Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 115, Issue -, Pages 311-325Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2016.02.072
Keywords
Pyridoisoindolones; Curtius rearrangement; Isocyanates; Valmerins; GSK3; CDK5; Molecular modeling; Kinase profiling; Cell effects
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Funding
- CNRS valorization service
- Canceropole Grand Ouest strand Valorisation des produits de la mer
- Region Centre Val de Loire (AMI APR program)
- Hubert Curien Program Volubilis [17207XJ]
- Ligue Nationale contre le Cancer (Comite Grand-Ouest)
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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. (C) 2016 Elsevier Masson SAS. All rights reserved.
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