Bis-Michael Acceptors as Novel Probes to Study the Keap1/Nrf2/ARE Pathway

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulator that promotes the transcription of cytoprotective genes in response to oxidative/electrophilic stress. Various Michael-type compounds were designed and synthesized, and their potency to activate the Keap1/Nrf2/ARE pathway was e...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2016-10, Vol.59 (20), p.9431-9442
Main Authors: Deny, Ludovic J, Traboulsi, Hussein, Cantin, André M, Marsault, Éric, Richter, Martin V, Bélanger, Guillaume
Format: Article
Language:English
Subjects:
Animals
Antioxidant Response Elements
Antioxidants - chemical synthesis
Antioxidants - chemistry
Antioxidants - pharmacology
Cell Line
Cell Survival - drug effects
Dose-Response Relationship, Drug
HEK293 Cells
Humans
Kelch-Like ECH-Associated Protein 1 - metabolism
Mice
Models, Molecular
Molecular Structure
NF-E2-Related Factor 2 - metabolism
Structure-Activity Relationship
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Summary:Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulator that promotes the transcription of cytoprotective genes in response to oxidative/electrophilic stress. Various Michael-type compounds were designed and synthesized, and their potency to activate the Keap1/Nrf2/ARE pathway was evaluated. Compounds bearing two Michael-type acceptors proved to be the most active. Tether length and rigidity between the acceptors was crucial. This study will help to understand how this feature disrupts the interaction between Keap1 and Nrf2.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.6b01132