Synthesis and kinase inhibitory activity of novel substituted indigoids

Anne Beauchard; Hélène Laborie; Hervé Rouillard; Olivier Lozach; Yoan Ferandin; Rémy Le Guével; Christiane Guguen-Guillouzo; Laurent Meijer; Thierry Besson; Valérie Thiéry

doi:10.1016/j.bmc.2009.07.051

Synthesis and kinase inhibitory activity of novel substituted indigoids

Bioorg Med Chem. 2009 Sep 1;17(17):6257-63. doi: 10.1016/j.bmc.2009.07.051. Epub 2009 Jul 25.

Authors

Anne Beauchard¹, Hélène Laborie, Hervé Rouillard, Olivier Lozach, Yoan Ferandin, Rémy Le Guével, Christiane Guguen-Guillouzo, Laurent Meijer, Thierry Besson, Valérie Thiéry

Affiliation

¹ Université de La Rochelle, UMR CNRS 6250, LIENSs, Bât. Curie, Equipe Molécules à Activités Biologiques, Avenue Michel Crépeau, F-17042 La Rochelle, France.

PMID: 19665384
DOI: 10.1016/j.bmc.2009.07.051

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).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / drug therapy
Casein Kinase I / antagonists & inhibitors
Casein Kinase I / metabolism
Cyclin B1 / antagonists & inhibitors*
Cyclin B1 / metabolism
Cyclin-Dependent Kinase 5 / antagonists & inhibitors
Cyclin-Dependent Kinase 5 / metabolism
Dyrk Kinases
Glycogen Synthase Kinase 3 / antagonists & inhibitors
Glycogen Synthase Kinase 3 / metabolism
Humans
Indoles / chemical synthesis*
Indoles / chemistry
Indoles / toxicity
Neuroprotective Agents / chemical synthesis*
Neuroprotective Agents / chemistry
Neuroprotective Agents / toxicity
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / toxicity
Protein Kinases / chemistry*
Protein Kinases / metabolism
Protein Serine-Threonine Kinases / antagonists & inhibitors
Protein Serine-Threonine Kinases / metabolism
Protein-Tyrosine Kinases / antagonists & inhibitors
Protein-Tyrosine Kinases / metabolism

Substances

Cyclin B1
Indoles
Neuroprotective Agents
Protein Kinase Inhibitors
Protein Kinases
Protein-Tyrosine Kinases
Casein Kinase I
Cyclin-Dependent Kinase 5
Protein Serine-Threonine Kinases
Glycogen Synthase Kinase 3
glycogen synthase kinase 3 alpha