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

Rajâa Boulahjar (1) , Aziz Ouach (1) , Stéphane Bourg (1) , Pascal Bonnet (1) , Olivier Lozach (2) , Laurent Meijer (2) , Christiane Guguen-Guillouzo (3, 4) , Rémy Le Guevel (3, 4) , Saïd Lazar (5) , Mohamed Akssira (5) , Yves Troin (6) , Gérald Guillaumet (1) , Sylvain Routier (1)

1 ICOA - Institut de Chimie Organique et Analytique
2 P3H - Phophorylation de protéines et Pathologies Humaines
3 Biosit : Biologie - Santé - Innovation Technologique - Structure Fédérative de Recherche en Biologie et Santé de Rennes
4 ImPACcell - Plate-forme ImPACcell
5 Laboratoire de Chimie, Bioorganique et analytique
6 ICCF - Institut de Chimie de Clermont-Ferrand

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.

Mots clés: In vitro assays; GSK3; CDK5; Kinase research; Pyridoisoindolone; Valmerin

Domaines: Chimie; Chimie thérapeutique; Cancer

Rajâa Boulahjar, Aziz Ouach, Stéphane Bourg, Pascal Bonnet, Olivier Lozach, et al.. Advances in tetrahydropyrido[1,2-a]isoindolone (valmerins) series: Potent glycogen synthase kinase 3 and cyclin dependent kinase 5 inhibitors.. European Journal of Medicinal Chemistry, 2015, 101, pp.274-287. ⟨10.1016/j.ejmech.2015.06.046⟩. ⟨hal-01212495⟩