Studies On Synthesis,Characterization And Antitumor Activity Of Copper(?) Complexes Based On Quinoline-8-carboxaldehyde Schiff Base

In recent decades,metallodrugs have numbers of potential applications in anti-tumor and other diseases.The design and studies on the metallodrugs are one of the most active domains in chemicobiology and inorganic pharmaceutical chemistry.This thesis focused on this theme,eleven new complexes,utilizing seven Schiff base ligands which were used quinoline modification from amino compounds,have been synthesized and characterized by element analysis,Fourier transform infrared spectrometer(FT-IR),high-resolution mass spectrometer(HRMS)and X-ray crystallographic methods.The interaction complexes with human serum albumins and DNA have been explored by multi-spectrum methods.Moreover,the anticancer activities and mechanisms of complexes were also investigated through MTT assay,cell cycle arrest,cell apoptosis,mitochondrial membrane potential and ROS.This thesis is divided into four parts.And the main contributions in this work are as follow:First part:including chapter 1 of thesis.Current status of copper complex anticancer drugs based on Schiff base was briefly introduced.And the meanings and basis of the topics were explained.Second part:including chapter 2,3 and 4 of thesis.Four hydrazone ligands 8-quinolinecarbaldehyde 3-methoxybenzoylhydrazone(L1),8-quinolinecarbaldehyde benzoylhydrazone(L2),8-quinolinecarbaldehyde o-vanilloylhydrazone(L3)and 8-quinolinecarbaldehyde salicylhydrazone(L4)and their corresponding mononuclear copper(?)complexes[Cu(L1)(NO3)2](1),[Cu(L2)(CH3O)NO3](2),[Cu(L1)NO3](3)and[Cu(L2)NO3](4)have been synthesized.Two of copper(?)-hydrazone(Cu(L3)(L5)(5)and Cu(L4)(L5)(6))complexes containing the non-steroidal anti-inflammatory drug(NSAID),ibuprofen(L5),are also synthesized.The structure of complexes 1,2,3,4,5 and 6 were characterized by X-ray crystallography,elemental analyses,FT-IR and HRMS.Efficient binding of the complexes with protein(human serum albumin,HSA)has been established by UV-vis,fluorescence,and synchronous fluorescence spectroscopy.Fluorescence spectrum show that both complexes strongly interact with protein.And the Trp residue,the intrinsic fluorophore in HSA,was induced to a less hydrophobic microenvironment with the addition of test complexes.Meanwhile,the fluorescence quenching mechanism was determined to be static quenching.Interaction of the complexes with calf-thymus DNA(ct-DNA)has been investigated by UV-vis and fluorescence methods which showed that the compounds interacted with CT-DNA through intercalation.In addition,the complexes 1 and 2 exhibited significant cytotoxicity against a human cervical cancer cell line(HeLa),and complexes showed better activity than cisplatin.The complexes could cause HeLa cell cycle arrest at the G2 phase.And MGC80-3 cells are more sensitive to complexes 3,4,5 and 6 relative to the normal liver cells.Cytotoxicity and action mechanism studies suggest complexes 3 and 4 could cause MGC80-3 cell cycle arrest at G1 phase,which is induced by limiting the supply of cyclins D1 and El and inhibiting the activity of G1-phase-promoting cyclin-Cdk complexes.And complexes 3 and 4 led to cell apoptosis via the activation of Bcl-2 protein.Moreover,mitochondrial dysfunction was induced by both of complexes.Third part:including chapter 5 of thesis.(E)-methyl 4-((quinolin-8-ylmethylene)amino)benzoate(L6)and(E)-ethyl 4-((quinolin-8-ylmethylene)amino)benzoate(L7)ligand and the corresponding copper(?)complexes([Cu(L6)ClNO3](7)?[Cu(L7)Cl2](8)and[Cu(L7)SO4](9))were synthesized and characterized.The complexes 9 exhibited significant cytotoxicity against HeLa cell line and meanwhile its activity better than cisplatin.The complexes could cause HeLa cell cycle arrest at the G1 phase,and mitochondria-mediated apoptosis by regulating the expression of Bcl-2 family proteins.Fourth part:including chapter 6 of thesis.(E)-2-(diethylamino)ethyl 4-((quinolin-8-ylmethylene)amino)benzoate hydrochloride(L8)was synthesized from a narcotic drug,procaine hydrochloride.Complex 10(Cu(L8)(NO3)2)and a water-soluble copper(?)complex Cu(L8)SO4(11)was synthesized by the corresponding metal salts.And their structures were characterized by X-ray crystallography,elemental analyses,FT-IR and HRMS.Efficient binding of the complexes with protein(human serum albumin,HSA)and ct-DNA has been established by spectroscopy.Toward all the tested human tumor cells,complexes 11 exhibited significantly enhanced cytotoxicity compared with the corresponding ligands,procaine hydrochloride,copper(?)salt and solvent.The antiproliferative efficiency of complexes 10 and 11 on the human normal liver cells(HL-7702)is lower than that on the other four tumor cell lines.The apoptosis mechanism of complex 11 against the MGC80-3 cell lines was tested by microscope observation,flow cytometry,and the molecular biology technology.The complex 11 could cleave DNA,activate p53 gene,and decrease the expression of cyclin D?cyclin E?CDK2,which induce the cancer cells were arrested at G1 phase.In the molecular mechanisms of apoptosis,the complexes 11 could activate p53 gene,increase the expression bax gene,and decrease the expression of bcl-2,which reduce the ability of protection from apoptosis.Meanwhile,the level of ROS in the cells was increased,resulting in the decrease of mitochondrial membrane potential,enhanced membrane permeability,Moreover,the complexes 11 up regulate the expression of caspase-3 protein.Therefore,the complexes 11 induce apoptosis through mitochondria-dependent and caspase-independent pathway.Furthermore,the complex 11 showing excellent water solubility,low toxicity and good stability.In this thesis,we synthesized the copper complex based Schiff base ligands which were used quinoline modification from amino compounds.The interaction mode and mechanism of complexes with HSA and ct-DNA have been explored by spectroscopy methods.In addition,we studied the antitumor activity and discussed the molecular mechanisms of anti-tumor activity of complexes,which lay the foundation of development of new efficient antitumor drug,and provide a new consideration for novel drug design and synthesis.