Ma Kaiqing, Yang He, Shen Tianruo, Yue Yongkang, Zhao Lingling, Liu Xiaogang, Huo Fangjun, Yin Caixia
Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Institute of Molecular Science, Shanxi University Taiyuan 030006 PR China
University of Technology and Design 487372 Singapore.
Chem Sci. 2022 Mar 2;13(13):3706-3712. doi: 10.1039/d2sc00328g. eCollection 2022 Mar 30.
To reveal the delicate function of mitochondria, spatiotemporally precise detection tools remain highly desirable. However, current probes with positively charged warheads for targeting mitochondria diffuse out of the mitochondria as the potential of the mitochondrial membrane changes, which directly influences the accuracy of the detection. Herein, we assembled carbonylpyridinium and chromene to afford the probe CM-Mit. Following the ultrafast response to thiol and the dissociation of carbonylpyridinium, the formation of -quinone methide from CM-Mit was proposed to label proteins, thus avoiding diffusion out of the mitochondria. Therefore, the accurate spatiotemporal detection of thiol in mitochondria was realized. With this excellent probe, ferroptosis inducers were proved to stimulate thiol starvation in mitochondria for the first time in cancer cells. Moreover, CM-Mit was used to screen a compound library developed in-house and the stemona alkaloid analog SA-11 was shown to induce ferroptosis in various cancer cell lines, including a drug-resistant one.
为了揭示线粒体的精细功能，仍然非常需要时空精确的检测工具。然而，目前用于靶向线粒体的带正电荷弹头的探针会随着线粒体膜电位的变化而扩散出线粒体，这直接影响检测的准确性。在此，我们将羰基吡啶鎓和色烯组装得到探针CM-Mit。在对硫醇的超快响应和羰基吡啶鎓解离之后，有人提出CM-Mit形成的醌甲基化物可标记蛋白质，从而避免扩散出线粒体。因此，实现了对线粒体中硫醇的准确时空检测。借助这种出色的探针，首次证明铁死亡诱导剂会刺激癌细胞线粒体中的硫醇饥饿。此外，CM-Mit被用于筛选内部开发的化合物库，并且显示百部生物碱类似物SA-11可在包括耐药细胞系在内的各种癌细胞系中诱导铁死亡。
