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

René V. Bensasson (Lead / Corresponding author), Albena T. Dinkova-Kostova, Suqing Zheng, Akira Saito, Wei Li, Vincent Zoete (Lead / Corresponding author), Tadashi Honda

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    3 Citations (Scopus)
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    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 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)] 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.

    Original languageEnglish
    Pages (from-to)4345-4349
    Number of pages5
    JournalBioorganic & Medicinal Chemistry Letters
    Volume26
    Issue number17
    Early online date15 Jul 2016
    DOIs
    Publication statusPublished - 1 Sep 2016

    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

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