Synthesis and Anti-HIV Activity of 5′-Homo-2′,3′-dideoxy-2′,3′-didehydro-4′-selenonucleosides (5′-Homo-4′-Se-d4 Ns)

On the hypothesis that one carbon homologation of 4′-selenonucleosides might relieve the steric repulsion between cellular kinases and bulky selenium, 5′-homo-4′-Se-d4Ns, 3 a–e, as anti-HIV agents were designed and synthesized stereoselectively from d-gulonic γ-lactone, with the conversion of 2′,3′-diol into the olefin as the key step. The anti-HIV activity of all synthesized compounds, 5′-homo-4′-Se-d4Ns, was toxicity-dependent, unlike normal 4′-Se-d4Ns, which were inactive against HIV-1. This result indicates that 5′-homo-4′-Se-d4Ns might be phosphorylated by cellular kinases as per the hypothesis.