Synthesis, structural studies, interaction with DNA/HSA and antitumor evaluation of new Cu(ii) complexes containing 2-(1H-imidazol-2-yl)pyridine and amino acids

Abstract

Copper complexes are considered as potential candidates for anticancer therapy and medical applications. In this paper, three new Cu(II) complexes, [Cu(IPY)₂](ClO₄)₂·H₂O (CuI1), [Cu(IPY)(L-Phe)H₂O]ClO₄·0.5H₂O (CuI2) and [Cu(IPY)(L-Val)H₂O]ClO₄ (CuI3) (where IPY = 2-(1H-imidazol-2-yl)pyridine, L-Phe = L-phenylalanine, and L-Val = L-valine), with good amphipathic properties were synthesized and characterized. Their single crystal X-ray diffraction results revealed that CuI1 was four-coordinated, while CuI2 and CuI3 both adopted a five-coordinated tetragonal pyramidal configuration. Multi-spectral methods, viscosity experiment and molecular docking technique showed that the three complexes interacted with DNA through insertion. The results of the gel electrophoresis experiments indicated that DNA was oxidatively cleaved by all the complexes in a concentration-dependent manner. Moreover, singlet oxygen (¹O₂), hydrogen peroxide (H₂O₂) and superoxide anion radicals (˙O₂⁻) were associated with the oxidative cleavage of DNA. All the complexes also had good binding affinity with human serum albumin (HSA). The MB degradation assay revealed that all complexes could react with H₂O₂ to form ˙OH through Fenton-like processes. The complexes displayed good antiproliferative activity against the tested human cancer cells in vitro, including cervical carcinoma cells (HeLa), liver cancer cells (HepG2 and BEL-7402) and gastric adenocarcinoma cells (SGC-7901), but showed lower toxicity to normal liver cells (LO2). The anticancer mechanism research revealed that CuI1, CuI2 and CuI3 arrested the cell cycle at the S phase, elevated intracellular reactive oxygen species (ROS) levels and induced loss of mitochondrial membrane potential (MMP). The results indicated that these Cu(II) complexes could induce DNA damage and ROS-mediated mitochondrial dysfunction, leading to cancer cell apoptosis. Our work provides a theoretical basis for the design of new low-toxicity and highly efficient anticancer Cu(II) complexes by incorporating biological metabolites and aromatic heterocyclic ligands.