Study On The Antitumor Activity Of Platinum(?) Complexes With Sterically Hindered Diamine And Functionalized Dicarboxylic Acids As Ligands

In this thesis, two types of sterically hindered platinum(II) complexes with functionalized dicarboxylic acids as leaving groups have been designed and synthesized, including 1) platinum(?) complexes with N-monoalkyl 1R,2R-cyclohexanediamine as carrier ligands and 1,1-cyclobutane dicarboxylate derivatives (ketone group was introduced to the 3 position of cyclobutyl) as leaving group; 2) 2-butyl, cyclopentyl and cyclohexyl mono-substituted 1R,2R-cyclohexanediamine as carrier ligands and malonate derivatives (methyl, ethyl and benzyl group was introduced to the 2 position of malonate) as leaving groups. These novel platinum(II) complexes were confirmed by IR,1H and 13C NMR spectra as well as ESI-MS spectroscopy.The in vitro cytotoxicity results of complexes 1-7 showed that these newly synthesized platinum(II) complexes with 1,1-cyclobutane dicarboxylate derivatives as leaving group exhibited unimpressive cytoxicity against the test cell lines except for complex 5. It is noted that minor changes on the leaving group can greatly influence the cytotoxic activity of the complexes. The addition of ketone group may decrease the dissociation rate and influence the biological properties of the platinum complexes. Comparing with the reported complexes 42 and 43, the steric hindrance effect of the substituted alkly group did not remarkably improve the cytotoxic activity of the resulting complexes and only the appropriate steric hindrance of pentyl could contribute to moderate activity. Among complexes 8a-10c, complexes 8a-9c showed moderate-potent cytotoxic effect on the tested four tumor cell lines. Espeacially,8b and 9a which modified by ethyl and methyl at the C-2 position of malonate respectively, exhibited enhanced cytotoxic activity compared to their precursor complexes. The cytotoxicity of 9a was even higher than cisplatin and oxaliplatin in HepG2 cells with an ICso value of 3.04?M. It is evident that a substituted group at the C-2 position of malonic acid could regulate the balance between lipophilicity and hydrophilicity of the platinum complexes, so that, they may promote transporting complexes to the target DNA inside the tested cell lines and result in good antiproliferative effects.Related mechanism of the most active complex 9a was conducted in HepG2 cells. Gel electrophoresis study revealed that complex 9a interacted with DNA in a different mode from that of cisplatin due to the steric hindrance effect of cycloalkyl group in the 1R,2R-DACH, indicating that 9a may possess different mechanism. Cell cycle and apoptosis assays indicated that 9a induced apoptosis by increasing the numbers of cells in G2 phase. Celluar uptake study showed that the platinum content of 9a was higher than cisplatin, indicating that 9a entered HepG2 cells more efficiently than cisplatin. Western blot indicated that 9a induced apoptosis may be caused by the mitochondrial dependent apoptotic pathway.