title: Advances in tetrahydropyrido[1,2-a]isoindolone (valmerins) series: Potent glycogen synthase kinase 3 and cyclin dependent kinase 5 inhibitors.
abstract: An efficient synthetic strategy was developed to modulate the structure of the tetrahydropyridine isoindolone (Valmerin) skeleton. A library of more than 30 novel final structures was generated. Biological activities on CDK5 and GSK3 as well as cellular effects on cancer cell lines were measured for each novel compound. Additionally docking studies were performed to support medicinal chemistry efforts. A strong GSK3/CDK5 dual inhibitor (38, IC50 GSK3/CDK5 32/84 nM) was obtained. A set of highly selective GSK3 inhibitors was synthesized by fine-tuning structural modifications (29 IC50 GSK3/CDK5 32/320 nM). Antiproliferative effects on cells were correlated with the in vitro kinase activities and the best effects were obtained with lung and colon cell lines.
authors.affiliation: Univ Orleans, CNRS UMR 7311, Institut de Chimie Organique et Analytique, rue de Chartres, BP 6759, 45067 Orléans Cedex 2, France.
authors.forename: Rajâa
authors.initials: R
authors.lastname: Boulahjar
authors.affiliation: Univ Orleans, CNRS UMR 7311, Institut de Chimie Organique et Analytique, rue de Chartres, BP 6759, 45067 Orléans Cedex 2, France.
authors.forename: Aziz
authors.initials: A
authors.lastname: Ouach
authors.affiliation: Univ Orleans, CNRS UMR 7311, Institut de Chimie Organique et Analytique, rue de Chartres, BP 6759, 45067 Orléans Cedex 2, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bourg
authors.affiliation: Univ Orleans, CNRS UMR 7311, Institut de Chimie Organique et Analytique, rue de Chartres, BP 6759, 45067 Orléans Cedex 2, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Bonnet
authors.affiliation: C.N.R.S., 'Protein Phosphorylation & Human Disease' Group, USR3151, Station Biologique, BP 74, 29682 Roscoff Cedex, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Lozach
authors.affiliation: C.N.R.S., 'Protein Phosphorylation & Human Disease' Group, USR3151, Station Biologique, BP 74, 29682 Roscoff Cedex, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.affiliation: Plateforme ImPACcell-SFR BIOSIT UMS-CNRS3480 UMS-INSERM018, Université de Rennes1, 35043 Rennes Cedex, France.
authors.forename: Christiane
authors.initials: C
authors.lastname: Guguen-Guillouzo
authors.affiliation: Plateforme ImPACcell-SFR BIOSIT UMS-CNRS3480 UMS-INSERM018, Université de Rennes1, 35043 Rennes Cedex, France.
authors.forename: Rémy
authors.initials: R
authors.lastname: Le Guevel
authors.affiliation: Laboratoire de Chimie, Bioorganique et Analytique, URAC 22 pôle Répam, Université Hassan II Mohammedia-Casablanca, BP 146, 28800 Mohammedia, Morocco.
authors.forename: Saïd
authors.initials: S
authors.lastname: Lazar
authors.affiliation: Laboratoire de Chimie, Bioorganique et Analytique, URAC 22 pôle Répam, Université Hassan II Mohammedia-Casablanca, BP 146, 28800 Mohammedia, Morocco.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Akssira
authors.affiliation: Clermont Université, ENSCCF, Laboratoire de Chimie des Hétérocycles et des Glucides, BP 10448, 63000 Clermont-Ferrand, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Troin
authors.affiliation: Univ Orleans, CNRS UMR 7311, Institut de Chimie Organique et Analytique, rue de Chartres, BP 6759, 45067 Orléans Cedex 2, France. Electronic address: gerald.guillaumet@univ-orleans.fr.
authors.forename: Gérald
authors.initials: G
authors.lastname: Guillaumet
authors.affiliation: Univ Orleans, CNRS UMR 7311, Institut de Chimie Organique et Analytique, rue de Chartres, BP 6759, 45067 Orléans Cedex 2, France. Electronic address: sylvain.routier@univ-orleans.fr.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Routier
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D054833:Isoindoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D054833:Isoindoles; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D051360:Cyclin-Dependent Kinase 5; D038362:Glycogen Synthase Kinase 3
keywords: CDK5; GSK3; In vitro assays; Kinase research; Pyridoisoindolone; Valmerin