4′-Ethynyl nucleoside analogues: Potent inhibitors active against multi-drug-resistant HIV variants

All the presently available nucleoside reverse transcriptase inhibitors (NRTIs) have a 2′,3′-dideoxyribofuranose configuration. We describe here a group of 4′-substituted nucleoside reverse transcriptase inhibitors, 4′-ethynyl-2′-deoxynucleosides (4′-E-dNs), which retain the 3′-hydroxyl group in the ribose moiety. Among such analogues, 4′-E-2′-deoxycytidine, 4′-E-2′-deoxyadenosine and 4′-E-2′-deoxyribofuranosyl-2, 6-diaminopurine exert potent activity against a variety of HIV-I strains, including multi-drug resistant clinical HIV-I variants in vitro. Despite the presence of the 3′-hydroxyl group, these 4′-E-dNs appear to function as viral DNA chain terminators and represent a new family of NRTIs.