title: Triazoloacridin-6-ones as novel inhibitors of the quinone oxidoreductases NQO1 and NQO2.
abstract: A range of triazoloacridin-6-ones functionalized at C5 and C8 have been synthesized and evaluated for ability to inhibit NQO1 and NQO2. The compounds were computationally docked into the active site of NQO1 and NQO2, and calculated binding affinities were compared with IC(50) values for enzyme inhibition. Excellent correlation coefficients were demonstrated suggesting a predictive QSAR model for this series of structurally similar analogues. From this we have identified some of these triazoloacridin-6-ones to be the most potent NQO2 inhibitors so far reported.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, University of Manchester and Manchester Cancer Research Center, Manchester M13 9PT, UK.
authors.forename: Karen A
authors.initials: KA
authors.lastname: Nolan
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Humphries
authors.forename: John
authors.initials: J
authors.lastname: Barnes
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Doncaster
authors.forename: Mary C
authors.initials: MC
authors.lastname: Caraher
authors.forename: Nicola
authors.initials: N
authors.lastname: Tirelli
authors.forename: Richard A
authors.initials: RA
authors.lastname: Bryce
authors.forename: Roger C
authors.initials: RC
authors.lastname: Whitehead
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Stratford
mesh_terms: D000166:Acridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004247:DNA / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors*; D011808:Quinone Reductases / Q000037:antagonists & inhibitors*; D012474:Salmon; D013094:Spermatozoa / Q000737:chemistry; D013329:Structure-Activity Relationship; D044366:Transition Temperature; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000166:Acridines; D004791:Enzyme Inhibitors; D014230:Triazoles; D004247:DNA; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C419642:NRH - quinone oxidoreductase2; D011808:Quinone Reductases