title: Synthesis and characterization of new transition metal {Cu(II), Ni(II) and Co(II)} L-phenylalanine-DACH conjugate complexes: in vitro DNA binding, cleavage and molecular docking studies.
abstract: The novel metal-based molecular entities {Cu(II), Ni(II) and Co(II)} 1-3, respectively were synthesized and characterized by elemental analysis and spectroscopic methods (IR, (1)H and (13)C NMR, EPR, UV-vis, ESI-MS and XRPD). The interaction studies of 1-3 with CT DNA have been investigated by UV-vis titrations, fluorescence and circular dichroic studies which revealed the electrostatic mode of binding and on the basis of intrinsic binding constant Kb (5.30×10(4), 1; 3.41×10(4), 2; and 2.74×10(4), 3; M(-1)), the extent of DNA binding was ascertained, following the order 1>2>3. Specifically, 1 exhibited greater binding propensity with CT DNA, therefore the cleavage activity of 1 with pBR322 DNA was evaluated by agarose gel electrophoresis assay. Complex 1 presented an impressive nuclease activity generating single- and double-strand breaks. Further mechanistic investigation revealed the efficiency of 1 to cleave DNA strands by an oxidative pathway involving the generation of ROS and preferential selectivity towards the DNA minor groove. Moreover, complex 1 exhibited significant inhibitory effects on the catalytic activity of topoisomerase I at a very low concentration ∼20 μM. Additionally, computer-aided molecular docking techniques were carried out to correlate and rationalize the observed binding affinities with docking studies towards the molecular target DNA and Topo-I.
authors.affiliation: Department of Chemistry, Aligarh Muslim University, Aligarh, UP 202002, India.
authors.forename: Manal
authors.initials: M
authors.lastname: Shamsi
authors.affiliation: Department of Chemistry, Aligarh Muslim University, Aligarh, UP 202002, India.
authors.forename: Shipra
authors.initials: S
authors.lastname: Yadav
authors.affiliation: Department of Chemistry, Aligarh Muslim University, Aligarh, UP 202002, India. Electronic address: farukh_arjmand@yahoo.co.in.
authors.forename: Farukh
authors.initials: F
authors.lastname: Arjmand
mesh_terms: D003035:Cobalt / Q000737:chemistry*; D056831:Coordination Complexes / Q000737:chemistry*; D003300:Copper / Q000737:chemistry*; D003514:Cyclohexylamines / Q000737:chemistry*; D004247:DNA / Q000737:chemistry; D053837:DNA Cleavage; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D062105:Molecular Docking Simulation; D009532:Nickel / Q000737:chemistry*; D010649:Phenylalanine / Q000737:chemistry*; D059004:Topoisomerase I Inhibitors / Q000737:chemistry
chemical_list: D056831:Coordination Complexes; D003514:Cyclohexylamines; D059004:Topoisomerase I Inhibitors; D003035:Cobalt; D010649:Phenylalanine; D003300:Copper; D009532:Nickel; D004247:DNA; C030435:1,2-cyclohexanediamine; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human
keywords: CT DNA binding studies; Cu(II)–DACH conjugate complex; Thermal denaturation; Topo-I inhibition; pBR322 plasmid cleavage