The structure of the pyranosyl nucleoside 1-(2′,3′-dideoxy-(β-D-erythro-hex-2′-enopyranosyl)thymine and a comparison with AZT

Abstract

Pyranosyl nucleosides are among the most recent modifications of natural nucleosides to receive attention as potential HIV inhibitors. As part of our studies involving modified nucleosides, the crystal structure of 1-(2′,3′-dideoxy-β-D-erythro-hex-2′-enopyranosyl)thymine was determined and its molecular structure and conformation compared with AZT in an effort to assess the title compound's potential activity against HIV. The compound crystallizes in the monoclinic space group P21 with cell dimensions a = 7.966(3), b = 18.004(3), c = 8.346(3) Å, β = 91.29(3)°. The crystal structure, solved by direct methods and refined to R = 0.032 and Rw = 0.041 for 1285 observed data, contains two independent molecules in the asymmetric unit, each displaying different torsion angles, χ (64.5(6)° and 72.7(6)°) and γ (62.0(7)° and 178.6(5)°). Molecular conformations, described as slightly distorted chairs with O5′ endo and C5′ exo and with equatorial substituents, are stabilized by a network of hydrogen bonds throughout the crystal. Despite the substantial difference in χ values with respect to AZT in the solid state, molecules appear to exhibit sufficient structural overlap with AZT to expect a similar capacity for binding to the active site of phosphorylation; the barrier to rotation about the N-glycosidic bond is only slightly greater for the title compound. The significant difference, on comparison with AZT, appears at the primary hydroxyl, which is so oriented as to probably preclude activity of this pyranosyl compound as an anti-HIV agent. The conformational parameters given are in accordance with the IUPAC–IUC Joint Commmission on Biochemical Nomenclature (Pure Appl Chem. 55, 1273 (1983)). Keywords: crystal structure, modified nucleoside, pyranosyl nucleoside, anti-HIV drugs.