Zinc(ii) complexes containing bis-benzimidazole derivatives as a new class of apoptosis inducers that trigger DNA damage-mediated p53 phosphorylation in cancer cells

Abstract

In the present study, two zinc(II) complexes containing bis-benzimidazole derivatives, Zn(bpbp)Cl₂ (1) and [Zn(bpbp)₂](ClO₄)₂·CH₃CH₂OH·H₂O (2) (bpbp = 2,6-bis(1-phenyl-1H-benzo[d]imidazol-2-yl)pyridine), have been designed, synthesized and evaluated for their in vitro anticancer activities. The underlying molecular mechanisms through which they caused the cancer cell death were also elucidated. The complexes were identified as potent antiproliferative agents against a panel of five human cancer cell lines by comparing with cisplatin. Complex 2 demonstrated dose-dependent growth inhibition on MCF-7 human breast carcinoma cells with IC₅₀ at 2.9 μM. Despite this potency, the complexes possessed great selectivity between human cancer cells and normal cells. Induction of apoptosis in MCF-7 cells by complex 2 was evidenced by accumulation of sub-G1 cell population, DNA fragmentation and nuclear condensation. Further investigation on intracellular mechanisms revealed that complex 2 was able to induce p53-dependent apoptosis in cancer cells by triggering DNA damage. On the basis of this evidence, we suggest that Zn(II) complexes containing bis-benzimidazole derivatives may be candidates for further evaluation as chemotherapeutic agents for human cancers.