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.

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.