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-?B 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.
Nagle, A. A., Reddy, S. A., Bertrand, H., Tajima, H., Dang, T-M., Wong, S-C., Hayes, J. D., Wells, G., & Chew, E-H. (2014). 3-(2-oxoethylidene)indolin-2-one derivatives activate Nrf2 and inhibit NF-κB: potential candidates for chemoprevention. ChemMedChem, 9(8), 1763-1774. https://doi.org/10.1002/cmdc.201402038