Synthesis and anti-HIV Activity of Some Novel Phosphorodiamidate Derivatives of 3′-azido-3′-deoxythymidine (AZT)

Abstract

The reaction of 3′-azido-3′-deoxythymidine (AZT) with phosphoryl chloride followed by amino acid methyl esters gave novel diamidate derivatives of AZT 5′-monophosphate (AZTMP). It was hoped that the 5′-phosphorodiamidates might act as membrane-soluble prodrugs of the bio-active free nucleotides of AZT. Five different amino acids were employed, covering a range of structures and polarities. The reaction was also conducted with propylamine, and with diethylamine. The derivatives were tested for their inhibitory effect on human immunodeficiency virus type 1 (HIV-1) proliferation in a human lymphoblastoid cell line. The amino acid derivatives were potent inhibitors of viral proliferation, small changes in structure leading to marked changes in activity.