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

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