[Reactions of 5'-H-phosphonates, 5'-F-phosphates, and 5'-phosphates of modified thymidines in human blood plasma]

Mechanisms and rates of hydrolytic dephosphorylation of 5'-hydrogen phosphonates, 5'-fluorophosphates, and 5'-phosphates of 3'-azido-3'-deoxythymidine, 3'-fluoro-3'-deoxythymidine, and thymidine in human blood serum were investigated. 5'-Hydrogen phosphonates of 3'-substituted thymidines are dephosphorylated 50-100 times slower than the corresponding 5'-phosphates. 5'-fluorophosphates of 3'-substituted thymidines are dephosphorylated 2 times slower than corresponding 5'-phosphates; first, substituted thymidine 5'-phosphates are formed, which are later dephosphorylated into substituted thymidines. These data illustrate probable molecular mechanisms of anti-HIV action of such nucleotides. 5'-hydrogen phosphonates of thymidines can serve as depot forms of corresponding thymidines, but other metabolic pathways are not excluded. Thymidine 5'-fluorophosphates can serve as depot-forms of both thymidines and their phosphates. Their fate in cells depends probably on their diffusion and on the activities of dephosphorylating and phosphorylating enzymes.