title: Novel optimization of valmerins (tetrahydropyrido[1,2-a]isoindolones) as potent dual CDK5/GSK3 inhibitors.
abstract: An efficient synthetic strategy able to modulate the structure of the tetrahydropyridine isoindolone (Valmerin) skeleton was developed. 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 to support the SAR, a docking study was performed. A potent GSK3/CDK5 dual inhibitor (37, IC50 CDK5/GSK3 35/7 nM) was obtained. Best antiproliferative effects were obtained on lung and prostate cell lines with IC50 = 20 nM.
authors.affiliation: Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311, Rue de Chartres, BP 6759, 45067, Orléans Cedex 2, France.
authors.forename: Aziz
authors.initials: A
authors.lastname: Ouach
authors.affiliation: Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311, Rue de Chartres, BP 6759, 45067, Orléans Cedex 2, France.
authors.forename: Rajâa
authors.initials: R
authors.lastname: Boulahjar
authors.affiliation: Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311, Rue de Chartres, BP 6759, 45067, Orléans Cedex 2, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Vala
authors.affiliation: Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311, Rue de Chartres, BP 6759, 45067, Orléans Cedex 2, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bourg
authors.affiliation: Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311, Rue de Chartres, BP 6759, 45067, Orléans Cedex 2, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Bonnet
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: Myriam
authors.initials: M
authors.lastname: Ravache
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: C.N.R.S., 'Protein Phosphorylation & Human Disease' Group, USR3151, Station Biologique, B.P. 74, 29682, Roscoff Cedex, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Lozach
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: Université Clermont Auvergne, Sigma-Clermont, Institut de Chimie de Clermont-Ferrand, UMR CNRS 6296, BP 10448, F-63000, Clermont-Ferrand, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Troin
authors.affiliation: C.N.R.S., 'Protein Phosphorylation & Human Disease' Group, USR3151, Station Biologique, B.P. 74, 29682, Roscoff Cedex, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.affiliation: C.N.R.S., 'Protein Phosphorylation & Human Disease' Group, USR3151, Station Biologique, B.P. 74, 29682, Roscoff Cedex, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Ruchaud
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: Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311, 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: Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311, 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; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D051360:Cyclin-Dependent Kinase 5; D000071679:Glycogen Synthase Kinase 3 beta; C495905:CDK5 protein, human
keywords: CDK5; Cell effects; Curtius rearrangement; GSK3; Isocyanates; Kinase profiling; Molecular modeling; Pyridoisoindolones; Valmerins