Study Of Antitumor Platinum (?) Complexes Containing Hindered Benzyl Groups

Twenty novel platinum(?) complexes derived from (1R,2R)-Nt-benzylcyclohexane-1,2-diamine derivatives with steric hindrance effect were designed and prepared. All ligands and complexes were characterized by polarimeter, elemental analysis, IR, 1H and 13C NMR spectra and ESI-MS for structure confirmation and characterization.In vitro cytotoxicity assay indicated that most complexes showed considerable activity against HepG2, SGC7901 and A2780 cell lines, especially la-4a had compatible or superior activity to cisplatin and oxaliplatin. So, the biological assay against SGC7901/CDDP and LO2 were also carried out. The result showing that complex 2a, as the most potent agent had compatible activity to cisplatin and sensitive to cisplatin resistant cell line as well as weak activity to normal cell. Among all the synthesized complexes, complexes with chloride ions as leaving groups exhibited good activity, others was reduced to some extent, it indicating that leaving group was important to the activity of complexes. In addition, the activity of o and p-fluorinion on benzyl was superior to m-fluorinion and p-fluorinion was the best. Thus, all of the leaving group and ligand are important to the cytotoxic activity of the complexes.In the mechanism study, the cellular uptake of complex 2a in SGC7901 and SGC7901/CDDP was higher than that of cisplatin and oxaliplatin. Research showing that complex 2a produces cytotoxic activity by the way of inducing cell apoptosis rather than necrosis and arrested SGC7901 cells in G2 and S phase, while HepG2 cells in G1 phase. Western blot indicating that the express of Bax/Bcl-2 increased markedly while procaspase-3 deregulated after treated with complex 2a. Thus, it means complex 2a can induce cell apoptosis by intrinsic mitochondrial pathway. In the reaction of complex 2a with Guanosine 5'-monophosphate (GMP), complex 2a was a mono-functional complex, while cisplatin and oxaliplatin analogues were bi-functional complexes. In the present of glutathione, the adduct of [Pt2(DACH)2(GMP)(GS)]2+ was observed as one of the main products of [Pt(DACH)Cl2], however, the co-binding product of GMP and GSH to platinum or the replaced product of GMP by GSH was not found in the corresponding reaction with complex 2a. Consequently, the steric hindrance effect originated from the ligand plays an important role in the cytotoxicity of complex 2a toward the cisplatin resistant cancer cells.