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Use of Dithiasuccinoyl‐Caged Amines Enables COS/H 2 S Release Lacking Electrophilic Byproducts
Author(s) -
Cerda Matthew M.,
Mancuso Jenna L.,
Mullen Emma J.,
Hendon Christopher H.,
Pluth Michael D.
Publication year - 2020
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201905577
Subject(s) - thiocarbamates , chemistry , electrophile , alkyl , amine gas treating , aryl , hydrogen sulfide , carbonyl sulfide , medicinal chemistry , combinatorial chemistry , carbonic anhydrase , stereochemistry , sulfur , enzyme , organic chemistry , catalysis
The enzymatic conversion of carbonyl sulfide (COS) to hydrogen sulfide (H 2 S) by carbonic anhydrase has been used to develop self‐immolating thiocarbamates as COS‐based H 2 S 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 H 2 S donors that can be activated by specific stimuli. A common limitation, however, is that many such donors result in the formation of an electrophilic quinone methide byproduct during donor activation. As a mild alternative, we demonstrate here that dithiasuccinoyl groups can function as COS/H 2 S donor motifs, and that these groups release two equivalents of COS/H 2 S and uncage an amine payload under physiologically relevant conditions. Additionally, we demonstrate that COS/H 2 S 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.