噻替哌和替哌水解机理的计算研究
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- 英文论文题名：Theoretical Study on the Hydrolysis of Thiotepa and Tepa
- 论文作者：徐佳禛 ; 李慧丹 ; 王燕妮 ; 王朝杰
- 英文论文作者：Jiazhen Xu ; Huidan Li ; Yanni Wang ; Chaojie Wang ; School of Pharmaceutical Sciences ; Wenzhou Medical University
- 年：2016
- 作者机构：温州医科大学药学院;
- 论文关键词：噻替哌 ; 替哌 ; 密度泛函 ; 水解
- 会议召开时间：2016-07-01
- 会议录名称：中国化学会第30届学术年会摘要集-第十九分会：化学中的量子与经典动力学
- 语种：中文
- 分类号：R979.1
- 学会代码：ZGHY
- 会议名称：中国化学会第30届学术年会-第十九分会 ; 化学中的量子与经典动力学
- 会议地点：中国辽宁大连
- 主办单位：中国化学会
- 学会名称：中国化学会
- 页数：1
- 文件大小：111k
- 原文格式：D
- 会议级别：全国
摘要
噻替哌和替哌是临床上广泛使用的广谱抗肿瘤药物~([1-2]),其分子结构见Fig.1。在CAM-B3LYP/6-311++G(d,p)理论水平上优化了[Thiotepa(Tepa)-nH_2O](n=1,4)反应过程中反应物、中间体、过渡态及产物的几何构型,并对各个过渡态和中间体进行了振动分析确认其真实性。同时,结合极化连续介质模型(PCM)研究Thiotepa(Tepa)在水环境中的水解反应过程并与真空环境中的计算结果进行比较。结果表明:两条水解途径和两种水解环境中的作用模式相似,最显著的结构变化发生在与P原子相连的三个氮杂环丙烷上。对于单分子水参与的水解反应,Thiotepa(Tepa)的第二步水解为限速步骤,其能垒分别为54.3和220.9 kJ·mol~(-1),速率常数为1.07×10~3和1.45×10~(-27)s~(-1),与文献~([3-4])在B3LYP/6-311++G(d,p)水平上计算结果一致。对于四分子水参与的水解反应,噻替哌限速步骤的能垒比单分子水参与的限速能垒高138.4 kJ·mol~(-1),不利于噻替哌水解.但替哌限速步骤的能垒则比单分子水参与的限速步骤能垒低43.7 kJ·mol~(-1),说明四分子水参与反应有利于替哌的水解.
Thiotepa and Tepa are antitumor drugs. The hydrolysis reactions of [Thiotepa(Tepa)-nH_2O](n=1,4) were calculated at the CAM-B3LYP/ 6-311++G(d,p) level. To characterize the solvent effect, the polarized continuum model was used to simulate the hydrolysis reaction. It is found that the second hydrolysis steps are the limiting rate steps of the reaction with 1H_2O. The rate constants showed good agreement with the literatures values at B3LYP/6-311++G(d,p) level. Compared with the 1H_2O involved in the hydrolysis reaction, the energy barrier of the Thiotepa with 4H_2O is higher 138.4 kJ ·mol~(-1), indicating that the reaction with 4H_2O was not benefit to hydrolysis of Thiotepa. Instead, the reaction with 4H_2O was benefit to hydrolysis of Tepa.
Thiotepa and Tepa are antitumor drugs. The hydrolysis reactions of [Thiotepa(Tepa)-nH_2O](n=1,4) were calculated at the CAM-B3LYP/ 6-311++G(d,p) level. To characterize the solvent effect, the polarized continuum model was used to simulate the hydrolysis reaction. It is found that the second hydrolysis steps are the limiting rate steps of the reaction with 1H_2O. The rate constants showed good agreement with the literatures values at B3LYP/6-311++G(d,p) level. Compared with the 1H_2O involved in the hydrolysis reaction, the energy barrier of the Thiotepa with 4H_2O is higher 138.4 kJ ·mol~(-1), indicating that the reaction with 4H_2O was not benefit to hydrolysis of Thiotepa. Instead, the reaction with 4H_2O was benefit to hydrolysis of Tepa.
引文
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[3]Hedieh,T.;Alierza,F.Struct.Chem.2013,24:1
[4]Hedieh,T.;Alierza,F.J.Mol.Model.2012,18:3563