Potent Anti‐HIV Activity of Alkyl‐Modified DiPPro‐Nucleotides

Abstract

Two convergent approaches for synthesizing a new class of nucleoside diphosphate prodrugs bearing different nucleoside analogs are reported herein. The DiPPro‐nucleotides comprise an acyloxybenzyl group in combination with a lipophilic alkyl residue at the β‐phosphate or β‐phosphonate group, respectively. They are selectively cleaved to form their corresponding β‐alkylated nucleoside diphosphate derivatives in chemical and biological hydrolysis studies. In contrast, there is a selective but slow cleavage observed in the hydrolysis of the DiPPro‐compounds bearing two different, nonbioreversible alkyl moieties in human CD4+ T‐lymphocyte CEM/0 cell extracts. In these studies, the delivery of nucleoside monophosphates rather than nucleoside diphosphates is being observed, most likely due to a pure chemical phosphoranhydride cleavage of the β‐phosph(on)ate moiety. The antiviral evaluation of these two types of prodrugs reveals that these compounds exhibit marked anti‐HIV efficacy in HIV‐2‐infected thymidine kinase‐deficient CD4+ CEM T‐cells (CEM/TK−), with significantly better activities (up to 6700‐fold) against HIV‐2 replication than the parent nucleosides. Primer extension assays demonstrate that the β‐dialkylphosphate‐modified nucleoside derivatives, β‐monoalkylated‐diphosphates, and nucleoside diphosphates serve as substrates for HIV reverse transcriptase for the viral DNA elongation.

Keywords

• antiviral compounds
• DNA polymerase
• nucleoside analogs
• nucleoside diphosphates
• prodrugs