ABSTRACT
Seven new amino acid derivatives (1-4 and 6-8) were isolated from MeOH extracts of the marine ascidian Herdmania momus. Planar structures were established on the basis of NMR, IR, and MS spectroscopic analyses. Absolute configurations of these compounds were derived from specific rotation and CD analysis. The peroxisome proliferator-activated receptor (PPAR)-γ agonistic activities of the compounds were investigated due to the similarity of the structural motif to that of the antidiabetic drug rosiglitazone. Analogues with indoleglyoxyl moieties (5, 6, and 8) showed significant PPAR-γ activation in Ac2F rat liver cells.
Subject(s)
Hypoglycemic Agents/isolation & purification , Indoles/isolation & purification , Indoles/pharmacology , PPAR gamma/agonists , Urochordata/chemistry , Animals , Hepatocytes/drug effects , Hepatocytes/metabolism , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Indoles/chemistry , Marine Biology , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Rats , Rosiglitazone , Thiazolidinediones/pharmacologyABSTRACT
On the basis of a marine fungal phthalide (paecilocin A) skeleton, we synthesized 20 analogs and evaluated them for peroxisome proliferator-activated receptor gamma (PPAR-γ) binding and activation. Among these analogs, 6 and 7 had significant PPAR-γ binding activity, and 7 showed further PPAR-γ activation in rat liver Ac2F cells. In docking simulation, 7 formed H bonds with key amino acid residues of the PPAR-γ binding domain, and the overall positioning was similar to rosiglitazone. This new phthalide derivative is considered an interesting new molecular class of PPAR-γ ligands.
