S-Acyl-2-thioethyl Aryl Phosphotriester Derivatives as Mononucleotide Prodrugs

The synthesis and biological activities of phosphotriester derivatives of 3‘-azido-2‘,3‘-dideoxythymidine (AZT) bearing a phenyl group or l-tyrosinyl residues are reported. The target compounds were obtained via either PV or PIII chemistry from the appropriate aryl precursors. All the derivatives were evaluated for their in vitro anti-HIV activity, and they appeared to be potent inhibitors of HIV-1 replication in various cell culture experiments, with EC50 values between the micro- and nanomolar range. Furthermore, compounds incorporating an amino- and/or acid-substituted tyrosinyl residue demonstrated significant anti-HIV effects in thymidine kinase-deficient (TK-) cells showing their ability to act as mononucleotide prodrugs. The proposed decomposition process of these mixed mononucleoside aryl phosphotriesters may involve esterase activation followed by phosphodiesterase hydrolysis.