A Domino-Synthesized Dicoordinate Copper(I) Bis-imidazopyridine Complex Triggering Cuproptosis/Ferroptosis for...

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 innovative 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 reactions. 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 exhibits 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 a rationally designed domino reaction.