Synthesis, bioactivation and anti-HIV activity of the bis(4-acyloxybenzyl) and mono(4-acyloxybenzyl) esters of the 5′-monophosphate of AZT

Abstract

To investigate the design of prodrugs of antiviral nucleosides for targeting to the central nervous system, the bis(4-acyloxybenzyl) esters of the 5′-monophosphate of AZT 5(R = Me, Et, Prⁱ or Bu^t) have been prepared. The reaction of the appropriate bis(4-acyloxybenzyl)N,N-diisopropylphosphoramidite 10(R = Me, Et, Prⁱ or Bu^t) with AZT in the presence of 1H-tetrazole, followed by oxidation of the P^III intermediate with 3-chlcroperoxybenzoic acid gave the required triesters 5 in good yield. The lithium salts of the mono (4-acyloxybenzyl) esters of the 5′-phosphate of AZT 7(R = Me, Et, Prⁱ or Bu^t) were prepared by treatment of the triesters 5 with lithium iodide. In the presence of porcine liver carboxyesterase the triesters 5 and diesters 7 decomposed readily to the 5′-monophosphate of AZT 9. The anti-HIV activities of the triesters 5 and diesters 7 were, with one exception, comparable to that of AZT, but the greater cytotoxicity of certain compounds in particular types of cell significantly reduced their selectivity indices.