Comprehensive conformational analysis of the nucleoside analogue 2'-beta-deoxy-6-azacytidine by DFT and MP2 calculations.

A comprehensive conformational analysis of isolated 2'-beta-deoxy-6-azacytidine (d6AC), an analogue of therapeutically active 6-azacytidine (6AC), has been performed by means of ab initio calculations at the MP2/6-311++G(2df,pd)//DFT B3LYP/6-31G(d,p) level of theory. Among the 81 conformers located within a 7.83 kcal/mol Gibbs energy range at T = 298.15 K, 38 contain syn-oriented bases with respect to 2'-deoxyribose; the other conformers include anti-oriented bases. Energetic analysis of these conformers shows that conformational equilibrium of isolated d6AC at T = 298.15 K is shifted to syn conformation with a syn/anti ratio estimated as 61.4%:38.6%. As far as the sugar conformation is concerned, 40 conformers contain north (N) (with 0.3 degrees < or = P < or = 40.1 degrees), and the rest possess south (S) (with 157.1 degrees < or = P < or = 207.0 degrees) puckers, where P is the pseudorotational angle of the furanose ring. The S/N occupancy ratio is estimated as 80.2%:19.8% (T = 298.15 K). The two most stable conformers are energetically quasidegenerate and correspond to both C2'-endo/syn conformers differing only by orientation of the O3'H hydroxyl group. They are both stabilized by means of similar intramolecular H-bonds, i.e., O5'H...O2, C2'H2...O2, and C2'H2...O5'. As examined by AIM criteria, from 1 to 3 H-bonds per conformer were identified among 13 possible interactions: O5'H...O2, O5'H...N6, O3'H...O5', O5'H...O3', C1'H...O2, C2'H2...O2, C2'H2...O5', C3'H...O2, C3'H...N6, C5'H1...O2, C5'H2...O2, C5'H1...N6, and C5'H2...N6. The biological effect of d6AC is conceived as an inhibition of replicative DNA polymerase caused by an unusual orientation of the sugar residue against the base in the only A form DNA-like conformer.