The cytoprotective Keap1/Nrf2/ARE pathway and the heat shock response are targets for cancer prevention and treatment of chronic inflammation, cardiovascular and neurodegenerative diseases.  Anti-inflammatory acetylenic tricyclic bis(cyano enones) bearing two highly electrophilic Michael acceptor moieties are potent inducers of these pathways and powerful protectors against the toxicity of electrophiles and oxidants in cells and in vivo.  Furthermore, these inducers have excellent systemic bioavailability in animals when applied either topically or incorporated in the diet.  Monocyclic cyano enones, representing fragments of rings A and C of the tricyclic compounds, reveal that exceptionally high (low nanomolar) inducer potency is the result of the simultaneous presence of two cyano enone functions within a rigid three�ring system, which is further enhanced by spatial proximity of an acetylenic function.  Detailed understanding of the structural elements that determine high potency is essential for the development of specific and selective lead compounds as clinically-relevant chemoprotective agents.

Targeting the Keap1/Nrf2/ARE pathway and the heat shock response for chemoprotection

244th National Meeting (2012)

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