PHOSPHORAMIDATES AS POTENT PRODRUGS OF ANTI-HIV NUCLEOTIDES - STUDIESIN THE AMINO REGION

Novel phosphoramidate derivatives of the anti-HIV nucleoside analogues AZT and d4T have been prepared by phosphorochloridate chemistry. Thes e materials are designed to act as labile membrane-soluble prodrugs of the bio-active free nucleotides. All compounds were fully characteris ed by a range of methods and were subjected to evaluation in vitro of their anti-HIV efficacy. A notable feature of the current study was th at any attempt to replace the amino acid moiety of the phosphoramidate with a simple amine lead to a marked, virtually total loss of activit y. Such simple phenyl alkylamino phosphate derivatives of either d4T o r AZT inhibit HIV replication at cytotoxic concentrations and have no detectable antiviral selectivity. This clearly highlights the vital ro le played by the amino acid in the antiviral efficacy of the blocked p hosphoramidates.