An analysis of the inhibition of replication of HOV and MULV by some 3′-blocked pyrimidine analogs

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Some 3′-blocked pyrimidine analogs were synthesized and tested as inhibitors of replication of human immunodeficiency virus (HTV) and Moloney-murine leukemia virus (MuLV). The analogs were of 3 kinds: (1) analogs of 3′-azido-3′-deoxythymidine (AZT) in which the C-5 CH 3 of the base was exchanged for H (AZU) or C 2H 5 (AZEU); (2) 3′-fluoro-3′-deoxythymidine (FLT) and analogs thereof, in which the C-5 CH 3 of the base was exchanged for H (FLU), C 2H 5 (FLEU) or nC 3H 7 (FLPU); (3) the threo analogs of AZT (AZT↑) and AZU (AZU↑). All analogs were less active inhibitors of HTV replication than AZT, except FLT, which was as active as AZT. The 3′-fluoro analogs and AZEU did not inhibit MuLV replication at non-cytotoxic concentrations. Oral administration of FLT to MuLV-infected mice result in antiviral effects only at toxic drug levels. AZU and FLU were less potent inhibitors of HIV replication than AZT or FLT, but the 2′-deoxy uridine analogs were also less cytotoxic to human embryonic fibroblasts than the thymidine analogs. The 5′-triphosphates of AZU, AZT, AZEU, FLT and FLEU were tested as inhibitors of the HIV-and MuLV-reverse transcriptases. Ranking of the K i K m values for HIV-RT resulted in the following order of potency of the 5′-triphosphates AZT = FLT > AZU > AZEU > FLEU. The 5′-triphosphates of AZEU, FLT and FLEU did not inhibit the MuLV-RT, which explains, in part, the lack of effect of these analogs against MuLV replication. The threo forms (azido “up”) of AZU and AZT were less active inhibitors of HIV replication than the erythro forms (azido “down”). A 15N-NMR and 1H-NMR study showed that the furanose moieties of analogs with the azido function “up” assume a conformation distinct from that of the analogs with azido “down”. This is due to intramolecular stabilisation of the “N” conformer in the threo (“up”) diastereomer, due to interaction of the azido functions with the nucleobase and possibly the OH group of C-5′ of the furanose. As discussed, this conformation might explain the decreased biological activity of threo forms compared with the erythro forms.