A Stereochemical Rationale for the Activity of Anti-HIV Nucleosides

Abstract

Crystallographic studies have shown that, in the solid state, nucleosides active against the human immunodeficiency virus (HIV) generally exhibit moderate to extreme S-type furanose conformations (pseudorotational phase angle up to 215°). Following this lead, it is shown that using principles of conformational analysis, one can rationalize the activity or inactivity of other nucleoside analogues (including many not yet studied by X-ray methods) in terms of the effects of substituents on the furanose ring conformation. An analysis of the various 1,4 interactions of the O4′ lone pairs, O4′ itself, and the substituents on C2′ and C3′ shows that S-type conformations are stabilized (relative to N-type) in all the active ribose analogues, whereas this effect is absent in most inactive compounds. The gauche effect is a major determinant of activity, and the O4′ lone pairs, which have been neglected in many previous force field studies, may also be involved in stabilizing extreme S-type conformations. In such conformations (particularly for P > 180°) the + sc orientation of O5′ is destabilized, increasing access to the ap orientation, which may be more favourable for activity.