Novel 6-methoxycarbonyl indolinones bearing a pyrrole Mannich base moiety as angiokinase inhibitors

Bioorg Med Chem. 2017 Mar 15;25(6):1778-1786. doi: 10.1016/j.bmc.2017.01.039. Epub 2017 Jan 25.

Abstract

Inhibition of tumor angiogenesis through simultaneously disturbing vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) mediated signaling pathways is a well-established approach in intervention of tumor. A series of 6-methoxycarbonyl indolinones bearing a pyrrole Mannich base moiety were synthesized and evaluated as potent angiokinase inhibitors. Compound 8a demonstrated favorable enzymatic activity against all subtypes of VEGFR and PDGFR. Also, it potently suppressed proliferation of HT-29 cells by inducing apoptosis. Compound 8a has emerged as a promising lead compound for development of angiokinase inhibitors targeting VEGFR and PDGFR.

Keywords: 6-Methoxycarbonyl indolinones; Angiokinase inhibitors; Antitumor activity; Conformational restriction strategy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • Humans
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Inhibitory Concentration 50
  • Mannich Bases / chemistry*
  • Molecular Docking Simulation
  • Neovascularization, Pathologic / prevention & control
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinases / drug effects*
  • Pyrroles / chemistry*
  • Receptor, Platelet-Derived Growth Factor beta / antagonists & inhibitors
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors

Substances

  • Indoles
  • Mannich Bases
  • Protein Kinase Inhibitors
  • Pyrroles
  • Vascular Endothelial Growth Factor A
  • Protein Kinases
  • Receptor, Platelet-Derived Growth Factor beta