Copper(II)-Mediated Mitochondria-Targeting in Cancer Cells

Mitochondria are attractive anticancer targets, but selective targeting remains challenging. We report a Cu 2+ -mediated strategy for mitochondria-directed activity based on intracellular metal coordination. Aminoferrocene drugs were functionalized with Cu 2+ -binding ligands to exploit elevated copper levels in cancer cells. Among these, the bipyridine conjugate AFb-L4 displays pronounced Cu 2+ -dependent cytotoxicity, with an IC 50 of 29 nM in ovarian carcinoma cells (∼500-fold enhancement upon Cu 2+ addition). Spectroscopic, magnetic, and mass spectrometric analyses confirm formation of a 1:1 AFb-L4–Cu 2+ complex without electronic coupling between the Cu 2+ and ferrocene centers. Intracellular Cu 2+ coordination converts AFb-L4 into a cationic species that accumulates in mitochondria, inducing loss of membrane potential, mitochondrial remodeling, and mitochondrial ROS generation. Structure–activity relationships show that stabilization of Cu 2+ is critical, as a sterically hindered isomer with reduced Cu 2+ binding is largely inactive. These results establish intracellular Cu 2+ coordination as a trigger for mitochondrial targeting.