Studies on fungal pyripyropenes, potent inhibitors of cholesterol metabolism

从土壤分离的烟曲霉FO-1289中发现一系列新的酰基辅酶A抑制剂：胆固醇酰基转移酶（ACAT）。通过溶剂萃取、硅胶柱色谱、液相色谱、ODS柱色谱和制备高效液相色谱等方法，从发酵液中分离得到19个化合物，命名为pyraipyraopenes A ~ S，分别为白色粉末或无色结晶。结构为e；经核磁共振和其他光谱研究证实。它们有一个共同的碳骨架，由吡啶、α -吡酮和倍半萜组成。通过x射线晶体学和Mosher核磁共振法的kakisaawa - kashman修饰，研究了pyripypypenes A的相对立体化学和绝对立体化学。采用各种[^<13>C]和[^<14>C]前体进行了投料实验，研究了pyripypypenes A的生物合成来源。^ < 13 > C NMR和退化分析提出pyridino-alpha-pyrone一半是通过冷凝产生的底漆烟酸有两个 ... cetates越多,倍半萜烯一半是由三个甲羟戊酸,然后介绍了三乙酰残留乙酸盐为核心的斯凯尔顿。用大鼠肝微粒体进行酶法测定ACAT抑制活性。其中，pyripypypenes C、A、L和B的IC_<50>分别为0.15、0.16、0.27和0.32 muM，显示出非常强的抑制活性，表明这些pyripypenes是迄今报道的最有效的天然ACAT抑制剂。羧基在R1和R2位置都是分子表现出有效的ACAT抑制所必需的。根据天然芘的构效关系，制备了约300个衍生物，找到了比芘A更有效的抑制剂（PR-45、PR-86和PR-109），并实现了芘A和E的全合成。在仓鼠模型中证实了吡咯烯A及其衍生物降低肠道胆固醇吸收的体内功效。少

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 … More 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