Τίτλος:
Indirubin core structure of glycogen synthase kinase-3 inhibitors as novel chemotype for intervention with 5-lipoxygenase
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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.
Συγγραφείς:
Pergola, C.
Gaboriaud-Kolar, N.
Jestädt, N.
König, S.
Kritsanida, M.
Schaible, A.M.
Li, H.
Garscha, U.
Weinigel, C.
Barz, D.
Albring, K.F.
Huber, O.
Skaltsounis, A.L.
Werz, O.
Περιοδικό:
Journal of Medicinal Chemistry
Εκδότης:
American Chemical Society
Λέξεις-κλειδιά:
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
