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1996 Fiscal Year Final Research Report Summary

Activation Mechanism of Prodrugs Releasing 5-Fluorouracil by Radiolytic Reduction

Research Project

Project/Area Number 07455339
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field 工業物理化学
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) OHOTANI Bunsho  Instructor, 工学研究科, 助手 (80176924)
KITAGAWA Toshikazu  Kyoto University Energy and Hydrocarbon Chemistry Lecturer, 工学研究科, 講師 (20183791)
FUJITA Shin-ichi  University of Osaka Prefecture Research Institute of Advanced Technology Associa, 先端科学研究所, 助教授 (60100210)
TAKEUCHI Kenichi  Kyoto University Energy and Hydrocarbon Chemistry Professor, 工学研究科, 教授 (50026358)
Project Period (FY) 1995 – 1996
KeywordsRadiation-Activating Prodrugs / Radiolytic Reduction / 5-Fluorouracil / N (1) -C (5) -Linked Dimer / Electrochemical Synthesis / 2-Oxo Compounds / pi^<**>-sigma^<**>Orbital Overlap / Pulse Radiolysis
Research Abstract

Various 1- (5FU) -substituted compounds possessing alpha-carbonyl group were synthesized to study activation mechanism via radiolytic reduction and structural effects on the rate selectivity of 5-fluorouracil (5FU) releasing reaction. The following results were obtained.
(1) Investigation the effect of reducting additives (aromatic amines and low valent transition metal ions) on the radiolytic reduction reactivity of homo-and hetero-dimers of 5FU,we concluded activation mechanism by which dimer radical anions release F^-ions preferentially to form oxidizing 5-yl radicals that undergo hydrolysis to release 5FU.
(2) Various 2-oxo compounds bearing releasing 5FU were synthesized to correlate the nucleophilic substitution by S_<RN>^1 mechanism with the activation mechanism of 5FU releasing via radiolytic reduction.
(3) X-Ray crystallography of 1- (5FU)-substituted compounds demonstrated degree of overlapping between carbonyl pi^<**>-orbital and sigma^<**>-orbital of C-N bond. This structural characteristics was correlated with one-electron reduction potential and activation mechanism of 5FU releasing.
(4) In the case of 4-substituted cyclohexanone derivatives possessing 2-oxo group the pi^<**>-sigma^<**> orbital overlapping is significantly different between cis and trans isomers, thereby the 5FU releasing reactivity was critically altered.
(5) The 5FU/uracil dimer released 5FU by OH radical reaction in the sonolysis of aqueous solution.
(6) On the basis of theoretical organic chemistry, the quantitative structure-activity relationship was characterized to get insight into molecular design of radiation activating prodrugs that is able to release antitumor 5FU via one-electron reduction.

  • Research Products

    (26 results)

All Other

All Publications (26 results)

  • [Publications] 周 玲: "Electron-Affinic Radiosensitizers Possessing NPSH-Reactive Side Chains : Cytotoxicity and Radiosensitizing Activity towards Hypoxic EMT6 Cells In Vitro" International Journal of Radiation Biology. 67. 335-346 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 西本清一: "A Pulse Radiolysis Study on Redox Reactivities of Carbon-and Nitrogen-Contered Amiono Acid Radicals Produced by OH Radical Reaction in Aqueous Solution" Amino Acids. 9. 9-9 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 岡本邦男: "Ionic Dissociation of Carbon-Carbon σ Bonds in Hydrocarbons and the Formation of Authentic Hydrocarbon Salts" Advanced of Physical Organic Chemistry. 30. 173-221 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 岡崎隆男: "Acid-Isomerization of 3,4-Dimethyl-4-homoadamantyl Cation to 3-Ethyl-5-methy-1-adamantyl Cation. A Unique Method for Construction of an Adamantyl Framework Having Two Alkyl Groups on the Bridgehead Positions" Chemistry Letters. 981-982 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 北川敏一: "Regiospecific Coordinationnation of tert-ButylfullerideIon and 1,4-Dicyclopropyltropylium Ion. Synthesis of a Dialkyldihydrofullerene Having a Heterolytically Dissociative Carbon-Carbon σ-Bond" Journal of Organic Chemistry. 60. 1490-1491 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 大谷文章: "Stereoselective Synthesis of Piperidine-2,6-dicarboxylic Acids by Photocatalytic Reaction of Aqueous Cadmium (II) Sulfide Dispersion" Tetrahedron Letters. 36. 3189-3192 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 戴偉民: "Synthesis of cis-Enediynes from 1,5-Diynes by Rearrangement of an Allylic Double Bond" Angewandte Chemie. International Edition in English. 35. 779-781 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 戴偉民: "DNA Cleavage of Novel Propargylic Sulfones. Enhancement of Potency via Intercalating Interaction" Bioorganic and Medicinal Chemistry Letters. 1093-1098 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 岡崎隆男: "Solvolysis of [3-13C]-3,4-Dimethyl-4-homoadamantyl p-Nitrobenzoate. Comparison of the Barriers to the Wagner-Meerwein Rearrangement of the Secondary and Tertiary 4-Homoadamantyl Cations" Tetrahedron Letters. 37. 1035-1038 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 徳永和彦: "Solvolysis of 2-Thioxo Bridgehead Compounds as Compared with their 2-Oxo Homologs : Evidence for Marked p-Conjugation in 2-Thioxo Carbocation" Tetrahedron Letters. 37. 2241-2244 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 岡崎隆男: "Generation and Reactions of 2-(1-Adamantyl) adamantene Rearrangement to 3-(1-Adamantyl)-4-protoadamantylidene" Bulletin of the Chemical Society Japan. 69. 2053-2062 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 竹内賢一: "現代化学増刊26" 東京化学同人, 123-129 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 竹内賢一: "現代化学増刊26" 東京化学同人, 136-143 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Zhou, L. ; Nishimoto, S.: "Electron-Affinic Radiosensitizers Possessing NPSH-Reactive Side Chains : Cytotoxicity and Radiosensitizing Activity towards Hypoxic EMT6 Cells In Vitro" Int.J.Radial.Biol.67. 335-346 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nishimoto, S. ; Morimoto, S. ; Fujita, S.: "A Pulse Radiolysis Study on Redox Reactivities of Carbon-and Nitrogen-CenteredAmino Acid Radicals Produced by OH Radical Reaction in Aqueous Solution" Amino Acids. 9. 9-9 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Okamoto, K. ; Takeuchi, K. ; Kitagawa, T.: "Ionic Dissociation of Carbon-Carbon s Bonds in Hydrocarbons and the Formation of Authentic Hydrocarbon Salts" Adv.Phys.Org.Chem.30. 173-221 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Okazaki, T. ; Kitagawa, T. ; Takeuchi, K.: "Acid-Isomerization of 3,4-Dimethyl-4-homoadamantyl Cation to 3-Ethyl-5-methyl-1-adamantyl Cation. A Unique Method for Construction of an Adamantyl Framework Having Two Alkyl Groups on the Bridgehead Positions" Chemistry Lett.981-982 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kitagawa, T. ; Tanaka, T. ; Takata, Y. ; Takeuchi, K. ; Komatsu, K.: "Regiospecific Coordinationnation of tert-ButylfullerideIon and 1,4-Dicyclopropyltropylium Ion. Synthesis of a Dialkyldihydrofullerene Having a Heterolytically Dissociative Carbon-Carbon s-Bond" J.Org.Chem.60. 1490-1491 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ohtani, B. ; Kusakabe, S. ; Okada, K. ; Tsuru, S. ; Izawa, K. ; Amino, Y. ; Nishimoto, S: "Stereoselective Synthesis of Piperidine-2,6-dicarboxylic Acids by Photocatalytic Reaction of Aqueous Cadmium (II) Sulfide Dispersion" Tetrahedron Lett.36. 3189-3192 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Dai, W.-M. ; Fong, K.C. ; Danjo, H. ; Nishimoto, S.: "Synthesis of cis-Enediynes from 1,5-Diynes by Rearrangement of an Allylic Double Bond" Angew.Chem.Int.Ed.Engl.35. 779-781 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Dai, W.-M. ; Fong, K.C. ; Danjo, H. ; Nishimoto, S. ; Solow, M. ; Mak, W.L, ; Yeung, L.: "DNA Cleavage of Novel Propargylic Sulfones. Enhancement of Potency via Intercalating Interaction" BioMed.Chem.Lett.1093-1098 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Okazaki, T, ; Terakawa, E. ; Kitagawa, T. ; Takeuchi, K.: "Solvolysis of [3-13C] -3,4-Dimethyl-4-homoadamantyl p-Nitro-benzoate. Comparison of the Barriers to the Wagner-Meerwein Rearrangement of the Secondary and Tertiary 4-Homoadamantyl Cations." Tetrahedron Lett.37. 1035-1038 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tokunaga, K. ; Ohga, Y. ; Takeuchi, K.: "Solvolysis of 2-Thioxo Bridgehead Compounds as Compared with their 2-Oxo Homologs : Evidence for Marked p-Conjugation in 2-Thioxo Carbocation" Tetrahedron Lett.37. 2241-2244 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Okazaki, T. ; Isobe, H. ; Kitagawa, T. ; Takeuchi, K.: "Generation and Reactions of 2- (1-Adamantyl) adamantene Rearrangement to 3- (1-Adamantyl) -4-proto-adamantylidene" Bull.Chem.Soc.Jpn.69. 2053-2062 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Takeuchi, K. ; Kinoshita, T.: "Caobocations : Hypothesis to Existence" Extra Issue of Chemistry Today. 26. 123-129 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Takeuchi, K.: "Stability and SN_1 Reactivity of Carbocations" Extra Issue of Chemistry Today. 26. 136-143 (1995)

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

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Published: 1999-03-09  

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