Synthesis, Anti-HIV Activity, and Stability Studies of 5′-Phosphorofluoridate Derivatives of AZT

The synthesis, in vitro anti-HIV activity and stability studies of the 5′-fluorophosphate derivative of 3′-azido-3′-deoxythymidine (AZT) are reported. The results support the hypothesis that this phosphorylated entity exerts its biological effect via the delivery of the corresponding 5′-mononucleotide through an enzymatic process. However, the antiviral evaluation in thymidine kinase-deficient CEM cells as well as the stability studies in culture medium and cell extract showed that this bioconversion is not specific to the intracellular medium. Attempts to improve the biological activity of mononucleoside 5′-fluorophosphates by the use of the S-pivaloyl-2-thioethyl (tBuSATE) group as biolabile phosphate protection are reported.