title: Synthesis of new pyridazino[4,5-b]indol-4-ones and pyridazin-3(2H)-one analogs as DYRK1A inhibitors.
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.
authors.affiliation: 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.
authors.forename: Amélie
authors.initials: A
authors.lastname: Bruel
authors.affiliation: 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.
authors.forename: Romain
authors.initials: R
authors.lastname: Bénéteau
authors.affiliation: 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.
authors.forename: Mylène
authors.initials: M
authors.lastname: Chabanne
authors.affiliation: Protein Phosphorylation & Human Disease Group, CNRS, USR 3151, Station Biologique, B.P. 74, 29682 Roscoff Cedex, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Lozach
authors.affiliation: Plate-forme ImPACcell, UMS-3480, Université de Rennes 1, Campus de Villejean, 2 avenue du Professeur Léon Bernard, 35043 Rennes Cedex, France.
authors.forename: Rémy
authors.initials: R
authors.lastname: Le Guevel
authors.affiliation: Plate-forme ImPACcell, UMS-3480, Université de Rennes 1, Campus de Villejean, 2 avenue du Professeur Léon Bernard, 35043 Rennes Cedex, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Ravache
authors.affiliation: Centre de Biophysique Moléculaire, CNRS, UPR 4301, Université d'Orléans et INSERM, rue Charles Sadron, 45071 Orléans Cedex 2, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Bénédetti
authors.affiliation: 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.
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.affiliation: 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.
authors.forename: Cédric
authors.initials: C
authors.lastname: Logé
authors.affiliation: 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.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Robert
mesh_terms: D001665:Binding Sites; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases; 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* / Q000494:pharmacology; D062105:Molecular Docking Simulation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D000097603:Dyrk Kinases
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D051360:Cyclin-Dependent Kinase 5; D038362:Glycogen Synthase Kinase 3; D007211:Indoles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011724:Pyridazines; D000097603:Dyrk Kinases; C484760:PIK3CA protein, human
keywords: 4-Oxo-3,4-dihydro-5H-pyridazino[4,5-b]indole; Anti-proliferative effects; DYRK1A inhibitors; Pyridazin-3(2H)-one; Synthesis