Design,Synthesis,Topoisomerase ? Inhibition And Anticancer Activities Of Polypyridine Platinum(?) Complexes

Deoxyribonucleic acid?DNA?,as the core of genetic information,has certain structural polymorphism and is the target of many drugs in cancer treatment.Nowadays,designing and synthesizing new small molecule metal complexes,constructing abundant complex structures and studying their interaction with DNA play an extremely important role in exploring the structure and function of nucleic acids and developing potential anti-cancer drugs.In my master's thesis,pyridine derivatives containing mononuclear,binuclear and trinuclear metal platinum?II?complexes were designed and synthesized,and their biological activities were studied by structural characterization,confirmation of target compounds,such as nuclear magnetic resonance?NMR?,high resolution mass spectrometry?HRMS?,and elemental analysis.During the experiment,some single crystals of ligands and complexes were obtained and analyzed.All ligands are modified gradually with pyridine as the basic unit in order to improve their activities,such as the spinning of double helix DNA,the binding of calf thymus DNA?CT DNA?,the competition of ethidium bromide,the inhibition of topoisomerase I?Topo I?activity,and the anti-proliferation of cancer cells.?1?Complexes Pt?dbbpy?Cl?1?and[Pt?dbbpy?₂]?PF₆?₂?2?were synthesized.The crystal structure of 1 exhibits?-?superposition interaction,while 2 exhibits remarkable flexural expansion due to the ions between its molecules.DNA binding experiments show that 1 binds DNA preferentially and can accelerate the deconvolution of nucleic acid.Ligand with two dbbpy has high surface area and high binding affinity to G-quadruplex DNA.Pt?dbbpy?Cl and[Pt?dbbpy?₂]?PF₆?₂ had significant inhibitory effects on Topo I,and the inhibitory effect of 2 was stronger than that 1.These complexes have anti-tumor activity on cancer cell lines,and show good selectivity with normal cell lines as a control.?2?The active group morpholine was introduced to synthesize morpholine-modified polypyridine ligands and different leaving groups complexes[Pt?L³?Cl]CF₃SO₃?3?,[Pt?L³??NH₃?]?CF₃SO₃?₂?4?and[Pt?L³??PPh₃?]?CF₃SO₃?₂?5?.The crystal structure showed that Pt?II?was in square plane conformation in 5,but there were two symmetrical anions CF₃SO₃^-,which caused steric hindrance effect.The binding constant K_b with CT DNA can reach 9.57×10⁶ M^-1,showing excellent affinity with DNA,which is stronger than the classical insertion agent EB.This may be related to the embedding and electrostatic interaction between them.Topo I inhibitory activity was observed in 3,4,5.3,4,5 had obvious antiproliferative activity,and its effect was stronger than cisplatin.?3?A new ligand L⁴ and three binuclear complexes[Pt₂?L⁴?Cl₂]Cl₂?6?,[Pt₂?L⁴?Br₂]Br₂?7?and[Pt₂?L⁴?I₂]I₂?8?were synthesized.The structure of L⁴ has been confirmed by X-ray crystallography.The existence of?-?superposition interaction was detected after the analysis of crystal data.The binding ability of these complexes to CT DNA was tested by ultraviolet and fluorescence methods.The maximum K_b of 8 is 8.72×10⁶ M^-1,which is higher than that of classical DNA insertion agents EB and 6,7.6had stronger spinning effect on plasmid DNA and Topo I inhibition than complex 7,8.8 had obvious anticancer activity to A549 and HepG2 cancer cells,which is similar to cisplatin.?4?A new ligand L⁶ and a trinuclear complex[Pt₃?L⁶?Cl₃]Cl₃?9?were synthesized.Uv-vis method was used to test the binding ability of the complexes to CT DNA.The maximum K_b of 9 was 8.20×10⁶ M^-1,which was higher than the classical DNA insertion agent EB and some previous complexes,and had stronger DNA binding affinity.9 with unwinding ability to plasmid DNA and Topo I inhibition was stronger than previous complexes,which also showed that the unwinding effect did increase significantly with the increase of core.