Conformational studies of anti-HIV nucleosides: A rationale for the activity of {alpha}-nucleosides
- Univ. of Georgia, Athens, GA (United States)
In the authors` computational studies of nucleosides, it has been found that the O-C-N anomeric effect is a major factor underlying the eastern barrier to pseudorotation, which has been measured by experimental methods (NMR). By adding torsional parameters for the O-C-N anomeric effect to the Kollman force field (SYBYL 5.5 implementation), the eastern barrier and compute realistic pseudorotational energy profiles for various nucleoside analogs can be reproduced. Although the contribution of the anomeric effect is partially neutralized in {beta}-nucleosides (since it is most favorable in the sterically hindered western conformations), in {alpha}-nucleosides it produces a distinct conformational minimum that is not sterically hindered, in which the 5`-CH{sub 2}OH is equatorial. This permits an {alpha}-nucleoside to mimic a {beta}-nucleoside only if the latter has an ap conformation of the 5`-CH{sub 2}OH, if one considers the relative orientations of O5` and the base, and the distance between O5` and the base nitrogen bonded to C1` (N1 or N9). This could account for the unexpected anti-HIV activity possessed by some {alpha}-nucleoside analogs (dioxolanes and oxathiolanes). The authors have also calculated pseudorotational energy profiles for various anti-HIV {beta}-nucleosides (like AZT, 3`-FDT, DDT, BCH-189, etc.), as well as inactive analogs, in order to quantitatively assess the role of conformational factors in anti-HIV activity.
- OSTI ID:
- 141129
- Report Number(s):
- CONF-930304-; TRN: 93:003688-0804
- Resource Relation:
- Conference: 205. American Chemical Society national meeting, Denver, CO (United States), 28 Mar - 2 Apr 1993; Other Information: PBD: 1993; Related Information: Is Part Of 205th ACS national meeting; PB: 1951 p.
- Country of Publication:
- United States
- Language:
- English
Similar Records
Synthesis of novel fluorocarbocyclic nucleosides and nucleotides as potential inhibitors of human immunodeficiency virus
Synthesis of optically pure dioxolane nucleosides and their anti-HIV activity