Activation Mechanism of Prodrugs Releasing 5-Fluorouracil by Radiolytic Reduction

放射还原释放5-氟尿嘧啶前药的激活机制

• 批准号: 07455339
• 负责人: NISHIMOTO Sei-ichi
• 金额: $ 4.29万
• 依托单位: Kyoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07455339/
• 关键词: Radiation-Activating Prodrugs; Radiolytic Reduction; 5-Fluorouracil; N (1) -C (5) -Linked Dimer; Electrochemical Synthesis; 2-Oxo Compounds; pi^<**>-sigma^<**>Orbital Overlap; Pulse Radiolysis

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.

合成了多种含α-羰基的1-(5FU)取代化合物，研究了辐射还原活化机理和结构对5-氟尿嘧啶(5FU)释放反应速率选择性的影响。(1)研究了还原添加剂(芳香胺和低价过渡金属离子)对5FU同二聚体和杂二聚体的辐射还原活性的影响，得出了二聚体阴离子优先释放F~(2-)形成氧化的5-基自由基的活化机理。(2)合成了各种含有释放5FU的2-氧代化合物，关联了S和lt；RN和GT；(3)1-(5FU)取代化合物的X-射线结晶学研究表明，C-N键的甲酰基pi^&lt；**&gt；**&gt；-轨道与sigma^&lt；**&gt；-轨道有一定程度的重叠。这种结构特征与单电子还原电势和5FU释放的活化机理有关。(4)对于含有2-氧基的4-取代环己酮衍生物，pi^&lt；**&gt；-sigma^&lt；**&gt；顺式和反式异构体之间的轨道重叠明显不同，从而使5FU的释放反应性发生了严重的改变。(5)在水溶液的超声分解过程中，5FU/尿嘧啶二聚体通过OH自由基反应释放5FU。(6)在理论有机化学的基础上，表征了定量构效关系，为能够通过单电子还原释放抗肿瘤5FU的放射激活前药的分子设计提供了新的思路。

项目成果

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Kunio Okamoto：“碳氢化合物中碳-碳 σ 键的离子解离和真实碳氢化合物盐的形成”物理有机化学进展 30. 173-221 (1995)。

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)

Toshikazu Kitakawa：“叔丁基富勒离子和 1,4-二环丙基托吡鎓离子的区域特异性配位。具有杂解离解碳-碳 σ-键的二烷基二氢富勒烯的合成”有机化学杂志 60。1490-1491 (1995)。

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

北川，T.；

Nishimoto, S. ; Morimoto, S. ; Fujita, S.: "A Pulse Radiolysis Study on Redox Reactivities of Carbon- and Nitrogen-Centered Amino Acid Radicals Produced by OH Radical Reaction in Aqueous Solution." Amino Acids. 9. 9-9 (1995)

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竹内賢一: "現代化学増刊26" 東京化学同人, 123-129 (1995)

竹内健一：《现代化学特别版26》东京化学同人，123-129（1995）