Metal Centre induced bidentate N3 ligand-based Cu(II) and Co(II) complexes as potential anticancer therapeutics: Design, synthesis, biological evaluation, and in silico molecular docking

Cancer constitutes a significant global public health issue, with the increasing burden of cancer-related morbidity worldwide. The present study explores the anticancer activity of a distorted square planar/ seesaw copper(II) and a distorted tetrahedral cobalt(II) metal complex containing two pyridine rings within the framework of a reduced Schiff base ligand N-[(pyridin-2-yl)methyl](pyridin-2-yl)amine ( L ). Cu( L )Cl 2 ( 1 ) and Co( L )Cl 2 ( 2 ) were characterized by single-crystal X-ray diffraction studies, Fourier transform infrared (FTIR) and electronic absorption spectroscopy (UV–Vis), thermogravimetric (TGA) and elemental analysis, electrochemistry, and Density Functional Theory (DFT) studies. Time-dependent DFT (TD-DFT) calculations have been employed to analyse the electronic transitions of the metal complexes. Moreover, both the complexes and ligand were investigated for their anticancer efficacy against cervical (HeLa, CaSki) and breast (MCF-7, MDA-MB-231) cancer cell lines, while the copper complex exhibited the most potent cytotoxicity against HeLa cells. Stability studies in DMSO, PBS, and FBS were conducted for both complexes. It was found that complex 1 is more stable in all cases than complex 2 . It was also found that complex 1 is more lipophilic than complex 2 . Thus, further studies were carried out with complex 1 against HeLa cells. Exposure of the 1 to HeLa cells resulted in the accumulation of copper ions within the cervical cancer cells, as determined by inductively coupled plasma-mass spectrometry (ICP-MS). The copper complex was demonstrated to induce cell cycle arrest in the S phase of HeLa cells. It also activated caspase-3, generated reactive oxygen species (ROS), and depolarized mitochondrial membrane potential (MMP), leading to the induction of apoptosis in HeLa cells. The potential of caspase-3 generation by complex 2 was also checked and found that it couldn't increase caspase-3 levels in HeLa cells. The copper complex also exhibited anti-migratory potential against HeLa cells as revealed by the wound healing assay. Furthermore, molecular docking studies revealed that the copper complex has comparable binding potential to thioredoxin reductase 1 as compared to auranofin, which is a clinically relevant inhibitor of Thioredoxin reductase. Therefore, the current study presents an approach to employing copper metal complexes as a prospective therapeutic agent for cervical cancer treatment.