Synthesis of PPAR-γ activators inspired by the marine natural product, paecilocin A

Mar Drugs. 2014 Feb 13;12(2):926-39. doi: 10.3390/md12020926.

Abstract

A series of N-substituted phthalimide derivatives were synthesized based on a pharmacophore study of paecilocin A (a natural PPAR-γ agonist) and synthetic leads. The introduction of hydrophilic and hydrophobic groups to the phthalimide skeleton yielded compounds 3-14. Compound 7 showed significant PPAR-γ activation in a luciferase assay using rat liver Ac2F cells. Docking simulations showed that a free hydroxyl group on the phthalimide head and a suitable hydrophilic tail, including a phenyl linker, were beneficial for PPAR-γ activation. Compound 7 and rosiglitazone concentration-dependently activated PPAR-γ with EC50 values of 0.67 μM and 0.028 μM, respectively. These phthalimide derivatives could be further investigated as a new class of PPAR-γ ligands.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzofurans / chemistry
  • Benzofurans / pharmacology*
  • Biological Products / chemistry
  • Biological Products / pharmacology
  • Cell Line
  • Dose-Response Relationship, Drug
  • Hydrophobic and Hydrophilic Interactions
  • Lactones / chemistry
  • Lactones / pharmacology*
  • Ligands
  • Liver / cytology
  • Liver / drug effects
  • Molecular Docking Simulation
  • PPAR gamma / drug effects*
  • PPAR gamma / metabolism
  • Phthalimides / chemical synthesis
  • Phthalimides / chemistry
  • Phthalimides / pharmacology*
  • Rats
  • Rosiglitazone
  • Thiazolidinediones / administration & dosage
  • Thiazolidinediones / pharmacology*

Substances

  • Benzofurans
  • Biological Products
  • Lactones
  • Ligands
  • PPAR gamma
  • Phthalimides
  • Thiazolidinediones
  • paecilocin A
  • Rosiglitazone