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

J Med Chem. 2012 May 24;55(10):4837-46. doi: 10.1021/jm3003922. Epub 2012 May 7.

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-α and IL-1β with potencies that are higher than those of bardoxolone methyl and TBE-31.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkynes / chemical synthesis*
  • Alkynes / chemistry
  • Alkynes / pharmacology
  • Amides / chemistry
  • Amides / pharmacology
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Anticarcinogenic Agents / chemical synthesis*
  • Anticarcinogenic Agents / chemistry
  • Anticarcinogenic Agents / pharmacology
  • Apoptosis / drug effects
  • Cell Line
  • Cell Line, Tumor
  • Cytoprotection
  • I-kappa B Kinase / antagonists & inhibitors
  • Interleukin-1beta / metabolism
  • Lipopolysaccharides / pharmacology
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • NAD(P)H Dehydrogenase (Quinone) / biosynthesis
  • Nitric Oxide / antagonists & inhibitors
  • Nitric Oxide / biosynthesis
  • Nitriles / chemical synthesis*
  • Nitriles / chemistry
  • Nitriles / pharmacology
  • Oleanolic Acid / analogs & derivatives
  • Oleanolic Acid / chemistry
  • Oleanolic Acid / pharmacology
  • Phenanthrenes / chemistry
  • Phenanthrenes / pharmacology
  • Thiophenes / chemistry
  • Thiophenes / pharmacology
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Alkynes
  • Amides
  • Anti-Inflammatory Agents, Non-Steroidal
  • Anticarcinogenic Agents
  • Interleukin-1beta
  • Lipopolysaccharides
  • Nitriles
  • Phenanthrenes
  • TBE 31
  • Thiophenes
  • Tumor Necrosis Factor-alpha
  • Nitric Oxide
  • Oleanolic Acid
  • 2-((aminocarbonyl)amino)-5-(4-fluorophenyl)-3-thiophenecarboxamide
  • methyl 2-cyano-3,12-dioxoolean-1,9-dien-28-oate
  • NAD(P)H Dehydrogenase (Quinone)
  • NQO1 protein, human
  • I-kappa B Kinase