Studies on fungal pyripyropenes, potent inhibitors of cholesterol metabolism

从土壤中分离到一株烟曲霉FO-1289，该菌株能产生一系列新型的酰基辅酶A：胆固醇酰基转移酶（ACAT）抑制剂。采用溶剂萃取、硅胶柱层析、LH 20和ODS柱层析、制备HPLC等方法，从该菌发酵液中分离得到19个化合物，分别命名为三萜吡喃烯A至S，均为白色粉末或无色晶体，其结构经NMR和其它波谱学方法鉴定。它们具有由吡啶、α-吡喃酮和倍半萜部分组成的共同碳骨架。通过X射线晶体学和Mosher NMR方法的Kakisawa-Kashman修正，阐明了啶南平A的相对和绝对立体化学。通过使用不同的[^ C]和[^ C]前体的进料实验研究了啶南平A的生物合成来源<13><14>。13 <13>C NMR和降解分析表明，吡啶并-α-吡喃酮部分是通过引物烟酸与两个 关于我们 从三个甲羟戊酸酯产生倍半萜部分，然后将三个乙酸残基从乙酸酯引入到核心倍半萜中。在使用大鼠肝微粒体的酶测定中测试ACAT抑制活性。其中啶南平类化合物C、A、L和B表现出非常强的抗ACAT活性，IC值<50>分别为0.15、0.16、0.27和0.32 μ M，表明这些啶南平类化合物代表了迄今报道的最强的天然存在的ACAT抑制剂。由于R1和R2位上的酰氧基对ACAT的抑制作用是必不可少的，因此基于天然结构的吡嘧酮类化合物的构效关系，合成了约300个衍生物，为寻找更有效的ACAT抑制剂奠定了基础（PR-45、PR-86和PR-109），啶南平A.还实现了啶南平A和E的全合成。啶南平A和所选衍生物的体内功效在减少肠胆固醇吸收的仓鼠模型中得到证实。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