New monocyclic, bicyclic, and tricyclic ethynylcyanodienones as activators of the Keap1/Nrf2/ARE pathway and inhibitors of inducible nitric oxide synthase

Wei Li, Suqing Zheng, Maureen Higgins, Rocco P. Morra, Anne T. Mendis, Chih-Wei Chien, Iwao Ojima, Dale F. Mierke, Albena T. Dinkova-Kostova, Tadashi Honda (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    23 Citations (Scopus)

    Abstract

    A monocyclic compound 3 (3-ethynyl-3-methyl-6-oxocyclohexa-1,4-dienecarbonitrile) is a highly reactive Michael acceptor leading to reversible adducts with nucleophiles, which displays equal or greater potency than the pentacyclic triterpenoid CDDO in inflammation and carcinogenesis related assays. Recently, reversible covalent drugs, which bind with protein targets but not permanently, have been gaining attention because of their unique features. To explore such reversible covalent drugs, we have synthesized monocyclic, bicyclic, and tricyclic compounds containing 3 as an electrophilic fragment and evaluated them as activators of the Keap1/Nrf2/ARE pathway and inhibitors of iNOS. Notably, these compounds maintain the unique features of the chemical reactivity and biological potency of 3. Among them, a monocyclic compound 5 is the most potent in these assays while a tricyclic compound 14 displays a more robust and specific activation profile compared to 5. In conclusion, we demonstrate that 3 is a useful electrophilic fragment for exploring reversible covalent drugs. (Chemical Equation Presented).

    Original languageEnglish
    Pages (from-to)4738-4748
    Number of pages11
    JournalJournal of Medicinal Chemistry
    Volume58
    Issue number11
    DOIs
    Publication statusPublished - 11 Jun 2015

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