Open AccessDevelopment of a Water-Soluble Indolylmaleimide Derivative IM-93 Showing Dual Inhibition of Ferroptosis and NETosis
Author(s) -
Kosuke Dodo,
Erika Kuboki,
Tadashi Shimizu,
Ryu Imamura,
Megumi Magarisawa,
Masahiro Takahashi,
Takuto Tokuhiro,
Satoshi Yotsumoto,
Kenichi Asano,
Shuhei Nakao,
Naoki Terayama,
Takashi Suda,
Masato Tanaka,
Mikiko Sodeoka
Publication year - 2019
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00142
Subject(s) - necroptosis , lipid peroxidation , pyroptosis , programmed cell death , derivative (finance) , oxidative stress , chemistry , in vivo , pharmacology , apoptosis , biochemistry , medicine , biology , financial economics , economics , microbiology and biotechnology
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.
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