Electron affinity of tricyclic, bicyclic, and monocyclic compounds containing cyanoenones correlates with their potency as inducers of a cytoprotective enzyme. Issue 17 (1st September 2016)

• Record Type: Journal Article
• Authors: Bensasson, René V.; Dinkova-Kostova, Albena T.; Zheng, Suqing; Saito, Akira; Li, Wei; Zoete, Vincent; Honda, Tadashi
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 17(2016)
• Page Start: 4345
• Page End: 4349
• Publication Date: 2016-09-01
• Subjects: Electron affinity -- Energy of the lowest unoccupied molecular orbital -- Keap1/Nrf2/ARE pathway -- Nrf2 activator -- NAD(P)H:quinone oxidoreductase 1 (NQO1) inducer -- QSAR; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.07.028
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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.