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Dithiasuccinoyl-Caged Amines Enables COS/H2S Release Lacking Electrophilic Byproducts

preprint
submitted on 11.12.2019 and posted on 18.12.2019 by Matthew M. Cerda, Jenna L. Mancuso, Emma J. Mullen, Christopher H. Hendon, Michael Pluth

The enzymatic conversion of carbonyl sulfide (COS) to hydrogen sulfide (H2S) by carbonic anhydrase has been used to develop self-immolating thiocarbamates as COS-based H2S donors to further elucidate the impact of reactive sulfur species in biology. The high modularity of this approach has provided a library of COS-based H2S donors that can be activated by specific stimuli. A common limitation, however, is that many such donors result in the intermediate formation of an electrophilic quinone methide byproduct during donor activation. As a mild alternative, we demonstrate here that dithiasuccinoyl groups can function as COS/H2S donor motifs and that these groups release two equivalents of COS/H2S and uncage an amine payload under physiologically relevant conditions. Additionally, we demonstrate that COS/H2S release from this donor motif can be altered by electronic modulation and alkyl substitution. These insights are further supported by DFT investigations, which reveal that aryl and alkyl thiocarbamates release COS with significantly different activation energies.

Funding

Chemical Tools for Delivery and Detection of Biological Hydrogen Sulfide

National Institute of General Medical Sciences

Find out more...

CHE-1427987

CHE-1625529

ACI-1548562

History

Email Address of Submitting Author

pluth@uoregon.edu

Institution

University of Oregon

Country

United States

ORCID For Submitting Author

0000-0003-3604-653X

Declaration of Conflict of Interest

No conflict of interest

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in Chemistry – A European Journal

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