Synthesis,Characterization And Mechanism Of Platinum Antitumor Metal Complexes

Chemotherapy is one of the most common treatments for cancer.Platinum drugs,represented by cisplatin,have been widely used as anticancer agents in the clinic.However,in the clinical application,it is found that platinum drugs have many drawbacks such as drug resistance and serious side effects,which will cause great harm to human body.Therefore,the search for new platinum-based antitumor drugs with high efficacy and low toxicity is one of the hot research areas in the world.Non-classical monofunctional platinum complexes act differently with DNA than cisplatin,which is expected to overcome the shortcomings such as drug resistance and toxic side effects of cisplatin and become a new generation of platinum drugs.So the design and synthesis of monofunctional mononuclear and multinuclear platinum antitumor complexes and their mechanism of their action have attracted much attention.In this paper,a series of research work has been carried out around monofunctional platinum complexes.The main work is as follows:1.Firstly,we used a 1,3,5-triazine core to bridge three N,N,O-donor tridentate chelating Pt（II）motifs to successfully obtain a novel trinuclear platinum complex[Pt₃（L-3H）Cl₃]（1,L=2,4,6-tris[（2-hydroxybenzyl）（2-pyridylmethyl）amine]-1,3,5-triazine）.The results of the MTT activity test in vitro showed that complex 1exhibited selectivity toward breast cancer cells and especially possessed 3.3-fold higher antiproliferative activity as compared with cisplatin against the TNBC cell line MDA-MB-231.2.Secondly,mechanistic studies of the above trinuclear platinum（II）complex were further explored at the molecular and cellular levels.The results showed that the complex could pass through the cell membrane,enter into the cell,mainly accumulate in the nuclei and mitochondria.On the one hand,the complex could bind to DNA in a cooperative groove-plainating binding mode,indue DNA damage,arrest the cell cycle in G1 phase.On the other hand,it could induce mitochondrial membrane depolarization,increase ROS generation,induce mitochondrial damage,and eventually lead to cell apoptosis.3.Finally,a mononuclear platinum（II）complex[Pt LCl]Cl（1,L=N-（4-（benzo[d]thiazol-2-yl）-phenyl）-2-（bis（pyridine-2-ylmethyl）-amino）acetamide） was synthesized by covalenty tethering a the planar structure benzothiazole pharmacophore to the chelating Pt（II）motifs.The cytotoxicity,DNA-binding ability,and reactivity with 5’-GMP and GSH of the complex.The results showed that the complex exhibited a cytotoxicity comparable to that of cisplatin against MCF-7 cell lines,and more potent activities against He La and A-549 cell lines.The complex could coordinate with N7-GMP and GSH to form the Pt-GMP adduct and Pt-GS complex,respectively.The coordination binding of 1 with GSH did not prevent the formation of a certain amount of the Pt-GMP adduct in the reaction process.Moreover,1 could bind to DNA through multiple binding modes involving non-covalent and covalent interaction.In summary,the potent cytotoxicity of the complex may result from the multiple DNA binding modes.The deeper mechanism needs further study.