Document Report Card

ID: ALA1833815

Journal: J Med Chem

Title: Novel inhibitors of NRH:quinone oxidoreductase 2 (NQO2): crystal structures, biochemical activity, and intracellular effects of imidazoacridin-6-ones.

Authors: Dunstan MS, Barnes J, Humphries M, Whitehead RC, Bryce RA, Leys D, Stratford IJ, Nolan KA.

Abstract: Imidazoacridin-6-ones are shown to be potent nanomolar inhibitors of the enzyme NQO2. By use of computational molecular modeling, a reliable QSAR was established, relating inhibitory potency with calculated binding affinity. Further, crystal structures of NQO2 containing two of the imidazoacridin-6-ones have been solved. To generate compounds with reduced off-target (DNA binding) effects, an N-oxide moiety was introduced into the tertiary aminoalkyl side chain of the imidazoacridin-6-ones. This resulted in substantially less toxicity in a panel of eight cancer cell lines, decreased protein binding, and reduced DNA binding and nuclear accumulation. Finally, one of the N-oxides showed potent ability to inhibit the enzymatic function of NQO2 in cells, and therefore, it may be useful as a pharmacological probe to study the properties of the enzyme in vitro and in vivo.

CiteXplore: 21859103

DOI: 10.1021/jm200416e