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Hydrolysis of New Transplatin Analogue Containing One Aliphatic and One Planar Heterocyclic Amine Ligand: A Density Functional Theory Study
Yan Gao, Li-xin Zhou*
Department of Chemistry, Jinan University, Guangzhou 510632, China
Abstract:
Herein we give a theoretical study of the hydrolysis processes of a novel anticancer drug trans-[PtCl2(3-pico)(ipa)] (3-pico=3-methylpyridine, ipa=isopropylamine). Two different models, model 1 relative to isolated reactant/product (R/P, wherein R=platinum complex+H2O, P=platinum complex+Cl-) and model 2 relative to reactant complex/product complex (RC/PC, wherein RC=(platinum complex)(H2O),PC=(platinum complex)(Cl-) are employed and the geometric structures are optimized at the B3LYP level of DFT method. It is found that the processes of the reactions follow the established theory for ligand substitution in square planar complexes; the geometries of the transition states (TS) agree with the previous related work and all of the reactions are endothermic. The effects originating from the inclusion of the attacking water/released chloride into the second coordination shell of platinum in RC/PC play an important role in the thermodynamic and kinetic profiles of the reactions, that is, the barrier heights of the reactions of model 2 are increased by ~6.3 and ~23.8 kJ/mol for step1 and step2 respectively, and the endother-micity is considerably decreased by ~420.5 and ~771.2 kJ/mol compared to model 1 in the gas phase. The consideration of the bulk solvation effects increase the barrier heights for both steps of model 1 by ~27.6 and ~6.7 kJ/mol respectively, whereas it reduces the barrier heights by ~7.9 and ~29.3 kJ/mol for model 2.The reaction energies are all decreased, especially for model 1, indicating more stable complexes solvated in the bulk aqueous solution than in the gas phase. Additionally, to get an accurate energy picture of the title complex, the relative free energies derived from the DFT-SCRF (density functional theory self-consistent field) calculations are compared with the relative total energies. The results are that activation energies rise for the first hydrolysis and fall for the second hydrolysis for all the systems, and for all the systems,the barrier height of the second hydrolysis is always higher than that of the first step. The rate constants indicate that transplatin analogue is kinetically comparable to cisplatin and its analogue in the hydrolysis process
Key words:  Trans platinum anticancer drug, Density functional theory, Hydrolysis, Aliphatic amine ligand, Heterocyclic amine ligand
FundProject:
Hydrolysis of New Transplatin Analogue Containing One Aliphatic and One Planar Heterocyclic Amine Ligand: A Density Functional Theory Study
高艳, 周立新*
暨南大学化学系,广州510632
摘要:
用密度泛函理论对一种新式反铂抗癌药物trans-[PtCl2(3-pico)(isopropylamine)]的水解机理进行了研究.研究中选用两个模型,即模型一为反应物和产物均为孤立状态,模型二为反应物和产物处于络合状态.运用B3LYP/6-31G**泛函方法对反应物、产物和过渡态的几何结构进行了全面优化.发现水解过程中过渡态结构与文献中报道的三角双锥结构吻合.反应络合物与产物络合物中所包含的进入基团(水分子)和离去基团(氯离子)对反应的热力学和动力学都产生了很大影响:模型二的两步反应活化能垒分别比模型一提高了约26.3和23.8 kJ/mol,吸热量比模型一分别降低了约420.5和771.2 kJ/mol.采用IEF-PCM模型进行水溶液计算,模型一两步反应的活化能垒比气相值分别提高约27.6和6.7 kJ/mol,模型二则分别降低约7.9和29.3 kJ/mol.经过熵修正后整个体系第一步水解的反应活化能全部上升了而第二步则恰好相反,第二步水解的活化能垒始终高于第一步.
关键词:  反铂抗癌药物,密度泛函,水解,脂肪胺,杂环胺
DOI:10.1088/1674-0068/21/04/346-352
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