Comprehensive Conformational Analysis of the Nucleoside Analogue 2'--Deoxy-6-azacytidine by DFT and MP2 Calculations
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- 作者：Yevgen P. Yurenko ; Roman O. Zhurakivsky ; Mahmoud Ghomi ; Svitlana P. Samijlenko ; Dmytro M. Hovorun
- 刊名：Journal of Physical Chemistry B
- 出版年：2007
- 出版时间：June 7, 2007
- 年：2007
- 卷：111
- 期：22
- 页码：6263 - 6271
- 全文大小：304K
- 年卷期：v.111,no.22(June 7, 2007)
- ISSN：1520-5207
文摘
A comprehensive conformational analysis of isolated 2'-
-deoxy-6-azacytidine (d6AC), an analogue oftherapeutically active 6-azacytidine (6AC), has been performed by means of ab initio calculations at theMP2/6-311++G(2df,pd)//DFT B3LYP/6-31G(d,p) level of theory. Among the 81 conformers located withina 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 showsthat conformational equilibrium of isolated d6AC at T = 298.15 K is shifted to syn conformation with asyn/anti ratio estimated as 61.4%:38.6%. As far as the sugar conformation is concerned, 40 conformers containnorth (N) (with 0.3
P 40.1), and the rest possess south (S) (with 157.1 P 207.0) puckers, whereP 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 bothC2'-endo/syn conformers differing only by orientation of the O3'H hydroxyl group. They are both stabilizedby means of similar intramolecular H-bonds, i.e., O5'H···O2, C2'H2···O2, and C2'H2···O5'. As examinedby 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 conceivedas an inhibition of replicative DNA polymerase caused by an unusual orientation of the sugar residue againstthe base in the only A form DNA-like conformer.
-deoxy-6-azacytidine (d6AC), an analogue oftherapeutically active 6-azacytidine (6AC), has been performed by means of ab initio calculations at theMP2/6-311++G(2df,pd)//DFT B3LYP/6-31G(d,p) level of theory. Among the 81 conformers located withina 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 showsthat conformational equilibrium of isolated d6AC at T = 298.15 K is shifted to syn conformation with asyn/anti ratio estimated as 61.4%:38.6%. As far as the sugar conformation is concerned, 40 conformers containnorth (N) (with 0.3 P 40.1), and the rest possess south (S) (with 157.1 P 207.0) puckers, whereP 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 bothC2'-endo/syn conformers differing only by orientation of the O3'H hydroxyl group. They are both stabilizedby means of similar intramolecular H-bonds, i.e., O5'H···O2, C2'H2···O2, and C2'H2···O5'. As examinedby 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 conceivedas an inhibition of replicative DNA polymerase caused by an unusual orientation of the sugar residue againstthe base in the only A form DNA-like conformer.