Kibdelone C 及其简化衍生物的合成与生物评价。
Synthesis and Biological Evaluation of Kibdelone C and Its Simplified Derivatives.
机构信息
Department of Biochemistry and ‡Department of Internal Medicine, UT Southwestern Medical Center , 5323 Harry Hines Boulevard, Dallas, Texas 75390-9038, United States.
出版信息
J Am Chem Soc. 2016 Aug 24;138(33):10561-70. doi: 10.1021/jacs.6b05484. Epub 2016 Aug 9.
Abstract
Poylcyclic tetrahydroxanthones comprise a large class of cytototoxic natural products. No mechanism of action has been described for any member of the family. We report the synthesis of kibdelone C and several simplified analogs. Both enantiomers of kibdeleone C show low nanomolar cytotoxicity toward multiple human cancer cell lines. Moreover, several simplified derivatives with improved chemical stability display higher activity than the natural product itself. In vitro studies rule out interaction with DNA or inhibition of topoisomerase, both of which are common modes of action for polycyclic aromatic compounds. However, celluar studies reveal that kibdelone C and its simplified derivatives disrupt the actin cytoseketon without directly binding actin or affecting its polymerization in vitro.
摘要
多环四氢黄酮类化合物是一类具有细胞毒性的天然产物，目前尚未有针对该家族任何成员的作用机制的描述。我们报告了 kibdelone C 及其几种简化类似物的合成。kibdeleone C 的两种对映异构体对多种人类癌细胞系均表现出低纳摩尔级别的细胞毒性。此外，几种简化衍生物具有更好的化学稳定性，其活性高于天然产物本身。体外研究排除了与 DNA 的相互作用或拓扑异构酶的抑制，这两种作用模式都是常见的多环芳烃化合物。然而，细胞研究表明，kibdelone C 及其简化衍生物破坏了肌动蛋白细胞骨架，而不是直接结合肌动蛋白或影响其在体外的聚合。
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