Theoretical Studies on the Water-Assisted Hydrolysis of N,N-Dimethyl-N′-(2′,3′-dideoxy-3′-thiacytidine) Formamidine with Three Water Molecules

被引:13
|
作者
Gao, Jie Ying [1 ]
Zeng, Yi [1 ]
Zhang, Cheng Hua [1 ]
Xue, Ying [1 ,2 ]
机构
[1] Sichuan Univ, Coll Chem, Key Lab Green Chem & Technol, Minist Educ, Chengdu 610064, Peoples R China
[2] Sichuan Univ, State Key Lab Biotherapy, Chengdu 610041, Peoples R China
来源
JOURNAL OF PHYSICAL CHEMISTRY A | 2009年 / 113卷 / 01期
基金
中国国家自然科学基金;
关键词
PROTON-TRANSFER; AB-INITIO; MECHANISM; DEAMINATION; ENERGIES;
D O I
10.1021/jp8069817
中图分类号
O64 [物理化学(理论化学)、化学物理学];
学科分类号
070304 ; 081704 ;
摘要
The water-assisted hydrolysis mechanism of N,N-dimethyl-N'-(2',3'-dideoxy-3'-thiacytidine) formamidine (MFA-3TC) with three water molecules was studied by use of computational techniques. Optimized structures for all of the stationary points in the gas phase were investigated using the B3LYP/6-31+G(d,p) method. Single-point energies were determined employing the ab initio MP2 method in conjunction with the 6-311++G(d,p) basis set. Two possible pathways in the title reaction are considered, involving the attack of water molecule at first to the C-(1)=N-(1) double bond (path A) and the attack of water molecule at first to the C-(1)-N-(2) single bond (path B), respectively. A local microhydration model concerning three water molecules is adopted to mimic the system for the two reaction mechanisms above, where one water molecule is the nucleophilic reactant and the others are the auxiliary molecules. The calculated results indicate that the first steps in both pathways are the rate-limiting processes, and path A is more favorable than path B in the gas phase. In addition, bulk solvent effect is tested at the geometry optimization level by means of the conductor-like polarized continuum model (CPCM). Single-point computation was done at the MP2/6-311++G(d,p) level based on the geometries in the solution phase. Our results exhibit that the rate-limiting process in both pathways in water is the first step reaction, and path A is still favored. Two pathways are stepwise and slightly endothermic processes.
引用
收藏
页码:325 / 331
页数:7
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