Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 54, Issue 12, Pages 4147-4159Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm2002348
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Funding
- NCI, National Institutes of Health [HSN261200800001E]
- National Institutes of Health [HL081205, 1U01HL105569]
- National Heart, Lung, and Blood Institute Specialized Centers [P50HL084945]
- Flight Attendant Medical Research Institute
- National Cancer Institute [5P50CA058184, 5R01CA140492]
- National Institute on Environmental Health Sciences [P50ES015903, P01 ES018176, ES03819]
- University of Delhi
- Department of Scientific and Industrial Research (DSIR, New Delhi)
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Nrf2-mediated activation of antioxidant response element is a central part of molecular mechanisms governing the protective function of phase II detoxification and antioxidant enzymes against carcinogenesis, oxidative stress, and inflammation. Nrf2 is sequestered in the cytoplasm by its repressor, Keap1. We have designed and synthesized novel chalcone derivatives as Nrf2 activators. The potency of these compounds was measured by the expression of Nrf2 dependent antioxidant genes GCLM, NQO1, and HO1 in human lung epithelial cells, while the cytotoxicity was analyzed using MTT assay. In vivo potency of identified lead compounds to activate Nrf2 was evaluated using a mouse model. Our studies showed 2-trifluoromethyl-2'-methoxychalone (2b) to be a potent activator of Nrf2, both in vitro and in mice. Additional experiments showed that the activation of Nrf2 by this compound is independent of reactive oxygen species or redox changes. We have discussed a quantitative structure-activity relationship and proposed a possible mechanism of Nrf2, activation.
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