Synthesis, chemical reactivity as Michael acceptors, and biological potency of monocyclic cyanoenones, novel and highly potent anti-inflammatory and cytoprotective agents

Suqing Zheng, Y. R. Santosh Laxmi, Emilie David, Albena T. Dinkova-Kostova, Katherine H. Shiavoni, Yanqing Ren, Ying Zheng, Isaac Trevino, Ronald Bumeister, Iwao Ojima, W. Christian Wigley, James B. Bliska, Dale F. Mierke, Tadashi Honda

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    Abstract

    Novel monocyclic cyanoenones examined to date display unique features regarding chemical reactivity as Michael acceptors and biological potency. Remarkably, in some biological assays, the simple structure is more potent than pentacyclic triterpenoids (e.g., CDDO and bardoxolone methyl) and tricycles (e.g., TBE-31). Among monocyclic cyanoenones, 1 is a highly reactive Michael acceptor with thiol nucleophiles. Furthermore, an important feature of 1 is that its Michael addition is reversible. For the inhibition of NO production, 1 shows the highest potency. Notably, its potency is about three times higher than CDDO, whose methyl ester (bardoxolone methyl) is presently in phase III clinical trials. For the induction of NQO1, 1 also demonstrated the highest potency. These results suggest that the reactivity of these Michael acceptors is closely related to their biological potency. Interestingly, in LPS-stimulated macrophages, 1 causes apoptosis and inhibits secretion of TNF-alpha and IL-1 beta with potencies that are higher than those of bardoxolone methyl and TBE-31.</p>
    Original languageEnglish
    Pages (from-to)4837-4846
    Number of pages10
    JournalJournal of Medicinal Chemistry
    Volume55
    Issue number10
    DOIs
    Publication statusPublished - 24 May 2012

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    Cite this

    Zheng, S., Laxmi, Y. R. S., David, E., Dinkova-Kostova, A. T., Shiavoni, K. H., Ren, Y., Zheng, Y., Trevino, I., Bumeister, R., Ojima, I., Wigley, W. C., Bliska, J. B., Mierke, D. F., & Honda, T. (2012). Synthesis, chemical reactivity as Michael acceptors, and biological potency of monocyclic cyanoenones, novel and highly potent anti-inflammatory and cytoprotective agents. Journal of Medicinal Chemistry, 55(10), 4837-4846. https://doi.org/10.1021/jm3003922