Theoretical Study Of Hydrolysis Mechanism Of Novel Non-classical Trans-platinum Anticancer Drugs

Platinum compounds are widely used anticancer drugs. Though novel trans platinum drugs with bulky aliphatic amine ligands, planar heterocycle amine ligands or nonplanar heterocycle amine ligands efficiently improve its antitumor activity even including tumor cells resistant to cisplatin, little theoretical investigation has been found to our knowledge. In this dissertation, we focus on the hydrolysis mechanism of these novel non-classical trans-platinum complexes.The hydrolysis processes of these platinum complexes were theoretically studied by the DFT/B3LYP method with a combined basis set of (Lanl2DZ+6-311+g(d,P)) or (LanL2DZ+6-31+g(d,P)) in structure optimizations and frequency validation(LanL2DZ basis set is only used on platinum), subsequently energies calculations in vacuo and in aqueous solution were performed using the isoelectric focusing polarized continuum model (IEF-PCM) solvation model with the 6-311++G(3df,2pd) or 6-31++G(3df,2pd) basis set (LanL2DZ on platinum). The calculated results show that the geometric changes mainly take place in the equatorial plane. In order to reduce the high steric effect in TS, it was found that there are smaller L-Pt-E angle and more lengthened Pt-L and Pt-E bonds, these will have a smaller Gibbs free energy change and accordingly the better hydrolysis yield. The sum of the concentric bond angles in the equatorial plane is almost 360°in TS. The solvent effect on these platinum complexes and reactions were found to be critical in determining the structures and energies in most cases. It assists the equatorial four atoms to be coplanar in TS.In our calculations, we find the first hydrolysis reaction is easier than the second process, so the hydrolysis product is mainly the monoaquated forms. And all hydrolysis reactions are endothermic processes.