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Synthesis and PKC binding of conformationally restricted indolactams by aza-Claisen rearrangement

Research Project

Project/Area Number 08660137
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Bioproduction chemistry/Bioorganic chemistry
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

IRIE Kazuhiro  Kyoto University, Graduate School of Agriculture, Division of Applied Life Sciences, Instructor, 農学研究科, 助手 (00168535)

Project Period (FY) 1996 – 1997
Project Status Completed (Fiscal Year 1997)
Budget Amount *help
¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 1997: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1996: ¥1,000,000 (Direct Cost: ¥1,000,000)
Keywordsaza-Claisen rearrangement / teleocidin / indolactam / tumor promoter / protein kinase C / conformation
Research Abstract

Protein kinase C (PKC) is a key enzyme family involved in cellular signal transduction and tumor promotion. It consists of a catalytic domain for protein phosphorylation and a regulatory domain which binds tumor promoters like phorbol esters and teleocidins. The tumor promoter-binding site in PKC is a cysteine-rich domain (CRD) at the N-terminal regulatory region. With the discovery of eleven PKC isozymes, increasing importance is placed on isozyme specific analysis of function. Isozyme-selective activators or inhibitors represent powerful tools to analyze the role of PKC and become new medicinal leads for diseases related to PKC activation like the vascular complications by hyperglycemia.
However, the development of such compounds has been hampered since pure PKC isozymes are not easily obtainable from natural sources. We have synthesized the CRD's of PKCgamma, delta, and eta consisting of ca.50 amino acids by solid phase strategy to establish the models of native PKCs. These peptides were efficiently folded upon zinc treatment to produce PKC regulatory domain surrogates that bind [^3H] phorbol 12,13-dibutyrate (PDBu) with high affinity comparable to native PKC itself, suggesting that these peptides serve as effective models for native PKCgamma, delta, and eta.
Teleocidins and its core structure (-) -indolactam-V are most promising as lead compounds for isozyme selective activation or inhibition of PKC since they are chemically very stable and easily synthesized. Using the PKC surrogate peptides, we have identified two new indolactam derivatives with high PKCgamma CRD selectivity based on our strategy for the design of conformationally restricted indolactam derivatives by aza-Claisen rearrangement. Bridge formation between position 5 and 13 of (-) -indolactam-V was proved to be one of the most effective methods to fix the molecule to the active conformation and to develop new PKC activators with high isozyme selectivity.

Report

(3 results)
  • 1997 Annual Research Report   Final Research Report Summary
  • 1996 Annual Research Report
  • Research Products

    (19 results)

All Other

All Publications (19 results)

  • [Publications] Kazuhiro Irie: "Synthesis and biological activities of new conformationally restricted analogues of (-) -indolactam-V : elucidation of the biologically active conformation of the tumor-promoting teleocidins" J.Am.Chem.Soc.118・44. 10733-10743 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Kazuhiro Irie: "Protein kinase C regulatory domain surrogate peptides : effects of metal ions on folding,phorbol ester-binding,and selectivity" Bioorg.Med.Chem.Lett.7・8. 965-970 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Yu Nakagawa: "Synthesis and biological activities of indolactone-V,the lactone analogue of the tumor promoter (-)-indolactam-V" Biosci.Biotech.Biochem.61・8. 1415-1417 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Kazuhiro Irie: "Comparison of chemical characteristics of the first and the second cysteine-rich domains of protein kinase Cγ" Bioorg.Med.Chem.5・8. 1725-1737 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Kazuhiro Irie: "Synthesis and characterization of model peptides incorporating the phorbol ester-binding domain of protein kinase C." Peptide Chemistry 1996. 209-212 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] 入江 一浩: "プロテインキナーゼCの2つのzinc fingerモチーフの機能と役割" 化学と生物. 35・9. 638-639 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Kazuhiro Irie et al.: "Synthesis and biological activities new conformationally restricted analogues of (-) -indolactam -V : elucidation of the biologically active conformation of the tumor-promoting teleocidins." J.Am.Chem.Soc.118(44). 10733-10743 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Kazuhiro Irie et al.: "Protein kinase C regulatory domain surrogate peptides : effects of metal ions on folding, phorbol ester-binding, and selectivity." Bioorg.Med.Chem.Lett.7(8). 965-970 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Yu Nakagawa, Kazuhiro Irie et al.: "Synthesis and biological activities of indolactone-V,the lactone analogue of the tumor promoter (-) -indolactam-V" Bioorg.Med.Chem.Lett.61(8). 1415-1417 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Kazuhiro Irie et al.: "Comparison of chemical characteristics of the first and the second cysteine-rich domains of protein kinase Cgamma." Bioorg.Med.Chem.5(8). 1725-1737 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Kazuhiro Irie et al.: "Synthesis and characterization of model peptides incorporating the phorbol ester-binding domain of protein kinase C." Peptide Chemistry. 1996. 209-212 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Kazuhiro Irie: "Function and role of the two zinc-finger motifs of protein kinase C." Kagaku-to-Seibutsu. 35(7). 638-639 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Kazuhiro Irie: "Synthesis and biological activities of new conformationally restricted analogues of(-)-indolac-tam-V:elucidation of the biologically active conformation of the tumor-promoting teleocidins" J.Am.Chem.Soc.118・44. 10733-10743 (1996)

    • Related Report
      1997 Annual Research Report
  • [Publications] Kazuhiro Irie: "Protein Kinase C regulatory domain surrogate peptides:effects of metal ions on folding,phorbol ester-binding,and selectivity" Bioorg.Med.Chem Lett.7・8. 965-970 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Yu Nakagawa: "Synthesis and biological activities of indolactone-V,the lactone analogue of the tumor promoter(-)-indolactam-V" Biosci.Biotech.Biochem.61・8. 1415-1417 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Kazuhiro Irie: "Comparision chemical characteristics of the first and the second cysteine-rich domains of protein kinase C_γ" Bioorg.Med.Chem.5・8. 1725-1737 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Kazuhiro Irie: "Synthesis and characterization of model peptides incorporating the phorbol ester-binding domain of protein kinase C." Peptide Chemistry 1996. 209-212 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] 入江一浩: "プロテインキナーゼCの2つのzinc fingerモチーフの機能と役割" 化学と生物. 35・9. 638-639 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Kazuhiro Irie: "Synthesis and biological activities of new conformationally restricted analogues of (-)-indolactam-V:elucidation of the biologically active conformation of the tumor-promoting teleocidins" J.Am.Chem.Soc.118・44. 10733-10743 (1996)

    • Related Report
      1996 Annual Research Report

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Published: 1996-04-01   Modified: 2016-04-21  

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