Conformational Analysis of Substituent Effects on the Sugar Puckering Mode and the anti-HIV Activity of 2′,3′-Dideoxypyrimidine Nucleosides

Abstract

A comparison between the conformational parameters of eleven active and inactive anti-HIV 2′,3′-dideoxypyrimidine nucleosides and a series of 73 uridine and thymidine structures, revealed that our compounds, all having N-glycosidic bond torsion angles χ in the anti range, have pseudorotation phase angles P well distributed over both N (C3′-endo) and S [C2′-endo and C3′-exo) type sugar conformations and have both +sc and ap C4′-C5′ conformations. This means that solid state conformations characterized by P, χ and γ do not provide decisive information for predicting possible anti-HIV activity. We also found that any rationalization of the activity or inactivity of nucleosides in terms of the gauche effect of electronegative substituents on the furanose ring conformation, could not be demonstrated by using the semiempirical quantum chemical AM 1 method. Calculations of C3′-X3′ bond polarities indicate that anti-HIV activity in C3′-substituted nucleoside analogues is consistent with the presence of a positive C3′-X3′ bond polarity. Exploration of the conformational space of χ vs. γ for C3′-endo, C2′-endo and C3′-exo sugar puckering modes using the same AM1 method, reveals that although the C3′-endo [P = 10°) region is about 2 kcal mol⁻¹ lower than the C2′-endo region (P = 170°), the C2′ -endo sugar puckering mode is the most accessible one due to the conformational flexibility about the minima. Our results also suggest that as P increases from 10°, through 170°, to 210°, the preferred range for -y dramatically shifts from almost exclusively around 50° (+sc) at P = 10° to almost exclusively non +sc at P = 210°.