Benzo[e]isoindole-1,3-diones as potential inhibitors of glycogen synthase kinase-3 (GSK-3). Synthesis, kinase inhibitory activity, zebrafish phenotype, and modeling of binding mode

J Med Chem. 2010 Feb 11;53(3):994-1003. doi: 10.1021/jm9013373.

Abstract

Benzo[e]isoindole-1,3-dione derivatives were synthesized, and the effects on GSK-3beta activity and zebrafish embryo growth were evaluated. A series of derivatives show obvious inhibitory activity against GSK-3beta. The most potent inhibitor, 7,8-dimethoxy-5-methylbenzo[e]isoindole-1,3-dione (8a), shows nanomolar IC(50) and obvious phenotype on zebrafish embryo growth associated with the inhibition of GSK-3beta at low micromolar concentration. The interaction mode between 8a and GSK-3beta was characterized by computational modeling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Embryo, Nonmammalian / drug effects*
  • Eye Abnormalities / drug therapy*
  • Eye Abnormalities / embryology
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 beta
  • Isoindoles / chemistry*
  • Models, Molecular
  • Phenotype
  • Phthalimides / chemical synthesis*
  • Phthalimides / chemistry
  • Phthalimides / pharmacology*
  • Protein Binding
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Zebrafish / embryology

Substances

  • 7,8-dimethoxy-5-methylbenzo(e)isoindole-1,3-dione
  • Isoindoles
  • Phthalimides
  • Protein Kinase Inhibitors
  • Glycogen Synthase Kinase 3 beta
  • Glycogen Synthase Kinase 3