Induction of Cuproptosis with a Highly Cytotoxic Tripodal Cu(II) Complex for Anticancer Therapy

Despite the widespread use of chemotherapeutic agents, their reliance on apoptosis often limits therapeutic efficacy and leads to drug resistance. To overcome these challenges, alternative cell death mechanisms such as cuproptosis have gained significant attention. While previous studies have primarily focused on incorporation of Cu into nanostructures, this work presents the first example of a molecular tripodal Cu(II) complex as a potent cuproptosis inducer. Herein, a series of tripodal Cu(II) complexes were chemically synthesized and biologically evaluated. The most promising compound demonstrated remarkable cytotoxicity in the low micromolar to nanomolar range. Mechanistic studies revealed that the compound catalytically produced hydroxyl radicals in the mitochondria of cancerous cells, causing protein oligomerization and the disruption of iron–sulfur cluster proteins, ultimately triggering cell death by cuproptosis. Contrary to traditional chemotherapeutic agents that cause reduction in tumor size, this compound induced the fragmentation of three-dimensional tumor spheroids.