A copper complex with a thiazole-modified tridentate ligand: synthesis, structural characterization, and anticancer activity in B16-F10 melanoma cells

Copper serves as a crucial trace element in various biological systems. Copper ions form complexes with different ligands, amplifying reactive oxygen species (ROS) levels and promoting intracellular ROS accumulation in multiple cancer cell types. In this study, a copper(II) complex, dichlorido[4-(5-bromothiazol-2-yl)-2,2'-bipyridine] copper(II) (Cu1), was synthesized using a terpyridine derivative as the ligand. Its structural configuration was confirmed through mass spectrometry and single-crystal X-ray diffraction analysis. The <i>in vitro</i> anticancer efficacy and mechanisms of Cu1 against B16-F10 cells were systematically examined using an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, apoptosis analysis, comet assay, invasion assay, wound healing assay, western blotting, and 3D tumor spheroid models. The findings demonstrated that Cu1 exhibited significant cytotoxicity toward B16-F10 cells and induced dose-dependent apoptosis. Additionally, Cu1 stimulated ROS generation and accumulation in B16-F10 melanoma cells, activating the NLRP3 (NOD-like receptor family pyrin domain-containing 3) inflammasome and caspase-1. Activated caspase-1 specifically cleaved gasdermin D (GSDMD), releasing its N-terminal domain (GSDMD-N), which formed pores in the cell membrane, leading to pyroptosis and DNA double-strand breaks. Cu1 also exhibited significant growth-inhibitory effects in 3D tumor spheroid models, underscoring its potential applicability in simulating <i>in vivo</i> tumor microenvironments.