含有一个非平面杂环胺配体的新型反铂抗癌药物的水解机理

用B3LYP杂化泛函和等电子聚焦极化连续模型(IEF-PCM)研究了trans-PtCl2(NH3)(Am)](Am: 非平面哌啶或哌嗪)新型反铂抗癌药物的水解反应机理. 对经由一般的SN2机理的第一步和第二步水解反应势能面上的稳定点进行了全优化和表征. 在水解中, 最显著的结构变化发生在反应过渡态和中间体的五配位三角双锥的赤道面上. 与经典顺铂(cisplatin)比较, 反式PtCl2(NH3)(piperazine)]的第一步和第二步水解活化能均低于顺铂, 而反式PtCl2(NH3)(piperidine)]的第一步水解活化能稍高于顺铂, 第二步水解活化能稍低于顺铂. 计算表明, 这些含有非平面杂环胺反铂的配合物减小了赤道面上的立体效应和水解势垒.

Hydrolysis Mechanism of New Anticancer Drug Transplatin Analogues Containing One Nonplanar Heterocyclic Amine Ligand

Hydrolysis processes of novel anticancer transplatin analogues, trans-PtCl_2(NH_3)(Am)](Am: nonplanar heterocycle piperidine or piperazine), were explored using the B3LYP hybrid functional and isoclectric focusing polarized continuum model (IEF-PCM). Stationary points on the potential energy surfaces for the first and second hydrolysis steps that proceed via a general S_N2 pathway were fully optimized and characterized. The most remarkable structural variations in the hydrolysis process were found to occur in the equatorial plane of five-coordinate trigonal-bipyramidal (TBP) like structures of the intermediates and transition states. We obtained lower activation energies for trans-PtCl_2(NH_3)(piperazine)] and a slightly higher activation energy for the first step and a slightly lower activation energy for the second step during the hydrolysis of trans-PtCl_2(NH_3)(piperidine)] by comparison to previous work on the hydrolysis reactions of cisplatin. Our calculations suggest that this class of non-classical transplatin analogues with one nonplanar heterocyclic amine decreases the equatorial steric effect and the hydrolysis reaction barriers.