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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.

The back cover picture shows lead and parent analogues of 3-(2-oxopropylidene)indolin-2-ones targeting Nrf2-Keap1 and NF-kB signaling pathways. At the cellular level, these compounds induce Nrf2-mediated expression of phase 2 enzymes and suppress NF-kB-directed inflammation, which makes them promising development candidates for chemoprevention. For more details, see the Full Paper by Geoffrey Wells, Eng-Hui Chew et al. on p. 1763 ff.