关键词: 反铂抗癌药物, 密度泛函理论, 水解反应, 反应机理, 溶剂化效应

Abstract: The hydrolysis process of the anticancer drug trans-[Pt(Ⅱ)Cl2(i-pra)(hmp)](i-pra= isopropylamine, hmp= 3-(hydroxylmethyl)-pyridine) with steric hindrance has been investigated by density functional theory at PBE1PBE level and CPCM model. The results exhibited that water molecules attack the Pt and Cl atoms perpendicularly to the quadrangular coordinate plane of Pt due to the steric effect. The hydrolysis is the synergistic effect of the H, O, Cl and Pt atom, acting as the 3p(Cl)→σ*(H-O), 5d(Pt)→σ*(H-O), LP(O)→LP*(Pt) and LP(O)→σ*(Pt-Cl) delocalizations. The transition state is an approximate trigonal-bipyramid geometry. In the processing of hydrolysis, the delocalization effect and the strength of Pt-O bond increase, while the strength of Pt-Cl bond decreases. Due to the solvent effects, energies of every reactant, transition state and product of the first and second hydrolysis are 63.6~386.3 kJ/mol lower than those of the gas phase, and the single-point energy barriers are 17.1~36.2 kJ/mol lower than those of the gas phase. The hydrolysis process is easier in the opposite direction of isopropyl with less steric hindrance. 1B and 2B are the dominant reaction paths of first and second hydrolysis, their enthalpy barrier (ΔH°298(aq)) are 79.7 kJ/mol and 87.8 kJ/mol respectively, which are higher than those of trans-[PtCl2(i-pra)2]. Moreover, the enthalpy barrier of second hydrolysis is much higher than cisplatin.

Key words: trans-Platinum complexes, density functional theory (DFT), hydrolysis reaction, reaction mechanism, solvent effect