title: An exceptionally potent inducer of cytoprotective enzymes: elucidation of the structural features that determine inducer potency and reactivity with Keap1.
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.
authors.affiliation: Biomedical Research Institute, University of Dundee, Dundee DD1 9SY, Scotland, United Kingdom.
authors.forename: Albena T
authors.initials: AT
authors.lastname: Dinkova-Kostova
authors.forename: Paul
authors.initials: P
authors.lastname: Talalay
authors.forename: John
authors.initials: J
authors.lastname: Sharkey
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: W David
authors.initials: WD
authors.lastname: Holtzclaw
authors.forename: Xiu Jun
authors.initials: XJ
authors.lastname: Wang
authors.forename: Emilie
authors.initials: E
authors.lastname: David
authors.forename: Katherine H
authors.initials: KH
authors.lastname: Schiavoni
authors.forename: Stewart
authors.initials: S
authors.lastname: Finlayson
authors.forename: Dale F
authors.initials: DF
authors.lastname: Mierke
authors.forename: Tadashi
authors.initials: T
authors.lastname: Honda
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D051379:Mice; D008956:Models, Chemical; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism; D018384:Oxidative Stress
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495636:Nfe2l2 protein, mouse; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C491732:Nqo1 protein, mouse
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