Developing a novel binuclear copper complex for enhanced cellular copper uptake and cancer treatment

Although elesclomol (Es) has been investigated as a copper ionophore in antitumor clinical trials, its therapeutic potential remains limited by suboptimal copper transport efficiency and a narrow mechanism of action. To overcome these limitations and improve the anticancer efficacy of copper ionophores, we designed and synthesized L1—a novel chelator capable of forming the binuclear copper complex C1. Our results demonstrate that C1 exhibits superior therapeutic properties compared to Elesclomol–Cu (Es Cu), including enhanced cellular copper uptake in gastric cancer cells and multiple anticancer mechanisms. These mechanisms include potent induction of cuproptosis (significantly stronger than Es Cu), generation of mitochondrial superoxide and intracellular reactive oxygen species, induction of autophagic lysosome accumulation, DNA damage, and activation of apoptosis. More importantly, in vivo studies revealed a remarkable tumor inhibition rate of 80.3 % for C1, substantially higher than that of Es Cu (45 %). These findings establish C1 as a promising next-generation copper-based anticancer agent with enhanced therapeutic potential.