title: New Monocyclic, Bicyclic, and Tricyclic Ethynylcyanodienones as Activators of the Keap1/Nrf2/ARE Pathway and Inhibitors of Inducible Nitric Oxide Synthase.
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.
authors.affiliation: †Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, New York 11794, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
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.affiliation: ‡Division of Cancer Research, Medical Research Institute, University of Dundee, Dundee DD1 9SY, Scotland United Kingdom.
authors.forename: Maureen
authors.initials: M
authors.lastname: Higgins
authors.affiliation: †Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, New York 11794, United States.
authors.forename: Rocco P
authors.initials: RP
authors.lastname: Morra
authors.affiliation: †Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, New York 11794, United States.
authors.forename: Anne T
authors.initials: AT
authors.lastname: Mendis
authors.affiliation: †Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, New York 11794, United States.
authors.forename: Chih-Wei
authors.initials: CW
authors.lastname: Chien
authors.affiliation: †Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, New York 11794, United States.|§Department of Chemistry, Stony Brook University, Stony Brook, New York 11794, United States.
authors.forename: Iwao
authors.initials: I
authors.lastname: Ojima
authors.affiliation: ∥Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755, United States.
authors.forename: Dale F
authors.initials: DF
authors.lastname: Mierke
authors.affiliation: ‡Division of Cancer Research, Medical Research Institute, University of Dundee, Dundee DD1 9SY, Scotland United Kingdom.|⊥Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States.
authors.forename: Albena T
authors.initials: AT
authors.lastname: Dinkova-Kostova
authors.affiliation: †Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, New York 11794, United States.|§Department of Chemistry, Stony Brook University, Stony Brook, New York 11794, United States.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Honda
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000480:Alkynes / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D003512:Cyclohexanones / Q000737:chemistry / Q000494:pharmacology*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000072019:Kelch-Like ECH-Associated Protein 1; D008070:Lipopolysaccharides / Q000494:pharmacology; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000480:Alkynes; D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D003512:Cyclohexanones; D003598:Cytoskeletal Proteins; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D052247:Nitric Oxide Synthase Type II; D002265:Carboxylic Ester Hydrolases; C019734:arylesterase