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

Aziz Ouach (1) , Rajâa Boulahjar (1) , Christine Vala (1) , Stéphane Bourg (1) , Pascal Bonnet (1) , Christiane Guguen-Guillouzo (2, 3) , Myriam Ravache (3) , Rémy Le Guevel (3) , Olivier Lozach (4) , Saïd Lazar (5) , Yves Troin (6) , Laurent Meijer (7, 4) , Sandrine Ruchaud (4) , Mohamed Akssira (5) , Gérald Guillaumet (1) , Sylvain Routier (1)

1 ICOA - Institut de Chimie Organique et Analytique
2 Foie, métabolismes et cancer
3 ImPACcell - Plate-forme ImPACcell
4 SBR - Station biologique de Roscoff [Roscoff]
5 Laboratoire de Chimie, Bioorganique et analytique
6 ICCF - Institut de Chimie de Clermont-Ferrand
7 P3H - Phophorylation de protéines et Pathologies Humaines

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

Domains: Life Sciences [q-bio]

Aziz Ouach, Rajâa Boulahjar, Christine Vala, Stéphane Bourg, Pascal Bonnet, et al.. Novel optimization of valmerins (tetrahydropyrido[1,2-a]isoindolones) as potent dual CDK5/GSK3 inhibitors. European Journal of Medicinal Chemistry, 2016, 115, pp.311--325. ⟨10.1016/j.ejmech.2016.02.072⟩. ⟨hal-01295635⟩