Isolation and structure elucidation of parnafungins, antifungal natural products that inhibit mRNA polyadenylation
Isolation and structure elucidation of parnafungins, antifungal natural products that inhibit mRNA polyadenylation
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DOI：
10.1021/ja711209p
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发表时间：
2008-06-04
影响因子：
15
通讯作者：
Harris, Guy
中科院分区：
文献类型：
--
作者：
Parish, Craig A.;Smith, Scott K.;Harris, Guy
白色念珠菌适应性测试是一种全细胞筛选平台，用于分析具有有趣作用机制的新型抗真菌天然产物的粗发酵提取物。具有内在抗真菌活性的提取物从真菌镰刀菌幼虫显示健身测试配置文件，强烈暗示mRNA加工作为负责抑制真菌生长的分子靶标。从该样品中分离出的活性成分鉴定出一类新的含异恶唑烷酮的天然产物，我们将其命名为parnafungins。这些天然产物被分离为四种结构和立体异构体的互变混合物。parnafungins的异构化是由于逆迈克尔开环和随后的改造的氧杂蒽酮环系统。这种相互转化被阻断的烯醇部分的甲基化。通过X射线晶体学和NMR分析完成纯化的帕那芬净衍生物的结构解析。这些天然产物的生化靶标已被确定为真菌聚腺苷聚合酶。Parnafungins表现出广谱抗真菌活性，对革兰氏阳性或革兰氏阴性细菌没有观察到活性。抗真菌活性需要完整的异恶唑烷酮环。此外，天然产物在播散性念珠菌病小鼠模型中有效。
The Candida albicans Fitness Test, a whole-cell screening platform, was used to profile crude fermentation extracts for novel antifungal natural products with interesting mechanisms of action. An extract with intrinsic antifungal activity from the fungus Fusarium larvarum displayed a Fitness Test profile that strongly implicated mRNA processing as the molecular target responsible for inhibition of fungal growth. Isolation of the active components from this sample identified a novel class of isoxazolidinone-containing natural products, which we have named parnafungins. These natural products were isolated as an interconverting mixture of four structural- and stereoisomers. The isomerization of the parnafungins was due to a retro-Michael ring-opening and subsequent reformation of a xanthone ring system. This interconversion was blocked by methylation of an enol moiety. Structure elucidation of purified parnafungin derivatives was accomplished by X-ray crystallography and NMR analysis. The biochemical target of these natural products has been identified as the fungal polyadenosine polymerase. Parnafungins demonstrated broad spectrum antifungal activity with no observed activity against Gram-positive or Gram-negative bacteria. The intact isoxazolidinone ring was required for antifungal activity. In addition, the natural products were efficacious in a mouse model of disseminated candidiasis.