S29434, a Quinone Reductase 2 Inhibitor: Main Biochemical and Cellular Characterization

Mol Pharmacol. 2019 Mar;95(3):269-285. doi: 10.1124/mol.118.114231. Epub 2018 Dec 19.


Quinone reductase 2 (QR2, E.C. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Hep G2 Cells
  • 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


  • N-(2-(2-methoxy-6H-dipyrido(2,3-a-3,2-e)pyrrolizin-11-yl)ethyl)-2-furamide
  • Pyridines
  • Pyrrolizidine Alkaloids
  • Reactive Oxygen Species
  • NAD(P)H Dehydrogenase (Quinone)
  • NRH - quinone oxidoreductase2
  • Quinone Reductases