Building skeletally diverse architectures on the Indoline Scaffold: the discovery of a chemical probe of focal adhesion kinase signaling networks

Bioorg Med Chem. 2008 Nov 1;16(21):9596-602. doi: 10.1016/j.bmc.2008.09.025. Epub 2008 Sep 12.

Abstract

Inspired by bioactive indoline alkaloid natural products, here, we report a divergent synthesis approach that led to skeletally diverse indoline alkaloid-inspired compounds. The natural product-inspired compounds obtained were then subjected to a series of in vitro and cellular assays to examine their properties as modulators of focal adhesion kinase (FAK) activity. This study resulted in the identification of a promising lead inhibitor of FAK (42), which also showed activity in a wound healing and cell invasion assay. The in silico study of the lead compound (42) was also undertaken.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Adhesion / drug effects
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Computer Simulation
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Focal Adhesion Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Humans
  • Indole Alkaloids / chemical synthesis
  • Indole Alkaloids / chemistry
  • Indole Alkaloids / pharmacology*
  • Indoles / chemical synthesis
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Phosphorylation / drug effects
  • Signal Transduction / drug effects*
  • Tumor Cells, Cultured
  • Wound Healing / drug effects

Substances

  • Enzyme Inhibitors
  • Indole Alkaloids
  • Indoles
  • indoline
  • Focal Adhesion Protein-Tyrosine Kinases