S29434, a Quinone Reductase 2 Inhibitor: Main Biochemical and Cellular Characterization
Résumé
Quinone reductase 2 (QR2, E.C. 1.10.5.1) is an enzyme with a feature that has attracted attention for several decades: in standard conditions, instead of recognizing NAD(P)H as an electron donor, it recognizes putative metabolites of NADH, such as N-methyl- and N-ribosyl-dihydronicotinamide. QR2 has been particularly associated with reactive oxygen species and memory, strongly suggesting a link among QR2 (as a possible key element in pro-oxidation), autophagy, and neurodegeneration. In molecular and cellular pharmacology, understanding physiopathological associations can be difficult because of a lack of specific and powerful tools. Here, we present a thorough description of the potent, nanomolar inhibitor [2-(2-methoxy-5H-1,4b,9-triaza(indeno[2,1-a]inden-10-yl)ethyl]-2-furamide (S29434 or NMDPEF; IC50 = 5-16 nM) of QR2 at different organizational levels. We provide full detailed syntheses, describe its cocrystallization with and behavior at QR2 on a millisecond timeline, show that it penetrates cell membranes and inhibits QR2-mediated reactive oxygen species (ROS) production within the 100 nM range, and describe its actions in several in vivo models and lack of actions in various ROS-producing systems. The inhibitor is fairly stable in vivo, penetrates cells, specifically inhibits QR2, and shows activities that suggest a key role for this enzyme in different pathologic conditions, including neurodegenerative diseases.
Mots clés
Animals
Cell Line / Tumor
Cell Membrane / drug effects
Hep G2 Cells
Cell Membrane / metabolism
Humans
Male
Mice
NAD(P)H Dehydrogenase (Quinone) / metabolism
Pyridines / pharmacology
Pyrrolizidine Alkaloids / pharmacology
Quinone Reductases / antagonists & inhibitors
Rats
Rats Wistar
Reactive Oxygen Species / metabolism
Origine : Fichiers produits par l'(les) auteur(s)
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