Anti-HIV-Active Nucleoside Triphosphate Prodrugs

We
disclose a study on nucleoside triphosphate (NTP) analogues
in which the γ-phosphate is covalently modified by two different
biodegradable masking units and d4T as nucleoside analogue that enable
the delivery of d4TTP with high selectivity in phosphate buffer (pH
7.3) and by enzyme-triggered reactions in human CD4+ T-lymphocyte
CEM cell extracts. This allows the bypass of all steps normally needed
in the intracellular phosphorylation. These TriPPPro-nucleotides comprising an acyloxybenzyl (AB; ester) or an alkoxycarbonyl­oxybenzyl
(ACB; carbonate) in combination with an ACB moiety are described as
NTP delivery systems. The introduction of these two different groups
led to the selective formation of γ-(ACB)-d4TTPs by chemical
hydrolysis and in particular by cell extract enzymes. γ-(AB)-d4TTPs
are faster cleaved than γ-(ACB)-d4TTPs. In antiviral assays,
the compounds are highly active against HIV-1 and HIV-2 in wild-type
CEM/O cells and more importantly in thymidine kinase-deficient CD4+ T-cells (CEM/TK–).