイ天然薬物 Melodorum fruticosum 由来NO産生抑制活性を有する Butenolide 類の全合成  [通常講演]
    田邉元三; 薗田直樹; 福田梨沙; 福田友紀; 萬瀬貴昭; 筒井 望; 二宮清文; 森川敏生; 村岡 修
    第 58 回天然有機化合物討論会 2016年09月
  • タイ天然薬物 Mammea siamensis 花部の機能性成分(7)-含有クマリン成分のアロマターゼ阻害活性  [通常講演]
    二宮清文; 柴谷華苗; 田邉元三; 筒井 望; 末吉真弓; 佐伯竣介; 杉田秀美; Chaipech Saowanee; Pongpiriyadacha Yutana; 早川堯夫; 村岡 修; 森川敏生
    日本生薬学会第 63 回年会 2016年09月
  • サラシア・キネンシスに含有される抗糖尿病作用成分  [通常講演]
    赤木淳二; 小林正和; 森川敏生; 二宮清文; 木内恵里; 田邉元三; Yutana Pongpiriyadacha; 吉川雅之; 村岡 修
    日本食品化学学会第 22 回総会・学術大会 2016年06月
  • Structure–activity relationship studies on acremomannolipin A, the potent calcium signal modulator with a novel glycolipid structure: role of acyl side chains on D-mannose  [通常講演]
    Nozomi Tsutsui; Genzoh Tanabe; Nami Ikeda; Saika Okamura; Marika Ogawa; Kuniko Miyazaki; Ayako Kita; Reiko Sugiura; Osamu Muraoka
    25th French- Japanese Symposium on Medicinal and Fine Chemistry (FJS 2016) 2016年05月
  • メラニン産生抑制活性を有する蓮華含有アルカロイド成分の安定性評価  [通常講演]
    二宮清文; 奥川周平; 甕 千明; 北川仁一朗; 田邉元三; 村岡 修; 森川敏生
    日本薬学会第 136 年会 2016年03月
  • タイ天然薬物 Melodorum fruticosum 由来 NO 産生抑制活性を有する Butenolide 類の全合成  [通常講演]
    田邉元三; 森川敏生; 小川哲平; 薗田直樹; 至田智行; 萬瀬貴昭; 二宮清文; 筒井 望; 村岡 修
    日本薬学会第 136 年会 2016年03月
  • タイ天然薬物 Melodorum fruticosum 由来 NO 産生抑制活性を有する Butenolide 類の全合成  [通常講演]
    至田智之; 田邉元三; 森川敏生; 萬瀬貴昭; 小川哲平; 薗田直樹; 二宮清文; 筒井 望; 村岡 修
    第 65 回日本薬学会近畿支部大会 2015年10月
  • アーユルベーダ天然薬物“サラシア”由来, チオ糖スルホニウム塩型α-グルコシダーゼ阻害剤の新規ジアステレオ選択的合成  [通常講演]
    田邉元三; 筒井 望; 村岡 修
    第41回反応と合成の進歩シンポジウム 2015年10月
  • 蓮華 (Nelumbo nucifera,花部) のメラニン産生抑制活性成分を指標とした品質評価  [通常講演]
    森川敏生; 北川仁一朗; 奥川修平; 甕 千明; 田邉元三; 亀井惟頼; 二宮清文; 吉川雅之; 村岡 修
    第 6 回食品薬学シンポジウム 2015年10月
  • タイ天然薬物 Melodorum fruticosum の由来 NO 産生抑制活性を有する Butenolide 類の全合成  [通常講演]
    田邉元三; 森川敏生; 小川哲平; 薗田直樹; 至田智行; 萬瀬貴昭; 二宮清文; 筒井 望; 村岡 修
    第 59 回香料・テルペンおよび精油化学に関する討論会 2015年09月
  • 紅豆蔲の機能性成分(6)-フェニルプロパノイド成分の肝細胞内中性脂肪代謝促進作用および構造活性相関構造-  [通常講演]
    二宮清文; 萬瀬貴昭; 橋本佳典; 酒井千恵; 二宮 与; Chaipech Saowanee; 早川堯夫; 村岡 修; 森川敏生
    日本生薬学会第 62 回年会 2015年09月
  • メース(Myristica fragrans,仮種皮)の機能性成分(6)-新規ネオリグナン成分の化学構造  [通常講演]
    二宮清文; 八幡郁子; 田邉元三; 早川堯夫; 村岡 修; 森川敏生
    日本生薬学会第 62 回年会 2015年09月
  • Suppressive effects of salacinol and related analogs, a new class of potent alpha-glucosidase inhibitors from Salacia genus plants, on postprandial blood glucose levels in mice  [通常講演]
    Toshio Morikawa; Eri Kinouchi; Junji Akaki; Kiyofumi Ninomiya; Genzoh Tanabe; Masayuki Yoshikawa; Osamu Muraoka
    Inaugural Symposium of the Phytochemical Society of Asia 2015 (ISPSA2015) 2015年08月
  • Salacinol and related analogs, new leads for type 2 diabetes therapeutic candidates from the stems of Salacia chinensis  [通常講演]
    Junji Akaki; Toshio Morikawa; Kiyofumi Ninomiya; Eri Kinouchi; Genzoh Tanabe; Yutana Pongpiriyadacha; Masayuki Yoshikawa; Osamu Muraoka
    12th Asian Congress of Nutrition (ACN2015) 2015年05月
  • 山岡奈樹; 横井里奈; 渡邉真一; 田邉元三; 村岡修
    日本薬学会第 135 年会 2015年03月
  • 田邉元三; 白戸美希; 菅野雄太; 森川敏夫; 二宮清文; 筒井望; 村岡修
    日本薬学会第 135 年会 2015年03月
  • 田邉元三; 至田智行; 松本裕朗; 筒井望; 村岡修
    日本薬学会第 135 年会 2015年03月
  • 森川敏生; 八幡郁子; 二宮清文; 早川堯夫; 田邉元三; 村岡修
    日本薬学会第 135 年会 2015年03月
  • 森川敏生; 赤木淳二; 二宮清文; 田邉元三; 吉川雅之; 村岡修
    生薬分析シンポジウム講演要旨 2014年11月
  • 田中美妃; 高橋奈美; 田邉元三; 村岡修; 吉松三博
    第106回有機合成シンポジウム 2014年11月
  • 田邉元三; 松田侑也; 筒井望; 森川敏生; 赤木淳二; 二宮清文; 仲西功; 中村真也; 吉川雅之; 村岡修
    天然薬物の開発と応用シンポジウム 2014年11月
  • 森川敏生; 赤木淳二; 二宮清文; 木内恵里; 田邉元三; 仲西功; 中村真也; 吉川雅之; 村岡修
    天然薬物の開発と応用シンポジウム 2014年11月
  • 筒井望; 田邉元三; 後藤元気; 森田直; 野村尚央; 岡山善知; 喜多綾子; 杉浦麗子; 村岡修
    メディシナルケミストリーシンポジウム 2014年11月
  • アーユルベーダ天然薬物“サラシア”由来スルホニウム塩型 -グルコシダーゼ阻害剤の効率的簡便合成法の開発―新規ジアステレオ選択的 neosalacinol 合成―  [通常講演]
    田邉元三; 松田侑也; 松本裕朗; 筒井 望; 村岡 修
    第64 回 日本薬学会近畿支部大会 2014年10月
  • アーユルベーダ天然薬物“サラシア”由来スルホニウム塩型 α-グルコシダーゼ阻害剤の新規ジアステレオ選択的合成法の開発  [通常講演]
    田邉元三; 松田侑也; 松本裕朗; 筒井 望; 村岡 修.アーユルベーダ天然薬物“サラシア”由来スルホニウム塩型; グルコシダーゼ阻害剤の新規ジアステレオ選択的合成法の開発
    第 56 回天然有機化合物討論会 2014年10月
  • Developement of a New Facile Route to Sulfonium Salts, a New Class of α-Glucosidase Inhibitors Isolated from Ayurvedic Medicine “Salacia”  [通常講演]
    Genzoh Tanabe; Youya Matsuda; Osamu Muraoka
    24th French-Japanese Symposium on Medicinal and Fine Chemistry 2014年09月
  • 森川敏生; 木内恵里; 赤木淳二; 二宮清文; 田邉元三; 仲西功; 中村真也; 吉川雅之; 村岡修
    第61回 日本生薬学会年会 2014年09月
  • サラシア属植物由来スルホニウム塩型および既存α-グルコシダーゼ阻害剤の同時分析  [通常講演]
    赤木淳二; 森川敏生; 二宮清文; 三宅荘八郎; 田邉元三; 吉川雅之; 村岡 修
    第 68 回日本栄養・食糧学会大会 2014年05月
  • Salacinol and related analogs, new leads for type 2 diabetes therapeutic candidates from Thai traditional natural medicine, Salacia chinensis  [通常講演]
    Toshio Morikawa; Junji Akaki; Kiyofumi Ninomiya; Eri Kinouchi; Genzoh Tanabe; Masayuki Yoshikawa; Osamu Muraoka
    5th International Conference on Natural Products for Health and Beauty (NATPRO5) 2014年05月
  • 異なる生物種由来α-glucosidaseに対するsalacinol類の阻害活性プロフィール  [通常講演]
    村岡 修; 赤木淳二; 二宮清文; 木内恵理; 田邉元三; 吉川雅之; 森川敏生
    日本薬学会第 134 年会 2014年03月
  • アーユルベーダ天然薬物“サラシア”由来α-グルコシダーゼ阻害剤, Neosalacinol の新規ジアステレオ選択的合成  [通常講演]
    田邉元三; 松田侑也; 枡見達陽; 筒井 望; 村岡 修
    日本薬学会第134年会 2014年03月
  • α-グルコシダーゼ阻害剤、salacinolの構造活性相関研究:3'位脂溶性化が活性に及ぼす効果  [通常講演]
    田邉元三; 中村真也; 國方雄介; 筒井 望; 赤木淳二; 森川敏生; 二宮清文; 仲西 功; 吉川雅之; 村岡 修
    第5回食品薬学シンポジウム 2013年11月
  • α-グルコシダーゼ阻害剤の酵素阻害活性におけるヒトとラットの種差の計算化学的解析  [通常講演]
    島田和子; 中村真也; 田邉元三; 村岡修; 仲西功
    第31回メディシナルケミストリーシンポジウム 2013年11月
  • α-グルコシダーゼ阻害剤、salacinolの構造活性相関研究:トルイル酸型置換基による3'位疎水化の効果  [通常講演]
    田邉元三; 中村真也; 國方雄介; 筒井 望; 赤木淳二; 森川敏生; 二宮清文; 仲西 功; 吉川雅之; 村岡 修
    第63回日本薬学会近畿支部大会 2013年10月
  • 新規calciumシグナル調節物質acremomannolipin Aの構造活性相関研究:糖アルコール構造が活性に及ぼす効果  [通常講演]
    筒井 望; 田邉元三; 後藤元気; 森田 直; 野村尚央; 岡山善知; 喜多綾子; 杉浦麗子; 村岡 修
    第63回日本薬学会近畿支部大会 2013年10月
  • Structure-activity relationship study on salacinol, a potent α-glucosidase inhibitor from Ayurbedic traditional medicine “Salacia”: effect of 3'-O-aralkylation with toluic acid  [通常講演]
    Genzoh Tanabe; Shinya Nakamura; Nozomi Tsutsui; Junji Akaki; Toshio Morikawa; Kiyofumi Ninomiya; Isao Nakanishi; Masayuki Yoshikawa; Osamu Muraoka
    9th AFMS International Medicinal Chemistry Symposium (AIMECS13) 2013年10月
  • ラットを用いたネオサラシノールの糖負荷後血糖上昇抑制効果について  [通常講演]
    北林広巳; 臼井俊行; 勝田公雄; 山本正敏; 田邉元三; 吉川雅之; 村岡 修
    第6 回サラシア属植物シンポジウム 2013年09月
  • α-グルコシダーゼ阻害剤、salacinolの構造活性相関研究-トルイル酸型置換基による3'位疎水化の効果-  [通常講演]
    田邉元三; 中村真也; 筒井 望; 赤木淳二; 森川敏生; 二宮清文; 仲西 功; 吉川雅之; 村岡 修
    第31回メディシナルケミストリーシンポジウム 2013年09月
  • The first total synthesis and structure-activity relationships of acremomannolipin A, the potential Ca2+ signal modulator with a characteristic glycolipid structure, isolated from the filamentous fungus Acremonium strictum  [通常講演]
    Nozomi Tsutsui; Genzoh Tanabe; Ayako Kita; Reiko Sugiura; Osamu Muraoka
    14th Tetrahedron Symposium, 2013年06月
  • Salacinol をシードとするスルホニウム塩型α-グルコシダーゼ阻害剤の in silico 設計,合成および評価:3'位アルキル化の効果  [通常講演]
    田邉元三; 國方雄介; 中村真也; 筒井 望; 赤木淳二; 森川敏生; 二宮清文; 仲西 功; 吉川雅之; 村岡 修
    日本薬学会第133年会 2013年03月
  • 新規calciumシグナル調節物質acremomannolipin Aの合成およびその構造活性相関:糖アルコール部の立体化学が及ぼす影響  [通常講演]
    筒井望; 田邉元三; 後藤元気; 森田 直; 野村尚央; 喜多綾子; 杉浦麗子; 村岡 修
    日本薬学会第133 年会 2013年03月
  • ヒトとラットにおけるα-グルコシダーゼ阻害剤アカルボースの酵素阻害活性の種差の検討  [通常講演]
    島田和子; 中村真也; 高平和典; 田逓元三; 村岡修; 仲西功
    日本薬学会第133 年会 2013年03月
  • ヒ卜α-グルコシダーゼ触媒ドメイン群と阻害剤の横断的構造活性相関  [通常講演]
    中村真也; 高平和典; 田邉元三; 村岡修; 仲西功
    日本薬学会第133 年会 2013年03月
  • Salacinolをシードとするスルホニウム塩型α-グルコシダーゼ阻害剤の in silico 設計,合成及び評価  [通常講演]
    田邉元三; 中村真也; 國方雄介; 土屋聡史; 吉長正紘; 筒井 望; 赤木淳二; 森川敏生; 二宮清文; 仲西 功; 吉川雅之; 村岡 修
    第19回天然薬物の開発と応用シンポジウム 2012年11月
  • In Silico Design, Synthesis and Evaluation of 3′-O-Benzylated Analogs of Salacinol, a Potent α-Glucosidase Inhibitor from Ayurvedic Traditional Medicine “Salacia”  [通常講演]
    Genzoh Tanabe; Shinya Nakamura; Nozomi Tsutsui; Masahiro Yoshinaga; Yusuke Kunikata; Junji Akaki; Toshio Morikawa; Kiyofumi Ninomiya; Isao Nakanishi; Masayuki Yoshikawa; Osamu Muraoka
    The 12th International Kyoto Conference on New Aspects of Organic Chemistry (IKCOC-12) 2012年11月
  • Phlorizin-sensitive transport of echnacoside and acteoside and enhanced intestinal absorption after application as an extract  [通常講演]
    Tadatoshi Tanino; Yuki Yamashita; Toshio Morikawa; Genzoh Tanabe; Osamu Muraoka; Masahiro Iwaki
    日本薬物動態学会第27回年会 2012年11月
  • Salacinol をシードとするスルホニウム塩型α-グルコシダーゼ阻害剤の in silico 設計,合成および評価  [通常講演]
    田邉元三; 中村真也; 筒井 望; 赤木淳二; 森川敏生; 二宮清文; 仲西 功; 吉川雅之; 村岡 修
    第30回メディシナルケミストリーシンポジウム 2012年11月
  • オンライン濃縮電気泳動法による Salacia chinensis 由来α-グルコシダーゼ阻害物質の分析  [通常講演]
    宇多田尚典; 森川敏生; 田邉元三; 村岡 修; 鈴木茂生
    第62回日本薬学会近畿支部大会 2012年10月
  • Salacinolをシードとするスルホニウム塩型α-グルコシダーゼ阻害剤のin silico設計,合成及び評価  [通常講演]
    田邉元三; 中村真也; 國方雄介; 土屋聡史; 吉長正紘; 筒井 望; 赤木淳二; 森川敏生; 二宮清文; 仲西 功; 吉川雅之; 村岡 修
    第62回日本薬学会近畿支部大会 2012年10月
  • Salacinol をシードとするスルホニウム塩型α-グルコシダーゼ阻害剤の in silico 設計,合成及び評価  [通常講演]
    田邉元三; 中村真也; 吉長正紘; 筒井 望; Gorre Balakishan; 赤木淳二; 森川敏生; 二宮清文; 仲西 功; 吉川雅之; 村岡 修
    第54回天然有機化合物討論会 2012年09月
  • 銅触媒下でのアルキニル化を伴う4-オキサヘプタ-1,6-ジイン類の分子内環化反応  [通常講演]
    佐々木瞳; 田邉元三; 村岡修; 吉松三博
    日本化学会第92春季年会 2012年03月
  • α-Glucosidase 阻害剤 salacinol の構造活性相関:3’位ベンジル化の効果  [通常講演]
    田邉元三; 土屋聡史; 筒井望; 峯松敏江; 赤木淳二; 中村真也; 仲西功; 吉川雅之; 村岡修
    日本薬学会第132年会 2012年03月
  • α-Glucosidase 阻害剤 salacinol の構造活性相関:3’位epi体の活性について  [通常講演]
    田邉元三; Gorre Balakishan; Mumen; F. A. Amer; 西村彩香; 早阪茉奈美; 筒井望; 峯松敏江; 吉川雅之; 村岡修
    日本薬学会第 132年会 2012年03月
  • α-Glucosidase 阻害剤 salacinol の3’位アルキル化体の合成および活性評価:3’位疎水性置換基が活性に及ぼす効果  [通常講演]
    田邉元三; Balakishan Gorre; 筒井望; 中村真也; 仲西功; 吉川雅之; 村岡修
    生物分子システムに基づく創薬科学フロンティア研究成果発表会 2012年02月
  • Biological Evaluation of 3’-O-Alkylated Analogs of Salacinol, the Role of Hydrophobic Alkyl Group at 3’ Position in the Side Chain on the α-Glucosidase Inhibitory Activity  [通常講演]
    Genzoh Tanabe; Nozomi Tsutsui; Misato Oka; Balakishan Gorre; Weijia Xie; Shinya Nakamura; Isao Nakanishi; Masayuki Yoshikawa; Osamu Muraoka
    th AFMC International Medicinal Chemistry Symposium "Frontier of Medicinal Science" 2011年11月
  • Binding mode prediction of salacinol derivatives with hydrophobic substituents as α-glucosidase inhibitors  [通常講演]
    Kazunori Takahira; Shinya Nakamura; Genzoh Tanabe; Osamu Muraoka; Isao Nakanishi
    8th AFMC International Medicinal Chemistry Symposium "Frontier of Medicinal Science" 2011年11月
  • アルコキシド及びフェノキシドを用いた4- オキソ-1,6-ヘプタジイン類の分子内環化反応  [通常講演]
    橋奈美; 長瀬雄哉; 田邉元三; 村岡修; 吉松三博
    第37回反応と合成の進歩シンポジウム 2011年11月
  • α-Glucosidase 阻害剤 salacinol の3’位疎水化の活性に及ぼす効果  [通常講演]
    田邉元三; 土屋聡史; 筒井望; 赤木淳二; 中村真也; 仲西功; 吉川雅之; 村岡修
    第61回 日本薬学会近畿支部大会 2011年10月
  • 3’-Epi-salacinol 型スルホニウム塩における3’-O-アルキル基の阻害活性への影響  [通常講演]
    田邉元三; 早阪茉奈美; 筒井望; Gorre Balakishan; 謝唯佳; 吉川雅之; 村岡修
    第61回 日本薬学会近畿支部大会 2011年10月
  • Synthesis and Biological Evaluation of 3’-O-Alkylated Salacinols as α-Glucosidase Inhibitors  [通常講演]
    G. Tanabe; T. Otani; H. Takemura; S. Tsuchiya; N. Tsutsui; B. Gorre; M. Yoshikawa; O. Muraoka
    22nd French-Japanese Symposium on Medicinal and Fine Chemistry 2011年09月
  • Biological Evaluation of 3’-O-Alkylated Analogs of Salacinol, the Role of Hydrophobic Alkyl Group at 3’ Position in the Side Chain on the α-Glucosidase Inhibitory Activity  [通常講演]
    G. Tanabe; T. Otani; N. Tsutsui; H. Takemura; W. Xie; B. Gorre; M. Yoshikawa; O. Muraoka
    3rd International Congress on Heterocyclic Chemistry 2011年08月
  • Isolation, Structure Identification and SAR Studies on Thiosugar Sulfonium Salts, Neosalaprinol and Neoponkoranol, as Potent α-Glucosidase Inhibitors  [通常講演]
    W. Xie; G. Tanabe; A. Nishimura; B. Gorre; M. Yoshikawa; O. Muraoka
    23rd International Congress on Heterocyclic Chemistry 2011年08月
  • α-Glucosidase 阻害剤 salacinol の側鎖部 3’-O-アルキル体の合成およびそれらの阻害活性評価  [通常講演]
    田邉元三; 大谷 徹; 二宮清文; 峯松敏江; 吉川雅之; 村岡 修
    日本薬学会第131年会 2011年03月
  • サラキア属植物由来 α-グルコシダーゼ阻害剤neoponkoranolの構造活性相関研究  [通常講演]
    謝 唯佳; 田邉元三; 二宮清文; 峯松敏江; 吉川雅之; 村岡 修
    日本薬学会第131年会 2011年03月
  • α-Glucosidase 阻害剤salacinolおよびkotalanolの側鎖部デオキシ体の合成およびそれらの阻害活性評価  [通常講演]
    田邉元三; 坂野実加; 峯松敏江; 二宮清文; 森川敏生; 吉川雅之; 村岡修
    第60回日本薬学会近畿支部大会 2010年10月
  • α-Glucosidase 阻害剤 neoponkoranol およびその関連物質の合成  [通常講演]
    謝 唯佳; 田邉元三; 峯松敏江; 二宮清文; 森川敏生; 吉川雅之; 村岡修
    第60回日本薬学会近畿支部大会 2010年10月
  • Binding mode prediction and analysis for salacinol derivatives as alpha-glucosidase inhibitors  [通常講演]
    Shinya Nakamura; Kazunori Takahira; Genzo Tanabe; Toshio Morikawa; Mika Sakano; Kiyofumi Ninomiya; Masayuki Yoshikawa; Osamu Muraoka; Isao Nakanishi
    18th European QSAR symposium 2010 2010年09月
  • Characteristic alkaline catalyzed degradation of kotalanol leading to anhydroheptitols: another structural proof  [通常講演]
    Xie W; Osaki S; Tanabe G; Minematsu T; Morikawa T; Yoshikawa M; Muraoka O
    第57回生薬学会 2010年09月
  • Syntheses of kotalanol related thiosugar-sulfonium salts with deoxygenated side chains and their evaluation as α-glucosidase inhibitors  [通常講演]
    Tanabe G; Sakano M; Minematsu T; Ninomiya K; Yoshikawa, M; Muraoka O
    第21回 日仏薬精密化学会議 2010年05月
  • SAR Studies on Kotalanol, a Potent Natural α-Glucosidase Inhibitor: Synthesis of Diastereomers on Side-chain Structure  [通常講演]
    Xie W; Tanabe G; Minematsu T; Yoshikawa M; Muraoka O
    1st Annual International Conference of Medichem-2010 2010年05月
  • α-Glucosidase 阻害剤 salacinol およびkotalanol の側鎖部デオキシ体の合成およびそれらの阻害活性評価  [通常講演]
    田邉元三; 坂野実加; 峯松敏江; 二宮清文; 森川敏生; 吉川雅之; 村岡修
    日本薬学会第130年会 2010年03月
  • サラキア属植物由来 α-グルコシダーゼ阻害剤kotalanolの構造活性相関研究  [通常講演]
    謝 唯佳; 田邉元三; 二宮清文; 峯松敏江; 吉川雅之; 村岡 修
    日本薬学会第130年会 2010年03月
  • サラキア属植物由来 α-グルコシダーゼ阻害剤salacinol の側鎖部に関する構造活性相関研究  [通常講演]
    叢 文英; 田邉元三; 二宮清文; 峯松敏江; 吉川雅之; 村岡 修
    日本薬学会第130年会 2010年03月
  • salacia 属植物有効成分のα グルコシダーゼ結合様式の推定  [通常講演]
    高平和典; 中村 真也; 田邉 元三; 村岡 修; 仲西 功
    本薬学会第130年会 2010年03月
  • α-グルコシダーゼ阻害剤 kotalanol の構造活性相関研究  [通常講演]
    謝 唯佳; 田邉元三; 二宮清文; 峯松敏江; 吉川雅之; 村岡 修
    第28回メディシナルケミストリーシンポジウム 2009年11月 ポスター発表
  • サラキア属植物由来 α-グルコシダーゼ阻害剤 kotalanol の構造活性相関研究  [通常講演]
    田邉元三; 坂野実加; 峯松敏江; 二宮清文; 森川敏生; 吉川雅之; 村岡修
    第28回メディシナルケミストリーシンポジウム 2009年11月
  • サラキア属植物由来抗糖尿病成分の構造と その関連化合物の活性評価  [通常講演]
    村岡 修; 田邉元三; 森川敏生; 二宮清文; 松田久司; 吉川雅之
    第51回天然有機化合物討論会 2009年10月
  • サラキア属植物由来新規チオ糖硫酸分子内塩 salaprinol の全合成、および長鎖アルキル側鎖をもつ関連類縁体のα-グルコシダーゼ阻害活性に関する構造活性相関研究  [通常講演]
    村岡 修; 田邉 元三; 峯松 敏江; 二宮 清文; 吉川雅之
    第59回日本薬学会近畿支部大会 2009年10月 ポスター発表
  • サラキア属植物由来α-グルコシダーゼ阻害活性成分, salaprinol の全合成  [通常講演]
    田邉元三; 坂野実加; 峯松敏江; 松田久司; 吉川雅之; 村岡修
    日本薬学会第129年会 2009年10月
  • サラキア属植物由来α-グルコシダーゼ阻害活性成分の構造について:Kotalanol の絶対構造の解明および新規活性寄与成分の文献提示構造の改訂  [通常講演]
    田邉元三; 謝 唯佳; 尾崎智美; 香川歩美; 森川敏生; 峯松敏江; 吉川雅之; 村岡 修
    第59回日本薬学会近畿支部大会 2009年10月
  • サラキア属植物由来 α-グルコシダーゼ阻害剤kotalanolの構造活性相関研究  [通常講演]
    謝 唯佳; 田邉元三; 二宮清文; 峯松敏江; 吉川雅之; 村岡 修
    第59回日本薬学会近畿支部大会 2009年10月
  • Synthetic Studies on Kotalanol Analogues.  [通常講演]
    M. F. A. Amer; G. Tanabe; M. Yoshikawa; O. Muraoka
    第59回日本薬学会近畿支部大会 2009年10月
  • 2’位に水酸基を有するアルキル側鎖をもつチオ糖スルホニウム塩の合成とその α-glucosidase阻害活性評価.  [通常講演]
    田邉元三; 濱田有希; 赤木淳二; 峯松敏江; 吉川雅之; 村岡修
    日本薬学会第129年会. 2009年03月
  • サラキア属植物由来α-グルコシダーゼ阻害活性成分の構造について:文献提示構造の改訂  [通常講演]
    村岡 修; 謝 唯佳; 田邉元三; Amer M. F. A; 峯松敏江; 吉川雅之
    日本薬学会第129年会 2009年03月
  • 非環式 salacinol 類縁体の合成とその α-glucosidase阻害活性評価  [通常講演]
    田邉元三; 長山麻衣子; 赤木淳二; 峯松敏江; 吉川雅之; 村岡修
    日本薬学会第129年会 2009年03月
  • Salacinol関連成分の合成研究とLCMS定量分析による品質評価  [通常講演]
    村岡 修; 田邉元三; 森川敏生; 三宅荘八郎; 赤木淳二; 二宮清文; 吉川雅之
    第17回 天然薬物の開発と応用シンポジウム 2008年11月
  • α-Glucosidase 阻害剤, Salacinol の脱硫酸エステル体の合成および阻害活性評価  [通常講演]
    田邉元三; 謝 唯佳; 松田久司; 吉川雅之; 村岡 修
    第58回日本薬学会近畿支部大会 2008年10月
  • A Facile Synthesis of de-O-sulfonated salacinol and its evaluation as an in vivo α-glucosidase inhibitor  [通常講演]
    Tanabe G; Xie W; Ogawa A; Minematsu T; Matsuda H; Yosikawa M; Muraoka O
    20th FJS on Medicinal and Fine Chemistry 2008年09月
  • α-Glucosidase阻害剤,Salacinol脱硫酸エステル体の合成および阻害活性評価  [通常講演]
    田邉元三; 小川 藍; 峯松敏江; 村岡 修; 二宮清文; 吉川雅之; 松田久司; 王 涛
    日本薬学会第128年会 2008年03月
  • α-グルコシダーゼ阻害剤, kotalanol類縁体の合成およびその活性評価  [通常講演]
    田邉元三; 松岡桓準; 能島梢司; 大上直人; 金城江里奈; 峯松敏江; 村岡 修; 吉川雅之; 松田久司
    日本薬学会第128年会 2008年03月
  • インド天然薬物Salacia prinoides のチオ糖スルホニウム硫酸分子内塩構造を有するα-グルコシダーゼ阻害成分  [通常講演]
    吉川雅之; 許 鳳鳴; 中村誠宏; 王 涛; 松田久司; 田邉元三; 村岡 修
    日本薬学会第128年会 2008年03月
  • 機能性食品素材“サラシア”の機能と生物活性成分およびその品質評価  [通常講演]
    村岡 修; 森川敏生; 二宮清文; 田邉元三; 松田久司; 吉川雅之
    第36回 生薬分析シンポジウム 2007年11月
  • α-グルコシダーゼ阻害剤, kotalanol 類縁体の合成およびその活性評価  [通常講演]
    田邉元三; 松岡桓準; 能島梢司; 峯松敏江; 松田久司; 吉川雅之; 村岡 修
    第57回日本薬学会近畿支部大会 2007年10月
  • α-Glucosidase阻害物質salacinolおよびkotalanolの類縁体合成と構造活性相関およびLC-MSによる品質評価  [通常講演]
    田邉元三; 松岡桓準; 峯松敏江; 森川敏生; 二宮清文; 松田久司; 吉川雅之; 村田英明; 村岡 修
    第2回食品薬学シンポジウム 2007年10月
  • α-グルコシダーゼ阻害剤, kotalanol の合成研究  [通常講演]
    田邉元三; 松岡桓準; 能島梢司; 大上直人; 金城江里奈; 峯松敏江; 曹長年; 村岡修; 松田久司; 吉川雅之
    第19回天然有機化合物討論会 2007年09月 ポスター発表
  • Synthesis of N-Polyhydroxyalkylated 1-Deoxynojirimycin Derivatives and Their Evaluation as α-Glucosidase Inhibitors  [通常講演]
    Genzoh TANABE; Takanori HATANAKA; Kazuya YOSHIKAI; Toshie MINEMATSU; Tao WANG; Hisashi MATSUDA; Masayuki YOSHIKAWA; Osamu MURAOKA
    第19回 日仏医薬精密化学会議 2007年05月 ポスター発表
  • α-Glucosidase 阻害剤 Salacinol の1,5-anhydro-5-aza-D-glucitol 型類縁体の合成および阻害活性評価  [通常講演]
    田邉元三; 峯松敏江; 畑中上憲; 村岡 修; 吉川雅之; 松田久司; 森川敏生; 王 涛
    日本薬学会第127年会 2007年03月
  • サラシノールのα-glucosidase阻害活性に関する構造と活性の相  [通常講演]
    村岡 修; 田邉元三; 畑中上憲; 松田久司; 吉川雅之
    第1回食品薬学シンポジウム 2006年10月
  • 保険薬局および病院実務実習に対する学生の意識調査  [通常講演]
    北小路 学; 石渡 俊二; 石本 真美子; 船上 仁範; 八軒 浩子; 多賀 淳; 八木秀樹; 和田 哲幸; 田邉 元三; 市田 成志; 西田 升三
    日本社会薬学会第25年会 2006年09月 徳島 日本社会薬学会第25年会
  • SYNTH SYNTHESIS OF 1,5-ANHYDRO-5-AZA-D-GLUCITOL ANALOGS OF SALACINOL AND THEIα-GLUCOSIDASE INHIBITORY ACTIVITIES  [通常講演]
    G. Tanabe; T. Hatanaka; K. Yoshikai; T. Minematsu; T. Wang; H. Matsuda; M. Yoshikawa; O. Muraoka
    International Conference on Biodiversity and Natural Products 2006年07月
  • α-Glucosidase 阻害剤,salacinolの構造活性相関研究:アザ類縁体における脱硫酸エステル体の合成とその活性について  [通常講演]
    田邉元三; 邵 穎; 松浦義治; 羽生恭子; 吉海和哉; 峯松敏江; 村岡 修; 王 涛; 森川敏生; 松田久司; 吉川雅之
    日本薬学会第126年会 2006年03月
  • α-Glucosidase 阻害剤,salacinolの構造活性相関研究:側鎖デオキシ体 の合成とその活性について  [通常講演]
    村岡 修; 吉海和哉; 畑中上憲; 峯松敏江; 田邉元三; 王 涛; 森川敏生; 松田久司; 吉川雅之
    第24回メディシナルケミストリーシンポジウム 2005年11月
  • Synthesis of 1,5-anhydro-5-thioglucitol analogue of salacinol  [通常講演]
    O. Muraoka; T. Hatanaka; T. Morimoto; T. Minematsu; G. Tanabe; H. Matsuda; M. Yoshikawa
    18th French-Japanese Symposium on Medicinal and Fine Chemistry (FIS-2005) 2005年09月
  • Synthesis of 1,5-anhydro-5-aza-D-glucitol analogue of salacinol and its α-glucosidase inhibitory activity  [通常講演]
    O. Muraoka; K. Yoshikai; T. Hatanaka; T. Minematsu; G. Tanabe; T. Wang; H. Matsuda; M. Yoshikawa
    18th French-Japanese Symposium on Medicinal and Fine Chemistry (FIS-2005) 2005年09月
  • 6員環チオ糖構造を有するSalacinol 類縁体の合成  [通常講演]
    村岡 修; 畑中上憲; 森本陽之; 峯松敏江; 田邉元三; 吉川雅之; 松田久司; 森川敏生
    日本薬学会 第125年会 2005年03月
  • α-Glucosidase 阻害剤 salacinol の 1,4-anhydro-L-arabinitol 型類縁体の合成および阻害活性評価  [通常講演]
    村岡 修; 森本陽之; 山本瑞穂; 峯松敏江; 田邉元三; 松田 久司; 吉川雅之
    第53回日本薬学会近畿支部大会 2003年11月
  • Essential structural factors for the α-glucosidase inhibitory activity of salacinol; role of the substituents on the side chain  [通常講演]
    村岡 修; 遠矢俊司; 峯松敏江; 松浦義治; 安原智久; 田邉元三
    19th International Congress of Heterocyclic Chemistry 2003年08月
  • Synthetic studies on salacinol analogue with sulfonium–carboxylate inner salt  [通常講演]
    村岡 修; 遠矢俊司; 峯松敏江; 松浦義治; 安原智久; 田邉元三
    19th International Congress of Heterocyclic Chemistry 2003年08月
  • ポリマー担持型次亜リン酸のベンゼンジアゾニウム塩還元能について  [通常講演]
    田邉元三; 金澤実希; 峯松敏江; 村岡 修
    日本薬学会 第123年会 2003年03月
  • α-Glucosidase 阻害剤 Salacinol のアザ類縁体の合成および阻害活性評価  [通常講演]
    村岡 修; 吉海和哉; 松浦義治; 山田恵理子; 羽生恭子; 峯松敏江; 田邉元三; 松田 久司; 吉川雅之
    第52回日本薬学会近畿支部大会 2002年10月
  • ポリマー担持型次亜リン酸のジスルフィド還元能について  [通常講演]
    村岡 修; 金澤実希; 高野友香里; 峯松敏江; 田邉元三
    第52回日本薬学会近畿支部大会 2002年10月
  • Synthesis of a ntrogen analogue of salacinol and its α-glucosidase inhibitory activity  [通常講演]
    村岡 修; 邵 穎; 吉海和哉; 松浦義治; 山田恵理子; 峯松敏江; 田邉元三; 松田 久司; 吉川雅之
    16th French-Japanese Symposium on Medicinal and Fine Chemistry 2002年09月
  • ポリマー担持型次亜リン酸のジスルフィド還元能について  [通常講演]
    村岡修; 吉海和哉; 滝野真偉美; 峯松敏江; 田邉元三
    日本薬学会 第122年会 2002年03月
  • 薬理活性を有するアダマンタンアミン誘導体の合成研究(3)  [通常講演]
    村岡 修; 田邉元三
    日本薬学会 第121年会 2001年03月
  • Synthesis of 2,3-dihydroinosine derivatives by reduction using BH3-THF  [通常講演]
    広田耕作; 服部龍司; 佐治木弘尚; 門口泰也; 村岡 修; 田邉元三
    第27回核酸化学シンポジウム 2000年10月
  • 新規な環変換反応を利用した薬理活性を有するアダマンタンアミン誘導体の簡便合成  [通常講演]
    田邉元三; 村岡 修; 中 芳治
    第50回日本薬学会近畿支部大会 2000年10月
  • Synthetic studies on adamantanamides with psychostimulant activity  [通常講演]
    村岡 修; 仁岸涼子; 中 芳治; 峯松敏江; 田邉元三
    8th International Kyoto Conference on New Aspects of Organic Chemistry 2000年07月
  • ジスルフィドの新規還元剤の開発 (III):次亜リン酸テトラブチルアンモニウムと次亜リン酸メチルの還元能について  [通常講演]
    村岡 修; 神田宣彦; 田邉元三
    日本薬学会 第120年会 2000年03月
  • 2,3-ジヒドロイノシン誘導体の新規合成法  [通常講演]
    服部龍司; 門口泰也; 佐治木弘尚; 広田耕作; 村岡 修; 田邉元三
    日本薬学会 第120年会 2000年03月
  • 中枢興奮作用を有するアダマンタン類の簡便合成とその応用  [通常講演]
    村岡 修; 中 芳治; 田邉元三
    第49回日本薬学会近畿支部大会 1999年10月
  • Synthetic studies on salacinol, a potent Antidiabetic principle from the ayurvedic traditional medicine “kotala himbutu” (Salacia reticulata WIGHT) in Sri Lanka  [通常講演]
    岡 修; 萬 秀利; 田邉元三; 吉川雅之
    14th French-Japanese Symposium on Medicinal and Fine Chemistry 1999年09月
  • Reactivity of ethyl-2-[(1H-benzimidazol-2-yl)sulfinylmethyl]-4-dimethylamino-5-pyrimidinecarboxylate, a potent H+/K+-ATPase Inhibitor associated with mucosal protective activity, under acidic comditions: A new route to triarylmethanes  [通常講演]
    村岡 修; 駒 理子; 峯松敏江; 田邉元三
    17th International Congress on Heterocyclic Chemistry 1999年08月
  • 中枢興奮作用を有するアダマンタン類の合成研究(2)  [通常講演]
    村岡 修; 仁岸涼子; 田邉元三
    日本薬学会 第119年会 1999年03月
  • 海南島産 Alpinia oxyphylla の果実ヤクチ (益智) の薬理活性セスキテルペノイド  [通常講演]
    村岡 修; 藤本学; 鄭 保忠; 田邉元三; 久保道徳; 吉川雅之
    第42回香料・テルペン及び精油化学に関する討論会 1998年11月
  • スリランカ産天然薬物 "Kotala himbutu" (Salacia reticulata) の 抗糖尿病作用成分:新奇なチオ糖スルホニウム硫酸分子内塩構造を有する α-グルコシダーゼ阻害成分Salacinol 及び Kotalanol の構造  [通常講演]
    吉川雅之; 村上敏之; 森川俊生; 社 謙一; 松田久司; 村岡 修; 田邉元三; 山原條二
    第40回天然有機化合物討論会 1998年10月
  • 中枢興奮作用を有するアダマンタン類の合成研究:1位置換 2-アダマンタナミン誘導体の簡便合成  [通常講演]
    村岡 修; 仁岸涼子; 田邉元三
    第48回日本薬学会近畿支部大会 1998年10月
  • Bicyclo[3.3.1]nonan-endo-diol 類の酸接触における反応特異性 (II)  [通常講演]
    村岡 修; 渋田憲一; 後藤康弘; 田邉元三
    日本薬学会 第118年会 1998年05月
  • Reactivity and mechanism of action of ethyl 2-[(1H-benzimidazol-2-yl)-sulfinylmethyl]-4-dimethylamino-5- pyrimidinecarboxylate, A New H+/K+- ATPase inhibitor associated with mucosal protective activity  [通常講演]
    村岡 修; 駒 理子; 田邉元三
    13th French-Japanese Symposium on Medicinal and Fine Chemistry 1998年05月
  • シクロプロパン環上の 1,2-スルホニルシフト反応  [通常講演]
    吉松三博; 小西圭子; 村岡 修; 田邉元三
    日本化学会 第74春期年会 1998年03月
  • Synthesis of α,α'-cis-substituted piperidine and pyrrolidine alkaloids by the tandem Beckmann and Huisgen-White rearrangement of (+)-2-ethyl-9-azabicyclo[3.3.1]nonan- 3-one  [通常講演]
    村岡 修; 鄭 保忠; 奥村一仁; 田邉元三
    16th International Congress on Heterocyclic Chemistry 1997年09月
  • Di-π-methane 転位を効率よく進めるためには:その立体電子的要件について  [通常講演]
    田邉元三; 村岡 修
    第47回日本薬学会近畿支部大会 1997年09月
  • フェニトインの消化管吸収改善に 関する基礎研究 (II): プロドラッグ化の影響と in vitro 加水分解性  [通常講演]
    谷野公俊; 小木曽太郎; 岩城正宏; 村岡 修; 田邉元三
    日本薬学会 第117年会 1997年03月
  • 1,3,4,7-Tetrahydroisobenzofuran-1- one 類の光転位反応における立体化学について  [通常講演]
    村岡 修; 田邉元三
    日本薬学会 第117年会 1997年03月
  • キラルなカゴ型化合物の合成研究 (1): (-)-4-プロトアダマンタノンおよびその 1-ヒドロキシル体の合成  [通常講演]
    村岡 修; 中谷真理; 田邉元三
    日本薬学会 第117年会 1997年03月
  • α-ハロケトンの新規還元剤、次亜リン酸テトラブチルアンモニウム  [通常講演]
    村岡 修; 萬 秀利; 宮下弘之; 石田敬宏; 田邉元三
    第46回日本薬学会近畿支部大会 1996年10月
  • 糖修飾フェニトインの小腸吸収特性  [通常講演]
    谷野公俊; 小木曽太郎; 岩城正宏; 瓦谷大; 村岡 修; 田邉元三; 掛樋一晃
    日本薬学会 第116年会 1996年03月
  • 9-オキサ-, 9-チアビシクロ[3.3.1]ノナン-3-オン類の光化学反応  [通常講演]
    村岡 修; 鄭 保忠; 伊野美佳; 田邉元三
    日本薬学会 第116年会 1996年03月
  • ジスルフィドの新規還元剤の開発 (II): 相間移動触媒能を有する還元剤、次亜リン酸テトラブチルアンモニウム  [通常講演]
    村岡 修; 青山 寛; 徳永裕子; 田邉元三
    日本薬学会 第116年会 1996年
  • ジスルフィドの新規還元剤の開発 (I): 相間移動触媒能を有する還元剤、次亜リン酸テトラブチルアンモニウム  [通常講演]
    村岡 修; 青山 寛; 徳永裕子; 田邉元三; 吉岡正人
    第45回日本薬学会近畿支部大会 1995年10月
  • ω-ヘテロビシクロ[3.n.1]アルカン-3-オン類の光化学反応  [通常講演]
    村岡 修; 鄭 保忠; 田邉元三; 伊野美佳
    第45回日本薬学会近畿支部大会 1995年10月
  • 1-アダマンタノールの橋頭位選択的酸素官能基化:7-メチレンビシクロ[3.3.1]ノナン-3-オンの簡易合成法の 開発とその三環性篭型化合物への変換  [通常講演]
    村岡 修; 王 亞楼; 田邉元三
    第45回日本薬学会近畿支部大会 1995年10月
  • Synthesis of 2-substituted 2- thiazoline derivatives via the reductive cyclization of N,N'-diacylcystamines  [通常講演]
    村岡 修; 青山 寛; 田邉元三
    15th International Congress on Heterocyclic Chemistry 1995年08月
  • 糖修飾フェニトインの体内動態と in vitro 加水分解性  [通常講演]
    谷野公俊; 小木曽太郎; 岩城正宏; 関口美香; 村岡 修; 田邉元三; 掛樋一晃
    日本薬学会 第115年会 1995年03月
  • 4,7-Dihydroisobenzofuran-1(3H)-one 類の光転位機構について  [通常講演]
    村岡 修; 田邉元三; 小野 勝; 百瀬雄章
    日本薬学会 第115年会 1995年03月
  • 2位置換2-チアゾリン誘導体の新規簡便合成法  [通常講演]
    村岡 修; 青山 寛; 中嶋啓子; 田邉元三; 吉岡正人
    日本薬学会 第115年会 1995年03月
  • 9-Oxa-, 9-thiabicyclo[3.3.1]nonan-3-one 類の光化学反応  [通常講演]
    村岡 修; 鄭 保忠; 西村麻衣子; 田邉元三
    日本薬学会 第115年会 1995年03月
  • )2-Alkyl-ω-azabicyclo[3.n.1]alkan-3α-ol の7位官能基化の試み  [通常講演]
    村岡 修; 田邉元三; 山内邦博; 西村麻衣子; 鄭 保忠; 王 礼探; 百瀬雄章
    第44回日本薬学会近畿支部大会 1994年10月
  • フェニトインの脳毛細血管内皮細胞の透過性改善に関する研究 (2): フェニトイン誘導体の物理化学的性質、タンパク結合性及び加水分解性  [通常講演]
    小木曽太郎; 岩城正宏; 谷野公俊; 野口裕子; 喜多容子; 村岡 修; 田邉元三
    日本薬学会 第114年会 1994年03月
  • Barton 反応を利用した 9-Azabicyclo-[3.3.1]nonan-3α-ol の7位官能基化の試み  [通常講演]
    村岡 修; 田邉元三; 奥村一仁; 百瀬雄章
    日本薬学会 第114年会 1994年03月
  • ビシクロ[3.3.1]ノナン-endo-ジオール類の酸接触における反応特異性  [通常講演]
    田邉 元三
    日本薬学会 第114年会 1994年03月
  • 1,2 位二置換アダマンタン及び3位置換 4-オキサホモアダマンタン類の合成及びその生成機構  [通常講演]
    村岡 修; 奥村正文; 田坂聡子; 田邉元三; 百瀬雄章
    第43回日本薬学会近畿支部大会 1993年10月
  • 9-Azabicyclo[3.3.1]nonan-3-one のタンデム型 Beckmann, Huisgen-White 転位: (+)-Pinidine の不斉合成  [通常講演]
    村岡 修; 奥村一仁; 田邉元三; 王 礼探; 百瀬雄章
    第43回日本薬学会近畿支部大会 1993年10月
  • Synthesis of α,α'-cis-substituted piperidine and pyrrolidine alkaloids by the regioselective α-cleavage of 2-alkyl-ω-azabicyclo[3.n.1]alkane-3-one  [通常講演]
    村岡 修; 奥村一仁; 奥村正文; 田邉元三; 百瀬雄章; C. H. Eugster
    14th International Congress on Heterocyclic Chemistry (ICHC-1993 1993年08月
  • Dihydropalustramic acid の不斉合成  [通常講演]
    村岡 修; 奥村一仁; 田邉元三; 百瀬雄章
    日本薬学会 第113年会 1993年03月
  • フェニトイン及びその誘導体の血中および脳内の pharmacokinetics  [通常講演]
    小木曽太郎; 岩城正宏; 谷野公俊; 野口裕子; 村岡 修; 田邉元三
    日本薬学会 第113年会 1993年03月
  • 4,7-二置換 dihydro-1(3H)-isobenzofuranone 類の光転位反応について  [通常講演]
    村岡 修; 田邉元三; 山口和彦; 山本江美; 百瀬雄章
    日本薬学会 第113年会 1993年03月
  • 2-alkyl-ω-azabicyclo[3.n.1]alkan-3-one の位置選択的α開裂を利用した α,α'位シス置換ピペリジン及びピロリジンアルカロイドの合成  [通常講演]
    村岡 修; 奥村一仁; 猪川香織; 前田知美; 田邉元三; 百瀬雄章
    第34回天然有機化合物討論会 1992年10月
  • 4-Phenyldihydro- および 4-Phenyl-tetrahydro-1(3H)-isobenzofuranone 類の光転位反応について  [通常講演]
    村岡 修; 田邉元三; 井垣裕子; 上坂友美; 百瀬雄章
    第42回日本薬学会近畿支部大会 1992年10月
  • 9-Azabicyclo[3.3.1]nonan-3-one のタンデム型 Beckmann, Huisgen- White 転位:Dihydropalustramic acid 及び pinidine の合成  [通常講演]
    村岡 修; 奥村一仁; 猪川香織; 田邉元三
    第42回日本薬学会近畿支部大会 1992年10月
  • 9-Oxabicyclo[3.3.1]nonan-3-one の光α開裂:Civet の香気成分 (cis-6-methyltetrahydropyran-2-yl)acetic acid の合成  [通常講演]
    村岡 修; 奥村正文; 田邉元三; 百瀬雄章
    第42回日本薬学会近畿支部大会 1992年10月
  • Phenyl-butenolidyl-methane 系の光反応  [通常講演]
    村岡 修; 田邉元三; 百瀬雄章
    第18回反応と合成の進歩シンポジウム 1992年10月
  • 2-Ethyl-9-azabicyclo[3.3.1]nonan-3-one の White 転位による 2,6(cis) 位置換ピペリジン誘導体への変換  [通常講演]
    村岡 修; 奥村一仁; 猪川香織; 田邉元三
    日本薬学会 第112年会 1992年03月
  • 立体拘束を有するα位ベンジル置換 2(5H)-furanone の光反応  [通常講演]
    村岡 修; 田邉元三; 辰巳尚美; 井垣裕子; 上坂友美; 百瀬雄章
    日本薬学会 第112年会 1992年03月
  • Synthesis of αα'-cis-substituted piperidine and pyrrolidine alkaloids by the regioselective α-cleavage of 2-alkyl-ω-aza-bicyclo[3.n.1]alkan- 3-one  [通常講演]
    村岡 修; 猪川香織; 前田知美; 田邉元三; 百瀬雄章
    The 5th International Kyoto Conference on New Aspects of Organic Chemistr 1991年11月
  • 含窒素架橋双環性ケトンの光α開裂を利用したピペリジンアルカロイドの合成研究  [通常講演]
    村岡 修; 藤原範行; 澤田智章; 田邉元三; 百瀬雄章
    日本薬学会 第111年会 1991年03月
  • 3-Benzyl-2(5H)-furanone 系の光閉環反応について  [通常講演]
    村岡 修; 田邉元三; 百瀬雄章
    第40回日本薬学会近畿支部大会 1990年11月
  • 9-Aza-, 9-Oxabicyclo[3.3.1]- nonan-3-one 類の光化学反応  [通常講演]
    村岡 修; 前田知美; 田邉元三; 百瀬雄章
    第40回日本薬学会近畿支部大会 1990年11月
  • (-)-Sugiresinol dimethyl ether とその関連化合物の不斉合成  [通常講演]
    村岡 修; 藤原範行; 澤田智章; 田邉元三; 百瀬雄章
    第16回反応と合成の進歩シンポジウム 1990年11月
  • -Ethyl-9-azabicyclo[3.3.1]- nonan-3-one の White 転位によるピペリジン誘導体への変換  [通常講演]
    村岡 修; 井村美千代; 牧本宣樹; 辻森久元; 田邉元三; 百瀬雄章
    日本薬学会 第110年会 1990年03月
  • 分子内に歪を持たせた Bicyclo[3.3.1]-nonan-3-one 類の光反応  [通常講演]
    田邉 元三
    日本薬学会 第110年会 1990年03月
  • Norlignan 類の立体選択合成 (2)  [通常講演]
    村岡 修; 藤原範行; 澤田智章; 田邉元三; 百瀬雄章
    第39回日本薬学会近畿支部大会 1989年10月
  • α位置換 Benzyl-2(5H)-furanone 系の 光転位反応  [通常講演]
    田邉元三; 佐野恭子; 村岡 修; 百瀬雄章
    第39回日本薬学会近畿支部大会 1989年10月
  • Norlignan 類の立体選択合成  [通常講演]
    百瀬雄章; 村岡 修; 田邉元三
    第38回日本薬学会近畿支部大会 1988年11月
  • 3,4-Dibenzyl-2(5H)-furanone 類における光転位生成物について  [通常講演]
    百瀬雄章; 今西一郎; 金井健一; 田邉元三
    第37回日本薬学会近畿支部大会 1987年11月

MISC

共同研究・競争的資金等の研究課題

  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2022年04月 -2025年03月 
    代表者 : 田辺 元三
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2019年04月 -2023年03月 
    代表者 : 杉浦 麗子; 田辺 元三
     
    杉浦が独自の創薬探索手法により発見したERK MAPKシグナル調節剤である<ACA-28>は、ERK活性依存的細胞死を、がん細胞選択的に誘導することにより、抗腫瘍効果を発揮する。本研究の目的は「ACA-28は、いかなる分子を標的として、ERK MAPKを活性化するのか?」「ACA-28を介するがん細胞選択的な増殖抑制メカニズムは?」という問いを明らかにすることにより、<ERK依存的細胞死>に関わる細胞内シグナル伝達経路を浮き彫りにすることである。今年度は、ACA-28およびそのリード化合物であるGT-7が各種のRas変異を有する膵臓がんに対して細胞死を誘導できることを証明した。特にKRasQ61H変異を有する膵臓がん細胞であるT3M4に対して、ERK依存的細胞死を誘導できることを世界で初めて証明した。一方、KRasG12V変異を有するPANC-1細胞はGT-7依存的な細胞死に抵抗性を示すこと、AKTの活性化がGT-7依存的な細胞死抵抗性のメカニズムであることも証明した。本研究により、KRAS変異を有する膵臓がん細胞に対してGT-7は有効なERK依存的細胞死を誘導するとともに、GT-7とAKT阻害剤の併用が膵臓がんの新たな治療戦略となりうることも明らかになった。ACA-28およびGT-7の標的分子に関しては、ACA-28にビオチン修飾を行った標識化合物を合成し、プルダウン実験と質量分析の手法によりACA-28結合タンパク質を複数同定した。また、リン酸化プロテオミクスの手法を用いてACA-28の標的候補因子群を同定している。現在これらの分子とACA-28の結合やACA-28依存的リン酸化のvalidationを行うとともに、これらの標的候補分子のノックダウンがACA-28あるいはGT-7依存的な細胞死に与える影響を解析している段階である。
  • サラシノールをシードとする高活性スルホニウム塩型食後過血糖改善薬の合成と活性評価
    公益財団法人篷庵社:平成29年度研究助成金
    研究期間 : 2017年04月 -2020年03月 
    代表者 : 田邉 元三
  • サラシノールをシードとする新規ジカチオン型高活性食後過血糖改善薬の合成と活性 評価
    日本学術振興会:科学研究費補助金
    研究期間 : 2017年04月 -2019年03月 
    代表者 : 田邉 元三
  • サラシノールをシードとする高活性スルホニウム塩型食後過血糖改善薬の合成と活性評価
    日本学術振興会:科学研究費補助金
    研究期間 : 2011年04月 -2013年03月 
    代表者 : 田邉 元三
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2002年 -2004年 
    代表者 : 村岡 修; 田邉 元三; 峯松 敏江
     
    報告者らは、1997年インドやスリランカの伝統医学であるアーユル・ヴェーダにおいて、糖尿病の特効薬として用いられている天然薬物、Salacia reticulata WIGHT(Celastraceae)の抽出エキスから、強力なα-glucosidase阻害作用を示す成分、salacinol(1)[Tetrahedron Lett.,8367(1997)]を単離し、絶対構造を含めたその新奇なスルホニウム硫酸分子内塩構造を明らかにしている。本研究では、化合物1の糖鎖上の置換基とその阻害活性との関わりを解明するために、1の側鎖部の水酸基及びヒドロキシメチル基を取り除いた類縁体1,4-dideoxy-1,4[(S)-[3-(sulfooxy)propyl]-,1,4-dideoxy-1,4-[(S)-[(2-hydroxy-3-(sulfooxy)propyl)-および1,4-dideoxy-1,4[(S)-[(3S)-4-hydroxy-3-(sulfooxy)butyl]episulfoniumylidene]-D-arabinitol inner salt(2,3,4)ならびに硫酸エステル基を除去したスルホニウム塩1,4-dideoxy-1,4-[[(2S,3S)-3,4-dibenzyloxy-2-hydroxybutyl]episulfoniumylidene]-D-Arabinitol chloride(5)を合成し、それらのα-glucosidase阻害活性を検定した。 化合物2-4の合成には、1の全合成に用いられた1,4-dideoxy-1,4-epithio-D-arabinitol(6a)と環状硫酸エステル1,3-propanediol 1,3-cyclic sulfate(7)、2-O-benzylglycerol 1,3-cyclic sulfate(8)及び4-O-tert-butyldimethylsilyl-2-deoxy-L-erythtitol 1,3-cyclic sulfate(9)のカップリング反応を応用した。また、5は、1の加メタノール分解で硫酸エステルを除去して合成した。2-4のα-glucosidase阻害活性を検定したところ、何れの化合物も活性が著しく低下し、1の側鎖の両極性官能基がα-glucosidase阻害活性の発現に重要な役割を果たしていることが明らかになった。一方、5は1に匹敵する酵素阻害活性を示すことを見出し、阻害活性の発現には硫酸エステルが必ずしも必要でない事も明らかにした。そこで、5の実用的な合成法を確立すべく、酸触媒存在下でのO-tribenzyl-1,4-dideoxy-1,4-epithio-D-arabinitol(6b)とエポキシ体,(2R)-2-((1S)-1,2-bisbenzyloxyethyl)oxirane(4)のカップリング反応を検討し、好収率で目的のスルホニウム塩5の合成を達成した。
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 1999年 -2001年 
    代表者 : 村岡 修; 田邉 元三; 峯松 敏江
     
    報告者らは,1997年インドやスリランカの伝承医学であるアーユル・ヴェーダで,糖尿病の治療に用いられている天然薬物Kotala himbutu(Salacia reticulata)の抽出エキスから,強力なα-glucosidase阻害作用を示す成分,salacinol(1)[Tetrahedron Lett,8367(1997)]を単離し,絶対構造を含めたその新奇なスルホニウム硫酸分子内塩構造を明らかにしている.本研究では,1のα-glucosidase阻害活性についての構造活性相関を検討するために,1の硫黄を窒素に変換したアザ類縁体2とその類縁体を合成し,それらのα-glucosidase阻害活性を検定した. 2の部分構造を成すアザ糖,1,4-dideoxy-1,4-imino-D-arabinitol(D-3)およびその側鎖部の導入に必要な2,4-O-isopropylidene-L-erythritol-1,3-cyclic sulfate(4)をいずれもD-glucose(5)から効率に合成する方法を確立した.D-3と4のカップリングに先立ち,まずpyrrolidine(6)を用いた予備実験を行い,首尾よくカップリング生成物であるアンモニウム塩(7)を80%の収率で得た.7は1とは異なり,sulfate anion部がammonium cation部と分子内塩を形成していないことが単結晶X線構造解析により明らかになった.D-3および4の反応も効率よく進行し,目的物2を好収率で得た.一方,D-3のエナンチオマーL-3は,1に匹敵する強いα-glucosidase阻害活性を示すことが知られている・そこでL-3をD-xylose(8)から42%の収率で合成し,2,4-benzylidene-D-erythritol-1,3-cyclic sulfate(9)とのカップリング反応に付して,2のエナンチオマー(10)の合成も行なった.2および10のα-glucosidase阻害活性を検定した結果,1の硫黄の窒素への変換は阻害活性を低下させることが判明した.また,L-3から合成した10の阻害活性は,L-3に比べ,著しく低下することも明らかになった.
  • Synthetic Studies on Pharmacologically Active Adamantane Derivatives by Use of the Bicyclo[3.3.1]nonane System as a Synthon
  • Studies on the Reactivity Reactivity of Tetra-n-butylammonium Hypophosphite as the New Reductant
  • Studies on Potent Antidiabetic Principle from the Ayurvedic Traditional Medicine Kotala himbutu(Salacia recticulata WIGHT)in Sri Lanka and India
  • サラシノールをシードとする新規スルホニウム塩型食後過血糖改善剤の合成と活性評価
    日本学術振興会:科学研究費補助金
    代表者 : 田邉 元三

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