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Molecular Function of Naturally Occurring Anti-microtubule Agent Phenylahistin (Determination of Structural Components Necessary for the Anti-microtubule activity t and Molecular Design for Drugs)

Research Project

Project/Area Number 12672162
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field 医薬分子機能学
Research InstitutionKyoto Pharmaceutical University

Principal Investigator

HAYASHI Yoshio  Kyoto Pharmaceutical University, Associate Professor, 薬学部, 助教授 (10322562)

Co-Investigator(Kenkyū-buntansha) KISO Yoshiaki  Pharmacy, Assistant, 薬学部, 教授 (40089107)
Project Period (FY) 2000 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2002: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2001: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2000: ¥1,200,000 (Direct Cost: ¥1,200,000)
Keywordsphenylahistin / inhibition of tubulin polymerization / anti-cancer drug / total synthesis / diketopiperazine derivatives / molecular function / medicinal chemistry / molecular design / 抗癌剤 / 創薬 / チューブリン阻害剤 / 抗ガン剤
Research Abstract

Taxanes and the vinca alkaloids are routinely used as the anti-microtubule agents in the clinic, however after long-term treatment, tumors typically become resistant to these compounds. Hence, there is a significant interest in the development of novel anti-microtubule agents for use in clinical oncology. As one of such candidates, we are focusing on a fungal product, phenylahistin (PLH), which belongs to a new class of peptidic colchicine-like microtubule-binding agents that exhibits cytotoxic activity against a wide variety of tumor cell lines. (-)-Phenylahistin (-)-1, a diketopiperazine derivative, consists of L-phenylalanine and a unique isoprenylated dehydrohistidine residue with a quaternary carbon at the 5-position of the imidazole ring. To develop more potent anti-tumor agents based on this diketopiperazine derivative, we investigated to elucidate the structural components necessary for the anti-microtubule activity of (-)-1, then performed the total synthesis of 1 for establish the synthetic route of its derivatives as well. From the biological evaluation of synthetic PLH derivatives, we found that a rigid and planar pseudo-tricyclic structure and the existence of the gem-dimethyl structure at the 5-position of the imidazole ring are important factors to elicit the potent cytotoxic activity. By utilizing this established synthetic route, we synthesized several derivatives of (-)-1, whose substituent at the 5-position of the imidazole ring was modified with different alkyl chains, to determine the effect of this moiety on the biological activity. From the evaluation of derivatives, it is suggested that the existence of the gem-dimethyl structure at this position is important to elicit higher cytotoxic activity.
Further derivatization of (-)-1 using the developed synthetic method will contribute to a better understanding on the structure-activity relationship of phenylahistin and to develop more potent antitumor agents based on the diketopiperazine structure.

Report

(4 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • Research Products

    (24 results)

All Other

All Publications (24 results)

  • [Publications] K.Kanoh, S.Kohno, J.Katada, J.Takahashi, I.Uno, Y.Hayashi: "Synthesis and Biological Activities of Phenylahistin Derivatives"Bioorganic Medicinal Chemistry. 7. 1451-1457 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] K.Kanoh, Y.Hayashi, J.Katada, S.Kohno, I.Uno, Y.Kiso: "Synthesis and Biological Activities of Phenylahistin Derivatives"Peptide Science. 1999. 409-412 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Y.Hayashi, S.Orikasa, K.Tanaka, K.Kanoh, Y.Kiso: "Total Synthesis of Anti-microtubule Diketopiperazine Derivatives : Phenylahistin and Aurantiamine"Journal of Organic Chemistry. 65. 8402-8405 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Y.Hayashi, S.Orikasa, K.Tanaka, K.Kanoh, Y.Kiso: "Synthetic Study of Anti-microtubule Diketopiperazines : Phenylahistin and Aurantiamine"Peptide Science. 2000. 73-76 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Y.Hayashi, Y.Kinoshita, K.Hidaka, A.Kiso, H.Uchibori, T.Kimura, Y.Kiso: "Analysis of Amide Bond Formation with an α-Hydroxy-β-amino Acid Derivative, 3-Amino-2-hydroxyl-4-phenylbutanoic Acid, as an Acyl Component : By-production of Homobislactone"Journal of Organic Chemistry. 66. 5537-5544 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] C.Aninat, Y.Hayashi, F.Andre, M.Delaforge: "Molecular Requirements for Inhibition of Cytochrome P450 Activities by Roquefortine"Chemical Research in Toxicology. 14. 1259-1265 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Y.Hayashi, S.Orikasa, K.Tanaka, K.Kanoh, Y.Kiso: "Phenylahistin, a Small Dipeptidic Colchicine-Like Anti-Microtuble Agent : Total Synthesis and SAR Study of the Derivatives"Peptides. 2001. 638-639 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Y.Hayashi, Y.Kinoshita, K.Hidaka, A.Kiso, H.Uchibori, T.Kimura, Y.Kiso: "Analysis of Side Reaction in the Amide Bond Formation with an α-Hydroxy-β-amino Acid as an Acyl Component"Peptide Science. 2001. 37-40 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kaneo Kanoh et al.: "Synthesis and Biological Activities of Phenylahistin Derivatives"Bioorganic Medicinal Chemistry. 7(7). 1451-1457 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kaneo Kanoh et al.: "Synthesis and Biological Activities of Phenylahistin Derivatives"Peptide Science. 1999. 409-412 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yoshio Hayashi et al.: "Total Synthesis of Anti-microtubule Diketopiperazine Derivatives: Phenylahistin and Aurantiamine"Journal of Organic Chemistry. 65(24). 8402-8405 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yoshio Hayashi et al.: "Synthetic Study of Anti-microtubule Diketopiperazines: Phenylahistin and Aurantiamine"Peptide Science. 2000. 73-76 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yoshio Hayashi et al.: "Analysis of Amide Bond Formation with an α-Hydroxy-β-amino Acid Derivative, 3-Amino-2-hydroxyl-4-phenylbutanoic Acid, as an Acyl Component: By-production of Homobislactone"Journal of Organic Chemistry. 66(16). 5537-5544 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Caroline Aninat et al.: "Molecular Requirements for Inhibition of Cytochrome P450 Activities by Roquefortine"Chemical Research Toxicology. 14(9). 1259-1265 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yoshio Hayashi et al.: "Phenylahistin, a Small Dipeptidic Colchicine-Like Anti-Microtubule Agent: Total Synthesis and SAR Study of the Derivatives"Peptides. 2001. 638-639 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yoshio Hayashi et al.: "Analysis of Side Reaction in the Amide Bond Formation with an α-Hydroxy-β-amino Acid as an Acyl Component"Peptide Science. 2001. 37-40 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] E.Ami, Y.Hayashi, Y.Kiso, 他4名: "Synthesis of novel amino acid, L-bis-tetrahydrofuranylglycines"Tetrahedron Letters. 43・16. 2931-2934 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Y.Hayashi, C, V, Ramesh, Y.Kiso, 他5名: "An Approach for Peptidic Aspartic Protease Inhibitors Using Ala-containing Oligopeptide Independent of the Substrate Sequence"Peptide Science. 2002. 295-296 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] V.Hayashi, Y.Kinoshita, K.Y.Kiso 他4名: "Analysis of amide bond formation with an α-hydroxy-β-amino acid derivatives, 3-amino-2-hydroxy-4-phenlybutanoic acids, as an acyl component"The Journal of Organic Chemistry. 66. 5537-5544 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] C.Aninat, Y.Hayashi, F.Andre, M.Delaforge: "Molecular Requirements for inhibition of cytochrome P450 activities by Roquefortine"Chemical Research in Toxicology. 14. 1259-1265 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Y.Hayashi, S.Orikasa, K.Tanaka, K.Kanoh, Y.Kiso: "Synthetic study of anti-microtubule diketopiperazines : phenylahistin and aurantiamine"Peptide Science. 2000. 73-76 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Y.Hayashi,S.Orikasa,K.Tanaka,K.Kanoh,Y.Kiso: "Total Synthesis of Anti-microtubule Diketopiperazine Derivatives : Phenylahistin and Aurantiamine."The Journal of Organic Chemistry. 65・24. 8402-8405 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Y.Hayashi,K.Iijima,J.Katada,Y.Kiso: "Structure-Activity Relationship Studies of Chloromethylketone Derivatives for Selective Human Chymase Inhibitors."Bioorganic & Medicinal Chemistry Letters. 10. 119-201 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] K.Kanoh Y.Hayashi,J.Katada,S.Kohno,I.Uno,Y.Kiso: "Synthesis and Biological Activitities of Phenylahistin Derivatives."Peptide Science. 1999. 409-412 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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