Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 17, Issue 17, Pages 6257-6263Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2009.07.051
Keywords
Indirubin; Cyclin-dependent kinases; Glycogen synthase kinase-3; Casein kinase 1; DYRK1A; Alzheimer's disease
Funding
- Ministere de la Recherche et de l'Enseignement Superieur
- Conseil General de Charente-Mari-time
- Comite de Charente-Maritime de la Ligue Nationale Contre le Cancer
- EEC [FP62002]
- PRO-KINASE Research
- Canceropole Grand-Ouest
- Association France-Alzheimer Finistere
- CRITT-Sante Bretagne
- Ligue Nationale contre le Cancer
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The bis-indole indigoids are a promising protein kinase inhibitor scaffold to be further evaluated against the numerous human diseases that imply abnormal regulation of kinases including neurodegenerative disorders. In an effort to identify new pharmacological inhibitors of disease-relevant protein kinases with increased potency and selectivity, we designed, synthesized new 5,7-disubstituted or 6-substituted bis-indole derivatives. On the basis of our previous synthetic work, 22 selected compounds were tested on CDK1/cyclin B, CDK5/p25, DYRK1A, CK1, and GSK-3 alpha/beta kinases, five kinases involved in Alzheimer's disease. Some of them were also evaluated for their cytotoxic and antiproliferative activities. 6-Nitro-3'-N-oxime-indirubin and 5-amino-3'- N-oxime-indirubin derivatives exhibited inhibitory activity in a submicromolar range against CDK1/cyclin B (0.18 and 0.1 mu M, respectively), CK1 (0.6 mu M and 0.13 mu M) and GSK3 (0.04 mu M and 0.36 mu M). (C) 2009 Elsevier Ltd. All rights reserved.
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