Half-Sandwich Ir(III) and Ru(II) Complexes Featuring a Coumarin-Based Chelating Core for Mitochondrial-Targeted Anticancer Activity

A set of half-sandwich organometallic compounds based on Ir(III) and Ru(II) supported by coumarin-derived acylhydrazone N,O-chelating ligands are reported. In contrast to our previously reported coumarin-appended salicylaldimine systems, the present design incorporates the coumarin scaffold directly into the coordination sphere through phenolic oxygen coordination, forming a stable N,O-chelation framework. This structural transformation converts the coumarin fragment from a peripheral fluorophore into a coordination-defining element. The resulting complexes exhibit slow hydrolysis kinetics and potent cytotoxic activities toward A549 and HeLa cancer cells (IC 50 = 6.49–43.11 μM). Compared with previously reported lysosome-targeting coumarin-modified complexes, the increased positive charge and hydrophobicity of the present system promote energy-dependent cellular uptake and preferential mitochondrial accumulation. Subsequent biological studies suggest that these complexes induce apoptosis through mitochondrial membrane depolarization and enhanced intracellular reactive oxygen species (ROS) generation. In addition, they disrupt cell-cycle progression and inhibit tumor cell migration.