| Co-Investigator(Kenkyū-buntansha) |
OBATA Rika The Kitasato Institute, Research Center for biological Function, Researcher, 生物機能研究所, 研究員 (20260078)
TABATA Noriko The Kitasato Institute, Researach Center for Basic Research, Researacher, 生物機能研究所, 研究員 (60260080)
SUNAZUKA Toshiaki Kitasato University, School of Pharmaceutical Sciences, Associate Praofessor, 薬学部, 講師 (30226592)
TOMODA Hiroshi The Kitasato Institute, Researach Center for Biological Function, Chief Researac, 生物機能研究所, 副所長 (70164043)
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| Research Abstract |
A soil isolated Aspergillus fumigatus FO-1289 was found to produce a series of novel inhibitors of acyl-CoA : cholesterol acyltransferase (ACAT). Nineteen compounds named pyraipyraopenes A to S 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.The structures were e ; icodated by NMR and other spectroscopic studies. They have a common carbon skeleton which consists of pyridine, alpha-pyrone and sesquiterpene moieties. The relative and absolute stereochemistry of pyripyropenes A was elucidated via X-ray crystallography and the Kakisawa-Kashman modification of Mosher's NMR method. The biosynthetic origin of pyripyropenes A was studied by feeding experiments using various [^<13>C] and [^<14>C]precursors. ^<13>C NMR and degradation analyzes proposed that the pyridino-alpha-pyrone moiety is produced via condensation of a primer nicotinic acid with two a
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cetates, the sesquiterpene moiety is produced from three mevalonates, and then three acetly residues are introduced from acetates into the core skelton. ACAT inhibitory activity was tested in an enzyme assay using rat liver microsomes. Among them pyripyropenes C,A,L and B showed very potent inhibirtory activity with IC_<50> values of 0.15,0.16,0.27 and 0.32 muM,respectively, indicating that these pyripyropenes represent the most potent naturally occurring ACAT inhibitors reported to date. Acyloxy groups are essential at both R1 and R2 positions in the molecules for exhibiting potent ACAT inhibition.
Based on the structure-activity relationships of nataural pyripyraopenes, about 300 derivatives were prepared, achieving to find more potent inhibitors (PR-45, PR-86 and PR-109) that pyripyropene A.Futhermore, total synthesis of pyripyropenes A and E were also achieved.
In vivo efficacy of pyripyropene A and selected derivatives was demonstrated in a hamster model reducing the cholesterol absorption from intestines. Less
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