title: Mixed-ligand copper(ii) Schiff base complexes: the role of the co-ligand in DNA binding, DNA cleavage, protein binding and cytotoxicity.
abstract: Four novel mononuclear Schiff base copper(ii) complexes, namely, [Cu(L)(OAc)]·H2O (), [Cu(HL)(C2O4)(EtOH)]·EtOH (), [Cu(L)(Bza)] () and [Cu(L)(Sal)] () (HL = 1-(((2-((2-hydroxypropyl)amino)ethyl)imino)methyl)naphthalene-2-ol), Bza = benzoic acid, Sal = salicylic acid), were synthesized and characterized by X-ray crystallography, elemental analysis and infrared spectroscopy. Single-crystal diffraction analysis revealed that all the complexes were mononuclear molecules, in which the Schiff base ligand exhibited different coordination modes and conformations. The N-HO and O-HO inter- and intramolecular hydrogen bonding interactions linked these molecules into multidimensional networks. Their interactions with calf thymus DNA (CT-DNA) were investigated by UV-visible and fluorescence spectrometry, as well as by viscosity measurements. The magnitude of the Kapp values of the four complexes was 10(5), indicating a moderate intercalative binding mode between the complexes and DNA. Electrophoresis results showed that all these complexes induced double strand breaks of pUC19 plasmid DNA in the presence of H2O2 through an oxidative pathway. In addition, the fluorescence spectrum of human serum albumin (HSA) with the complexes suggested that the quenching mechanism of HSA by the complexes was a static process. Moreover, the antiproliferative activity of the four complexes against HeLa (human cervical carcinoma) and HepG-2 (human liver hepatocellular carcinoma) cells evaluated by colorimetric cell proliferation assay and clonogenic assay revealed that all four complexes had improved cytotoxicity against cancer cells. Inspiringly, complex , with salicylic acid as the auxiliary ligand, displayed a stronger anticancer activity, suggesting that a synergistic effect of the Schiff base complex and the nonsteroidal anti-inflammatory drug may be involved in the cell killing process. The biological features of mixed-ligand copper(ii) Schiff base complexes and how acetic auxiliary ligands manipulate these features are also discussed.
authors.affiliation: Department of Chemical Biology and Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, P.R. China. xujingyuan@tmu.edu.cn qiaoxin@tmu.edu.cn.
authors.forename: Wen-Jing
authors.initials: WJ
authors.lastname: Lian
authors.affiliation: Department of Chemical Biology and Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, P.R. China. xujingyuan@tmu.edu.cn qiaoxin@tmu.edu.cn.
authors.forename: Xin-Tian
authors.initials: XT
authors.lastname: Wang
authors.affiliation: Department of Chemical Biology and Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, P.R. China. xujingyuan@tmu.edu.cn qiaoxin@tmu.edu.cn.
authors.forename: Cheng-Zhi
authors.initials: CZ
authors.lastname: Xie
authors.affiliation: Department of Chemical Biology and Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, P.R. China. xujingyuan@tmu.edu.cn qiaoxin@tmu.edu.cn.
authors.forename: He
authors.initials: H
authors.lastname: Tian
authors.affiliation: Department of Chemical Biology and Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, P.R. China. xujingyuan@tmu.edu.cn qiaoxin@tmu.edu.cn.
authors.forename: Xue-Qing
authors.initials: XQ
authors.lastname: Song
authors.affiliation: Department of Chemical Biology and Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, P.R. China. xujingyuan@tmu.edu.cn qiaoxin@tmu.edu.cn.
authors.forename: He-Ting
authors.initials: HT
authors.lastname: Pan
authors.affiliation: Department of Chemical Biology and Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, P.R. China. xujingyuan@tmu.edu.cn qiaoxin@tmu.edu.cn.
authors.forename: Xin
authors.initials: X
authors.lastname: Qiao
authors.affiliation: Department of Chemical Biology and Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, P.R. China. xujingyuan@tmu.edu.cn qiaoxin@tmu.edu.cn.
authors.forename: Jing-Yuan
authors.initials: JY
authors.lastname: Xu
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019817:Benzoic Acid / Q000737:chemistry / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D003300:Copper / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry / Q000187:drug effects*; D053837:DNA Cleavage; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D006860:Hydrogen Bonding; D007364:Intercalating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008968:Molecular Conformation; D011485:Protein Binding / Q000187:drug effects; D020156:Salicylic Acid / Q000737:chemistry / Q000494:pharmacology; D012545:Schiff Bases / Q000138:chemical synthesis / Q000494:pharmacology; D000075462:Serum Albumin, Human / Q000737:chemistry; D013050:Spectrometry, Fluorescence; D013055:Spectrophotometry, Infrared
chemical_list: D000970:Antineoplastic Agents; D007364:Intercalating Agents; D012545:Schiff Bases; D003300:Copper; D019817:Benzoic Acid; D004247:DNA; C427203:calf thymus DNA; D020156:Salicylic Acid; D000075462:Serum Albumin, Human