TY - JOUR
TI - Indirubin core structure of glycogen synthase kinase-3 inhibitors as novel chemotype for intervention with 5-lipoxygenase
AU - Pergola, C.
AU - Gaboriaud-Kolar, N.
AU - Jestädt, N.
AU - König, S.
AU - Kritsanida, M.
AU - Schaible, A.M.
AU - Li, H.
AU - Garscha, U.
AU - Weinigel, C.
AU - Barz, D.
AU - Albring, K.F.
AU - Huber, O.
AU - Skaltsounis, A.L.
AU - Werz, O.
JO - Journal of Medicinal Chemistry
PY - 2014
VL - 57
TODO - 9
SP - 3715-3723
PB - American Chemical Society
SN - 0022-2623, 1520-4804
TODO - 10.1021/jm401740w
TODO - 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
TODO - 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.
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