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Novel chalcone derivatives as potent Nrf2 activators in mice and human lung epithelial cells
Vineet Kumar1, Sarvesh Kumar, Mohammad Hassan
1Laboratory of Synthetic Chemistry, SAIC Frederick, Inc., National Cancer Institute at Frederick, Frederick, Maryland 21702, United States.
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.
Insights
Researchers developed novel chalcone derivatives that activate the Nrf2 pathway, enhancing antioxidant defenses. Compound 2b demonstrated potent Nrf2 activation in vitro and in vivo, independent of reactive oxygen species.
Area of Science:
- Molecular biology
- Pharmacology
- Biochemistry
Background:
- Nuclear factor erythroid 2-related factor 2 (Nrf2) governs protective enzymes against oxidative stress and inflammation.
- Nrf2 activity is regulated by its repressor, Kelch-like ECH-associated protein 1 (Keap1).
Purpose of the Study:
- To design and synthesize novel chalcone derivatives as activators of the Nrf2 pathway.
- To evaluate the in vitro and in vivo potency and mechanism of these compounds.
Main Methods:
- Synthesis of chalcone derivatives.
- Measurement of Nrf2-dependent gene expression (GCLM, NQO1, HO1) in human lung epithelial cells.
- Cytotoxicity assessment using MTT assay.
- In vivo evaluation in a mouse model.
Main Results:
- Novel chalcone derivatives were synthesized and identified as Nrf2 activators.
- Compound 2-trifluoromethyl-2'-methoxychalone (2b) showed potent Nrf2 activation both in vitro and in vivo.
- Nrf2 activation by compound 2b was independent of reactive oxygen species or redox changes.
Conclusions:
- Chalcone derivatives, particularly compound 2b, are effective Nrf2 activators.
- Compound 2b represents a promising therapeutic lead for conditions involving oxidative stress and inflammation.
- Further studies on the quantitative structure-activity relationship and mechanism of Nrf2 activation are warranted.