Synthesis,Characterization And Antitumor Mechanism Of Novel Platinum(Ⅱ) Complexes

At present,cancer is the second leading cause of premature death and a major challenge in the field of medicine.The metal platinum is one of the most effective and widely used drugs in clinical treatment of tumors.Since cisplatin was found to have antineoplastic properties,thousands of platinum anticancer compounds have been reported,but few of them have entered the clinic because of their strong toxic and side effects.Therefore,it is particularly important to design and synthesize new platinum antineoplastic drugs with high anticancer activity and low toxicity.Nitrogen heterocyclic carbene(NHCs)is a neutral two-electron donor,which can be easily combined with hard or soft metals to achieve functionalization.Its metal complexes have attracted much attention in the field of antineoplastic drug research and development because of their stable structure,modifiability,low toxicity and good biological activity.At present,there are few reports on the anti-tumor effect of nitrogen heterocyclic carbene(NHCs)platinum complexes,and its anti-tumor mechanism remains to be further studied.The purpose of this study is to design and synthesize new nitrogen heterocyclic carbene platinum complexes and study their antitumor activity and mechanism,so as to provide new research ideas for the development of platinum antineoplastic drugs.In this paper,ten complexes of nitrogen heterocyclic carbene platinum(Ⅱ)with different substituents were designed and synthesized,and their structures were determined by means of NMR and X-crystal diffraction.The UV and fluorescence spectra of 10 complexes were determined in PBS solution,dichloromethane and acetonitrile.Then the tumor activity and its mechanism of the complexes were studied as follows1)The cytotoxicity of 10 platinum(Ⅱ)complexes and cisplatin to four different cancer cell lines and human normal liver cells(LO2)were determined by MTT method.The results showed that 10 platinum(Ⅱ)complexes had good anti-tumor activity against four cancer cell lines,but also accompanied with high toxicity.2)After screening among complexes 1-4,it was found that platinum(Ⅱ)complex 2 had selective killing effect on human colon cancer cells(SW480),and its anti-tumor effect was much higher than that of cisplatin.Then,the anti-tumor mechanism of platinum(Ⅱ)complex 2 was further studied.apoptosis experiments showed that platinum(Ⅱ)complex 2 could effectively induce apoptosis of human colon cancer cells(SW480).Western blotting showed it could effectively promote the expression of pro-apoptotic protein(BIM)and inhibit the expression of anti-apoptotic protein(MCL-1).Western blotting also showed that the complexes inhibited the expression of AKT/PI3 K signal pathway and growth factor(VEGF).The UV titration experiment of ct-DNA with platinum(Ⅱ)complex 2 also shows that it can bind with DNA.3)The activity of complex 5-8 against different tumor cell lines was screened by MTT method.It was found that complex 5 had selective killing effect on human liver cancer cells(Huh7),and its anti-tumor effect was higher than that of cisplatin.Apoptosis experiments showed that complex 5 could effectively induce apoptosis of human hepatocellular carcinoma cells(Huh7).