2. Academic Validation
  3. Novel optimization of valmerins (tetrahydropyrido[1,2-a]isoindolones) as potent dual CDK5/GSK3 inhibitors

Novel optimization of valmerins (tetrahydropyrido[1,2-a]isoindolones) as potent dual CDK5/GSK3 inhibitors

  • Eur J Med Chem. 2016 Jun 10:115:311-25. doi: 10.1016/j.ejmech.2016.02.072.
Aziz Ouach 1,  Rajâa Boulahjar 1,  Christine Vala 1,  Stéphane Bourg 1,  Pascal Bonnet 1,  Christiane Guguen-Guillouzo 2,  Myriam Ravache 2,  Rémy Le Guevel 2,  Olivier Lozach 3,  Saïd Lazar 4,  Yves Troin 5,  Laurent Meijer 3,  Sandrine Ruchaud 3,  Mohamed Akssira 4,  Gérald Guillaumet 6,  Sylvain Routier 7
Affiliations

Affiliations

  • 1 Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311, Rue de Chartres, BP 6759, 45067, Orléans Cedex 2, France.
  • 2 Plateforme ImPACcell-SFR BIOSIT UMS-CNRS3480 UMS-INSERM018, Université de Rennes1, 35043, Rennes Cedex, France.
  • 3 C.N.R.S., 'Protein Phosphorylation & Human Disease' Group, USR3151, Station Biologique, B.P. 74, 29682, Roscoff Cedex, France.
  • 4 Laboratoire de Chimie, Bioorganique et Analytique, URAC 22 pôle Répam, Université Hassan II Mohammedia-Casablanca, BP 146, 28800, Mohammedia, Morocco.
  • 5 Université Clermont Auvergne, Sigma-Clermont, Institut de Chimie de Clermont-Ferrand, UMR CNRS 6296, BP 10448, F-63000, Clermont-Ferrand, France.
  • 6 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.
  • 7 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.
PMID: 27019296 DOI: 10.1016/j.ejmech.2016.02.072
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.

Keywords

CDK5; Cell effects; Curtius rearrangement; GSK3; Isocyanates; Kinase profiling; Molecular modeling; Pyridoisoindolones; Valmerins.

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