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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Synthesis, cellular evaluation, and mechanism of action of piperlongumine analogs
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Synthesis, cellular evaluation, and mechanism of action of piperlongumine analogs

机译：哌隆明类似物的合成，细胞评价及作用机理

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摘要

Piperlongumine is a naturally occurring small molecule recently identified to be toxic selectively to cancer cells in vitro and in vivo. This compound was found to elevate cellular levels of reactive oxygen species (ROS) selectively in cancer cell lines. The synthesis of 80 piperlongumine analogs has revealed structural modifications that retain, enhance, and ablate key piperlongumine-associated effects on cells, including elevation of ROS, cancer cell death, and selectivity for cancer cells over nontransformed cell types. Structure/activity relationships suggest that the electrophilicity of the C2-C3 olefin is critical for the observed effects on cells. Furthermore, we show that analogs lacking a reactive C7-C8 olefin can elevate ROS to levels observed with piperlongumine but show markedly reduced cell death, suggesting that ROS-independent mechanisms, including cellular cross-linking events, may also con-tribute to piperlongumine's induction of apoptosis. In particular, we have identified irreversible protein glutathionylation as a process associated with cellular toxicity. We propose a mechanism of action for piperlongumine that may be relevant to other small molecules having two sites of reactivity, one with greater and the other with lesser electrophilicity.
机译：哌隆定是一种天然存在的小分子，最近被鉴定为在体外和体内对癌细胞有选择性的毒性。发现该化合物可选择性提高癌细胞系中活性氧物质（ROS）的细胞水平。合成了80种哌隆基类似物，揭示了保留，增强和消除与哌隆基相关的细胞关键作用的结构修饰，包括ROS升高，癌细胞死亡以及癌细胞对非转化细胞类型的选择性。结构/活性关系表明，C2-C3烯烃的亲电性对于观察到的对细胞的影响至关重要。此外，我们发现缺乏反应性C7-C8烯烃的类似物可将ROS升高至哌隆定所观察到的水平，但显示出明显的细胞死亡减少，这表明ROS依赖性机制（包括细胞交联事件）也可能有助于哌隆定的诱导凋亡。特别是，我们已经确定不可逆的蛋白质谷胱甘肽酰化是与细胞毒性有关的过程。我们提出了哌隆胺的作用机制，该作用机制可能与具有两个反应位点的另一个小分子有关，一个具有较大的亲电性，另一个具有较小的亲电性。

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    Drew J. Adams; Mingji Dai; Giovanni Pellegrino; Bridget K. Wagner; Andrew M. Stern; Alykhan F. Shamji; Stuart L. Schreiber;

  • 作者单位

    Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142,Howard Hughes Medical Institute, 7 Cambridge Center, Cambridge, MA 02142;

    Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142,Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138;

    Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142;

    Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142;

    Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142;

    Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142;

    Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142,Howard Hughes Medical Institute, 7 Cambridge Center, Cambridge, MA 02142,Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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