1067884-35-8Relevant articles and documents
Indirubin core structure of glycogen synthase kinase-3 inhibitors as novel chemotype for intervention with 5-lipoxygenase
Pergola, Carlo,Gaboriaud-Kolar, Nicolas,Jest?dt, Nadine,K?nig, Stefanie,Kritsanida, Marina,Schaible, Anja M.,Li, Haokun,Garscha, Ulrike,Weinigel, Christina,Barz, Dagmar,Albring, Kai F.,Huber, Otmar,Skaltsounis, Alexios L.,Werz, Oliver
, p. 3715 - 3723 (2014/05/20)
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 μM), 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.
Soluble 3′,6-substituted indirubins with enhanced selectivity toward glycogen synthase kinase -3 alter circadian period
Vougogiannopoulou, Konstantina,Ferandin, Yoan,Bettayeb, Karima,Myrianthopoulos, Vassilios,Lozach, Olivier,Fan, Yunzhen,Johnson, Carl Hirschie,Magiatis, Prokopios,Skaltsounis, Alexios-Leandros,Mikros, Emmanuel,Meijer, Laurent
experimental part, p. 6421 - 6431 (2009/10/23)
Glycogen synthase kinase -3 (GSK-3) is a key enzyme involved in numerous physiological events and in major diseases, such as Alzheimer's disease, diabetes, and cardiac hypertrophy. Indirubins are bis-indoles that can be generated from various natural sources or chemically synthesized. While rather potent and selective as GSK-3 inhibitors, most indirubins exhibit low water solubility. To address the issue of solubility, we have designed novel analogues of 6-bromo-indirubin-3′-oxime with increased hydrophilicity based on the GSK-3/indirubins cocrystal structures. The new derivatives with an extended amino side chain attached at position 3′ showed potent GSK-3 inhibitory activity, enhanced selectivity, and dramatically increased water solubility. Furthermore, some of them displayed little or no cytotoxicity. The new indirubins inhibit GSK-3 in a cellular reporter model. They alter the circadian period measured in rhythmically expressing cell cultures, suggesting that they might constitute tools to investigate circadian rhythm regulation.
