The Synthesis and Biological Properties of some Aryl bis(Nucleosid-5′-yl) Phosphates Using Nucleosides with Proven Anti-HIV Activity

Abstract The synthesis of a series of aryl bis(nucleosid-5′-yl)phosphates in which the nucleosides are either 2′,3′-dideoxy-(d2-) or 2′,3′-didehydro-2′,3′-dideoxy-(d4-) nucleosides is described. These were tested for anti-HIV activity and their efficacy and toxicity compared with the parent nucleosides. Only the 4-(methylsulphonyl)phenyl derivatives of d4T and d2A had any significant activity and had selectivity indices of the same order as the parent nucleosides. These findings can be explained by uptake of the triesters into cells followed by a slow release of nucleoside and nucleotide. In the case of some compounds (such as d2T and d2U) the 5′-monophosphate of which is known to inhibit thymidylate kinase, it is possible that the levels of nucleotide liberated are such that they are not processed into the 5′-triphosphate and hence no antiviral effect is seen.