The Keap1/Nrf2 pathway is an essential component of the cell’s antioxidant defense and possesses a therapeutic potential for diseases involving oxidative stress such as cancers, diabetes or neurodegenerative disorders (Suzuki, Trends in Pharmacol. Sci. 2013). Keap1 is a cytosolic chaperone protein that sequesters the Nrf2 (Nuclear factor erythroid-related 2-like 2) transcription factor in the cytosol, preventing the transcription of genes associated with the ARE (Antioxidant Response Element). Keap1 is a cysteine-rich protein whose nucleophilic thiols can be modulated with small molecules. In this respect, Nazarov acceptors (see scheme) have raised our interest, based on the reasoning that a compound able to react with more than one cysteine could be highly potent and selective. Herein, we present a series of compounds aimed at understanding the synergy between two acceptors. We have identified the relative position (tether length and rigidity) of the electrophilic centers as a key parameter in activity. We strongly believe our study will help in the understanding of the Keap1/Nrf2 pathway.

New agonists of the Keap1 – Nrf2 pathway: A potential solution for oxidative stress related diseases

250th National Meeting (2015)

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