Pronucleotides of 2′,3′-Dideoxy-2′,3′-Didehydrothymidine as Potent Anti-HIV Compounds

We report on the synthesis and evaluation of three different
nucleotide
prodrug systems: (i) nucleoside triphosphate analogues in which the
γ-phosph(on)ate has two different lipophilic nonbioreversible
alkyl residues with d4TDP as the released nucleotide analogue; (ii)
nucleoside diphosphate analogues bearing a bioreversible and a stable
β-alkyl group; or (iii) nucleoside diphosphate analogues bearing
two nonhydrolysable lipophilic alkyl moieties. The delivery of d4TDP
(for the triphosphate precursor) and d4TMP (for the diphosphate precursor)
was demonstrated in CD4+ T-lymphocyte CEM cell extracts
as well as in phosphate buffer saline (PBS). In primer extension assay,
we found that γ-dialkylated d4TTP derivatives and d4TDP were
accepted as substrates by HIV-RT. Several of these compounds were
observed to be extremely active against HIV-1/2 replication in HIV-infected
cells. A more than 45,000-fold increase in the anti-HIV activity was
detected for compound 18a as compared to the parent d4T
which results in a selectivity index value of 37,000.