title: Novel chalcone derivatives as potent Nrf2 activators in mice and human lung epithelial cells.
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.
authors.affiliation: Laboratory of Synthetic Chemistry, SAIC Frederick, Inc., National Cancer Institute at Frederick, Frederick, Maryland 21702, United States.
authors.forename: Vineet
authors.initials: V
authors.lastname: Kumar
authors.forename: Sarvesh
authors.initials: S
authors.lastname: Kumar
authors.forename: Mohammad
authors.initials: M
authors.lastname: Hassan
authors.forename: Hailong
authors.initials: H
authors.lastname: Wu
authors.forename: Rajesh K
authors.initials: RK
authors.lastname: Thimmulappa
authors.forename: Amit
authors.initials: A
authors.lastname: Kumar
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Sharma
authors.forename: Virinder S
authors.initials: VS
authors.lastname: Parmar
authors.forename: Shyam
authors.initials: S
authors.lastname: Biswal
authors.forename: Sanjay V
authors.initials: SV
authors.lastname: Malhotra
mesh_terms: D000818:Animals; D001980:Bronchi / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D047188:Chalcones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020536:Enzyme Activators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005721:Glutamate-Cysteine Ligase / Q000096:biosynthesis / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010084:Oxidation-Reduction; D021281:Quantitative Structure-Activity Relationship; D017382:Reactive Oxygen Species / Q000378:metabolism; D013237:Stereoisomerism; D014158:Transcription, Genetic
chemical_list: C561055:2-trifluoromethyl-2'-methoxychalone; D047188:Chalcones; D020536:Enzyme Activators; D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C546365:GCLM protein, human; D005721:Glutamate-Cysteine Ligase