title: Synthesis, characterization, biological activity, DNA and BSA binding study: novel copper(ii) complexes with 2-hydroxy-4-aryl-4-oxo-2-butenoate.
abstract: A serie of novel square pyramidal copper(ii) complexes [Cu(L)2H2O] (3a-d) with O,O-bidentate ligands [L = ethyl-2-hydroxy-4-aryl-4-oxo-2-butenoate; aryl = 3-methoxyphenyl-2a, (E)-2-phenylvinyl-2b, (E)-2-(4'-hydroxy-3'-methoxyphenyl)vinyl-2c, 3-nitrophenyl-2d, 2-thienyl-2e] were synthesized and characterized by spectral (UV-Vis, IR, ESI-MS and EPR), elemental and X-ray analysis. The antimicrobial activity was estimated by the determination of the minimal inhibitory concentration (MIC) using the broth microdilution method. The most active antibacterial compounds were 3c and 3d, while the best antifungal activity was showed by complexes 3b and 3e. The lowest MIC value (0.048 mg mL-1) was measured for 3c against Proteus mirabilis. The cytotoxic activity was tested using the MTT method on human epithelial carcinoma HeLa cells, human lung carcinoma A549 cells and human colon carcinoma LS174 cells. All complexes showed extremely better cytotoxic activity compared to cisplatin at all tested concentrations. Compound 3d expressed the best activity against all tested cell lines with IC50values ranging from 7.45 to 7.91 μg mL-1. The type of cell death and the impact on the cell cycle for 3d and 3e were evaluated by flow cytometry. Both compounds induced apoptosis and S phase cell cycle arrest. The interactions between selected complexes (3d and 3e) and CT-DNA or bovine serum albumin (BSA) were investigated by the fluorescence spectroscopic method. Competitive experiments with ethidium bromide (EB) indicated that 3d and 3e have a propensity to displace EB from the EB-DNA complex through intercalation suggesting strong competition with EB [Ksv= (1.4 ± 0.2) and (2.9 ± 0.1) × 104M-1, respectively]. Ksvvalues indicate that these complexes bind to DNA covalently and non-covalently. The achieved results in the fluorescence titration of BSA with 3d and 3e [Ka= (2.9 ± 0.2) × 106and (2.5 ± 0.2) × 105M, respectively] showed that the fluorescence quenching of BSA is a result of the formation of the 3d- and 3e-BSA complexes. The obtained Kavalues are high enough to ensure that a significant amount of 3d and 3e gets transported and distributed through the cells.
authors.affiliation: Faculty of Science, University of Kragujevac, Department of Chemistry, Radoja Domanovića 12, 34000 Kragujevac, Serbia. nenad.jankovic@kg.ac.rs.
authors.forename: Nenad
authors.initials: N
authors.lastname: Joksimović
authors.affiliation: Centre for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovića 69, 34000 Kragujevac, Serbia.
authors.forename: Dejan
authors.initials: D
authors.lastname: Baskić
authors.affiliation: Centre for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovića 69, 34000 Kragujevac, Serbia.
authors.forename: Suzana
authors.initials: S
authors.lastname: Popović
authors.affiliation: Department of Biochemistry, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovića 69, 34000 Kragujevac, Serbia.
authors.forename: Milan
authors.initials: M
authors.lastname: Zarić
authors.affiliation: Faculty of Science, University of Kragujevac, Department of Biology and Ecology, Radoja Domanovića 12, 34000 Kragujevac, Serbia.
authors.forename: Marijana
authors.initials: M
authors.lastname: Kosanić
authors.affiliation: Faculty of Science, University of Kragujevac, Department of Biology and Ecology, Radoja Domanovića 12, 34000 Kragujevac, Serbia.
authors.forename: Branislav
authors.initials: B
authors.lastname: Ranković
authors.affiliation: Institute of Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Stanojković
authors.affiliation: Vinča Institute of Nuclear Science, University of Belgrade University of Belgrade, P.O. Box 522, 11001, Belgrade, Serbia.
authors.forename: Sladjana B
authors.initials: SB
authors.lastname: Novaković
authors.affiliation: Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovića 69, 34000 Kragujevac, Serbia.
authors.forename: Goran
authors.initials: G
authors.lastname: Davidović
authors.affiliation: Faculty of Science, University of Kragujevac, Department of Chemistry, Radoja Domanovića 12, 34000 Kragujevac, Serbia. nenad.jankovic@kg.ac.rs.
authors.forename: Zorica
authors.initials: Z
authors.lastname: Bugarčić
authors.affiliation: Faculty of Science, University of Kragujevac, Department of Chemistry, Radoja Domanovića 12, 34000 Kragujevac, Serbia. nenad.jankovic@kg.ac.rs.
authors.forename: Nenad
authors.initials: N
authors.lastname: Janković
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001419:Bacteria / Q000187:drug effects / Q000254:growth & development; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D056831:Coordination Complexes / Q000737:chemistry / Q000494:pharmacology; D003300:Copper / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000737:chemistry; D005658:Fungi / Q000187:drug effects / Q000254:growth & development; D006801:Humans; D012710:Serum Albumin, Bovine / Q000737:chemistry; D014753:Vinyl Compounds / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D000970:Antineoplastic Agents; D056831:Coordination Complexes; D014753:Vinyl Compounds; D012710:Serum Albumin, Bovine; D003300:Copper; D004247:DNA