Copper complexes based on chiral Schiff-base ligands: DNA/BSA binding ability, DNA cleavage activity, cytotoxicity and mechanism of apoptosis

• DOI: 10.1016/j.ejmech.2016.02.055
• Publication Date: 2016-02-28T13:48:35Z
• Authors: Xue-Quan Zhou; Yang Li; Dong-Yan Zhang; Yan Nie; Zong-Jin Li; Wen Gu; Xin Liu; Jin-Lei Tian; Shi-Ping Yan
• Keywords: Models, Molecular; Binding Sites; Dose-Response Relationship, Drug; Molecular Structure; Antineoplastic Agents; Apoptosis; Serum Albumin, Bovine; DNA; Crystallography, X-Ray; Ligands; 7. Clean energy; 01 natural sciences; 3. Good health; 0104 chemical sciences; 13. Climate action; Cell Line, Tumor; Organometallic Compounds; Animals; Humans; Cattle; DNA Cleavage; Drug Screening Assays, Antitumor; Copper; Schiff Bases; Cell Proliferation

Four copper(II) complexes with chiral Schiff-base ligands, [Cu(R-L(1))2]·EtOAc (1) and [Cu(S-L(1))2]·EtOAc (2), [Cu(R-L(2))2]·EtOAc (3) and [Cu(S-L(2))2]·EtOAc (4), (R/S-HL(1) = (R/S)-(1-naththyl)-salicylaldimine, R/S-HL(2) = (R/S)-(1-naththyl)-3-methoxysalicylaldimine, EtOAc = ethyl acetate) were synthesized to serve as artificial nucleases and anticancer drugs. All complexes and R/S-HL(1) ligands were structurally characterized by X-ray crystallography. The interaction of these complexes with CT-DNA was researched via several spectroscopy methods, which indicates that complexes bind to CT-DNA by moderate intercalation binding mode. Moreover, DNA cleavage experiments revealed that the complexes exhibited remarkable DNA cleavage activities in the presence of H2O2via the generation of hydroxyl radical. Particularly, complex 4 also could nick DNA with the production of (1)O2. And all complexes exhibited excellent cytotoxicity to MDA-MB-231, A549 and Hela human cancer cells in micromole magnitude. Furthermore, complex 4 exhibited comparable cytotoxic effect to cisplatin against the proliferation of MDA-MB-231 and A549 cancer cells, as well as showed better anticancer ability to the three cancer cells than the other complexes. The results of cell cycle analysis indicated that complexes 3-4 could induce G2/M phase cell cycle arrest. Furthermore, MDA-MB-231 cells treated with 3 and 4 were subjected to apoptosis and death by generation of ROS and the activation of caspase-3. Interestingly, the chiral complexes 3 and 4 may induce cell apoptosis through extrinsic and mitochondrial intrinsic pathway, respectively.