Activation Mechanism of Prodrugs Releasing 5-Fluorouracil by Radiolytic Reduction

点击翻译按钮获取中文摘要

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.