生理活性物質の実用的合成と活性増強

• Project/Area Number: 16073220
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Science and Engineering
• Research Institution: Waseda University
• Principal Investigator: 竜田 邦明 Waseda University, 理工学術院, 教授 (40051627)
• Co-Investigator(Kenkyū-buntansha): 細川 誠二郎 早稲田大学, 理工学術院, 講師 (10307712)
• Project Period (FY): 2004 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥32,100,000 (Direct Cost: ¥32,100,000); Fiscal Year 2007: ¥8,200,000 (Direct Cost: ¥8,200,000); Fiscal Year 2006: ¥9,200,000 (Direct Cost: ¥9,200,000); Fiscal Year 2005: ¥10,100,000 (Direct Cost: ¥10,100,000); Fiscal Year 2004: ¥4,600,000 (Direct Cost: ¥4,600,000)
• Keywords: 生理活性物質 / ナノバイオサイエンス / 構造-活性相関 / 天然物 / 全合成 / 抗生物質 / 有機工業化学 / 医薬品

Research Abstract

多様な生理活性を併せもつ天然生理活性物質(天然物)においては、ある活性が他の活性の副作用として働き、実用化に問題を生じる場合が少なくない。したがって、それらの活性発現機構を明らかにすることによって、活性を構造ユニット別に分離することができれば、副作用の低減のみならず望みの活性を増強できる可能性がある。それはナノレベル以下で精密に分子設計・合成することにより初めて成し遂げられる。
本年度は、以下の4種の天然生理活性物質の全合成を達成した。1)Ca2+シグナル阻害活性を示すYCM1008Aの最初の全合成を、N-および0-付加環化反応を連続的に起こさせ立体選択的に基本骨格と末端のメチル基を構築する方法を開発することにより、想定される4つの異性体をすべて合成して達成すると共に絶対構造を決定した。さらに、この構造-活性相関研究の結果、末端のメチル基の有無と立体配置が活性に関係していることを見いだした。2)エンドセリン変換酵素阻害物質TMC-66の最初の全合成を、連続する七環式構造の効率的かつ立体選択的な構築法を新規の銅酸化剤による閉環反応を見いだして完成し、絶対配置も決定した。3)制がん活性を示す(+)-BE-52440Aの全合成を、既に全合成したnanaomycin類の鍵中間体から立体選択的な酸化反応と付加反応を開発することにより達成すると共に絶対構造も決定した。また、構造-活性相関研究の結果、二量体に相当する架橋構造をもつとnanaomycin類には認められない制がん活性を示すが抗菌活性を示さないことを明らかにした。4)抗アレルギー物質(-)-TMC-264の全合成を、位置選択的ハロゲン化、保護、環化およびキノールの構築法を開発することにより達成すると共に絶対配置を決定した。

Research Products

• [Journal Article] FoxA1 as a Lineage-Specific Oncogene in Luminal Type Breast Cancer. (2008)
  • Author(s): N. Yamaguchi, E. Ito, S. Azuma, R. Honma, Y. Yanagisawa, K. Tatsuta
  • Journal Title: Biochem. Biophys. Res. Commun. 365 Pages: 711-717
  • Peer Reviewed
• [Journal Article] Asymmtric Vinylogous Mukaiyama Aldol Reactions using Vinylketene N,O-Acetals in Total Syntheses of Natural Products. (2008)
  • Author(s): S. Hosokawa and K. Tatsuta
  • Journal Title: Mini-Reviews in Organic Chemistry 5(1) Pages: 1-18
  • Peer Reviewed
• [Journal Article] The First Total Synthesis and Structural Determination of TMC-264. (2008)
  • Author(s): K. Tatsuta, A. Furuyama, T. Yano, Y. Suzuki, T. Ogura and S. Hosokawa
  • Journal Title: Tetrahedron Lett. (in press)
  • Peer Reviewed
• [Journal Article] Total Synthesis and Development of Bioactive Natural Products. (2008)
  • Author(s): K. Tatsuta
  • Journal Title: Proc. Jpn. Acad., Ser. B 84(in press)
  • NAID: 130000093940
  • Peer Reviewed
• [Journal Article] The First Total Synthesis and Structural Determination of YCM1008A. (2007)
  • Author(s): K. Tatsuta, T. Yamaguchi, Y. Tsuda, Y. Yamaguchi, S. Hosokawa
  • Journal Title: Tetrahedron Lett. 48(24) Pages: 4187-4190
  • Peer Reviewed
• [Journal Article] YCM1008A, a Novel Ca2+ -Signaling Inhibitor, Produced by fusarium sp. YCM1008. (2007)
  • Author(s): F. Koizumi, N. Fukumitsu, J. Zhao, S. Hosokawa, K. Tatsuta
  • Journal Title: J. Antibiot. 60(7) Pages: 455-458
  • NAID: 10019831379
  • Peer Reviewed
• [Journal Article] The First Total Synthesis and Structural Determination of (+)-BE-52440A. (2007)
  • Author(s): K. Tatsuta, Y. Suzuki, T. Toriumi, Y. Furuya and S. Hosokawa
  • Journal Title: Tetrahedron Lett. 48(45) Pages: 8018-8021
  • Peer Reviewed
• [Journal Article] The First Total Synthesis and Structural Determination of TMC-66. (2007)
  • Author(s): S. Hosokawa, H. Fumiyama, H. Fukuda, T. Fukuda, M. Seki and K. Tatsuta
  • Journal Title: Tetrahedron Lett. 48(41) Pages: 7305-7308
  • Peer Reviewed
• [Journal Article] The First Total Synthesis of Vinaxanthone, a Fungus Metabolite Possessing Multiple Bioactivities. (2007)
  • Author(s): K.Tatsuta, S.Kasai, Y.Amano, M.Yamaguchi, M.Seki, S.Hosokawa
  • Journal Title: Chem. Lett. 32(1) Pages: 10-11
  • NAID: 10018662349
• [Journal Article] Anti-hypertensive Effect and Safety of Long-term Intake of a Drink Containing Salmon Peptide on High-normal Blood Pressure and Mild Hypertensive Subjects. (2006)
  • Author(s): razaki, K., Tatsuta, R., Takeno, O., Kajimoto
  • Journal Title: Jpn. Pharmacol. Ther. 34(10) Pages: 1119-1135
• [Journal Article] Structure-activity Relationships of Xanthocillin Derivatives as Thrombopoietin Receptor Agonist. (2006)
  • Author(s): T.Yamaguchi, Y.Miyake, A.Miyamura, N.Ishiwata, K.Tatsuta
  • Journal Title: J. Antibiot. 59(11) Pages: 729-734
  • NAID: 10019271215
• [Journal Article] The First Total Synthesis and Structural Determination of Actinopyrone A. (2006)
  • Author(s): S.Hosokawa, K.Yokota, K.Imamura, Y.Suzuki, M.Kawarasaki, K.Tatsuta
  • Journal Title: Tetrahedron Lett. 47(30) Pages: 5415-5418
• [Journal Article] The First Total Synthesis and Structural Determination of Lagunamycin. (2006)
  • Author(s): S.Hosokawa, S.Kuroda, K.Imamura, K.Tatsuta
  • Journal Title: Tetrahedron Lett. 47(35) Pages: 6183-6186
• [Journal Article] 生理活性物質の全合成とその実践的展開の重要性 (2006)
  • Author(s): 竜田邦明
  • Journal Title: 有合化 64(5) Pages: 458-470
  • NAID: 10017486563
• [Journal Article] Total Synthesis of Bioactive Natural Products from Carbohydrates. (2006)
  • Author(s): K.Tatsuta, S.Hosokawa
  • Journal Title: Sci. ＆ Tech. Adv. Materials 7 Pages: 397-410
• [Journal Article] Total Synthesis of Polyketide-Derived Bioactive Natural Products. (2006)
  • Author(s): K.Tatsuta
  • Journal Title: Chemical Record 6(4) Pages: 217-233
• [Journal Article] Total Synthesis of Selected Bioactive Natural Products : Illustration of Strategy and Design. (2005)
  • Author(s): Tatsuta, K., Hosokawa, S.
  • Journal Title: Chem.Rev. 105(12) Pages: 4707-4729
• [Journal Article] The First Total Synthesis of Trichostatin D. (2005)
  • Author(s): Hosokawa, S., Ogura, T., Togashi, H., Tatsuta, K.
  • Journal Title: Tetrahedron Lett. 46(2) Pages: 333-337
• [Journal Article] The First Stereoselective Total Synthesis of Antiviral Antibiotic, Xanthocillin X Dimethylether, and its Stereoisomer. (2005)
  • Author(s): Tatsuta, K., Yamaguchi, T.
  • Journal Title: Tetrahedron Lett. 46(30) Pages: 5017-5020
• [Journal Article] The First Total Syntheis of Trichostatin D (2005)
  • Journal Title: Tetrahedron Lett. 46(2) Pages: 333-337
• [Journal Article] The First Total Synthesis of a Pyranonaphthoguinone Antitumor, BE-54238B (2004)
  • Journal Title: J.Antibiot. 57(4) Pages: 291-297
• [Journal Article] The First Total Synthesis of Lymphostin (2004)
  • Journal Title: Tetrahedron Lett. 45(13) Pages: 2847-2850
• [Journal Article] The First Total Synthesis of Cochleamycin A and Determination of the Absolute Structure (2003)
  • Journal Title: J.Antibiot. 56(6) Pages: 584-590
• [Journal Article] Isolation and Synthesis of a New Bioactive Ellagic Acid Derivative from Combretum yunnanensis (2003)
  • Journal Title: J.Nat.Prod. 66(5) Pages: 729-731
• [Journal Article] Synthetic Inhibitors of Proline-Rich Ligand-Mediated Protein-Protein Interaction Potent Analogs of UCS15A (2003)
  • Journal Title: Chem.& Biol. 10 Pages: 443-451
• [Journal Article] Isolation and Structural Determination of Spilacleosides A and B Having a Novel 1,3-Dioxolan-4-one ring (2003)
  • Journal Title: Tetrahedron Lett. 44 Pages: 2737-3739
• [Journal Article] Total Synthesis of a Tetracyclic Anti-tumor, UCE6 (2002)
  • Journal Title: J.Antibiot. 55 Pages: 1076-1080
• [Journal Article] The First Total Synthesis of Napyradiomycin A1 (2002)
  • Journal Title: Chem.Lett. 2002 Pages: 14-15
• [Journal Article] Total Synthesis of an Antitubercular Lactone Antibiotic, (+)-Tubelactomicin A.
  • Author(s): Hosokawa, S., Seki, M., Fukuda, H., Tatsuta, K.
  • Journal Title: Tetrahedron Lett. in press
• [Journal Article] The First Total Synthesis of a Tetracyclic Antibiotic (-)-Tetrodecamycin.
  • Author(s): Tatsuta, K., Suzuki, Y., Furuyama, A., Ikegami, H.
  • Journal Title: Tetrahedron Lett. in press
• [Book] 天然物の全合成-華麗な戦略と方法- (2006)
  • Author(s): 竜田邦明
  • Total Pages: 256
  • Publisher: 朝倉書店