Synthesis and biological evaluation of tetrahydro[1,4]diazepino[1,2-a]indol-1-ones as cyclin-dependent kinase inhibitors

Eur J Med Chem. 2014 Aug 18:83:617-29. doi: 10.1016/j.ejmech.2014.06.063. Epub 2014 Jun 28.

Abstract

New series of 2,3,4,5-tetrahydro[1,4]diazepino[1,2-a]indol-1-ones and 3,4,5,10-tetrahydro-2H-diazepino[3,4-b]indol-1-ones have been synthesized through an iodolactonisation/lactone-to-lactam rearrangement sequence. These compounds were evaluated as potential protein kinase inhibitors (CDK1, CDK5 and GSK-3). 11-Iodo-2,3,4,5-tetrahydro[1,4]diazepino[1,2-a]indol-1-one derivatives exhibited sub-micromolar inhibitory activity against cyclin-dependent kinases. Docking studies were realized to determine the binding mode of the inhibitors into the ATP binding domain of the CDK5 catalytic site. Our result highlighted two weak Van-der-Waals bonding interactions established between the iodine atom and both phenyl group of Phe 80 and ammonium end of Lys 33.

Keywords: CDK; Docking; GSK-3; Indole; Inhibitor; Iodolactonisation; Kinase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Catalytic Domain
  • Chemistry Techniques, Synthetic
  • Cyclin-Dependent Kinases / antagonists & inhibitors*
  • Cyclin-Dependent Kinases / chemistry
  • Cyclin-Dependent Kinases / metabolism
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Indoles / metabolism
  • Indoles / pharmacology*
  • Molecular Docking Simulation
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Indoles
  • Protein Kinase Inhibitors
  • Cyclin-Dependent Kinases