title: Mixed ligand μ-phenoxo-bridged dinuclear copper(II) complexes with diimine co-ligands: efficient chemical nuclease and protease activities and cytotoxicity.
abstract: The water soluble mixed ligand copper(II) complexes of the type [Cu(sal)(diimine)(ClO4)]21-5, where sal is salicylaldehyde and diimine is 2,2'-bipyridine (bpy, 1), 1,10-phenanthroline (phen, 2), 5,6-dimethyl-1,10-phenanthroline (5,6-dmp, 3), 3,4,7,8-tetramethyl-1,10-phenanthroline (3,4,7,8-tmp, 4) or dipyrido[3,2-d:2',3'-f]quinoxaline (dpq, 5), and [Cu(sal)(phen)(NO3)]2 (2a) have been successfully isolated and characterized by elemental analysis and other spectral techniques. The DNA binding and cleavage properties of 1-5 have been explored by using various physical and biochemical methods. The coordination geometry around copper(II) in the X-ray structures of 1, 2, 2a and 4 is described as an elongated octahedron. The UV-Vis and EPR spectral and ESI-MS studies reveal that in solution the dinuclear complexes dissociate into essentially mononuclear [Cu(sal)(diimine)]+ species with square-based geometry. The absorption spectral titrations and competitive DNA binding studies reveal that the intrinsic DNA binding affinity of the complexes depends upon the diimine co-ligand and is of the order of dpq (5) > 3,4,7,8-tmp (4) > 5,6-dmp (3) > phen (2) > bpy (1). The complexes 2 and 5 are involved in a partial intercalative interaction with DNA base pairs, while 3 and 4 are involved in a hydrophobic interaction with DNA and 1 is involved in an electrostatic interaction with DNA, which is supported by viscosity studies. Interestingly, only 3 and 4 are selective in exhibiting a positive induced CD band (ICD) upon binding to DNA suggesting that they induce a B to A conformational change in DNA. All the complexes exhibit an oxidative DNA cleavage ability, which varies as 5 > 4 > 3 > 2 > 1. While 4 and 5 are unique in displaying prominent double-strand DNA cleavage even in the absence of an activator, 2 and 3 display only single-strand DNA cleavage. Interestingly, all the complexes exhibit oxidative double-strand DNA cleavage in the presence of ascorbic acid, with 4 and 5 showing a DNA cleavage activity more prominent than 1 and 2. The ability of the complexes to bind and cleave the protein BSA varies in the order, 4 > 3 > 5 > 2 > 1. Interestingly, 3 and 4 cleave the protein in the presence of H2O2 as an activator in a non-specific manner suggesting that they can act as chemical proteases. It is remarkable that all the complexes exhibit cytotoxicity against human breast cancer cell lines (MCF-7) with a potency more than the widely used drug cisplatin indicating that they have the potential to act as effective anticancer drugs in a time dependent manner. The morphological assessment data obtained by using Hoechst 33258 staining reveal that 3 and 4 induce apoptosis much more effectively than the other complexes. Also, the alkaline single-cell gel electrophoresis study (comet assay) suggests that the same complexes induce DNA fragmentation more efficiently than others.
authors.affiliation: Department of Chemistry, Central University of Tamil Nadu, Thiruvarur 610004, Tamil Nadu, India. palanim51@yahoo.com palaniandavar@cutn.ac.in.
authors.forename: Rangasamy
authors.initials: R
authors.lastname: Loganathan
authors.forename: Sethu
authors.initials: S
authors.lastname: Ramakrishnan
authors.forename: Eringathodi
authors.initials: E
authors.lastname: Suresh
authors.forename: Mallayan
authors.initials: M
authors.lastname: Palaniandavar
authors.forename: Anvarbatcha
authors.initials: A
authors.lastname: Riyasdeen
authors.forename: Mohamad Abdulkadhar
authors.initials: MA
authors.lastname: Akbarsha
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D020552:Comet Assay; D056831:Coordination Complexes / Q000737:chemistry / Q000494:pharmacology; D003300:Copper / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000737:chemistry; D053837:DNA Cleavage; D003851:Deoxyribonucleases / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007097:Imines / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D061986:MCF-7 Cells; D010447:Peptide Hydrolases / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D012710:Serum Albumin, Bovine / Q000378:metabolism
chemical_list: D056831:Coordination Complexes; D007097:Imines; D008024:Ligands; D012710:Serum Albumin, Bovine; D003300:Copper; D004247:DNA; C427203:calf thymus DNA; D003851:Deoxyribonucleases; D010447:Peptide Hydrolases