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.