A mitochondriotropic derivative of quercetin: a strategy to increase the effectiveness of polyphenols.
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.
Mattarei
Andrea
A
Department of Chemical Sciences, Università di Padova via Marzolo 1, 35131 Padova, Italy.
Biasutto
Lucia
L
Marotta
Ester
E
De Marchi
Umberto
U
Sassi
Nicola
N
Garbisa
Spiridione
S
Zoratti
Mario
M
Paradisi
Cristina
C
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005419:Flavonoids / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D010636:Phenols / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D059808:Polyphenols; D011794:Quercetin / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D012995:Solubility; D014867:Water / Q000737:chemistry
D005419:Flavonoids; D010636:Phenols; D059808:Polyphenols; D014867:Water; D011794:Quercetin