Rational Design of Schiff Base Copper Chelators as Potent Necroptosis Inducers for Anticancer Therapy

Targeting the unique "copper addiction" of cancer cells has emerged as a promising anticancer strategy, as copper is indispensable for tumor proliferation, angiogenesis, and survival. Copper chelators deplete bioavailable copper to disrupt oncogenic processes, but traditional agents are hampered by limitations including nonspecific metal binding and suboptimal bioactivity. Schiff bases, endowed with tunable structures and high copper specificity, stand as ideal platforms for next-generation chelators. Herein, we report a rational design, synthesis, and activity evaluation of novel Schiff base copper chelators. Structural modifications, including aromatic system expansion and triphenylphosphonium (TPP), were employed to enhance cellular uptake, induce mitochondrial damage, and improve bioactivity. 2d disrupts redox homeostasis by depleting copper, leading to reactive oxygen species (ROS)-mediated mitochondrial damage and necroptosis, and exhibits potent, nontoxic tumor suppression in vivo. This study presents both an effective optimization strategy for Schiff base copper chelators and a promising anticancer candidate.