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Novel Chalcone Derivatives as Potent Nrf2 Activators in Mice and Human Lung Epithelial Cells

  1. Author:
    Kumar, V.
    Kumar, S.
    Hassan, M.
    Wu, H. L.
    Thimmulappa, R. K.
    Kumar, A.
    Sharma, S. K.
    Parmar, V. S.
    Biswal, S.
    Malhotra, S. V.

  2. Author Address

    [Kumar, S; Wu, HL; Thimmulappa, RK; Biswal, S] Johns Hopkins Univ, Dept Environm Hlth Sci, Johns Hopkins Sch Publ Hlth, Baltimore, MD 21205 USA [Kumar, V; Hassan, M; Malhotra, SV] NCI, Lab Synthet Chem, SAIC Frederick Inc, Frederick, MD 21702 USA [Kumar, A; Sharma, SK; Parmar, VS] Univ Delhi, Dept Chem, Bioorgan Lab, Delhi 110007, India;Biswal, S (reprint author), Johns Hopkins Univ, Dept Environm Hlth Sci, Johns Hopkins Sch Publ Hlth, Baltimore, MD 21205 USA;sbiswal@jhsph.edu malhotrasa@mail.nih.gov
    1. Year: 2011
    2. Date: Jun
  2. Journal: Journal of Medicinal Chemistry
    1. 54
    2. 12
    3. Pages: 4147-4159
  4. Type of Article: Article
  5. ISSN: 0022-2623
  1. Abstract:

    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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External Sources

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  2. DOI: 10.1021/jm2002348
  3. View record in Web of Science®
  4. WOS: 000291709100013

Library Notes

  1. Fiscal Year: FY2010-2011
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