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 contribute 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.

中文翻译：

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Piperlongumine 类似物的合成、细胞评价和作用机制。


Piperlongumine 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具有选择性毒性。人们发现这种化合物可以选择性地提高癌细胞系中活性氧 (ROS) 的水平。 80 种胡椒长明类似物的合成揭示了结构修饰，这些结构修饰保留、增强和消除了胡椒长明对细胞的关键相关作用，包括 ROS 升高、癌细胞死亡以及癌细胞相对于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 烯烃的类似物可以将 ROS 提高到用胡椒长明观察到的水平，但细胞死亡显着减少，这表明 ROS 独立机制，包括细胞交联事件，也可能有助于胡椒长明诱导细胞凋亡。特别是，我们已经确定不可逆的蛋白质谷胱甘肽化是与细胞毒性相关的过程。我们提出了胡椒长明的一种作用机制，该机制可能与具有两个反应位点的其他小分子有关，一个具有较大的亲电性，另一个具有较小的亲电性。