Recently, the Ming-Hua Zeng team from the School of Chemistry and Chemical Engineering (School of Carbon Neutrality Future Technology) at Shantou University made new progress in the research field of "Coordination-Directed Domino Reactions". The related research findings were published under the title "A Domino-Synthesized Dicoordinate Copper(I) Bis-imidazopyridine Complex Triggering Cuproptosis/Ferroptosis for Enhanced Cancer Immunotherapy" in the top journal "Angewandte Chemie International Edition" (impact factor 17.6) in the field of inorganic chemistry.

Authors:

Ning Tian, Haoyu Ju, Yu Liu, Jinmei Huang, Zhenggang Luan, Qifeng Hou, Qing Chen, Bin Zhang, Jin Huang*, Ming-Hua Zeng*.

Paper information:

Angew. Chem. Int. Ed. 2026, 65, e5756541.

Paper link:

https://doi.org/10.1002/anie.5756541

English abstract of the paper:

Novel synthetic methods offer significant potential to accelerate drug development, yet there remains a largely unexplored area for efficiently synthesizing metal-based anticancer agents. Herein, we report a novel solvothermal domino reaction of pyridine-2-methylamine (and its 4-OCH₃-substituted derivative), benzaldehyde and CuCl₂∙2H₂O, which simultaneously achieves ligand synthesis and coordination assembly in one pot, and facilely affords innovate dinuclear dicoordinate copper(I) complexes (Cu1 and Cu2) with the in situ-formed bulky steric-hindering tetraarylethane ligands featuring the bis-imidazo[1,5-a]pyridine scaffold. The unique geometry of Cu1 and Cu2 confers physiological stability and vacant coordination sites for efficiently catalyzing Fenton-like reaction. Further studies reveal that Cu2 effectively elevates intracellular copper ion levels to induce cuproptosis, concurrently disrupting cellular redox homeostasis to trigger ferroptosis. The concurrent cuproptosis-ferroptosis activation finally elicits significantly enhanced immunogenic cell death (ICD), which facilitates the antitumor activity of Cu2. Moreover, in combination with immune checkpoint inhibitor αPD-1, Cu2 exhibited improved immunotherapy effects. This work introduces the first small-molecule copper complex that achieves immunotherapy potentiation through cuproptosis-ferroptosis-ICD induction, and provides a new pathway for accessing innovative metal-based antitumor agents through such rationally designed domino reaction.