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

Eur J Med Chem. 2015 Aug 28:101:274-87. doi: 10.1016/j.ejmech.2015.06.046. Epub 2015 Jun 27.

Abstract

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.

Keywords: CDK5; GSK3; In vitro assays; Kinase research; Pyridoisoindolone; Valmerin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cyclin-Dependent Kinase 5 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 5 / metabolism
  • Dose-Response Relationship, Drug
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 / metabolism
  • Humans
  • Isoindoles / chemical synthesis
  • Isoindoles / chemistry
  • Isoindoles / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Piperidines / chemical synthesis
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Isoindoles
  • Piperidines
  • Protein Kinase Inhibitors
  • Cyclin-Dependent Kinase 5
  • Glycogen Synthase Kinase 3