Synthesis of new pyridazino[4,5-b]indol-4-ones and pyridazin-3(2H)-one analogs as DYRK1A inhibitors

Amélie Bruel; Romain Bénéteau; Mylène Chabanne; Olivier Lozach; Rémy Le Guevel; Myriam Ravache; Hélène Bénédetti; Laurent Meijer; Cédric Logé; Jean-Michel Robert

doi:10.1016/j.bmcl.2014.09.017

Synthesis of new pyridazino[4,5-b]indol-4-ones and pyridazin-3(2H)-one analogs as DYRK1A inhibitors

Bioorg Med Chem Lett. 2014 Nov 1;24(21):5037-40. doi: 10.1016/j.bmcl.2014.09.017. Epub 2014 Sep 16.

Affiliations

¹ Université de Nantes, Nantes Atlantique Universités, Laboratoire de Chimie Thérapeutique, Cibles et Médicaments des Infections et du Cancer, IICIMED-EA 1155, UFR Sciences Pharmaceutiques, 1 rue Gaston Veil, Nantes F-44035 Cedex 1, France.
² Protein Phosphorylation & Human Disease Group, CNRS, USR 3151, Station Biologique, B.P. 74, 29682 Roscoff Cedex, France.
³ Plate-forme ImPACcell, UMS-3480, Université de Rennes 1, Campus de Villejean, 2 avenue du Professeur Léon Bernard, 35043 Rennes Cedex, France.
⁴ Centre de Biophysique Moléculaire, CNRS, UPR 4301, Université d'Orléans et INSERM, rue Charles Sadron, 45071 Orléans Cedex 2, France.
⁵ Protein Phosphorylation & Human Disease Group, CNRS, USR 3151, Station Biologique, B.P. 74, 29682 Roscoff Cedex, France; ManRos Therapeutics, Centre de Perharidy, 29680 Roscoff, France.
⁶ Université de Nantes, Nantes Atlantique Universités, Laboratoire de Chimie Thérapeutique, Cibles et Médicaments des Infections et du Cancer, IICIMED-EA 1155, UFR Sciences Pharmaceutiques, 1 rue Gaston Veil, Nantes F-44035 Cedex 1, France. Electronic address: cedric.loge@univ-nantes.fr.

PMID: 25248682
DOI: 10.1016/j.bmcl.2014.09.017

Abstract

New pyridazino[4,5-b]indol-4-ones and pyridazin-3(2H)-one analogs were synthesized and their inhibitory activities against DYRK1A, CDK5/p25, GSK3α/β and p110-α isoform of PI3K evaluated using harmine as reference. Both furan-2-yl 10 and pyridin-4-yl 19 from the two different series, exhibited submicromolar IC50 against DYRK1A with no activities against the three other kinases. In addition, compound 10 exhibited antiproliferative activities in the Huh-7, Caco2 and MDA-MB-231 cell lines.

Keywords: 4-Oxo-3,4-dihydro-5H-pyridazino[4,5-b]indole; Anti-proliferative effects; DYRK1A inhibitors; Pyridazin-3(2H)-one; Synthesis.

Publication types

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

MeSH terms

Binding Sites
Caco-2 Cells
Cell Line, Tumor
Cell Proliferation / drug effects
Class I Phosphatidylinositol 3-Kinases
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 / pharmacology
Molecular Docking Simulation
Phosphatidylinositol 3-Kinases / metabolism
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / metabolism
Protein Structure, Tertiary
Protein-Tyrosine Kinases / antagonists & inhibitors*
Protein-Tyrosine Kinases / metabolism
Pyridazines / chemical synthesis
Pyridazines / chemistry*
Pyridazines / pharmacology
Structure-Activity Relationship

Substances

Indoles
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors
Pyridazines
Class I Phosphatidylinositol 3-Kinases
PIK3CA protein, human
Protein-Tyrosine Kinases
Cyclin-Dependent Kinase 5
Protein Serine-Threonine Kinases
Glycogen Synthase Kinase 3