Water soluble transition metal [Ni(ii), Cu(ii) and Zn(ii)] complexes of N-phthaloylglycinate bis(1,2-diaminocyclohexane). DNA binding, pBR322 cleavage and cytotoxicity

Abstract

To validate the effect of metal ions in analogous ligand scaffolds on DNA binding and cytotoxic response, we have synthesized a series of water-soluble ionic N-phthaloylglycinate conjugated bis(diaminocyclohexane)M²⁺ complexes where M = Ni(II), Cu(II) and Zn(II) (1–3). The structural characterization of the complexes (1–3) was achieved by spectroscopic {FT-IR, EPR, UV–vis absorption data, ¹H NMR, ESI-MS and elemental analysis} and single crystal X-ray diffraction studies, which revealed different topologies for the late 3d-transition metals. The Ni(II) and Zn(II) complexes exhibited an octahedral geometry with coordinated labile water molecules in the P space group while the Cu(II) complex revealed a square planar geometry with the P2₁/c space lattice. In vitro DNA-complexation studies were performed employing various complementary biophysical methods to quantify the intrinsic binding constant K_b and K_sv values and to envisage the binding modes and binding affinity of (1–3) at the therapeutic targets. The corroborative results of these experiments revealed a substantial geometric and electronic effect of (1–3) on DNA binding and the following inferences were observed, (i) high K_b and K_sv values, (ii) remarkable cleavage efficiency via an oxidative pathway, (iii) condensation behavior and (iv) good cytotoxic response to HepG2 and PTEN-caP8 cancer cell lines, with copper(II) complex 2 outperforming the other two complexes as a most promising anticancer drug candidate. Copper(II) complexes have been proven in the literature to be good anticancer drug entities, displaying inhibition of uncontrolled-cell growth by multiple pathways viz., anti-angiogenesis, inducing apoptosis and reactive oxygen species mediated cell death phenomena. Nickel(II) and zinc(II) ionic complexes 1 and 3 have also demonstrated good chemotherapeutic potential in vitro and the bioactive 1,2-diaminocyclohexane fragment in these complexes plays an instrumental role in anticancer activity.