The hydrolysis mechanism of the anticancer agent trans-dichloro(ammine)(quinoline) platinum complex:: A theoretical study

Hydrolysis of trans-dichloro(ammine)(quinoline) platinum, a novel potential anticancer drug, is believed to be the key activation step before the drug reaches its intracellular target DNA. To obtain an accurate hydrolysis mechanism for this nonclassical class of square-planar Pt(II) complex, five different models were used at the experimental temperature with the solvent effect B3LYP/PCM using hybrid density functional theory. The stationary points on the potential energy surfaces for the first and second hydrolysis steps, proceeding via a five-coordinate trigonal-bipyramidal (TBP)-like structure of transition state, were fully optimized and characterized. The most remarkable structural variations in the hydrolysis process were found to occur in the equatorial plane of the TBP-like structures of the intermediates and transition states. It was found that the explicit solvent effect originating from the inclusion of extra water molecules into the system is significantly stronger than those arising from the bulk aqueous medium, especially for the first aquation step, which emphasizes the use of appropriate models for these types of problems. The results give detailed energy profiles for the mechanism of hydrolysis of trans-dichloro(ammine)(quinoline) platinum, which may assist in understanding the reaction mechanism of the drug with DNA target and in the design of novel platinum-based anticancer drugs with trans geometries.