title: 3-(2-oxoethylidene)indolin-2-one derivatives activate Nrf2 and inhibit NF-κB: potential candidates for chemoprevention.
abstract: Induction of cytoprotective phase 2 enzymes through inhibition of Keap1, a repressor of transcription factor Nrf2, is a cancer-prevention strategy. Compounds that elicit antiinflammatory and cytoprotective effects are promising candidates for chemoprevention. Novel analogues of 1-methyl-3-(2-oxopropylidene)indolin-2-one ('supercinnamaldehyde'; SCA) were synthesized, and their abilities to induce cytoprotective responses through Nrf2 induction and to suppress inflammatory responses were examined. 1-Methyl-3-(2-oxo-2-phenylethylidene)indolin-2-one (6) was identified as the lead compound. The compounds showed induction of Nrf2-dependent phase 2 enzymes in Keap1+/+ mouse embryonic fibroblasts (MEFs), which was abrogated in Keap1-/- MEFs. The compounds also displayed a suppressive effect on NF-κB signaling that was at least partly responsible for inhibition of lipopolysaccharideinduced inflammatory responses. These SCA analogues exhibited cytoprotective and anti-inflammatory activities and may be developed further as chemopreventive agents.
authors.affiliation: Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543 (Republic of Singapore).
authors.forename: Amrita A
authors.initials: AA
authors.lastname: Nagle
authors.forename: Shridhivya A
authors.initials: SA
authors.lastname: Reddy
authors.forename: Helene
authors.initials: H
authors.lastname: Bertrand
authors.forename: Hisashi
authors.initials: H
authors.lastname: Tajima
authors.forename: Truong-Minh
authors.initials: TM
authors.lastname: Dang
authors.forename: Siew-Cheng
authors.initials: SC
authors.lastname: Wong
authors.forename: John D
authors.initials: JD
authors.lastname: Hayes
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Wells
authors.forename: Eng-Hui
authors.initials: EH
authors.lastname: Chew
mesh_terms: D000171:Acrolein / Q000031:analogs & derivatives / Q000737:chemistry; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D002470:Cell Survival; D016207:Cytokines / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D000072019:Kelch-Like ECH-Associated Protein 1; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000819:agonists* / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D003598:Cytoskeletal Proteins; D007211:Indoles; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C456900:indolin-2-one; D000171:Acrolein; C012843:cinnamaldehyde
keywords: anti-inflammatory agents; chemoprevention; indolinones; inhibition; supercinnamaldehydes; transcription factors