Open AccessDevelopment of Acid-Mediated H2S/COS Donors That Respond to a Specific pH Window
Author(s) -
Annie K. Gilbert,
Yu Zhao,
Claire E. Otteson,
Michael D. Pluth
Publication year - 2019
Publication title -
journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.2
H-Index - 228
eISSN - 1520-6904
pISSN - 0022-3263
DOI - 10.1021/acs.joc.9b01873
Subject(s) - chemistry , imine , hydrogen sulfide , hydrolysis , aniline , carbonic anhydrase , protonation , combinatorial chemistry , carbonyl sulfide , thiocarbamates , small molecule , sulfide , organic chemistry , enzyme , biochemistry , catalysis , sulfur , ion
Hydrogen sulfide (H 2 S) is a biologically relevant molecule, and recent efforts have focused on developing small molecular donors that deliver H 2 S on demand. Acid-activated donors have garnered significant interest due to the potential application of such systems in myocardial ischemia injury or for suppressing tumor growth. In this work, we report a new strategy for tuning H 2 S delivery to a specific pH window. Specifically, we utilize self-immolative thiocarbamates with an imine-derived triggering group. After imine hydrolysis, the self-immolative decomposition releases carbonyl sulfide (COS), which is quickly hydrolyzed to H 2 S by carbonic anhydrase. Although acid-mediated hydrolysis results in imine cleavage, environments that are too acidic result in protonation of the aniline intermediate and results in inhibition of COS/H 2 S release. Taken together, this mechanism enables access to donor motifs that are only activated within specific pH windows. Here, we demonstrate the design, preparation, and pH evaluation of a series of imine-based COS/H 2 S donor motifs, which we anticipate that will have utility in investigating H 2 S in acidic microenvironments.