Indirubin Core Structure of Glycogen Synthase Kinase-3 Inhibitors as Novel Chemotype for Intervention with 5-Lipoxygenase
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- 作者：Carlo Pergola ; Nicolas Gaboriaud-Kolar ; Nadine Jest盲dt ; Stefanie K枚nig ; Marina Kritsanida ; Anja M. Schaible ; Haokun Li ; Ulrike Garscha ; Christina Weinigel ; Dagmar Barz ; Kai F. Albring ; Otmar Huber ; Alexios L. Skaltsounis ; Oliver Werz
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：May 8, 2014
- 年：2014
- 卷：57
- 期：9
- 页码：3715-3723
- 全文大小：449K
- 年卷期：v.57,no.9(May 8, 2014)
- ISSN：1520-4804
文摘
The enzymes 5-lipoxygenase (5-LO) and glycogen synthase kinase (GSK)-3 represent promising drug targets in inflammation. We made use of the bisindole core of indirubin, present in GSK-3 inhibitors, to innovatively target 5-LO at the ATP-binding site for the design of dual 5-LO/GSK-3 inhibitors. Evaluation of substituted indirubin derivatives led to the identification of (3Z)-6-bromo-3-[(3E)-3-hydroxyiminoindolin-2-ylidene]indolin-2-one (15) as a potent, direct, and reversible 5-LO inhibitor (IC50 = 1.5 渭M), with comparable cellular effectiveness on 5-LO and GSK-3. Together, we present indirubins as novel chemotypes for the development of 5-LO inhibitors, the interference with the ATP-binding site as a novel strategy for 5-LO targeting, and dual 5-LO/GSK-3 inhibition as an unconventional and promising concept for anti-inflammatory intervention.