Structure and conformation of 3′-azido-3′-deoxythymidine (AZT), an inhibitor of the HIV (AIDS) virus

Abstract

3′-Azido-3′-deoxythymidine (AZT), an inhibitor of HIV (human immunodeficiency virus) replication, was recently found to improve the condition of patients suffering from AIDS (acquired immunodeficiency syndrome) or ARC (AIDS-related complex). An X-ray analysis of AZT was undertaken in order to determine the three-dimensional structure of this thymidine analogue. The crystals belong to the monoclinic space group P21 and the cell dimensions are a = 5.6282(4), b = 12.0130(7), c = 17.5072(10) Å, β = 95.946(5)°. The structure was determined by direct methods and refined to R = 0.028 for 2029 observed reflections. Two crystallographically independent molecules were found in the asymmetric unit. One of them, molecule A, adopts a conformation which is fairly common in nucleosides, viz. a C2′ endo/C3′ exo pucker of the furanose ring and a glycosidic torsion angle χCN = 53.4°. However, the conformation of molecule B is highly unusual. The sugar ring pucker is C3′ exo/C4′ endo and χCN = 2.3°. This high-energy conformation may represent the biologically active form of AZT. Its determination may therefore assist in the design of other inhibitors of HIV.