Design, Synthesis and Biological Evaluation of Stilbene Derivatives as Novel Inhibitors of Protein Tyrosine Phosphatase 1B

Molecules. 2016 Dec 16;21(12):1722. doi: 10.3390/molecules21121722.

Abstract

By imitating the scaffold of lithocholic acid (LCA), a natural steroidal compound displaying Protein Tyrosine Phosphatase 1B (PTP1B) inhibitory activity, a series of stilbene derivatives containing phenyl-substituted isoxazoles were designed and synthesized. The structures of the title compounds were confirmed by ¹H-NMR, 13C-NMR and HRMS. Activities of the title compounds were evaluated on PTP1B and the homologous enzyme TCPTP by using a colorimetric assay. Most of the target compounds had good activities against PTP1B. Among them, compound 29 (IC50 = 0.91 ± 0.33 μM), characterized by a 5-(2,3-dichlorophenyl) isoxazole moiety, exhibited an activity about 14-fold higher than the lead compound LCA and a 4.2-fold selectivity over TCPTP. Compound 29 was identified as a competitive inhibitor of PTP1B with a Ki value of 0.78 μM in enzyme kinetic studies.

Keywords: inhibitor; lithocholic acid; protein tyrosine phosphatase 1B (PTP1B); stilbene.

MeSH terms

  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Inhibitory Concentration 50
  • Isoxazoles / chemical synthesis
  • Isoxazoles / chemistry*
  • Lithocholic Acid / chemistry
  • Mass Spectrometry
  • Molecular Structure
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
  • Proton Magnetic Resonance Spectroscopy
  • Stilbenes / chemical synthesis
  • Stilbenes / chemistry*
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Isoxazoles
  • Stilbenes
  • Lithocholic Acid
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1