Synthesis, Characterization And Biological Activity Research Of Copper(?)-Dipeptide Complexes Of N,N-donor Heterocycle Ligands

In recent decades, cancer has become one of the most serious and dreadful diseases as the leading cause of death in the world. Therefore, it is fascinating to develop novel drugs with more-effective, less toxic and target-specific DNA in the field of pharmaceutical chemistry and biological chemistry in the 21 st century. Metal complexes own wide range of coordination numbers and flexible geometries in physiological conditions, so they have better pharmaceutical activity than organic compounds. Moreover,it is of great significance to improve efficacy and reduce side effects of drugs by choosing proper metallic elements and organic compounds, in consideration of the synergistic effect.Focused on the above topic, nine new ternary copper?II? complexes containing aromatic heterocycles and dipeptide were designed, synthesized and characterized by elemental analysis, UV–vis, IR, ESI-MS, molar conductivity and ESR. The DNA interaction, antioxidant property and their antitumor activity have been researched.This thesis includes four sections.In section 1, it summarized the research progress of the ternary aromatic heterocyclic derivatives based Cu?II?-dipeptide complexes, which focused chiefly on their biological activities, and also illuminated the research significance of this dissertation.In section 2, the experimental materials and methods were listed and introduced.In section 3, as the main body of this thesis, nine new copper?II? complexes were synthesized and characterized, which were as following: [Cu?Gly-L-val??HPB??H₂O?]ClO₄·1.5H₂O?1?, [Cu?Gly-L-val??TBZ??H₂O?]ClO₄?2?, [Cu?Gly-L-val??PBT??H₂O?]ClO₄?3?, [Cu?Gly-gly??PBO??H₂O?]ClO₄·1.5H₂O?4?, [Cu?Gly-L-val??PBO??H₂O?]ClO₄?5?,[Cu?Gly-L-leu??PBO??H₂O?]ClO₄?6?, [Cu?Gly-gly??HPBM??H₂O?]ClO₄·0.5H₂O?7?, [Cu?Gly-L-val??HPBM??H₂O?]ClO₄·H₂O?8?, [Cu?Gly-L-leu??HPBM??H₂O?]ClO₄?9??primaryligands: HPB = 2-?2'-pyridyl?benzimidazole, PBT = 2-?2'-pyridyl?benzothiazole?, TBZ =2-?4?-thiazolyl?benzimidazole, PBO = 2-?2'-pyridyl?benzoxazole), HPBM = 5- methyl-2-?2'-pyridyl?benzimidazole; ancillary ligands: Gly-gly = Glycyl-glycine anion, Gly-L-val =Glycyl-L-valine anion, Gly-L-leu = Glycyl-L-leucine anion). Firstly, the structures of the nine copper?II? complexes were confirmed by multiple physicochemical methods. A five-coordinate approximate square-pyramidal geometry was demonstrated for each complex, where four equatorial positions were occupied by N-aromatic heterocycles?N, N?and dipeptide?N, O?, and the axial position was occupied by a water molecule?O?. Then,the interactions of these complexes with DNA were studied by multispectroscopic techniques?UV-vis, fluorimetry and CD?, electrochemistry, viscosity and the molecular docking as well as agarose gel electrophoresis. These studies confirmed the mode of the complexes bound to CT-DNA through insertion. In the fluorimetric experiments of thermodynamics, the hydrophobic interaction played a major role in the process of the complexes with DNA. And the process was entropy increasing process and entropy-driven.The complexes displayed oxidative cleavage of p BR322 plasmid DNA in the presence of VC, probably induced by ·OH as a reactive oxygen specie. In addition, superoxide dismutase?SOD? like activity studies were performed using the mean of nitroblue tetrazolium?NBT?photoreduction, the complexes exhibited excellent antioxidant activities. Finally, the in vitro cytotoxicity of the copper?II? complexes against three different human tumor cell lines of He La?cervical?, PC-3?prostatic? and A549?pulmonary? were studied by MTT assay,indicated the complexes of pyridyl- benzimidazole own higher cytotoxicity against the three tumor cell lines than the widely used drug cisplatin, one of the most used anticancer drugs against malignancies. The complexes of pyridyl-benzimidazole have the potential to act as promising broad spectrum chemotherapeutic drugs. Complex 3 performed better cytotoxicity against He La than PC-3 and A549, indicated 3 was active on He La and it can be researched as a promising narrow spectrum chemotherapeutic drug.In section 4, the research conclusion and expectation were listed.