Department of Chemistry and Biochemistry, Materials Science Institute, Institute of Molecular Biology , University of Oregon , Eugene , Oregon 97403 , United States.
ACS Chem Biol. 2019 Feb 15;14(2):170-175. doi: 10.1021/acschembio.8b00981. Epub 2019 Jan 17.
Hydrogen sulfide (HS) is an important gasotransmitter and biomolecule, and many synthetic small-molecule HS donors have been developed for HS-related research. One important class of triggerable HS donors is self-immolative thiocarbamates, which function by releasing carbonyl sulfide (COS), which is rapidly converted to HS by the ubiquitous enzyme carbonic anhydrase (CA). Prior studies of esterase-triggered thiocarbamate donors reported significant inhibition of mitochondrial bioenergetics and toxicity when compared to direct sulfide donors, suggesting that COS may function differently than HS. Here, we report a suite of modular esterase-triggered self-immolative COS donors and include the synthesis, HS release profiles, and cytotoxicity of the developed donors. We demonstrate that the rate of ester hydrolysis correlates directly with the observed cytotoxicity in cell culture, which further supports the hypothesis that COS functions as more than a simple HS shuttle in certain biological systems.
硫化氢（HS）是一种重要的气体递质和生物分子，许多合成的小分子 HS 供体已被开发用于 HS 相关研究。一类重要的可触发 HS 供体是自毁性硫代氨基甲酸酯，其通过释放羰基硫（COS）起作用，COS 被普遍存在的酶碳酸酐酶（CA）迅速转化为 HS。与直接的硫化物供体相比，先前关于酯酶触发的硫代氨基甲酸酯供体的研究报告显示，线粒体生物能学和毒性受到显著抑制，这表明 COS 的作用可能与 HS 不同。在这里，我们报告了一系列模块化的酯酶触发的自毁性 COS 供体，并包括所开发供体的 HS 释放曲线和细胞毒性。我们证明，酯水解的速率与细胞培养中观察到的细胞毒性直接相关，这进一步支持了 COS 在某些生物系统中不仅仅是简单 HS 穿梭物的假说。
