Copper(II) Complexes of Pyrazolopyrimidine Derivatives as Anticancer Agents with Enhanced Chemodynamic Therapy through Bimodal Apoptosis and Ferroptosis.

We reported 10 new copper(II) complexes 1-10 with pyrazolopyrimidine derivatives as ligands. Complexes 2 and 4 reacted with glutathione (GSH) in cells through Fenton-like reaction to generate highly toxic hydroxyl radical (·OH) for chemodynamic therapy (CDT), and reduced endogenous glutathione peroxidase 4 (GPX4) to induce ferroptosis. In addition, these complexes effectively caused mitochondrial dysfunction and induced apoptosis and autophagy in tumor cells. Furthermore, 2 and 4 effectively inhibited the bladder cancer cell growth in a xenograft model. This study presents new copper(II) complexes that can significantly induce bladder cancer cells death by enhanced CDT through bimodal apoptosis and ferroptosis, providing a promising approach for cancer therapy.