Nrf2-mediated activation of antioxidant response element (ARE) target genes is a central part of molecular mechanisms governing the protective function of phase II detoxification and antioxidant enzymes against chemical carcinogenesis and oxidative stress. Nrf2 is sequestered in the cytoplasm by interacting with its inhibitor Keap-1. Interaction with cysteine thiol groups located in Keap1 leads to the formation of disulfide bonds which results in a conformational change that renders Keap-1 unable to bind to Nrf2, thereby translocating Nrf2 to the nucleus. A wide variety of dietary and synthetic compounds that function as potent inducers of ARE-regulated gene expression have been shown to exert chemopreventive activities, e.g. sulforaphane, dithiolethione, curcumin, caffeic acid phenethyl ester (CAPE), etc. It is notable that both curcumin and CAPE bear an a,b-unsaturated ketone moiety, and can therefore act as Michael acceptors that are able to modify cycteine thios present in Keap-1. Chalcones or 1,2-diphenyl-2-propen-1-ones are also Michael acceptors and have been reported to possess wide variety of biological properties including anti-inflammatory, analgesic, antipyretic, antioxidant, antibacterial, antifungal and antiprotozoal activities. Our ongoing studies of chalocones have lead to design of novel compounds which show Nrf2 activation on human bronchial epithelial cells. Further, the Structure-Activity Relationship studies have resulted in potent compound that is more active and less toxic than clinical candidates. Detailed results and possible mechanism of action will be discussed. Acknowledgement: This Project has been funded with federal funds from the National Cancer Institute, NIH under contract No. HSN261200800001E

Design and synthesis of novel chalcone derivatives as potent Nrf2 activators in mice and human lung epithelial cells

241st National Meeting (2011)

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