摘要
用DFT-B3LYP方法和IEF-PCM溶剂化模型研究了反铂抗癌药物trans-[PtCl2(piperidine)(Am)](Am=2-picoline(1),3-picoline(2),4-picoline(3)),trans-[PtCl2(piperidine)(piperazine)](4),trans-[PtCl2(pipera-zine)2](5)and trans-[PtCl2(iminoether)2](6)的水解过程.水解反应是药物与DNA靶分子作用的关键活化步骤.全优化和表征了一水解和二水解反应经由一般的SN2路径过程所有物种的势能面稳定点.结果发现反应过程遵循已经建立的平面正方形配合物的配体取代反应理论,即取代反应通常通过一个三角双锥过渡态结构的铂配体交换反应发生.得到的过渡态结构与以前的相关工作一致,所有反应都是吸热反应;所有体系的二水解能垒都高于一水解.与顺铂相比,这些配合物都有更快的水解反应速率;并与以前类似的反铂配合物的研究做了比较.研究结果提供了这些配合物水解反应过程的详细能量变化,对理解药物与DNA靶分子的作用机理和新型反铂抗癌药物的设计有帮助.
In this work, the hydrolysis processes of the anticancer drugs trans-EPtC12 （piperi- dine） （Am）l, Am =2-picoline（1）, 3-picoline（2）, 4-picoline（3）, trans-[-PtC12 （piperidine） （piperazine） ] （ 4 ）, trans-[ PtC12 （piperazine） 2 ] （ 5 ） and trans-[ PtC12 （iminoether） 2 ] （ 6 ） have been studied using hybrid density functional theory （B3LYP） and iso-electric focusing polarized continuum model （IEF-PCM） solvation models. The hydrolysis reactions leading to the activated drug form a key step for the reaction with the target DNA. The stationary points on the potential energy surfaces for the first and second hydrolysis steps, proceeding via a general SN2 pathway, were fully optimized and characterized. It is found that the processes of the reactions follow the established theory for ligand substitution in square planar complexes, that is, substitution reactions usually occur via Pt-ligand exchange reactions with a trigonal-bipyramidal transition state structure; the geometries of the transition states （TS） agree with the previous related work and all of the reactions are endothermic; the barrier height of the second hydrolysis is always higher than that of the first step for all the systems. In comparison with previous work on cisplatin, a faster rate of hydrolysis is determined for the reaction. We make a comparison with previous work on the hydrolysis processes of analogous trans platinum-based anticancer drugs. The results provide detailed energy profiles for the mechanism of hydrolysis of 1, 2, 3, 4, 5 and 6, which may assist in understanding the reaction mechanism of the drug with the DNA target and in the design of novel Pt-based anticancer drugs with trans geometries.
出处
《化学研究》
CAS
2012年第5期44-51,共8页
Chemical Research
基金
国家自然科学基金资助项目(20971056)
关键词
密度泛函理论
反铂抗癌药物
水解
过渡态
反应机理
density functional theory
trans platinum-based anticancer drug
hydrolysis
transition state
reaction mechanism
