Bioorthogonal Delivery of Carbon Disulfide in Living Cells.

Carbon disulfide (CS 2 ) is an environmental contaminant, which is deadly hazardous to the workers under chronic or acute exposure. However, the toxicity mechanisms of CS 2 are still unclear due to the scarcity of biocompatible donors, which can release CS 2 in cells. Here we developed the first bioorthogonal CS 2 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 CS 2 release and investigated the causes of CS 2 -induced hepatotoxicity, including oxidative stress, proteotoxic stress and copper-dependent cell death. It is found that CS 2 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 CS 2 in combination with copper by introducing a copper chelating group in our CS 2 delivery system.