Benzimidazole-based mononuclear polypyridyl Cu(ii) complexes: DNA binding, cleavage, and in vitro antiproliferative studies

Abstract

This paper addresses the synthesis, characterization, DNA binding, cleavage, and in vitro antiproliferative activity studies of a series of heteroleptic mononuclear copper(II) complexes [Cu(L)(bpy)](ClO₄)₂, {1}; [Cu(L)(phen)](ClO₄)₂, {2}; and [Cu(L)(Mephen)](ClO₄)₂, {3} derived from different polypyridyl ligands, where in the complex architecture, one 2,6-bis(1-methyl-1H-benzo[d]imidazol-2-yl)pyridine(Mebzimpy) (L) moiety is connected to the central Cu metal in a tridentate fashion and the bidentate co-ligands are 2,2′-bipyridine (bpy), 1,10-phenanthroline (phen) and 2,9-dimethyl-1,10-phenanthroline (Mephen). All the synthesized complexes were characterized using various spectroscopic and analytical methods, along with the single-crystal X-ray diffraction (SCXRD) technique. The complexes crystallize in a penta-coordinated distorted square pyramidal geometry. The redox properties of the complexes were also studied by using cyclic voltammetry (CV) and differential pulse voltammetry (DPV). The DNA binding nature of the complexes was investigated utilizing absorbance spectral measurement and fluorescence quenching experiments with ethidium bromide (EB) as a DNA intercalator, employing double-stranded salmon sperm DNA (ss-DNA). Both the binding constant (K_b) and the Stern–Volmer constant (K_SV) were found to be in the order of 10⁴. In silico molecular docking analysis confirmed that all the complexes could interact with the minor groove of duplex DNA. The DNA cleaving ability of the complexes was studied by gel electrophoresis using supercoiled plasmid DNA; however, no DNA cleavage was found. DNA-binding polypyridyl complexes are well known to disrupt DNA metabolic pathways and cause cytotoxicity to rapidly growing cancer cells. Hence, cell viability analysis was also carried out with complexes 1–3. It was observed that complexes 2 and 3 prevented the proliferation of the human osteosarcoma cell line U2OS and the triple-negative breast cancer cell line MDA-MB-231. Overall, these findings could be beneficial in the design and development of future antitumor agents.