Synthesis,Properties And Application Of Aromatic Heterocyclic Compound-copper(?)-Gluconic Acid/Amino Acid Complexes

Cisplatin[Pt(NH3)2Cl2]and some other Pt-based complexes were widely used in clinical since the 1970 s,but the side effects were gradually exposed.Therefore,the synthesis of metal complexes with high-efficient antibacterial and antitumor activities has received considerable attention in the field of drug discovery.The studies have found that the copper(?)complexes have antibacterial,antiviral,anti-inflammatory,anti-tumor,chemical nuclease activities,and possesses the advantages of low toxicity and drug resistance,which have attracted extensive attention of the researchers.Aromatic heterocyclic compounds and their derivatives are a class of organic compounds that widely used in biological medicine,food additives pesticides and so on.When the aromatic heterocyclic compounds coordinated with metals,the biological activities will be strengthen,such as antibacterial and anticancer.Amino acids,dipeptide and carbohydrate compounds are the important metabolic compositions in the organism,as it coordinated to the metals,the water solubility and biologic activity will be improved,which is benefit to the absorption and utilization of the complexes as drugs,and could reduce the toxic side effects of metal or other ligands.Therefore,three 5-substituted-2-(2'-pyridyl)benzimidazole copper(?)complexes with gluconic acid and one 6-(pyrazin-2-yl)-1,3,5-triazine-2,4-diamine copper(?)complex with L-methionine were synthesized and characterized,and all of these complexes have good solubility in water.At the same time,the combination properties of the complexes with biological macromolecules were studied,and their antioxidant,antibacterial,cytotoxic activities were further investigated.In this paper,the main work done is as follows:The first part is the introduction.The research progress of the copper(?)complexes were summarized at the beginning,and then the heterocyclic copper(?)complexes and ternary "Casiopeinas" complexes were clarified.Besides,the ways to study the combination of metal complexes with DNA were introduce detailed.Finally,we illuminated the research significance of this paper.In section 2,three new water-soluble copper(II)complexes[Cu(HPB)(Gluc)(H20)]G1uc(1),[Cu(HPBM)(G1uc)(H20)]Gluc(2),[Cu(HPBC)(Gluc)(H20)]Gluc(3)(primary ligands:HPB = 2-(2'-pyridyl)benzimidazole,HPBM = 5-methyl-2-(2'-pyridyl)benzimidazole,HPBC = 5-chloro-2-(2'-pyridyl)benzimidazole;Co-ligand:Glue =Gluconic acid anion)were synthesized and characterized.Firstly,multiple physicochemical methods confirmed that the structure of the complexes is a five-coordinate square-pyramidal geometry,where four equatorial positions were occupied by 5-substituted 2-(2'-pyridyl)benzimidazole(N,N)and gluconic acid carboxylic groups and the ?-hydroxylic(O,O),and the axial position was occupied by a water molecule(O).Then,the interactions of these complexes with DNA were studied by electronic absorption spectroscopy,fluorescence spectroscopy and viscosity methods,as well as molecular docking technologies.These studies confirmed that the complexes bind to DNA through the intercalation and groove binding mode,and the binding forces are mainly hydrophobic interaction and hydrogen-bond,following the order:3>2>1.Scavenging superoxide anion radical(O2�-)and hydroxyl radical(OH)activities of the complexes were determined by nitroblue tetrazolium chloride(NBT)photoreduction and Fenton-type reaction,and the complexes exhibited excellent antioxidant activities,especially for scavenging O2�-.In addition,the antimicrobial activities of the complexes and ligand were assessed by oxford cup methods,the results showed that the complexes can inhibit the growth of Gram-positive bacteria,and selectively inhibit the growth of Gram-negative bacteria(escherichia coli),but show no activity to the Fungi(Asporgillus).Finally,the cytotoxicities of the complexes were measured by MTT methods,the result showed that the complexes exhibited considerable in vitro cytotoxicity against four human cell lines(HeLa,A549,SGC-7901 and L02)with IC50 and GI50 values following the trend:3>2>1 and HeLa>A549>LO2>SGC-7901,where complex 3 showed perfect anticancer abilities towards to three tumor cell lines(IC50 = 3.74?6.45 ?M;GI50 = 1.32?4.18 ?M).In addition,the apoptosis and cycle assays showed that the complexes induced apoptosis of HeLa cell lines,and arrest the cell cycle in G2/M phase,thus achieving the goal of inhibiting the proliferation of tumor cells.In section 3,the ternary copper complex of 6-(pyrazin-2-yl)-1,3,5-triazine-2,4-diamino-Cu(?)-L-Argininate(L-ArgH)[Cu(pzta)(L-ArgH)(H2O)](ClO4)2(4)synthesized previously in our research group,and one new water-soluble copper(?)complexes of pzta and L-Methioninate(L-Met),[Cu(pzta)(L-Met)(H2O)]ClO4�3H2O(5)were synthesized.Complex 5 was characterized by elemental analyses,molar conductance and spectroscopy methods.The X-ray crystallographic structure determination showed that complex 5 exhibited distorted square-pyramidal coordination geometry.The binding properties of the two complexes toward DNA were measured by isothermal titration calorimetry(ITC)and molecular docking technologies,the results showed that the complexes bound to DNA through a grooving binding mode,the positive ?H and ?S values indicated that the hydrophobic interaction was the main force in the binding between the complexes and DNA.Besides,the protein binding properties of the complexes were detected by electronic absorption spectroscopy,fluorescence spectroscopy,ITC and molecular docking technologies,which revealed that the complexes caused the fluorescence quenching of HSA through a static quenching procedure,and changed the secondary structures and microenvironments of the Trp-214 residue.The ITC experiments suggested the bindings of the complexes to HSA were a spontaneous process,and the negative values of ?H and T?S indicated that the predominant forces in the interactions between the complexes and HSA,and the complexes preferably bound to subdomain ?A of HSA driven by hydrophobic and hydrogen-bond interactions.Furthermore,O2�-scavenging activities were performed using the mean of NBT photoreduction,and the complexes exhibited excellent antioxidant activities.Finally,the in vitro cytotoxicities of the complexes against three human carcinoma cell lines(A549,PC-3 and HeLa)were assayed,the results showed the cytotoxicity of complex 5 toward A549 were higher than HeLa and PC-3 cell lines,indicating that 5 could selectively inhibit the proliferation of A549 cell lines.In section 4,the research conclusion and expectation were listed.