title: Electron affinity of tricyclic, bicyclic, and monocyclic compounds containing cyanoenones correlates with their potency as inducers of a cytoprotective enzyme.
abstract: Tricyclic, bicyclic, and monocyclic compounds containing cyanoenones induce various anti-inflammatory and cytoprotective enzymes through activation of the Keap1/Nrf2/ARE (antioxidant response element) pathway. The potency of these compounds as Nrf2 activators was determined using a prototypic cytoprotective enzyme
  
  
  
  quinone oxidoreductase 1 (NQO1) in Hepa1c1c7 murine hepatoma cells. The electron affinity (EA) of the compounds, expressed as the energy of their lowest unoccupied molecular orbital [E (LUMO)], was evaluated using two types of quantum mechanical calculations: the semiempirical (AM1) and the density functional theory (DFT) methods. We observed striking linear correlations [r=0.897 (AM1) and 0.936 (DFT)] between NQO1 inducer potency of these compounds and their E (LUMO) regardless of the molecule size. Importantly and interestingly, this finding demonstrates that the EA is the essentially important factor that determines the reactivity of the cyanoenones with Keap1.
authors.affiliation: Muséum National d'Histoire Naturelle, Molécules de Communication et Adaptation des Microorganismes (MCAM), Dept RDDM, UMR 7245 CNRS-MNHN, CP54, 63 rue Buffon, Paris 75005, France. Electronic address: rvb@mnhn.fr.
authors.forename: René V
authors.initials: RV
authors.lastname: Bensasson
authors.affiliation: Division of Cancer Research, Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States.
authors.forename: Albena T
authors.initials: AT
authors.lastname: Dinkova-Kostova
authors.affiliation: Department of Chemistry and Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, NY 11794-3400, USA.
authors.forename: Suqing
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Department of Chemistry and Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, NY 11794-3400, USA.
authors.forename: Akira
authors.initials: A
authors.lastname: Saito
authors.affiliation: Department of Chemistry and Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, NY 11794-3400, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: SIB Swiss Institute of Bioinformatics, Molecular Modeling Group, Quartier Sorge-Batiment Genopode, CH-1015 Lausanne, Switzerland. Electronic address: Vincent.Zoete@isb-sib.ch.
authors.forename: Vincent
authors.initials: V
authors.lastname: Zoete
authors.affiliation: Department of Chemistry and Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, NY 11794-3400, USA. Electronic address: tadashi.honda@stonybrook.edu.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Honda
mesh_terms: D000475:Alkenes / Q000737:chemistry; D000818:Animals; D045744:Cell Line, Tumor; D003500:Cyclization; D019610:Cytoprotection; D004583:Electrons; D004790:Enzyme Induction / Q000187:drug effects*; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000235:genetics / Q000378:metabolism; D007659:Ketones / Q000737:chemistry; D051379:Mice; D015394:Molecular Structure; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology*; D011789:Quantum Theory; D015398:Signal Transduction / Q000187:drug effects; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000475:Alkenes; D000072019:Kelch-Like ECH-Associated Protein 1; D007659:Ketones; D009570:Nitriles; D013438:Sulfhydryl Compounds; C553940:cyanoethenethiol; D016660:NAD(P)H Dehydrogenase (Quinone)
keywords: Electron affinity; Energy of the lowest unoccupied molecular orbital; Keap1/Nrf2/ARE pathway; NAD(P)H:quinone oxidoreductase 1 (NQO1) inducer; Nrf2 activator; QSAR