Indirubin core structure of glycogen synthase kinase-3 inhibitors as novel chemotype for intervention with 5-lipoxygenase.
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.
Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University , Jena 07743, Germany.
Carlo
C
Pergola
Nicolas
N
Gaboriaud-Kolar
Nadine
N
Jestädt
Stefanie
S
König
Marina
M
Kritsanida
Anja M
AM
Schaible
Haokun
H
Li
Ulrike
U
Garscha
Christina
C
Weinigel
Dagmar
D
Barz
Kai F
KF
Albring
Otmar
O
Huber
Alexios L
AL
Skaltsounis
Oliver
O
Werz
D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000737:chemistry; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism
D016207:Cytokines; D004791:Enzyme Inhibitors; D007211:Indoles; D001094:Arachidonate 5-Lipoxygenase; D038362:Glycogen Synthase Kinase 3; C027185:indirubin