Synthesis and antitumor activity of copper(II) complexes of imidazole derivatives

Abstract

Complexes [Cu(PI)₂(H₂O)](NO₃)₂ (1), [Cu(PBI)₂(NO₃)]NO₃ (2), [Cu(TBI)₂(NO₃)]NO₃ (3), [Cu(BBIP)₂](ClO₄)₂ (4) and [Cu(BBIP)(CH₃OH)(ClO₄)₂] (5) were synthesized from the reactions of Cu(II) salts with 2-(2′-pyridyl)imidazole (PI), (2-(2′-pyridyl)benzimidazole (PBI), 2-(4′-thiazolyl)-benzimidazole (TBI), 2,6-bis(benzimidazol-2-yl)-pyridine (BBIP), respectively. Their compositions and crystal structures were determined. Their in-vitro antitumor activities were screened on four cancer cell lines and one normal cell line (HL-7702) using cisplatin as the positive control. Complexes 2 and 4 show higher cytotoxicity than the other three complexes. The cytotoxicity of complex 2 are comparable to those for cisplatin, and the cytotoxicity for 4 are much higher than those for cisplatin. From a viewpoint of antitumor, 2 might be a nice choice on the tumor cell line of T24 because its IC50 values on T24 and HL-7702 are 15.03 ± 1.10 and 21.34 ± 0.35, respectively. Thus, a mechanistic study for complexes 2 and 4 on T24 cells was conducted. It revealed that they can reduce mitochondrial membrane potential and increase mitochondrial membrane permeability, resulting in increased intracellular ROS levels, Ca²⁺ inward flow, dysfunctional mitochondria and the eventual cell apoptosis. In conclusion, they can induce cell apoptosis through mitochondrial dysfunction. These findings could be useful in the development of new antitumor agents.