Development of a Water-Soluble Indolylmaleimide Derivative IM-93 Showing Dual Inhibition of Ferroptosis and NETosis
| Autor: | Tadashi Shimizu, Kenichi Asano, Masahiro Takahashi, Takashi Suda, Shuhei Nakao, Mikiko Sodeoka, Megumi Magarisawa, Naoki Terayama, Kosuke Dodo, Satoshi Yotsumoto, Takuto Tokuhiro, Erika Kuboki, Masato Tanaka, Ryu Imamura |
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| Rok vydání: | 2019 |
| Předmět: |
Dual inhibition
Letter 010405 organic chemistry Chemistry Ferroptosis Necroptosis Organic Chemistry Pyroptosis NETosis Indolylmaleimide Pharmacology 01 natural sciences Biochemistry ferroptosis Necrotic cell necrosis 0104 chemical sciences Lipid peroxidation 010404 medicinal & biomolecular chemistry chemistry.chemical_compound cell death Water soluble In vivo Drug Discovery |
| Zdroj: | ACS Medicinal Chemistry Letters |
| ISSN: | 1948-5875 |
| DOI: | 10.1021/acsmedchemlett.9b00142 |
| Popis: | The indolylmaleimide (IM) derivative IM-17 shows inhibitory activity against oxidative-stress-induced necrotic cell death and cardioprotective activity in rat ischemia-reperfusion injury models. In order to develop a more potent derivative, we conducted a detailed structure–activity relationship study of IM derivatives and identified IM-93 as the most potent derivative with good water solubility. IM-93 inhibited ferroptosis and NETosis, but not necroptosis or pyroptosis. In contrast, ferrostatin-1 (Fer-1), a ferroptosis inhibitor, did not inhibit NETosis, although the accompanying lipid peroxidation was partially inhibited by Fer-1, as well as by IM-93. Thus, IM derivatives have a unique activity profile and appear to be promising candidates for in vivo application. |
| Databáze: | OpenAIRE |
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