Potent Anti-HIV Activity of Alkyl-Modified DiPPro-Nucleotides
SMALL STRUCTURES(2024)
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 beta-phosphate or beta-phosphonate group, respectively. They are selectively cleaved to form their corresponding beta-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 beta-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 beta-dialkylphosphate-modified nucleoside derivatives, beta-monoalkylated-diphosphates, and nucleoside diphosphates serve as substrates for HIV reverse transcriptase for the viral DNA elongation.
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Key words
antiviral compounds,DNA polymerase,nucleoside analogs,nucleoside diphosphates,prodrugs
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