@article{3060977,
    title = "Indirubin core structure of glycogen synthase kinase-3 inhibitors as novel chemotype for intervention with 5-lipoxygenase",
    author = "Pergola, C. and Gaboriaud-Kolar, N. and Jestädt, N. and König, S. and Kritsanida, M. and Schaible, A.M. and Li, H. and Garscha, U. and Weinigel, C. and Barz, D. and Albring, K.F. and Huber, O. and Skaltsounis, A.L. and Werz, O.",
    journal = "Journal of Medicinal Chemistry",
    year = "2014",
    volume = "57",
    number = "9",
    pages = "3715-3723",
    publisher = "American Chemical Society",
    issn = "0022-2623, 1520-4804",
    doi = "10.1021/jm401740w",
    keywords = "6 bromo 3 (3 hydroxyiminoindolin 2 ylidene)indolin 2 one;  arachidonate 5 lipoxygenase;  glycogen synthase kinase 3 inhibitor;  indirubin;  lipoxygenase inhibitor;  unclassified drug, antiinflammatory activity;  article;  drug structure;  drug synthesis;  enzyme inhibition;  inflammation, Arachidonate 5-Lipoxygenase;  Cytokines;  Enzyme Inhibitors;  Glycogen Synthase Kinase 3;  HEK293 Cells;  Humans;  Indoles;  Inhibitory Concentration 50;  Molecular Structure;  Monocytes",
    abstract = "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. © 2014 American Chemical Society."
}