Two new Cu(II) dipeptide complexes based on 5-methyl-2-(2′-pyridyl)benzimidazole as potential antimicrobial and anticancer drugs: Special exploration of their possible anticancer mechanism

Abstract

In the search for more effective anticancer drugs with less toxic side effects, dipeptides were introduced into the Cu(II) complex of 5-methyl-2-(2′-pyridyl)benzimidazole (HPBM). Analytical and spectroscopic techniques were employed to thoroughly characterize complexes [Cu(Gly-gly)(HPBM)(H2O)]ClO4·0.5H2O (1) and [Cu(Gly-L-leu)(HPBM)(H2O)]ClO4 (2) (where Gly-gly = Glycyl-glycine anion, Gly-L-leu = Glycyl-l-leucine anion). The solution stability studies performed by ultraviolet–visible (UV–Vis) spectroscopy confirmed the stability of the complexes in the buffer solutions. The DNA binding affinity was evaluated using multi-spectroscopy, viscosity measurement and molecular docking methods and further quantified by Kb and Kapp values, revealing an intercalative mode. Moreover, gel electrophoresis analysis revealed that the complexes could damage CT DNA through a hydroxyl radical pathway in the presence of ascorbic acid. All the complexes displayed favorable antimicrobial and cytotoxic activities toward the tested microorganisms (Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa) and cancer cells (A549, HeLa and PC-3). Most importantly, the possible anticancer mechanism of the complexes was explored by determining the cells morphological changes, intracellular reactive oxygen species (ROS) levels, location in mitochondria, mitochondrial membrane potentials and the expression of Bcl-2 family proteins. The results showed that the complexes could induce apoptosis in HeLa cells through an ROS-mediated mitochondrial dysfunction pathway, which was accompanied by the regulation of Bcl-2 family proteins.