Abstract
To study the mechanisms underlying the toxicity of benzimidazole-based copper (Cu) complexes based on their molecular structure, [Cu2(bpbmb)Br4(CH3OH)4/3]2·(CH3OH)4 (1) and Cu2(bpbmb)Cl3·(CH3O) (2) were synthesized through the reaction between 4,4′-bis ((2-(pyrazin-2-yl)-1H-benzoimidazol-1-yl)methyl)-1,1′-biphenyl (bpbmb) and Cu salts. Complexes 1 and 2 showed potent in vitro cytotoxicity against four human tumor cell lines (BGC823, HT29, HCT116, and SMMC7721), especially against HCT116 cells. Furthermore, the activity of complex 1 was investigated in-depth. Absorption spectral titration and ethidium bromide displacement assays revealed that complex 1 shows affinity towards DNA. Complex 1 was found to cleave pBR322 DNA in the presence of ascorbic acid, and to pass through the cell membrane and accumulate in cell nuclei and mitochondria, damaging DNA, which was confirmed by inductively coupled plasma mass spectrometry (ICP-MS) and comet assay. The generation of increased intracellular reactive oxygen species (ROS) levels was observed in complex 1 treated cells, compared with those determined in the untreated control. Flow cytometric analyses indicated that complex 1 can inhibit the growth of tumor cells through G0/G1 cell cycle arrest, mitochondrial transmembrane potential dissipation, and the induction of apoptosis. Moreover, protein binding ability of this complex was analyzed by the static quenching of human serum albumin (HSA) emission. These results indicated that complex 1 acts as a potent anticancer agent, inducing the apoptosis of HCT116 cells by promoting DNA damage, mitochondrial dysfunction, and ROS production.
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