Abstract:
Carbon disulfide (CS2) is an environmental contaminant, which is deadly hazardous to the workers under chronic or acute exposure. However, the toxicity mechanisms of CS2 are still unclear due to the scarcity of biocompatible donors, which can release CS2 in cells. Here we developed the first bioorthogonal CS2 delivery system based on the \"click-and-release\" reactions between mesoionic 1,3-thiazolium-5-thiolates (TATs) and strained cyclooctyne exo-BCN-OH. We successfully realized intracellular CS2 release and investigated the causes of CS2-induced hepatotoxicity, including oxidative stress, proteotoxic stress and copper-dependent cell death. It is found that CS2 can be copper vehicles bypassing copper transporters after reacting with nucleophiles in cytoplasm, and extra copper supplementation will exacerbate the loss of homeostasis of cells and ultimately cell death. These findings inspired us to explore the anticancer activity of CS2 in combination with copper by introducing a copper chelating group in our CS2 delivery system.
摘要:
二硫化碳(CS2)是一种环境污染物,这对长期或急性暴露的工人来说是致命的危险。然而,CS2的毒性机制尚不清楚,由于生物相容性供体的稀缺性,它可以在细胞中释放CS2。在这里,我们基于中离子1,3-噻唑5-硫醇盐(TAT)和应变环辛炔外切BCN-OH之间的“点击和释放”反应,开发了第一个生物正交CS2递送系统。我们成功地实现了细胞内CS2的释放,并研究了CS2诱导的肝毒性的原因,包括氧化应激,蛋白毒性应激和铜依赖性细胞死亡。发现CS2与细胞质中的亲核试剂反应后,可以成为绕过铜转运蛋白的铜载体,和额外的铜补充将加剧细胞内稳态的丧失和最终细胞死亡。这些发现启发我们通过在我们的CS2递送系统中引入铜螯合基团来探索CS2与铜结合的抗癌活性。