Cytotoxic BODIPY-Appended Half-Sandwich Iridium(III) Complex Forms Protein Adducts and Induces ER Stress.

Half-sandwich complexes of iridium(III) are currently being developed as anticancer drug candidates. In this context, we introduce for which the C^N chelating phenyloxazoline ligand carries a fluorescent and lipophilic BODIPY reporter group, designed for intracellular tracking and hydrophobic compartment tropism. High-resolution analysis of cells cultured with showed that it quickly permeates the plasma membrane and accumulates in the mitochondria and endoplasmic reticulum (ER), generating ER stress, dispersal of the Golgi apparatus, cell proliferation arrest and apoptotic cell death. Moreover, forms fluorescent adducts with a subset of amino acids, namely histidine and cysteine, coordination of N or S donor atoms of their side chains. Consistently, formation of covalent adducts with specific proteins is demonstrated, providing a molecular basis for the observed cytotoxicity and cellular response. Collectively, these results provide a new entry to the development of half-sandwich iridium-based anticancer drugs.