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, 1H and 13C 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 × 104, 1; 3.41 × 104, 2; and 2.74 × 104, 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.