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

Mitochondria are attractive anticancer targets, but selective targeting remains challenging. We report a Cu2+-mediated strategy for mitochondria-directed activity based on intracellular metal coordination. Aminoferrocene drugs were functionalized with Cu2+-binding ligands to exploit elevated copper levels in cancer cells. Among these, the bipyridine conjugate AFb-L4 displays pronounced Cu2+-dependent cytotoxicity, with an IC50 of 29 nM in ovarian carcinoma cells (∼500-fold enhancement upon Cu2+ addition). Spectroscopic, magnetic, and mass spectrometric analyses confirm formation of a 1:1 AFb-L4-Cu2+ complex without electronic coupling between the Cu2+ and ferrocene centers. Intracellular Cu2+ 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 Cu2+ is critical, as a sterically hindered isomer with reduced Cu2+ binding is largely inactive. These results establish intracellular Cu2+ coordination as a trigger for mitochondrial targeting.