期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 61, 期 22, 页码 10126-10140出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b01299
关键词
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资金
- Fonds Wetenschappelijk Onderzoek (FWO) Flanders [11Z815N, 11Z817N]
- FWO [G078713N, G0B7118N]
- FWO Excellence of Science program [G0G6618N, 30826052]
- Belgian grants (Interuniversity Attraction Poles) [IAP 7/32]
- Flemish grant (Research Foundation Flanders) [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]
- Flemish grant (Foundation against Cancer) [2012-188]
- Ghent University grants (MRP, GROUP-ID consortium)
- Flanders Institute for Biotechnology (VIB)
- Flemish Government [BOF09/01M00709]
Ferroptosis is an iron-catalyzed, nonapoptotic form of regulated necrosis that results in oxidative lipid damage in cell membranes that can be inhibited by the radical-trapping antioxidant Ferrostatin-1 (Fer-1). Novel inhibitors derived from the Fer-1 scaffold inhibited ferroptosis potently but suffered from solubility issues. In this paper, we report the synthesis of a more stable and readily soluble series of Fer-1 analogues that potently inhibit ferroptosis. The most promising compounds (37, 38, and 39) showed an improved protection compared to Fer-1 against multiorgan injury in mice. No toxicity was observed in mice after daily injection of 39 (UAMC-3203) for 4 weeks. UAMC-3203 inserts rapidly in a phospholipid bilayer in silico, which aligns with the current understanding of the mechanism of action of these compounds. In conclusion, these analogues have superior properties compared to Fer-1, show in vivo efficacy, and represent novel lead compounds with therapeutic potential in relevant ferroptosis-driven disease models.
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