title: Synthesis, chemical reactivity as Michael acceptors, and biological potency of monocyclic cyanoenones, novel and highly potent anti-inflammatory and cytoprotective agents.
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.
authors.affiliation: Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, New York 11794, United States.
authors.forename: Suqing
authors.initials: S
authors.lastname: Zheng
authors.forename: Y R
authors.initials: YR
authors.lastname: Santosh Laxmi
authors.forename: Emilie
authors.initials: E
authors.lastname: David
authors.forename: Albena T
authors.initials: AT
authors.lastname: Dinkova-Kostova
authors.forename: Katherine H
authors.initials: KH
authors.lastname: Shiavoni
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Ren
authors.forename: Ying
authors.initials: Y
authors.lastname: Zheng
authors.forename: Isaac
authors.initials: I
authors.lastname: Trevino
authors.forename: Ronald
authors.initials: R
authors.lastname: Bumeister
authors.forename: Iwao
authors.initials: I
authors.lastname: Ojima
authors.forename: W Christian
authors.initials: WC
authors.lastname: Wigley
authors.forename: James B
authors.initials: JB
authors.lastname: Bliska
authors.forename: Dale F
authors.initials: DF
authors.lastname: Mierke
authors.forename: Tadashi
authors.initials: T
authors.lastname: Honda
mesh_terms: D000480:Alkynes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000577:Amides / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016588:Anticarcinogenic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D019610:Cytoprotection; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009828:Oleanolic Acid / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D010616:Phenanthrenes / Q000737:chemistry / Q000494:pharmacology; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000480:Alkynes; D000577:Amides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016588:Anticarcinogenic Agents; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D009570:Nitriles; D010616:Phenanthrenes; C531972:TBE 31; D013876:Thiophenes; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D009828:Oleanolic Acid; C499326:2-((aminocarbonyl)amino)-5-(4-fluorophenyl)-3-thiophenecarboxamide; C445068:bardoxolone methyl; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D051550:I-kappa B Kinase