Plakilactones from the Marine Sponge Plakinastrella mamillaris. Discovery of a New Class of Marine Ligands of Peroxisome Proliferator-Activated Receptor 纬

详细信息    查看全文

• 作者：Carmen Festa ; Gianluigi Lauro ; Simona De Marino ; Maria Valeria D鈥橝uria ; Maria Chiara Monti ; Agostino Casapullo ; Claudio D鈥橝more ; Barbara Renga ; Andrea Mencarelli ; Sylvain Petek ; Giuseppe Bifulco ; Stefano Fiorucci ; Angela Zampella
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：October 11, 2012
• 年：2012
• 卷：55
• 期：19
• 页码：8303-8317
• 全文大小：686K
• 年卷期：v.55,no.19(October 11, 2012)
• ISSN：1520-4804

文摘

In this paper we report the isolation and the molecular characterization of a new class of PPAR纬 ligands from the marine environment. Biochemical characterization of a library of 13 oxygenated polyketides isolated from the marine sponge Plakinastrella mamillaris allowed the discovery of gracilioether B and plakilactone C as selective PPAR纬 ligands in transactivation assays. Both agents covalently bind to the PPAR纬 ligand binding domain through a Michael addition reaction involving a protein cysteine residue and the 伪,尾-unsaturated ketone in their side chains. Additionally, gracilioether C is a noncovalent agonist for PPAR纬, and methyl esters 1 and 2 are noncovalent antagonists. Structural requirements for the interaction of these agents within the PPAR纬 ligand binding domain were obtained by docking analysis. Gracilioether B and plakilactone C regulate the expression of PPAR纬-dependent genes in the liver and inhibit the generation of inflammatory mediators by macrophages.