Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA.
Proc Natl Acad Sci U S A. 2012 Sep 18;109(38):15115-20. doi: 10.1073/pnas.1212802109. Epub 2012 Sep 4.
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.
胡椒碱是一种天然存在的小分子，最近被发现能够在体外和体内选择性地杀伤癌细胞。该化合物被发现能够选择性地在癌细胞系中升高细胞内活性氧（ROS）的水平。对 80 种胡椒碱类似物的合成揭示了结构修饰，这些修饰保留、增强和消除了与胡椒碱相关的对细胞的关键作用，包括升高 ROS、癌细胞死亡以及对癌细胞的选择性，而非转化细胞类型。结构/活性关系表明，C2-C3 双键的亲电性对于观察到的细胞效应至关重要。此外，我们还表明，缺乏反应性 C7-C8 双键的类似物可以将 ROS 升高到与胡椒碱观察到的水平，但细胞死亡明显减少，这表明 ROS 不依赖的机制，包括细胞交联事件，也可能有助于胡椒碱诱导细胞凋亡。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。我们提出了胡椒碱的作用机制，该机制可能与具有两个反应部位的其他小分子有关，一个部位具有更高的亲电性，另一个部位具有较低的亲电性。
