文摘
Model 3?azido-3?deoxynucleosides with thiol or vicinal dithiol substituents at C2?or C5?were synthesized to study reactions postulated to occur during inhibition of ribonucleotide reductases by 2?azido-2?deoxynucleotides. Esterification of 5?(tert-butyldiphenylsilyl)-3?azido-3?deoxyadenosine and 3?azido-3?deoxythymidine (AZT) with 2,3-S-isopropylidene-2,3-dimercaptopropanoic acid or N-Boc-S-trityl-L-cysteine and deprotection gave 3?azido-3?deoxy-2?O-(2,3-dimercaptopropanoyl or cysteinyl)adenosine and the 3?azido-3?deoxy-5?O-(2,3-dimercaptopropanoyl or cysteinyl)thymidine analogs. Density functional calculations predicted that intramolecular reactions between generated thiyl radicals and an azido group on such model compounds would be exothermic by 33.6-41.2 kcal/mol and have low energy barriers of 10.4-13.5 kcal/mol. Reduction of the azido group occurred to give 3?amino-3?deoxythymidine, which was postulated to occur with thiyl radicals generated by treatment of 3?azido-3?deoxy-5?O-(2,3-dimercaptopropanoyl)thymidine with 2,2?azobis-(2-methyl-2-propionamidine) dihydrochloride. Gamma radiolysis of N2O-saturated aqueous solutions of AZT and cysteine produced 3?amino-3?deoxythymidine and thymine most likely by both radical and ionic processes.
