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

  • J Med Chem. 2025 Apr 10;68(7):7137-7152. doi: 10.1021/acs.jmedchem.4c02515.
Kun Yang  1 ,  Qian Chen  1 ,  Juan Chen  1 ,  Lu-Fei Geng  1 ,  Meng-Xue Ma  1 ,  Yun-Qiong Gu  1 ,  Muhammad Iqbal Choudhary  2 ,  Hong Liang  1 ,  Zhen-Feng Chen  1
Affiliations
  • 1. State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China.
  • 2. International Center for Chemical and Biological Sciences, University of Karachi, Karachi 74270, Pakistan.
PMID: 40138496 DOI: 10.1021/acs.jmedchem.4c02515
Abstract

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.

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