2′,3′-Didehydro-2′,3′-dideoxy-5-chlorocytidine is a selective anti-retrovirus agent

Abstract

2′,3′-Didehydro-2′,3′-dideoxy-5-chlorocytidine (D4CC) is, in contrast with 2′,3′-dideoxy-5-chlorocytidine (ddClCyd) and 2′,3′-didehydro-2′,3′-dideoxy-5-chlorouridine (D4CU), a potent and selective inhibitor of the replication of human immunodeficiency virus (HIV) types 1 and 2, simian immunodeficiency virus (SIV) and simian AIDS related virus (SRV). D4CC is a poor inhibitor of the phosphorylation of [5- 3H]2′-deoxycytidine (dCyd) by partially purified MT-4 cell dCyd kinase (K i: 612 μM). The findings that ( i) D4CC has little, if any, affinity for MT-4 cell Cyd/dCyd deaminase, ( ii) D4CU is not antivirally active and ( iii) the antiretroviral action of D4CC can be reversed by dCyd, but not dThd, indicate that D4CC is antivirally active as its Cyd metabolite (D4CC 5′-triphosphate) and does not need to be deaminated (to the corresponding Urd metabolite) to exert its antiretroviral action.