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

René V. Bensasson, Albena T. Dinkova-Kostova, Suqing Zheng, Akira Saito, Wei Li, Vincent Zoete, Tadashi Honda

Research output: Contribution to journalArticlepeer-review

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 (US)
Pages (from-to)4345-4349
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume26
Issue number17
DOIs
StatePublished - 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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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