Study On The Synthesis,Structure,Antitumor Activity And Mechanism Of Metal Complexes Of Thiosemicarbazone And Phenylhydrazones

In this paper,two kinds of metal complexes were synthesized.The first category:It is based on N-phenyl thiosemicarbazide(4-phenyl-3-thiourea)and 2-quinolinecarboxaldehyde as raw materials to synthesize thiosemicarbazone ligand,and then the mononuclear iron(Ⅲ)complexes was synthesized with iron(Ⅲ)salt.The second type:4-hydroxybenzohydrazide and 2-pyridinecarboxaldehyde as raw materials to synthesize phenylhydrazone ligands,and then with copper(Ⅱ),nickel(Ⅱ),zinc(Ⅱ)salt coordination to form three kinds of mononuclear copper(Ⅱ),nickel(Ⅱ),and zinc(Ⅱ)complexes.We investigated the antitumor activity of the compounds in terms of chemical and biological characteristics:(1)Characterization of these structure by means of elemental analysis,infrared,mass spectrometry and single crystal X-ray diffraction analysis;(2)At the cellular level,the anti-tumor activity of the metal complexes and the mechanism of tumor cell apoptosis induced by MTT assay,flow cytometry and fluorescence photography were studied;(3)At the molecular level,the effects of these metal complexes on the expression of apoptosis related proteins and cycle related proteins were detected by Blot(Western).The main contents of this paper are as follows:The first chapter:A brief introduction to tumors,antitumor studies on schiff base and metal complexes and on this basis,briefly describes the basis of this thesis and the research content.The second chapter:the Fe(Ⅲ)complex(Cl)was synthesized by solution method using Schiff base as the ligand(La)formed by the reaction of 2-quinolinecarboxaldehyde and 4-phenyl-3-thiosemicarbazone.The crystal structure of the complex was analyzed by single crystal X-ray diffraction analysis.The redox properties of the complexes were studied by electrochemical method and ascorbic acid oxidation method.The results show that C1 has strong redox properties and the oxidation and reduction potential of FeⅢ/Ⅱ is the oxidant and reducing agent which can be sustained in the cells within range.The interaction between La and C1 and DNA was studied by absorption spectroscopy,emission spectroscopy and viscosity analysis.The results showed that C showed better binding and was bound to DNA by intercalation.The results of agarose gel electrophoresis showed that the ability of C1 to cleave pBR322 DNA was stronger than that of La.In vitro cell antitumor activity experiments show that:(a)C1 has more significant anticancer activity than free La;(b)C1 can induce the production of reactive oxygen species(ROS),promote DNA damage,leading to activation of the p53 pathway;(c)C1 induce apoptosis by reducing the mitochondrial membrane potential;(d)Western Blot showed that the expression of Caspase-3,Caspase-9,Bax and Cyt-C in the cells were significantly higher than those in the control group(P<0.05).The expression level of anti-apoptotic protein Bcl-2 and Bcl-xl was significantly decreased.The third chapter:In the third chapter,three metal complexes were synthesized by using 4-hydroxybenzohydrazide and 2-pyridinecarboxaldehyde as follows.[Cu(Lb)2](C1);[Ni(Lb)2];[Zn(Lb)2](C3).The structure of the metal complex was analyzed by single crystal X-ray diffraction(XRD).The results of single crystal structure show that the three kinds of phenylhydrazone Schiff base metal complexes are mononuclear structures.These three complexes can bind to HSA(human serum albumin)in the IIA subdomain region by fluorescence spectroscopy and molecular docking.The antitumor activity and mechanism of the three metal complexes were studied by in vitro cell experiments:(a)MTT assay showed that these three kinds of complexes showed more obvious cells on the three tumor cell lines of HepG2,T24 and MGC-803 in vitro;(b)the use of flow cytometry detection of C1 anti-tumor function study found that C1 can induce apoptosis,to promote intracellular ROS production,cell cycle arrest in the S phase(P<0.05);(c)The expression of Caspase-3,Caspase-9,Bax and Cyt-C in the cells were significantly increased,and the expression of anti-apoptotic protein Bcl-2,the expression of Bcl-xl was significantly decreased.The fourth chapter:The work of this thesis is summarized,which provides experimental and theoretical basis for the development of new anticancer metal complexes in the future.