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2002 Fiscal Year Final Research Report Summary

Radiosensitizing Effect of Antitumor Enediyne Prodrugs Possessing DNA-Cleaving Activity under Hypoxic Conditions

Research Project

Project/Area Number 12557075
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Radiation science
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

NISHIMOTO Sei-ichi  Kyoto University, Energy and Hydrocarbon Chemistry, Professor, 工学研究科, 教授 (10115909)

Co-Investigator(Kenkyū-buntansha) TANABE Kazuhito  Kyoto University, Energy and Hydrocarbon Chemistry, Instructor, 工学研究科, 助手 (40346086)
SHIBAMOTO Yuta  Nagoya City University, Medicine, Professor, 医学研究科, 教授 (20144719)
Project Period (FY) 2000 – 2002
KeywordsEnediyne / Nitroazole / Hypoxic Tumor Cells / DNA Strand Breaks / Intercalation / Cytotoxicity / Radiosensitizing Effect / Structure-Activity Relationship
Research Abstract

DNA-Cleaving activity and applicability to radiation therapy of hypoxic-tumor cells are evaluated for three classes of compounds: (A) 10-membered 1,5-diyne compounds that are rearranged to unstable enediyne structures by bioactivation, (B) propargylic sulfones that are base-induced isomerized to activated allenic forms, (C) propargylic sulfones with electron-affinic nitroazole structures possessing hypoxic-cell sensitizing activity. The following conclusions were obtained.
(1) 10-Membered 1,5-diyne compounds are confirmed to be prodrugs showing DNA-cleaving activity under acidic conditions that are characteristic of hypoxic cells. The compounds with leaving ester groups were 10 times more active than the analogues with hydroxyl group or methoxy group.
(2) While 10-membered 1,5-diyne compounds with phenyl group and 2-naphtyl group, respectively, have almost equivalent DNA-intercalating ability, the latter showed higher DNA-cleaving activity. This indicates that the DNA cleavage may be str … More ongly influenced by the spatial arrangement upon intercalation into DNA double strand.
(3) Propargylic sulfones bearing 2-nitroimidazole structures were confirmed to be prodrugs that showed hypoxic selective cytotoxicity towards EMT6/KU cells. The DNA-cleaving activity, glutathione-capturing reactivity, cell permeability, and radiosensitizing activity of these novel propargylic sulfones were evaluated.
(4) Propargylic sulfones bearing various substituents were synthesized to evaluate rate of the isomerization to activated allenic forms, DNA-cleaving activity, and cytotoxicity towards mouse tumor cells, thus elucidating activation mechanism of the prodrugs.
(5) Upon introduction of electron withdrawing nitro group the propargylic sulfone compounds have higher glutathione capturing reactivity but less hydrophilic property. This was improved by introduction of additional hydrophilic groups, by which the propargylic sulfone compounds recovered solubility in water with maintaining relatively high glutathione-capturing reactivity. Less

  • Research Products

    (11 results)

All Other

All Publications (11 results)

  • [Publications] 西本清一: "DNA Cleaving Potency, Cytotoxicity, and Mechanism of Action of a Novel Class of Endiyne Prodrugs"Journal of Medicinal Chemistry. 45・4. 758-761 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 芝本雄太: "Comparison of 5-Fluorouracil and 5-Fluoro-2'-deoxyuridine as an Effector in Radiation-Activated Prodrugs"Journal of Chemotherapy. 14. 390-396 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 田邉一仁: "Control of Photo-Induced Drug Release by the Use of Conformational Change of DNA"Nucleic Acids Research Supplemental. 2. 167-168 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 西本清一: "N(1)-C(5)-Linked Dimer Hydrates of 5-Substituted Uracils Produced by Electrolytic Oxidation in Aqueous Solution"Journal of Organic Chemistry. 66・7. 2232-2239 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 西本清一: "Stereo-Electronic Effect on One-Electron Reductive Release of 5-Fluorouracil from 5-Fluoro-1-(2'-oxocycloalkyl)uracilas a New Class of Radiation-Actevated Prodrugs"Journal of Organic Chemistry. 65・15. 4641-4647 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 芝本雄太: "A Novel Class of Antitumor Prodrug, 1-(2-Oxoporpyl)-5-fluorouracil (OFU001) that Release 5-Fluorouracil upon Hypoxic Irradiation"Japanese Journal of Cancer Research. 91・4. 433-438 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Dai, W.-M, Wu, A., Hamaguchi, W., Lee, M. Y. H., Zhou, L., Atsushi Ishii, Nishimoto, S.: "DNA Cleaving Potency, Cytotoxicity, and Mechanism of Action of a Novel Class of Endiyne Prodrugs"Journal of Medicinal Chemistry. 45. 758-761 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Shibamoto, Y., Mimasu, Y., Tachi, Y., Hatta, H., Nishimoto, S.: "Comparison of 5-Fluorouracil and 5-Fluoro-2'-deoxyuridine as an Effector in Radiation-Activated Prodrugs"Journal of Chemotherapy. 14. 390-396 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tanabe, K., Inasaki, T., Okamoto, A., Nishimoto, S., Saito, I: "Control of Photo-Induced Drug Release Using the Conformational Change of DNA"Nucleic Acids Research Supplement. 2. 167-168 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Hatta, H., Zhou, L., Mori, M., Teshima, S., Nishimoto, S: "N(1)-C(5)-Linked Dimer Hydrates of 5-Substituted Uracils Produced by Electrolytic Oxidation in Aqueous Solution"Journal of Organic Chemistry. 66. 2232-2239 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Mori, M., Hatta, H., Nishimoto, S: "Stereo-Electronic Effect on One-Electron Reductive Release of 5-Fluorouracil from 5-Fluoro-1-(2'-oxocycloalkyl) uracil as a New Class of Radiation-Actevated Prodrugs"Journal of Organic Chemistry. 65. 4641-4647 (2000)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2004-04-14  

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