Electron affinity of tricyclic, bicyclic, and monocyclic compounds containing cyanoenones correlates with their potency as inducers of a cytoprotective enzyme

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:26

Article

Bensasson, Rene V.¹  Dinkova-Kostova, Albena T.^2,3  Zheng, Suqing^4,5  Saito, Akira^4,5  Li, Wei^4,5  Zoete, Vincent⁶  Honda, Tadashi^4,5 

[1] Museum Natl Hist Nat, MCAM, Dept RDDM, UMR 7245,CNRS, CP54,63 Rue Buffon, F-75005 Paris, France

[2] Univ Dundee, Div Canc Res, Med Res Inst, Ninewells Hosp & Med Sch, Dundee DD1 9SY, Scotland

[3] Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA

[4] SUNY Stony Brook, Dept Chem, Stony Brook, NY 11794 USA

[5] SUNY Stony Brook, Inst Chem Biol & Drug Discovery, Stony Brook, NY 11794 USA

[6] SIB Swiss Inst Bioinformat, Mol Modeling Grp, Quartier Sorge Batiment Genopode, CH-1015 Lausanne, Switzerland

关键词: Electron affinity;    Energy of the lowest unoccupied molecular orbital;    Keap1/Nrf2/ARE pathway;    Nrf2 activator;    NAD(P)H:quinone oxidoreductase 1 (NQO1) inducer;    QSAR;   

DOI  :  10.1016/j.bmcl.2016.07.028

来源: Elsevier

【 摘 要 】

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 NAD(P)H: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)1 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. (C) 2016 Elsevier Ltd. All rights reserved.

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