Indirubin core structure of glycogen synthase kinase-3 inhibitors as novel chemotype for intervention with 5-lipoxygenase.

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.

• Authors: Carlo Pergola, Nicolas Gaboriaud-Kolar, Nadine Jestädt, Stefanie König, Marina Kritsanida, Anja M Schaible, Haokun Li, Ulrike Garscha, Christina Weinigel, Dagmar Barz, Kai F Albring, Otmar Huber, Alexios L Skaltsounis, Oliver Werz
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 57 Issue 9 Pg. 3715-23 (May 08 2014) ISSN: 1520-4804 [Electronic] United States
• PMID: 24697244 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Enzyme Inhibitors
• Indoles
• Arachidonate 5-Lipoxygenase
• Glycogen Synthase Kinase 3
• indirubin

Topics

• Arachidonate 5-Lipoxygenase (metabolism)
• Cytokines (biosynthesis)
• Enzyme Inhibitors (chemistry, pharmacology)
• Glycogen Synthase Kinase 3 (antagonists & inhibitors)
• HEK293 Cells
• Humans
• Indoles (chemistry)
• Inhibitory Concentration 50
• Molecular Structure
• Monocytes (drug effects, metabolism)