Antimicrobial And Antitumor Activities Of Ternary Mixed-ligand Copper(?) Complexes

In recent years,copper?II?complexes have been considered as one of the most promising drugs in the search for non-platinum transition metal drugs that overcome cancer and microbial infections.The research shows that copper?II?complexes not only potentially avoid drug resistance associated with platinum-based drugs,but also have higher biological activity and less toxic side effects.At present,the research of copper?II?complexes is focuses mainly on the antibacterial activity,cytotoxicity,and so on.However,there is little systemic research on the mechanism of the antitumor,which is important for the design and development of new copper?II?complexes with higher efficiency and lower toxicity.The main research works include the following aspects:In section 1,the antimicrobial and antitumor activities of quinolones/dipeptides-copper?II?-aromatic heterocyclic complexes are summarized,and the significant of this work is further illuminated.In section 2,three new copper?II?complexes[Cu?Hsf??HPB??H₂O?]·2ClO₄?1?,[Cu?Hsf??PBT??H₂O?]·2ClO₄?2?,[Cu?sf??PYTA??H₂O?]·ClO₄·3.5H₂O?3??where sf=5-amino-1-cyclopropyl-7-?cis-3,5-dimethyl-1-piperaziny?-6,8-difluoro-1,4-dihydro-4-oxoq uinoline-3-carboxylic acid,HPB=2-?2'-pyridyl?benzimidazole,PBT=2-?4'-pyridyl?benzothiazole,PYTA=2,4-diamino-6-?2'-pyridyl?-1,3,5-triazine?were designed and synthesized.The complexes were characterized by elemental analyses,conductivity and various spectroscopic techniques.The results show that the three complexes have a five-coordinate distorted square-pyramidal geometry where four equatorial positions are occupied by one carbonyl O atom as well as one carboxylate O atom of sparfloxacin?sf?and two nitrogen atoms of aromatic heterocyclic,and the apical position is occupied by a O atom of H₂O.The binding mode of the complexes with DNA was evaluated using electronic absorption spectroscopy,fluorescence spectroscopy,viscosity measurement and molecular docking,and the corresponding binding constants?K_b?was further calculated.It was found that the complexes bind to DNA through an intercalation mode,with the order:1(K_b=7.80×10⁴ M^-1)>2(K_b=2.80×10⁴ M^-1)>3(K_b=1.23×10⁴ M^-1).Moreover,all the complexes displayed favorable antimicrobial?d=8.0±0.5²0.0±0.1 mm?and cytotoxic(IC₅₀=14.1±0.5⁷7.6±1.4?M)activities toward the tested microorganisms?Bacillus subtilis,Staphylococcus aureus,Escherichia coli and Pseudomonas aeruginosa?and cancer cells?A549,Bel-7402,Eca-109 and 3T3?.Finally,the antitumor mechanism of the complexes was explored by single cell gel electrophoresis assay,Hoechst 33342staining,flow cytometry,change of mitochondrial membrane potential,detection of Cytochrome C and detection of intracellular Ca²⁺.The results showed that the complexes could induce apoptosis in Eca-109 cells through a mitochondrial pathway,and damage DNA,which was accompanied by cell cycle changes.Among them,complexes 1 and 2inhibit the cell growth at G2/M phase,while complex 3 inhibit at S phase.In section 3,the antimicrobial and antitumor activities of copper?II?complexes[Cu?Gly-L-leu??HPBM??H₂O?]·ClO₄?1?,[Cu?Gly-L-val??HPBM??H₂O?]·ClO₄·H₂O?2?,[Cu?Gly-gly??HPBM??H₂O?]·ClO₄·0.5H₂O?3?,[Cu?Gly-L-val??TBZ??H₂O?]·ClO₄?4?,[Cu?Gly-L-val??PBO??H₂O?]·ClO₄?5??Gly-L-leu=Glycyl-L-leucine anion,Gly-gly=Glycyl-glycine anion,Gly-L-val=Glycyl-L-valine anion,HPBM=5-methyl-2-?2'-pyridyl?benzimidazole,TBZ=2-?4'-thiazolyl?benzimidazole,PBO=2-?2'-pyridyl?benzoxazole?were evaluated.And all the complexes displayed favorable antimicrobial activity?MIC=8⁴00?g/mL?and lower cytotoxicity(IC₅₀=34.67±0.5¹15.03±1.8?M)toward the tested microorganisms?Bacillus subtilis,Staphylococcus aureus,Escherichia coli and Pseudomonas aeruginosa?and normal cells LO₂,respectively.Moreover,the antitumor mechanism of complexes 1 and 3 was explored.The experiments of AO/EB double staining and Annexin V-FITC/PI double staining indicated that the complexes could induce HeLa cell apoptosis.Meanwhile,the signal pathway of apoptosis was explored by intracellular reactive oxygen species?ROS?levels,location in mitochondria,mitochondrial membrane potentials as well as the expression of Bcl-2 family proteins.The results showed that the complexes could induce apoptosis in HeLa cells through a ROS-mediated mitochondrial dysfunction pathway,which was accompanied by the regulation of Bcl-2 family proteins.In section 4,the studies of the copper?II?complexes were summarized,and the next research directions were prospected.