期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 59, 期 5, 页码 2041-2053出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b01641
关键词
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资金
- fund for Scientific Research Flanders (FWO) [G078713N]
- FWO [11Z81SN]
- Belgian grants [IAP 7/32]
- Flemish grants [FWO G.0875.11, FWO G.0973.11, FWO G.0A45.12, FWO G.0172.12, FWO G.0787.13N, FWO G.0C31.14N, FWO KAN 31528711, FWO KAN 1504813N]
- Foundation against Cancer [2012-188]
- Ghent University
- Flanders Institute for Biotechnology (VIB)
- Flemish Government [BOF09/01M00709]
Ferroptosis is a nonapoptotic, iron-catalyzed form of regulated necrosis that is critically dependent on glutathione peroxidase 4 (GPX4). It has been shown to contribute to liver and kidney ischemia reperfusion injury in mice. A chemical inhibitor discovered by high throughput screening displayed inhibition of ferroptosis with nanomolar activity and was dubbed ferrostatin-1 (fer-1). Ferrostatins inhibit oxidative lipid damage, but suffer from inherent stability problems due to the presence of an ester moiety. This limits the application of these molecules in vivo, due to rapid hydrolysis of the ester into the inactive carboxylic acid. Previous studies highlighted the importance of the ethyl ester and suggested steric modifications of the ester for generating improved molecules. In this study, we report the synthesis of novel ferroptosis inhibitors containing amide and sulfonamide moieties with improved stability, single digit nanomolar antiferroptotic activity, and good ADME properties suitable for application in in vivo disease models.
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