title: Synthesis and kinase inhibitory activity of novel substituted indigoids.
abstract: 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-3alpha/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 microM, respectively), CK1 (0.6 microM and 0.13 microM) and GSK3 (0.04 microM and 0.36 microM).
authors: Université de La Rochelle, UMR CNRS 6250, LIENSs, Bât. Curie, Equipe Molécules à Activités Biologiques, Avenue Michel Crépeau, F-17042 La Rochelle, France.
authors: Anne
authors: A
authors: Beauchard
authors: Hélène
authors: H
authors: Laborie
authors: Hervé
authors: H
authors: Rouillard
authors: Olivier
authors: O
authors: Lozach
authors: Yoan
authors: Y
authors: Ferandin
authors: Rémy
authors: R
authors: Le Guével
authors: Christiane
authors: C
authors: Guguen-Guillouzo
authors: Laurent
authors: L
authors: Meijer
authors: Thierry
authors: T
authors: Besson
authors: Valérie
authors: V
authors: Thiéry
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D047389:Casein Kinase I / Q000037:antagonists & inhibitors / Q000378:metabolism; D056744:Cyclin B1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000097603:Dyrk Kinases
chemical_list: D047389:Casein Kinase I; D056744:Cyclin B1; D051360:Cyclin-Dependent Kinase 5; D038362:Glycogen Synthase Kinase 3; D007211:Indoles; D018696:Neuroprotective Agents; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases; C448021:glycogen synthase kinase 3 alpha