2. Academic Validation
  3. Advances in tetrahydropyrido[1,2-a]isoindolone (valmerins) series: Potent glycogen synthase kinase 3 and cyclin dependent kinase 5 inhibitors

Advances in tetrahydropyrido[1,2-a]isoindolone (valmerins) series: Potent glycogen synthase kinase 3 and cyclin dependent kinase 5 inhibitors

  • Eur J Med Chem. 2015 Aug 28:101:274-87. doi: 10.1016/j.ejmech.2015.06.046.
Rajâa Boulahjar 1,  Aziz Ouach 1,  Stéphane Bourg 1,  Pascal Bonnet 1,  Olivier Lozach 2,  Laurent Meijer 2,  Christiane Guguen-Guillouzo 3,  Rémy Le Guevel 3,  Saïd Lazar 4,  Mohamed Akssira 4,  Yves Troin 5,  Gérald Guillaumet 6,  Sylvain Routier 7
Affiliations

Affiliations

  • 1 Univ Orleans, CNRS UMR 7311, Institut de Chimie Organique et Analytique, rue de Chartres, BP 6759, 45067 Orléans Cedex 2, France.
  • 2 C.N.R.S., 'Protein Phosphorylation & Human Disease' Group, USR3151, Station Biologique, BP 74, 29682 Roscoff Cedex, France.
  • 3 Plateforme ImPACcell-SFR BIOSIT UMS-CNRS3480 UMS-INSERM018, Université de Rennes1, 35043 Rennes Cedex, France.
  • 4 Laboratoire de Chimie, Bioorganique et Analytique, URAC 22 pôle Répam, Université Hassan II Mohammedia-Casablanca, BP 146, 28800 Mohammedia, Morocco.
  • 5 Clermont Université, ENSCCF, Laboratoire de Chimie des Hétérocycles et des Glucides, BP 10448, 63000 Clermont-Ferrand, France.
  • 6 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.
  • 7 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.
PMID: 26142492 DOI: 10.1016/j.ejmech.2015.06.046
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.

Keywords

CDK5; GSK3; In vitro assays; Kinase research; Pyridoisoindolone; Valmerin.

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