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Regulators of Microtubule Assembly : Molecular Recognition Mechanism and Developement of New Regulators.

Research Project

Project/Area Number 05453178
Research Category

Grant-in-Aid for General Scientific Research (B)

Allocation TypeSingle-year Grants
Research Field Chemical pharmacy
Research InstitutionInstitute of Molecular and Cellular Biosciences The University of Tokyo

Principal Investigator

IWASAKI Shigeo  Institute of Molecular and Cellular Biosciences The University of Tokyo., Professor, 分子細胞生物学研究所, 教授 (00013326)

Co-Investigator(Kenkyū-buntansha) SHIRAI Ryuichi  Institute of Molecular and Cellular Biosciences The University of Tokyo., Assist, 分子細胞生物学研究所, 助手 (80183838)
Project Period (FY) 1993 – 1994
Project Status Completed (Fiscal Year 1994)
Budget Amount *help
¥7,500,000 (Direct Cost: ¥7,500,000)
Fiscal Year 1994: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 1993: ¥5,600,000 (Direct Cost: ¥5,600,000)
Keywordsmicrotubules / tubulin / molecular recognition / ustiloxin / aza-combretastatin / curacin / 有糸分裂阻害剤 / 分子確認 / キュラシンA / 微小管機能制御物質 / 分子認識 / リゾキシン / フォモプシン
Research Abstract

In the course of our studies on the antimitotic agents, inhibitors of microtubule assembly, we have discovered a number of inhibitors as the natural and synthetic compounds. Their action mechanisms have also been clarified. In this research project, the followings have been achieved.
Ustiloxins A-D,13-membered cyclic peptides, were isolated from the water extract of false smut balls (ina-kouji), and their structures were determined. Ustiloxins A-D strongly inhibited microtubule assembly. The IC_<50> values were ; A (0.7 uM), B (2.8 uM), C (4.4 uM), D (6.6 uM). Competitive binding assys revealed that their binding site on tubulin is identical to that of rhizoxin/phomopsin. Approaches to find the minimal structure of ustiloxin/phomopsin class antibiotics to bind to tubulin have been attempted by both chemical transformation of ustiloxin D and total synthasis.
Aza-analogs of combretastatin were deviced as the colchicine-site ligands to study the function of this drug-binding site. Some compounds synthesized were postent inhibitors of microtubule assembly.
Synthesis of the partial structure of curacin A,a novel colchicine site ligand having potent antimitotic activity, were attempted to clarify its stereochemistry and action mechanism, and also to develope new cytotoxic agents.

Report

(3 results)
  • 1994 Annual Research Report   Final Research Report Summary
  • 1993 Annual Research Report
  • Research Products

    (24 results)

All Other

All Publications (24 results)

  • [Publications] R.Shirai et al: "Synthesis and anti-tubulin activity of aza-combretastatine" BioMed.Chem.Lett.4. 699-704 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Y.Koiso et al.: "Ustiloxins,antimitotic cyclic peptides from false smut balls on rice panicles caused by Ustilaginoidea virens" J.Antibiotics. 47. 801-809 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Y.Li et al.: "Interaction of marine toxin dolastatin 10 with porcine brain tubulin. Competitive inhibition of rhizoxin and phomopsin A binding" Chemico-Bio Interactions. 93. 175-183 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] R.F.Luduena et al.: "Interaction of ustiloxin A with bovine brain tubulin" Biochem.Pharmacol.47. 1593-1599 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] R.Mutoh et al.: "Synthetivc approach toward the minimal active structure of phomopsin-ustiloxin class of antibiotics" Heterocycles. 41. 9-12 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Y.Li et al.: "Ustiloxins,new antitumor cyclic peptides : Interaction with porcine brain tubulin" Biochem.Pharmacol.48. (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] R.Shirai et al.: "Synthesis and anti-tubulin activity of aza-combretastatine" BioMed.Chem.Lett.4. 699-704 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Y.Koiso et al.: "Ustiloxins, antimitotic cyclic peptides from false smut balls on rice panicles caused by Ustilaginoidea virens" J.Antibiotics. 47. 801-809

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Y.Li et al.: "Interaction of marine toxin dolastatin 10 with porcine brain tubulin. Competitive inhibition of rhizoxin and phomopsin A binding" Chemico-Bio Interactions. 93. 175-183 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] R.F.Luduena et al.: "Interaction of ustiloxin A with bovine brain tubulin" Biochem.Pharmacol. 47. 1593-1599 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] R.Mutoh et al.: "Synthetic approach toward the minimal active structure of phomopsin-ustiloxin class of antibiotics" Heterocycles. 41. 9-12 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Y.Li et al.: "Ustiloxins, new antitumor cyclic peptides : Interaction with porcine brain tubulin" Biochem.Pharmacol.48 (in press). (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Y.Koiso,他: "Ustiloxins,antimitotri cyclic peptides from false smut balls〜" J.Antibiotics. 47. 801-809 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Y.Li,他: "Interaction of a marine toxin dolastatin 10 with porcin 〜" Chemico-Bio.Interactions. 93. 175-183 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] R.F.Induena 他: "Interaction of ustiloxin A with bovine brain tubulin.〜" Biothem.Pharmacol.47. 1593-1599 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] J.Kobayashi,他: "Taxuspines A-C,new taxoid from Japanese new Taxus〜" Tetrahedron. 50. 7401-7416 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] R.Mutoh,他: "Syntheti approach toward the winimal active〜" Heterocycles. 41. 42-52 (1995)

    • Related Report
      1994 Annual Research Report
  • [Publications] Y.Li,他: "Ustiloxins,new antitumn cyclic peptides〜" Biochemical Pharmacel. 48(in press). (1995)

    • Related Report
      1994 Annual Research Report
  • [Publications] Nakada M.et al.: "The first total synthesis of the antitumor macrolide rhizoxin:Synthesis of the key building block" Tetrahedron Lett.34. 1035-1038 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Nakada M.et al.: "The first total synthesis of the antitumor macrolide rhizoxin." Tetrahedron Lett.34. 1039-1042 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Sawada T.et al.: "Identification of the fragment photoaffinity-labeled with azidodansyl-rhizoxin as Met-363〜Lys-379 on β-tubulin" Biochem.Pharanacol.45. 1387-1394 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Sawada T.et al.: "A fluorescent broke and a photoaffinity labeling reagents to study the building site of maytansin and rhizoxin on tubulin" Biocongugate Chemistry. 4. 284-289 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Li Y.et al.: "Interaction of a marine toxin dolastatin 10 with porcine brain tubulin:Competitive inhibition of rhizoxin and phomopsin binding" Chemieo-Biol.Interaction. (印刷中).

    • Related Report
      1993 Annual Research Report
  • [Publications] Shirai R.et al.: "Synthesis and anti-tubulin activity of azo-comhretastatins" Bioorg.Med.Chem.Lett.4. 699-704 (1994)

    • Related Report
      1993 Annual Research Report

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Published: 1993-04-01   Modified: 2016-04-21  

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