Controllable Cycloadditions between 2H-(Thio)pyran-2-(thi)ones and Strained Alkynes: A Click-and-Release Strategy for COS/H₂S Generation

Abstract

In this work, we carried out computational studies to predict the cycloaddition efficiency of strained alkynes with 2H-pyran-2-one and its three sulfur-containing analogues: 2H-pyran-2-thione, 2H-thiopyran-2-one, and 2H-thiopyran-2-thione. It was predicted that the decreased aromaticity of the substrate would yield higher reactivity. Experimental studies confirmed the calculation results, and 2H-pyan-2-thiones were found to be the most reactive substrates. This reaction proceeded effectively in aqueous buffers and in cellular environments. It also produced COS as the byproduct, which could be converted into hydrogen sulfide (H2S) in the presence of carbonate anhydrase. This click-and-release approach may serve as a unique way to deliver COS/H2S to specific locations.

Pyranthiones/Pyrones: “Click and Release” Donors for Subcellular Hydrogen Sulfide Delivery and Labeling**

“…It should be noted that, during the preparation of this manuscript, a similar strategy based on known pyranthione substrates for H 2 S generation in fixed cells was reported. [45] However, compared to the work we show here, that previous report explored fewer substrates, did not develop analogs with sites for further bioconjugation, and was limited to H 2 S delivery in fixed cells.…”

“…These compounds enabled us to examine the relationship between reactivity and biorthogonality and explore pyranthione as potential H 2 S/COS donors with both tunable release kinetics as well as high release efficiency in subcellular H 2 S delivery in living cells. It should be noted that, during the preparation of this manuscript, a similar strategy based on known pyranthione substrates for H 2 S generation in fixed cells was reported [45] . However, compared to the work we show here, that previous report explored fewer substrates, did not develop analogs with sites for further bioconjugation, and was limited to H 2 S delivery in fixed cells.…”

2H-Thiopyran-2-thione sulfine, a compound for converting H2S to HSOH/H2S2 and increasing intracellular sulfane sulfur levels

“…Our recent work showed that thiocarbonyl-containing heterocycles such as 2H -thiopyran-2-thiones (TT) could serve as CS 2 donors upon bio-orthogonal cycloaddition with strained alkynes 26 . Thus, these heterocycles may be appropriate substrates to use for sulfine preparation and allow us to test our hypothesis.…”

Pyranthiones/Pyrones: “Click and Release” Donors for Subcellular Hydrogen Sulfide Delivery and Labeling

“…This click and release reaction enriches the click reaction toolkits and provides a tunable and high efficiency method for subcellular H2S delivery in living cells. It should be noted that, during the preparation of this manuscript, a similar strategy [26] for H2S generation, albeit in fixed cells, was reported.…”