The Design, Synthesis And Study On Biological Activity Of Copper Complexes

DNA is the carrier and messenger of genetic information and it is the most important biological macromolecule in life. The study on the interaction between small molecules and DNA can help us to understand the biological phenomena in the molecular level, which has special significance on the theory research and practical application. Metal complexes as efficient metallonucleases or anticancer agents have been explored because of their structural and functional varieties. The research of the thesis is focused on copper complexes because they possess biologically accessible redox potentials and high nucleobase affinities and usually display high DNA cleavage efficiency or favourable cytotoxicity.This thesis consists of following four chapters which covers the introductory backgrounds of the research and our research results.In Chapter 1, the research background and development status were briefly reviewed from three aspects: artificial nucleases, the interaction between metal complexes and serum albumin, and the development of non-platinum-based antitumor agents.In Chapter 2, two copper(II) complexes, [Cu2II(L1-3H)Cl](1) and[Cu2II(L2-3H)Cl](2), have been synthesized using two phenolate-bridged binucleating ligands, 2,6-bis{[(2-hydroxybenzyl)(2-benzimidazolylethyl)amino]methyl}-4-methylphenol(L1) and 2,6-bis{[(2-hydroxybenzyl)(2-benzimidazolylmethyl)-amino]methyl}-4-methylphenol(L2). Their mononuclear analogues, [Cu II(L1a-1H)Cl](3) and [Cu II(L2a-1H)Cl](4) have also been synthesized. The DNA binding properties of the complexes have been investigated by using UV-vis absorption, fluorescence,and circular dichroism(CD). The experimental results suggest complexes 1 and 2could strongly bind to calf thymus DNA and induce a remarkable conformational variation of DNA. Agarose gel electrophoresis revealed both the complexes could efficiently cleave the supercoiled p UC19 plasmid DNA into its nicked and linear forms in the presence of excessive ascorbic acid(Vc) under nearly physiological conditions. However, their mononuclear analogues, [Cu II(L1a-1H)Cl](3) and[Cu II(L2a-1H)Cl](4), could not exhibit DNA cleavage activity at the same conditions,suggesting a synergistic effect of the Cu2+ centers in 1 or 2. Mechanism studies demonstrated diffusible × OH, H2O2, and 1O2 are not the effective reactive oxygen species(ROS) in the cleavage process mediated by the complexes and the copper-oxo species might be responsible for the cleavage.In Chapter 3, the reactivities towards DNA and protein of a benzimidazole derived mononuclear copper(II) complex, [Cu(EDTB)](NO3)2 × C2H5OH(EDTB =N,N,N’,N’-tetrakis(2’-benzimidazolyl methyl)-1,2-ethanediamine), was investigated under physiological conditions using UV-vis absorption, fluorescence, and circular dichroism(CD). The experimental results suggest the complex could strongly bind to calf thymus DNA and induce a remarkable conformational variation of DNA. The evalution of the protein binding ability shows the complex could interact with BSA and exhibit the appropriate affinity towards BSA. Further, the complex demonstrates a significant inhibition against human cervical cancer(He La), human lung cancer(A-549), and human mammary cancer(MCF-7) cell lines.In Chapter 4, a binuclear copper(II) complex of Schiff base ligand has been synthesized and characterized. The reactivity towards DNA of the complex was investigated using UV-vis absorption, fluorescence, and circular dichroism(CD). The experimental results suggest the complex could strongly bind to calf thymus DNA by the groove binding mode and induce a remarkable conformational variation of DNA.Agarose gel electrophoresis revealed the complex could efficiently cleave the supercoiled p BR322 plasmid DNA into its nicked and linear forms in the presence of excessive ascorbic acid(Vc) under nearly physiological conditions and displayed high DNA cleavage efficiency.