Structure-Activity Correlations of 2′,3′-Dideoxy- and 2′,3′-Didehydro-2′,3′-Dideoxypyrimidine Nucleosides as Potential Anti-HIV Drugs

Abstract

The first compound approved for the clinical treatment of human immunodeficiency virus (HIV) was the nucleoside analog 3′-azido-3′-deoxythymidine (AZT; zidovudine).1 Discovery of its antiviral activity prompted extensive evaluation of other nucleosides for anti-HIV efficacy and to date 2′,3′-dideoxyinosine (ddl; didanosine) and 2′,3′-dideoxy-cytidine (ddC; zalcitabine) additionally have been approved on a limited basis for clinical treatment of this virus. These nucleosides share a common mode of action, namely phosphorylation to the corresponding 5′-triphosphates which act as inhibitors of the virus-encoded reverse transcriptase.2.3 Substantial effort also has been directed towards developing non-nucleoside drugs (e.g. protease inhibitors, tat antagonists) which inhibit viral targets other than reverse transcriptase.4 The pursuit of more effective nucleoside analogs nonetheless remains an area of high interest to many investigators. This review provides detailed structure-activity data for two classes of nucleosides, the 2′,3′-dideoxy-and 2′,3′-didehydro-2′,3′-dideoxypyrimidine nucleosides, in the hopes it will prove useful to investigators in identifying new synthetic target molecules while avoiding unnecessary duplication of previous synthetic efforts.