SYNTHESIS, BIOACTIVATION AND ANTI-HIV ACTIVITY OF THE BIS(4-ACYLOXYBENZYL) AND MONO(4-ACYLOXYBENZYL) ESTERS OF THE 5'-MONOPHOSPHATE OF AZT

To investigate the design of prodrugs of antiviral nucleosides for tar geting to the central nervous system, the bis(4-acyloxybenzyl) esters of the 5'-monophosphate of AZT 5 (R = Me, Et, Pr(i) or Bu(t)) have bee n prepared. The reaction of the appropriate bis(4-acyloxybenzyl) N,N-d iisopropylphosphoramidite 10 (R = Me, Et, Pr(i) or Bu(t)) with AZT in the presence of 1H-tetrazole, followed by oxidation of the P(III) inte rmediate with 3-chloroperoxybenzoic 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, Pr(i) or Bu(t)) were prepare d by treatment of the triesters 5 with lithium iodide. In the presence of porcine liver carboxyesterase the triesters 5 and diesters 7 decom posed readily to the 5'-monophosphate of AZT 9. The anti-HIV activitie s of the triesters 5 and diesters 7 were, with one exception, comparab le to that of AZT, but the greater cytotoxicity of certain compounds i n particular types of cell significantly reduced their selectivity ind ices.