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

ABSTRACT: A series of N-substituted phthalimide derivatives were synthesized based on a pharmacophore study of paecilocin A (a natural PPAR-? agonist) and synthetic leads. The introduction of hydrophilic and hydrophobic groups to the phthalimide skeleton yielded compounds 3-14. Compound 7 showed significant PPAR-? 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-? activation. Compound 7 and rosiglitazone concentration-dependently activated PPAR-? with EC50 values of 0.67 ?M and 0.028 ?M, respectively. These phthalimide derivatives could be further investigated as a new class of PPAR-? ligands.

SUBMITTER: Xiao B 

PROVIDER: S-EPMC3944523 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature