Structure and antitumor activity of cupric complexes incorporating 2-(2-pyridyl)benzimidazole derivatives

Six mononuclear Cu^II complexes, formulated as [Cu(PBDⁿ)₂(NO₃)]NO₃ (Cu1-Cu6) were synthesized and structurally characterized, in which PBDⁿ (n = 1-6) represent the 2-(2-pyridyl)benzimidazole derivatives bearing the substitution groups of 7-methyl-, 6,7-dimethyl-, 7-fluoro-, 7-chloro-, 7-bromo- and 1-benzyl-, respectively. In these complexes, the Cu^II ions adopt severely distorted octahedral geometries with the two coordinated pyridylbenzimidazole derivative ligands twisted in a distinct dihedral angle. These complexes can promote the Fenton-like catalytic generation of ∙OH and demonstrate higher inhibitory activity against selected cancer cell lines than cisplatin. Notably, the halogen-substituted derivatives are superior to those with the other substituents. It was found that they promote apoptosis through mitochondrial dysfunction with decreased membrane potential, increased permeability, Ca²⁺ influx and elevated intracellular ROS levels. Among these complexes, Cu5 demonstrates the best in vitro activity and was therefore selected for further evaluation in HeLa tumor-bearing mice. It markedly suppressed solid tumor growth with efficacy comparable to cisplatin. These findings highlighted the titled complexes as promising candidates for anticancer therapy.