A Mitochondriotropic Derivative of Quercetin: A Strategy to Increase the Effectiveness of Polyphenols

Abstract Mitochondria‐targeted compounds are needed to act on a variety of processes that take place in these subcellular organelles and that have great pathophysiological relevance. In particular, redox‐active molecules that are capable of homing in on mitochondria provide a tool to intervene on a major cellular source of reactive oxygen species and on the processes they induce, notably the mitochondrial permeability transition and cell death. We have linked the 3‐OH of quercetin (3,3′,4′,5,7‐pentahydroxy flavone), a model polyphenol, and the triphenylphosphonium moiety, a membrane‐permeant cationic group, to produce proof‐of‐principle mitochondriotropic quercetin derivatives. The remaining hydroxyls were sometimes acetylated to hinder metabolism and improve solubility. The new compounds accumulate in mitochondria in a transmembrane potential‐driven process and are only slowly metabolised by cultured human colon cells. They inhibit mitochondrial ATPase activity much as quercetin does, and are toxic for fast‐growing cells.