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Similar to hydrogen sulfide (H 2 S), its chalcogen congener, Hydrogen selenide (H 2 Se), is an emerging molecule of interest given its endogenous expression and purported biological activity. However, unlike H 2 S, detailed investigations into the chemical biology of H 2 Se are limited and little is known about its innate physiological functions, cellular targets, and therapeutic potential. The obscurity surrounding these fundamental questions is largely due to a lack of small molecule donors that can effectively increase the bioavailability of H 2 Se through their continuous liberation of the transient biomolecule under physiologically relevant conditions. Driven by this unmet demand for H 2 Se-releasing moieties, we report that γ-keto selenides provide a useful platform for H 2 Se donation via an α-deprotonation/β-elimination pathway that is highly dependent on both pH and alpha proton acidity. These attributes afforded a small library of donors with highly variable rates of release (higher alpha proton acidity = faster selenide liberation), which is accelerated under neutral to slightly basic conditions—a feature that is unique and complimentary to previously reported H 2 Se donors. We also demonstrate the impressive anticancer activity of γ-keto selenides in both HeLa and HCT116 cells in culture, which is likely to stimulate additional interest and research into the biological activity and anticancer effects of H 2 Se. Collectively, these results indicate that γ-keto selenides provide a highly versatile and effective framework for H 2 Se donation.
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Development of a hydrolysis-based small-molecule hydrogen selenide (H 2 Se) donor
Selenium is essential to human physiology and has recently shown potential in the treatment of common pathophysiological conditions ranging from arsenic poisoning to cancer. Although the precise metabolic and chemical pathways of selenium incorporation into biomolecules remain somewhat unclear, many such pathways proceed through hydrogen selenide (H 2 Se/HSe − ) formation. Despite this importance, well-characterized chemistry that enables H 2 Se release under controlled conditions remains lacking. Motivated by this need, we report here the development of a hydrolysis-based H 2 Se donor (TDN1042). Utilizing 31 P and 77 Se NMR experiments, we demonstrate the pH dependence of H 2 Se release and characterize observed reaction intermediates during the hydrolysis mechanism. Finally, we confirm H 2 Se release using electrophilic trapping reagents, which not only demonstrates the fidelity of this donor platform but also provides an efficient method for investigating future H 2 Se donor motifs. Taken together, this work provides an early example of an H 2 Se donor that functions through a well-defined and characterized mechanism.
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- Award ID(s):
- 1625529
- PAR ID:
- 10309012
- Date Published:
- Journal Name:
- Chemical Science
- Volume:
- 10
- Issue:
- 46
- ISSN:
- 2041-6520
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1039/c9sc04616j
