Benzothiazole hydrazone Cu(II) complex for therapeutic anticancer enhancement via PARP-1 inhibition

DNA serves as the primary target for numerous metal complexes in suppression tumor cell proliferation, and Poly ADP ribose polymerase-1 (PARP-1) is critical for DNA repair. In this study, benzothiazole hydrazone was used as a framework to design and synthesize a series of Cu(II) complexes (Cu1-Cu3), which functions as novel PARP-1 inhibitors. These Cu(II) complexes not only effectively inhibited the proliferation of a panel of tumor cells (IC₅₀ range: 0.51-5.37 μM) but also exhibited potent PARP-1 inhibitory activity (IC₅₀ range: 0.45-1.52 μM). Notably, complex Cu3 had the most potent activities, exhibiting strong cytotoxicity against T98G cells (IC₅₀ = 0.51 μM) and significant PARP-1 inhibition (IC₅₀ = 0.45 μM). Additionally, Cu3 effectively inhibited the migration of T98G cells. Mechanistic studies revealed that Cu3 generated excessive reactive oxygen species (ROS), induced DNA damage, exacerbated DNA double-strand breaks by inhibiting PARP-1 activity, and promoted apoptosis in tumor cells via the mitochondrial pathway.