Synthesis and biological evaluation of geniposide derivatives as potent and selective PTPlB inhibitors

Eur J Med Chem. 2020 Nov 1:205:112508. doi: 10.1016/j.ejmech.2020.112508. Epub 2020 Jul 19.

Abstract

Herein a series of Geniposide derivatives were designed, synthesized and evaluated as protein tyrosine phosphatase 1B (PTPlB) inhibitors. Most of these compounds exhibited potent in vitro PTP1B inhibitory activities, the representative 7a and 17f were found to be the most potent inhibitors against the enzyme with IC50 values of 0.35 and 0.41 μM, respectively. More importantly, they showcased 4 to10-fold selectivity over SHP2 and 3-fold over TCPTP. Further biological activity studies revealed that compounds 7a, 17b and 17f could effectively enhance insulin-stimulated glucose uptake with no significant cytotoxicity. Subsequent molecular docking and structural activity relationship analyses demonstrated that the glucose scaffold, benzylated glycosyl groups, and arylethenesulfonic acid ester significantly impact on the activity and selectivity.

Keywords: Genipin; Geniposide; PTP1B inhibitors; Selectivity; Type 2 diabetes mellitus.

MeSH terms

  • Biological Transport / drug effects
  • Cell Line
  • Chemistry Techniques, Synthetic
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Glucose / metabolism
  • Inhibitory Concentration 50
  • Insulin / pharmacology
  • Iridoids / chemical synthesis*
  • Iridoids / chemistry
  • Iridoids / pharmacology*
  • Molecular Docking Simulation
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Sulfonic Acids / chemistry

Substances

  • Enzyme Inhibitors
  • Insulin
  • Iridoids
  • Sulfonic Acids
  • geniposide
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Glucose