Hydrolysis of New Transplatin Analogue Containing One Aliphatic and One Planar Heterocyclic Amine Ligand: A Density Functional Theory Study

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. Theconsideration 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