A multifunctional molecular entity CuII-SnIV heterobimetallic complex as a potential cancer chemotherapeutic agent: DNA binding/cleavage, SOD mimetic, topoisomerase Iα inhibitory and in vitro cytotoxic activities

Abstract

New chiral l-valine-derived Schiff base complexes with the bioactive heterocyclic ligand scaffold pyrazole (Hpz) were designed and synthesized with a view to find their potential as anticancer chemotherapeutic drug candidates. The monometallic chemical entities CuII (1) and ZnII (2), and heterobimetallic CuII-SnIV (3), and ZnII-SnIV (4) were synthesized and characterized adopting various spectroscopic (UV-vis, IR, 1H 13C and 119Sn NMR, EPR and ESI-MS) and analytical methods. In vitro, CT-DNA-binding profiles of 1-4 were studied by UV-vis, fluorescence spectroscopy, and circular dichroism. The results display the significantly higher binding affinity of heterobimetallic complexes 3 and 4 than monometallic complexes 1 and 2. This could be attributed to the dual binding mode facilitating a preferential electrostatic interaction via SnIV towards the surface phosphate oxygen of the sugar-phosphate backbone of the DNA double helix, in addition to the covalent overlap of CuII to N7 of the guanine of the DNA. Moreover, complex 3 exhibited significantly efficient DNA cleavage activity involving the formation of the superoxide radical as well as the hydroxyl radical as the reactive species. The SOD-like activity of 3 and 4 was evaluated using a xanthine/xanthine oxidase assay, which showed SOD activity in the micromolar range for both the heterobimetallic complexes viz., (IC50) 0.082 μM for 3 and 12 μM for 4. Furthermore, 3 showed high inhibitory activity against Topo-Iα at a concentration of 20 μM as IC50, suggesting that complex 3 is an efficient DNA cleaving agent. In vitro studies on the anticancer activity against the HepG2 hepatocellular carcinoma cell line revealed that both complexes 3 and 4 have the capability to kill the chosen cancer cell, but the efficiency of complex 3 is 10 times higher than 4. The mode of cell death induced by complex 3 is primarily apoptosis as revealed by AO/EB staining, Hoechst 33258 staining, and assessment of the mitochondrial trans-membrane potential.