P-2 糸状菌の生産するACAT阻害剤pyripyropeneに関する研究(ポスター発表の部)

概要

論文の詳細を見る
A soil-isolated Aspergillus fumigatus FO-1289 was found to produce a series of novel inhibitors of acyl-CoA: cholesterol acyltransferase (ACAT). Twelve compounds named pyripyropenes A to L (1-12) were isolated as white powders or colorless crystals from the fermentation broth of the producer by solvent extraction, silica gel, LH20 and ODS column chromatographies, and preparative HPLC. Structures of 1-12 were elucidated by NMR and other spectroscopic studies. They have a common carbon skeleton which consists of pyridine, α-pyrone and sesquiterpene moieties. The relative and absolute stereochemistry of 1 was also elucidated via X-ray crystallography and the Kakisawa-Kashman modification of Mosher's NMR method. The biosynthetic origin of 1 was studied by feeding experiments using various [^<13>C] and [^<14>C] precursors. ^<13>C NMR and degradation analyses proposed that the pyridino-α-pyrone moiety is produced via condensation of a primer nicotinic acid with two acetates, the sesquiterpene moiety is produced from three mevalonates, and then three acetyl residues are introduced from acetates into the core skeleton. ACAT inhibitory activity was tested in an enzyme assay using rat liver microsomes. Among them 3, 1, 12 and 2 showed very potent inhibitory activity with IC_<50> values of 0.15, 0.16, 0.27 and 0.32μm, respectively, indicating that they represent the most potent naturally occurring ACAT inhibitors reported to date. Acyloxy groups are essential at both R_1 and R_2 positions in the molecules for exhibiting potent ACAT inhibition. Furthermore, 1 proved to be orally active in a hamster model, reducing cholesterol absorption by 32-46% after single doses of 25-75mg/kg.
天然有機化合物討論会の論文
1995-09-01

P-2 糸状菌の生産するACAT阻害剤pyripyropeneに関する研究(ポスター発表の部)

スポンサーリンク

概要

著者

関連論文

スポンサーリンク