期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 101, 期 -, 页码 274-287出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2015.06.046
关键词
Pyridoisoindolone; Valmerin; GSK3; CDK5; Kinase research; In vitro assays
资金
- CNRS valorization service
- Canceropole Grand Ouest axis Valorisation des produits de la mer
- Association pour la Recherche contre le Cancer
- Program Hubert Curien Volubilis
- Ligue Nationale contre le Cancer (Comite Grand-Ouest)
An efficient synthetic strategy was developed to modulate the structure of the tetrahydropyridine iso-indolone (Valmerin) skeleton. A library of more than 30 novel final structures was generated. Biological activities on CDK5 and GSM 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. (C) 2015 Elsevier Masson SAS. All rights reserved.
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