3-(2-oxoethylidene)indolin-2-one derivatives activate Nrf2 and inhibit NF-κB: potential candidates for chemoprevention

A. A. Nagle; S. A. Reddy; H. Bertrand; H. Tajima; T.-M. Dang; S.-C. Wong; J. D. Hayes; G. Wells; E.-H. Chew

doi:10.1002/cmdc.201402038

3-(2-oxoethylidene)indolin-2-one derivatives activate Nrf2 and inhibit NF-κB: potential candidates for chemoprevention

A. A. Nagle
, S. A. Reddy
, H. Bertrand
, H. Tajima
, T.-M. Dang
, S.-C. Wong
, J. D. Hayes
, G. Wells (Lead / Corresponding author)
, E.-H. Chew (Lead / Corresponding author)

Research output: Contribution to journal › Article › peer-review

12 Citations (Scopus)

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-?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.

Original language	English
Pages (from-to)	1763-1774
Number of pages	12
Journal	ChemMedChem
Volume	9
Issue number	8
DOIs	https://doi.org/10.1002/cmdc.201402038
Publication status	Published - 2014

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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-?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.",

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T1 - 3-(2-oxoethylidene)indolin-2-one derivatives activate Nrf2 and inhibit NF-κB

T2 - potential candidates for chemoprevention

AU - Nagle, A. A.

AU - Reddy, S. A.

AU - Bertrand, H.

AU - Tajima, H.

AU - Dang, T.-M.

AU - Wong, S.-C.

AU - Hayes, J. D.

AU - Wells, G.

AU - Chew, E.-H.

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84905160424

U2 - 10.1002/cmdc.201402038

DO - 10.1002/cmdc.201402038

M3 - Article

C2 - 24819554

AN - SCOPUS:84905160424

SN - 1860-7179

VL - 9

SP - 1763

EP - 1774

JO - ChemMedChem

JF - ChemMedChem

IS - 8

ER -

3-(2-oxoethylidene)indolin-2-one derivatives activate Nrf2 and inhibit NF-κB: potential candidates for chemoprevention

Abstract

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