Novel chalcone derivatives as potent Nrf2 activators in mice and human lung epithelial cells

Vineet Kumar, Sarvesh Kumar, Mohammad Hassan, Hailong Wu, Rajesh K. Thimmulappa, Amit Kumar, Sunil K. Sharma, Virinder S. Parmar, Shyam Biswal, Sanjay V. Malhotra

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)4147-4159
Number of pages13
JournalJournal of medicinal chemistry
Volume54
Issue number12
DOIs
StatePublished - Jun 23 2011

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Kumar, V., Kumar, S., Hassan, M., Wu, H., Thimmulappa, R. K., Kumar, A., Sharma, S. K., Parmar, V. S., Biswal, S., & Malhotra, S. V. (2011). Novel chalcone derivatives as potent Nrf2 activators in mice and human lung epithelial cells. Journal of medicinal chemistry, 54(12), 4147-4159. https://doi.org/10.1021/jm2002348