Synthesis and kinase inhibitory activity of novel substituted indigoids.
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).
Beauchard
Anne
A
Université de La Rochelle, UMR CNRS 6250, LIENSs, Bât. Curie, Equipe Molécules à Activités Biologiques, Avenue Michel Crépeau, F-17042 La Rochelle, France.
Laborie
Hélène
H
Rouillard
Hervé
H
Lozach
Olivier
O
Ferandin
Yoan
Y
Le Guével
Rémy
R
Guguen-Guillouzo
Christiane
C
Meijer
Laurent
L
Besson
Thierry
T
Thiéry
Valérie
V
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
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