New trinuclear nickel(II) complexes as potential topoisomerase I/II alpha inhibitors: in vitro DNA binding, cleavage and cytotoxicity against human cancer cell lines

Nickel (II) complexes containing p-substitute (-H, -CI, -CH3, -OCH3) isonitrosoacetophenone-based bis(oxime) ligands were synthesized by metal template method and characterized by elemental analyses, molar conductance, magnetic susceptibility, IR, H-1-NMR, UV-visible and mass spectra. Analytical data showed that all the complexes exhibited 3:2 (metal/ligand) ratio. The binding profile of the complexes with calf thymus DNA (CT-DNA) was carried out by absorption spectra measurements. The experimental results revealed binding of the complex with CT-DNA via groove binding. The concentration and time-dependent DNA cleavage studies including cleavage mechanism of complexes were performed by employing gel electrophoresis assay, where all complexes have been found to cleave supercoiled DNA with high efficiency. Topoisomerase I and II alpha inhibition assays with complexes 1-4 were performed. Complexes showed strong inhibition against both enzymes at 25 mu M. The cytotoxic activity of the complexes was performed on human cell lines, lung carcinoma cell line (A549), colorectal adenocarcinoma cell line (HT29), hepatocellular carcinoma cell line (HepG2), breast cancer cell line (MDA-MB-231), prostate cancer cell lines (LNCaP) and human embryonic kidney cells (HEK-293) by MTT assay. The complex 2 exhibited remarkably good cytotoxic potential on cancer cell lines for 24, 48 and 72 h. Annexin V assay was carried out for complex 2 with various concentrations on MBD-BD-231, and results showed that complex 2 induced apoptosis and showed cytotoxic selectivity higher than cisplatin on MBD-BD-231 cell line for 48 h.