An Exceptionally Potent Inducer of Cytoprotective Enzymes elucidation of the structural features that determine inducer potency and reactivity with Keap1

Albena T. Dinkova-Kostova, Paul Talalay, John Sharkey, Ying Zhang, W. David Holtzclaw, Xiu Jun Wang, Emilie David, Katherine H. Schiavoni, Stewart Finlayson, Dale F. Mierke, Tadashi Honda

    Research output: Contribution to journalArticlepeer-review

    81 Citations (Scopus)

    Abstract

    The Keap1/Nrf2/ARE pathway controls a network of cytoprotective genes that defend against the damaging effects of oxidative and electrophilic stress, and inflammation. Induction of this pathway is a highly effective strategy in combating the risk of cancer and chronic degenerative diseases, including atherosclerosis and neurodegeneration. An acetylenic tricyclic bis(cyano enone) bearing two highly electrophilic Michael acceptors is an extremely potent inducer in cells and in vivo. We demonstrate spectroscopically that both cyano enone functions of the tricyclic molecule react with cysteine residues of Keap1 and activate transcription of cytoprotective genes. Novel monocyclic cyano enones, representing fragments of rings A and C of the tricyclic compound, reveal that the contribution to inducer potency of the ring C Michael acceptor is much greater than that of ring A, and that potency is further enhanced by spatial proximity of an acetylenic function. Critically, the simultaneous presence of two cyano enone functions in rings A and C within a rigid three-ring system results in exceptionally high inducer potency. Detailed understanding of the structural elements that contribute to the reactivity with the protein sensor Keap1 and to high potency of induction is essential for the development of specific and selective lead compounds as clinically relevant chemoprotective agents.

    Original languageEnglish
    Pages (from-to)33747-33755
    Number of pages9
    JournalJournal of Biological Chemistry
    Volume285
    Issue number44
    DOIs
    Publication statusPublished - 29 Oct 2010

    Keywords

    • NITRIC-OXIDE PRODUCTION
    • MICHAEL REACTION ACCEPTORS
    • HIGHLY-ACTIVE INHIBITORS
    • TRANSGENIC MOUSE MODEL
    • CDDO-METHYL ESTER
    • MOLECULAR-MECHANISM
    • TRICYCLIC COMPOUNDS
    • SULFHYDRYL-GROUPS
    • ETHYL AMIDE
    • RING-A

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