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首页> 外文期刊>Chemistry: A European journal >Total Synthesis and Biological Evaluation of Amphidinolide V and Analogues
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Total Synthesis and Biological Evaluation of Amphidinolide V and Analogues

机译：安非他命V及其类似物的全合成及生物学评价

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摘要

A sequence of ring-closing alkyne metathesis followed by an intermolecular enyne metathesis of the resulting cycloalkyne with ethene was used to forge the macrocyclic skeleton and to set the vicinal exo-methylene branches characteristic for the cytotoxic marine natural product amphidinolide V (1). Comparison of the synthetic material with all authentic sample of this extremely scarce metabolite isolated from a dinoflagellate of the Amphidinium sp. eliminated any, doubts about its structure and allowed the absolute configuration of amphidinolide V to be determined as 8R,9S,10S,13R. Moreover, the flexibility inherent to the underlying Synthesis blueprint also opened access to a comprehensive set of diastereomers of I as well as to synthetic analogues differing from the natural lead in the lipophilic chains appended to the macrocyclic core. This set of designed analogues gave first insights into structure-activity relationships, which revealed that the stereo-structure Of the macrolactone is a highly critical parameter, whereas the examined alterations of the side chain did not diminish the cytotoxicity, of the compounds to any notable extent.
机译：一系列闭环炔烃复分解反应，然后将所得的环炔烃与乙烯进行分子间烯烃复分解反应，以锻造大环骨架并设置具有细胞毒性海洋天然产物两性霉素V（1）的邻位外亚甲基支链。合成材料与该真实稀有代谢物的所有真实样品的比较，该代谢物是从Amphidinium sp。的鞭毛虫中分离得到的。消除了对其结构的任何疑问，并允许将安非他命内酯V的绝对构型确定为8R，9S，10S，13R。此外，基础合成蓝图固有的灵活性也使人们能够获得一整套I的非对映异构体以及不同于与大环核心相连的亲脂性链中的天然铅的合成类似物。这组设计的类似物提供了对结构-活性关系的初步了解，这揭示了大内酯的立体结构是一个非常关键的参数，而所研究的侧链变化并没有降低化合物的细胞毒性，对任何显着影响程度。

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