Study On The Chemical Kinetics Of Some Antitumor Platinum(?) Complexes And Platinum(?) Complexes

Two platinum???complexesI-1/2 with 3,3-dimethoxycyclobutane-1,1-dicarboxylic acid as the leaving group and three platinum???complexes II-1/2/3 with N-isopropyl-1R,2R-diaminocyclohexane as carrier ligand and different axial ligands were synthesized.All of these complexes were characterized by ¹H-NMR,¹³C-NMR,elementary analysis and ESI-MS spectra.Some of them were also characterized by X-ray crystallography.The cytotoxic activities of complexes I-1/2 against HepG2?hepatocellular carcinoma?and A549?non-small cell lung cancer?cell lines were investigated by MTT assay.The results demonstrated that the complex I-2 showed potent in vitro anticancer activity comparable to cisplatin.Notably,the in vitro anticancer activity of complex I-2 was nearly6 times of the parent complex Pt?dach??CBDCA?which possesses a similar structure with complex I-2 except two methoxy groups.This result demonstrated that the introduction of two methoxy groups in the leaving ligand could improve the anticancer activity of the resulting platinum???complexes.Comparison of the chemical reactivity of Pt?dach??CBDCA?and complex I-2 with biologically relevant nucleophiles?L-Met and thiourea?via a kinetic method was studied by UV-Vis technique.The results showed that the reaction rates of complex I-2 with nucleophiles were faster than those of Pt?dach??CBDCA?.DFT calculations showed that Pt?dach??CBDCA?had slightly higher activation energies than complex I-2 for the studied reactions,which was corresponded with the experimental results.The cytotoxic activity of complexes II-1/2/3 against HepG2?hepatocellular carcinoma?,A549?non-small cell lung cancer?and HCT116?colorectal cancer?cell lines showed that complex II-3 was the most active compound among them.The IC₅₀ value of complex II-3 was even much lower than the positive drug.The results demonstrated that the structure of the axial group ligand had a great influence on the in vitro antitumor activity of the platinum???complex.The hydrolytic behavior of complexes II-1/2/3 was studied by a kinetic method at three different pH values,and the results indicated that the hydrolysis of the studied platinum???complexes depended on pH,which proceeded much faster at basic pH.According to the analysis of the hydrolysis product,the hydrolysis occured in the different positions.The axial ligand was replaced by OH^-in complex II-3which contained two dichloroacetate groups as the axial group ligands,while the hydrolysis took place in the equatorial position in complex II-2 which contained two OAc^-groups as the axial group ligands.Futhermore,the complexes II-2/4/5 and Satraplatin which contained the same axial group ligand?OAc^-?,leaving group ligand?Cl^-?and different non-leaving group ligand were studied by the kinetic research.The data showed that the hydrolysis rates were affected by the structures of the non-leaving group ligands.The order was corresponded with the structure of NH₃<NH₂R<NHR₂,and it could be concluded that increasing?-donor ability of the carrier ligand could improve the hydrolysis rates of the corresponding complexes.DFT calculations were applied to elucidate the hydrolysis mechanism of complexes II-1/2/3/4/5 and Satraplatin,and the results could prove the conclusion of the experiments.