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Action mechanism and molecular design of biologically active enediyne compounds

Research Project

Project/Area Number 07408033
Research Category

Grant-in-Aid for Scientific Research (A)

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

Principal Investigator

SUGIURA Yukio  Kyoto Univ., Inst.Chem.Res., Prof., 化学研究所, 教授 (40025698)

Co-Investigator(Kenkyū-buntansha) OKUNO Yasushi  Kyoto Univ.Inst.Chem.Res., Instructor, 化学研究所, 教務職員 (20283666)
OTSUKA Masami  Kumamoto Univ.Dept.Pharm.Sci., Prof., 薬学部, 教授 (40126008)
Project Period (FY) 1995 – 1997
Project Status Completed (Fiscal Year 1997)
Budget Amount *help
¥7,400,000 (Direct Cost: ¥7,400,000)
Fiscal Year 1997: ¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 1996: ¥5,100,000 (Direct Cost: ¥5,100,000)
KeywordsAntitumor antibiotic / DNA cleavage / Radical formation / Enediyne / Dynemicin / C-1027 / Esperamicin / Molecular design / 抗生物質 / DNA設計 / DNA認識 / 抗癌活性 / 作用発現機構
Research Abstract

The enediyne antibiotics possess unprecedented chemical structure, potent anticancer activity, and a fascinating mode of bioligical action.In order to clarify the action mechanism of a new enediyne antibiotic C-1027 isolated in Japan, we investigated the C-1027 chromophore-d (GTATC)_2 interaction mode by high resolution NMR method. The NMR results clearly indicate both intercalation and minor groove binding modes with the enediyne chromophore. In the NOESY spectra, the disruption of the sequential connectivities of the base and sugar protons strongly supports intercalative binding at the T_4-A_5 step. The NMR observation is also consistent with intercalation of the benzoxazolinate at the (T_4・A_3)-(A_5・T_2) step. The complex model shows that the DNA oligomer remains in a B-form conformation, although minor groove width (6.04*) are somewhat widened by the occupation of the bulky chromophore. On the other hand, we designed and synthesized 9-membered masked enediyne analogues with DNA intercalator and/or sugar moiety. These new compounds gave high DNA cleaving activity and sequence-specific cleavage. In particular, the sugar attached enediyne analogues are of great promise in respect of antitumor activity and bio-targeting.

Report

(4 results)
  • 1997 Annual Research Report   Final Research Report Summary
  • 1996 Annual Research Report
  • 1995 Annual Research Report
  • Research Products

    (15 results)

All Other

All Publications (15 results)

  • [Publications] Y.Okuno: "Interaction of C-1027 chromophore with d (GTATAC) _2 : A binding model based on NMR experiments" J.Am.Chem.Soc.118. 4729-4730 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] T.Takahashi: "DNA cleavage by a nine-membered masked enediyne an analogue of the kedarcidin and C-1027" Angew.Chem.Int.Ed.Engl.35. 1835-1837 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] 杉浦 幸雄: "DNA塩基配列およびDNA湾曲の認識" 有機合成化学協会誌. 55. 384-392 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Y.Sugiura: "Selective cleavage of tRNA^<phe> with secondary and tertiary structures by enediyne antiumor antibiotics" Bioorg.Med.Chem.5. 205-215 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] T.Takahashi: "Synthesis of nine-membered,masked enediyne an alogues with DNA intercalators." Angew.Chem.Int.Ed.Engl.36. 1524-1526 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Okuno, Y.et al.: "Interaction of C-1027 chromophore with d (GTATAC)_2 : A binding model based on NMR experiments" J.Am.Chem.Soc.118. 4729-4730 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Takahashi, T.et al.: "DNA cleavage by a nine membered masked enediyne, an analogue of the kedarcidin and C-1027" Angew.Chem.Int.Ed.Engl.35. 1835-1837 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Sugiura, Y.et al.: "Recognition of DNA sequence and DNA bending : Molecular desing for artificial repressors" J.Syn.Org.Chem.Jpn.55. 384-392 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Sugiura, Y.et al.: "Selective ckeavage of tRNA^<Phe> with secondary and tertiary structures by enediyne antitumor antibiotics" Bioorg.Med.Chem.5. 205-215 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Takahashi, T..et al.: "Synthesis of nine-membered, masked enediyne analogues with DNA intercalators" Angew.Chem.Int.Ed.Engl.36. 1524-1526 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] 杉浦幸雄: "DNA塩基配列およびDNA湾曲の認識" 有機合成化学協会誌. 55. 384-392 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Y.Sugiura: "Selective Cleavage of tRNA^<phe> with Secondary and Tertiary Structures by Enediyne Antitumor Antibiotics" Bioorg.Med.Chem.5. 205-215 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] T.Takahashi: "Synthesis of Nine-membered,Masked Enediyne Analogues with DNA Intercalators" Angew.Chem.Int.Ed.Engl.36. 1524-1526 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Y.Okuno: "Interaction of C-1027 chromophore with d (GTATAC)_2 : A binding model based on NMR experiments" J.Am.Chem.Soc.118・19. 4729-4730 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] T.Takahashi: "DNA cleavage by a nine-membered masked enediyne,an analogue of the kedarcidin and C-1027 chromophores" Angew.Chem.Int.Ed.Engl.35・16. 1835-1837 (1996)

    • Related Report
      1996 Annual Research Report

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

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