Anticancer copper pyridine benzimidazole complexes: ROS generation, biomolecule interactions, and cytotoxicity

The Cu(II) complex CuCl2(pbzH), pbzH=2-(2-pyridyl)benzimidazole, and derivatives modified at the non-coordinated nitrogen of the benzimidazole fragment, have been studied as anticancer agents. These compounds show promising cytotoxicity against A549 adenocarcinomic alveolar basal epithelial cells with IC50 values in the range of 5–10μM. Importantly, this activity is higher than either CuCl2·2H2O or the individual ligands, demonstrating that ligand coordination to the Cu(II) centres of the complexes is required for full activity. Electron paramagnetic resonance (EPR) and UV–Vis spectroscopies were used to characterize the solution behaviour of the complexes. These studies demonstrate: (i) two types of solvated species in buffer, (ii) both coordinate and non-coordinate interactions with albumin, and (iii) weak interactions with DNA. Further DNA studies using agarose gel electrophoresis demonstrate strand cleavage by the complexes in the presence of ascorbate, which is mediated by reactive oxygen species (ROS). Through a fluorescence-based in vitro assay, intracellular ROS generation in the A549 cell line was observed; indicating that damage by ROS is responsible for the observed activity of the complexes. Cytotoxic redox-active copper complexes with functionalized bidentate nitrogen donor ligands and exchangeable chlorides are described. These compounds bind to albumin but interact weakly with DNA. The complexes cleave DNA in the presence of reducing agents and generate reactive oxygen species in cells. [Display omitted] •Synergy between copper centres and ligands generates cytotoxicity.•Coordinate and non-coordinate interactions with albumin.•Complexes cause DNA cleavage in the presence of ascorbate via hydroxyl radicals.•Complexes generate elevated levels of reactive oxygen species in A549 cells.