title: Novel inhibitors of NRH:quinone oxidoreductase 2 (NQO2): crystal structures, biochemical activity, and intracellular effects of imidazoacridin-6-ones.
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.
authors.affiliation: Manchester Interdisciplinary Biocentre, University of Manchester and Manchester Cancer Research Centre, Manchester M13 9PT, U.K.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Dunstan
authors.forename: John
authors.initials: J
authors.lastname: Barnes
authors.forename: Matthew
authors.initials: M
authors.lastname: Humphries
authors.forename: Roger C
authors.initials: RC
authors.lastname: Whitehead
authors.forename: Richard A
authors.initials: RA
authors.lastname: Bryce
authors.forename: David
authors.initials: D
authors.lastname: Leys
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Stratford
authors.forename: Karen A
authors.initials: KA
authors.lastname: Nolan
mesh_terms: D000166:Acridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D011808:Quinone Reductases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000166:Acridines; D007093:Imidazoles; C419642:NRH - quinone oxidoreductase2; D011808:Quinone Reductases