Galangin 3-benzyl-5-methylether derivatives function as an adiponectin synthesis-promoting peroxisome proliferator-activated receptor γ partial agonist

Bioorg Med Chem. 2022 Jan 15:54:116564. doi: 10.1016/j.bmc.2021.116564. Epub 2021 Dec 15.

Abstract

The upregulation of adiponectin production has been suggested as a novel strategy for the treatment of metabolic diseases. Galangin, a natural flavonoid, exhibited adiponectin synthesis-promoting activity during adipogenesis in human bone marrow mesenchymal stem cells. In target identification, galangin bound both peroxisome proliferator-activated receptor (PPAR) γ and estrogen receptor (ER) β. Novel galangin derivatives were synthesized to improve adiponectin synthesis-promoting compounds by increasing the PPARγ activity of galangin and reducing its ERβ activity, because PPARγ functions can be inhibited by ERβ. Three galangin 3-benzyl-5-methylether derivatives significantly promoted adiponectin production by 2.88-, 4.47-, and 2.76-fold, respectively, compared to the effect of galangin. The most potent compound, galangin 3-benzyl-5,7-dimethylether, selectively bound to PPARγ (Ki, 1.7 μM), whereas it did not bind to ERβ. Galangin 3-benzyl-5,7-dimethylether was identified as a PPARγ partial agonist in docking and pharmacological competition studies, suggesting that it may have diverse therapeutic potential in a variety of metabolic diseases.

Keywords: Adiponectin; Estrogen receptor beta; Galangin derivatives; Human bone marrow mesenchymal stem cells; Peroxisome proliferator-activated receptor gamma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adiponectin / biosynthesis*
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Flavonoids / chemical synthesis
  • Flavonoids / chemistry
  • Flavonoids / pharmacology*
  • Humans
  • Hypoglycemic Agents / chemical synthesis
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / pharmacology*
  • Molecular Docking Simulation
  • Molecular Structure
  • PPAR gamma / agonists*
  • PPAR gamma / metabolism
  • Structure-Activity Relationship

Substances

  • Adiponectin
  • Flavonoids
  • Hypoglycemic Agents
  • PPAR gamma
  • galangin