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. Epub 2016 Mar 2.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cyclin-Dependent Kinase 5 / antagonists & inhibitors*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Glycogen Synthase Kinase 3 beta / antagonists & inhibitors*
  • Humans
  • Indoles / pharmacology*
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Indoles
  • Cyclin-Dependent Kinase 5
  • Glycogen Synthase Kinase 3 beta
  • CDK5 protein, human