S-Acyl-2-thioethyl Phosphoramidate Diester Derivatives as Mononucleotide Prodrugs

The synthesis and in vitro anti-HIV activity of phosphoramidate diester derivatives of 3'-azido-2',3'-dideoxythymidine (AZT) bearing one S-pivaloyl-2-thioethyl (tBuSATE) group and various amino residues are reported. These compounds were obtained from an H-phosphonate strategy using an amidative oxidation step. Most of these derivatives appeared to inhibit HIV-1 replication, with EC(50) values at micromolar concentration in thymidine kinase-deficient (TK-) cells, revealing a less restrictive intracellular decomposition process than previously reported for other phosphoramidate prodrugs. The proposed decomposition pathway of this new series of mixed pronucleotides may successively involve an esterase and a phosphoramidase hydrolysis.