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Structures and Synthesis of Natural Antitumor/Carcinogenic Substances.

Research Project

Project/Area Number 04403009
Research Category

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

Allocation TypeSingle-year Grants
Research Field 天然物有機化学
Research InstitutionNagoya University

Principal Investigator

YAMADA Kiyoyuki  Nagoya University Faculty of Science Professor, 理学部, 教授 (90022540)

Co-Investigator(Kenkyū-buntansha) KIGOSHI Hideo  Nagoya University Faculty of Science Research Associate, 理学部, 助手 (90169839)
OJIKA Makoto  Nagoya University Faculty of Science Research Associate, 理学部, 助手 (50152492)
NIWA Haruki  Nagoya University Faculty of Science Associate Professor, 理学部, 助教授 (20135297)
Project Period (FY) 1992 – 1994
Project Status Completed (Fiscal Year 1994)
Budget Amount *help
¥36,600,000 (Direct Cost: ¥36,600,000)
Fiscal Year 1994: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 1993: ¥4,400,000 (Direct Cost: ¥4,400,000)
Fiscal Year 1992: ¥30,800,000 (Direct Cost: ¥30,800,000)
Keywordsantitumor / cytotoxic / enantioselective sybthesis / marine mollusc / bracken carcinogen / DNA damage / 海産抗腫瘍性物質 / 海産細胞毒性物質 / 構造活性相関 / 合成 / わらび究極発癌物質 / DNA切断 / 全合成 / 絶対立体構造 / 全合成研究 / 求電子活性物質 / DNAアルキル化
Research Abstract

Studies on the structures and synthesis of natural antitumor/carcinogenic substances have been made.
1. Antitumor substances. Absolute stereostructure of aplyronine A,a potent antitumor substance isolated as a minute constituent of the sea hare Aplysia kurodai was determined by NMR spectral analysis any by organic synthetic method. The enantioselective total synthesis of aplyronine A was achieved. The congeners aplyronines B and C were isolated from the sea hare and their structures were established : the role of the trimethylserine group in aplyronine A with respect to the cytotoxicity was clarified by comparison of the cytotoxicity of aplyronine A,B,and C.
2. Cytotoxic substances. From the sea hare Dolabella auricularia new cytotoxic substances such as dolastatins C,D,E,and doliculide were isolated, the structures of which were subsequently determined. The structures of these cytotoxic substances were confirmed by the synthesis unambiguously. Doliculide was synthesized on a large scale sufficient for the evaluation of its antitumor activity.
3. Carcinogenic substances. The ultimate carcinogen derived from ptaquiloside, a potent bracken carcinogenic substance was allowed to react with DNA.Thus, the alkylation of DNA with the ultimate carcinogen took place and subsequently cleavage of DNA occurred : the molecular mechanism of DNA cleavage was clarified in details. The simple analogue of the natural ultimate carcinogen was synthesized, which was shown to have the DNA cleaving activity comparable to that of natural ultimate carcinogen.

Report

(4 results)
  • 1994 Annual Research Report   Final Research Report Summary
  • 1993 Annual Research Report
  • 1992 Annual Research Report
  • Research Products

    (25 results)

All Other

All Publications (25 results)

  • [Publications] Makoto Ojika: "Absolute Stereochemistry of Aplyronine A,a Potent Antitumor Substance of Marine Origin." Journal of the American Chemical Society. 116. 7441-7442 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Hideo Kigoshi: "Total Synthesis of Aplyronine A,a Potent Antitumor Substance of Marine Origin." Journal of the American Chemical Society. 116. 7443-7444 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Tatsushi Kushida: "DNA Damage by Ptaquiloside,a Potent Carcinogen: Detection of Selective Strand Breaks and Identification of DNA Cleavage Products." Journal of the American Chemical Society. 116. 479-486 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Hiroyuki Ishiwata: "Isolation and Stereochemistry of Doliculide,a Cytotoxic Cyclodepsipeptide from the Japanese Sea Hare-----." Journal of Organic Chemistry. 59. 4710-4711 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Kiyoyuki Yamada: "Aplyronine A,a Potent Antitumor Substance,and the Congeners Aplyronines B and C Isolated from the Sea--" Journal of the American Chemical Society. 115. 11020-11021 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Hideo Kigoshi: "Total Synthesis of Natural(-)-Ptaquilosin,the Aglycon of a Potent Bracken Carcinogen Ptaquiloside,and the (+)-Enantiomer and Their DNA Cleaving Activities." Journal of the American Chemical Society. 115. 3056-3065 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Makoto Ojika, Hideo Kigoshi, Takeshi Ishigaki, Itaru Tsukada, Takaya Tuboi, Takeshi Ogawa, and Kiyoyuki Yamada: "Absolute Stereochemistry of Aplyronine A,a Potent Antitumor Substance of Marine Origin." Journal of the American Chemical Society. Vol.116, No.16. 7441-7442 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Hideo Kigoshi, Makoto Ojika, Takeshi Ishigaki, Kiyotake Suenaga, Tsuyoshi Mutou, Akira Sakakura, Takeshi Ogawa, and Kiyoyuki Yamada: "Total Synthesis of Aplyronine A,a Potent Antitumor Substance of Marine Origin." Journal of the American Chemical Society. Vol.116, No.16. 7443-7444 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Tatsushi Kushida, Motonari Uesugi, Yukio Sugiura, Hideo Kigoshi, Hideyuki Tanaka, Junichi Hirokawa, Makoto Ojika, and Kiyoyuki Yamada: "DNA Damage by Ptaquiloside, a Potent Carcinogen : Detection of Selective Stand Breaks and Identification of DNA Cleavage Products." Journal of the American Chemical Society. Vol.116, No.2. 479-486 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Hiroyuki Ishiwata, Takayuki Nemoto, Makoto Ojika, and Kiyoyuki Yamada: "Total Synthesis of Doliculide, a Potent Cytotoxic Cyclodepsipetide from the Japanese Sea Hare Dolabella auricularia" The Journal of Organic Chemistry. Vol.59, No.17. 4710-4711 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Kiyoyuki Yamada, Makoto Ojika, Takeshi Ishigaki, Yoshifumi Yoshida, Hisao Ekimoto, and Masayuki Arakawa: "Aplyronine A,a Potent Antitumor Substance, and the Congeners Aplyronines B and C Isolated from the Sea Hare Aplysia kurodai." Journal of the American Chemical Society. Vol.115, No.23. 11020-11021 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Hideo Kigoshi, Yoshifumi Imamura, Kazuhiro Mizuta, Haruki Niwa, and Kiyoyuki Yamada: "Total Synthesis of Natural (-) -Ptaquilosin, the Aglycon of a Potent Bracken Carcinogen Ptaquiloside, and the (+) -Enantiomer and Their DNA Cleaving Activities." Journal of the American Chemical Society. Vol.115, No.8. 3056-3065 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Makoto Ojika: "Absolute Stereochemistry of Aplyronine A,a Potent Antitumor Substance of Marine Origin." Journal of the American Chemical Society. 116. 7441-7442 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Hideo Kigoshi: "Total Synthesis of Aplyronine A, a Potent Antitumor Substance of Marine Origin." Journal of the American Chemical Society. 116. 7443-7444 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Hiroyuki Ishiwata: "Isolation and Stereostructure of Doliculide,a Cytotoxic eyclodepsipeptide from the Japanese Sea Hare Dolabella--" The Journal of Organic Chemistry. 59. 4710-4711 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Hiroyuki Ishiwata: "Total Synthesis of Doliculide,a Potent Cytotoxic Cyclodepsipeptide from the Japanese Sea Hare Dolabella--" The Journal of Organic Chemistry. 59. 4712-4713 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Hiroyuki Ishiwata: "Enantioselective Total Synthesis of Doliculide,a Potent Cytotoxic Cyclodepsipeptide of Marine Origin and Structure- --" Tetrahedron. 50. 12853-12882 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Hideo Kigoshi: "Total Synthesis of Natural (-)-Ptaquilosin,the Aglycon of a Potent Bracken Carcinogen Ptaquiloside,and the (+)-Enantiomer --" Journal of the American Chemical Society. 115. 3056-3065 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Kiyoyuki Yamada: "Aplyronine A,a Potent Antitumor Substance,and the Congeners Aplyronines B and C Isolated from the Sea Hare Aplysia kurodai." Journal of the American Chemical Society. 115. 11020-11021 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Makoto Ojika: "Further Studies on Aplyronine A,an Antitumor Substance Isolated from the Sea Hare Aplysia kurodai." Tetrahedron Letters. 34. 8501-8504 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Makoto Ojika: "Studies on the Stereochemistry of Aplyronine A:Determination of the Stereochemistry of the C21-C34 Fragment." Tetrahedron Letters. 34. 8505-8508 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Hideo Kigoshi: "Synthetic Studies on Aplyronine A,a Potent Antitumor Substance of Marine Origin:Stereocontrolled Synthesis of the C21-C34 ---" Tetrahedron Letters. 35. (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] Tatsushi Kushida: "DNA Damage by Ptaquiloside,a Potent Bracken Carcinogen:Detection of Selective Strand Breaks and Identification of ---" Journal of the American Chemical Society. 116. (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] Hideo Kigoshi: "Syntesis of Analogues of a Bracken Ultimate Carcinogen and Their DNA Cleaving Acitivities." Tetrahedron Letters. 33. 6647-6650 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Hideo Kigoshi: "Total Synthesis of Natural (-)-Ptaquilosin,the Aglycon of a Potent Bracken Carcinogen Ptaquiloside and the (+)-Enantiomer,and Their DNA Cleaving Activities." Journal of the American Chemical Society. 115. (1993)

    • Related Report
      1992 Annual Research Report

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Published: 1992-04-01   Modified: 2016-04-21  

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