Anti-retrovirus activity of 3′-fluoro- and 3′-azido-substituted pyrimidine 2′,3′-dideoxynucleoside analogues

摘要: Abstract The 3′-fluoro-and 3′-azido-substituted derivatives of 2′,3′-dideoxythymidine (ddThd), 2′,3′-dideoxyuridine (ddUrd), 2′,3′-dideoxy-5-ethyluridine (ddEtUrd) and 2′,3′-dideoxycytidine (ddCyd) have been synthesized evaluated for their anti-retrovirus activity [against human immunodeficiency virus (HIV) murine Moloney sarcoma (MSV)]. Based on 50% effective doses the most potent inhibitors HIV replication in MT4 lymphocytes were: FddThd (0.001 μM), AzddThd (0.004 FddUrd (0.04 μM) AzddUrd (0.36 μm). Their selectivity indexes were 197, 5000, 500 677, respectively. In contrast, none 3′-substituted ddEtUrd had a marked anti-viral effect. 2′,3′-dideoxynucleoside analogues showed poor, if any, substrate affinity (bacterial) dThd phosphorylase. inhibited kinase to much greater extent ( K i / m : 0.66 3.4, respectively) than did or 71 171, respectively). values FddCyd AzddCyd dCyd about 60. Although phosphorylation is prerequisite derivatives, there no close correlation between potency 3′-fluoro- ddUrd, ddThd, ddCyd kinase.