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Development of Acid-Mediated H2S/COS Donors That Respond to a Specific pH Window.

ABSTRACT: Hydrogen sulfide (H2S) is a biologically relevant molecule, and recent efforts have focused on developing small molecular donors that deliver H2S 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 H2S 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 H2S 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/H2S 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/H2S donor motifs, which we anticipate that will have utility in investigating H2S in acidic microenvironments.

SUBMITTER: Gilbert AK

PROVIDER: S-EPMC7024054 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Development of Acid-Mediated H2S/COS Donors That Respond to a Specific pH Window.

Gilbert Annie K AK Zhao Yu Y Otteson Claire E CE Pluth Michael D MD

The Journal of organic chemistry 20190918 22

Hydrogen sulfide (H2S) is a biologically relevant molecule, and recent efforts have focused on developing small molecular donors that deliver H2S 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 H2S delivery to a specific pH window. Specifically, we utilize self-immolative thiocarbamat ...[more]

PMID: 31479268

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Project description:Over the last decade, hydrogen sulfide (H2S) has emerged as an important endogenous gasotransmitter in mammalian cells and tissues. Similar to the previously characterized gasotransmitters nitric oxide and carbon monoxide, H2S is produced by various enzymatic reactions and regulates a host of physiologic and pathophysiological processes in various cells and tissues. H2S levels are decreased in a number of conditions (e.g., diabetes mellitus, ischemia, and aging) and are increased in other states (e.g., inflammation, critical illness, and cancer). Over the last decades, multiple approaches have been identified for the therapeutic exploitation of H2S, either based on H2S donation or inhibition of H2S biosynthesis. H2S donation can be achieved through the inhalation of H2S gas and/or the parenteral or enteral administration of so-called fast-releasing H2S donors (salts of H2S such as NaHS and Na2S) or slow-releasing H2S donors (GYY4137 being the prototypical compound used in hundreds of studies in vitro and in vivo). Recent work also identifies various donors with regulated H2S release profiles, including oxidant-triggered donors, pH-dependent donors, esterase-activated donors, and organelle-targeted (e.g., mitochondrial) compounds. There are also approaches where existing, clinically approved drugs of various classes (e.g., nonsteroidal anti-inflammatories) are coupled with H2S-donating groups (the most advanced compound in clinical trials is ATB-346, an H2S-donating derivative of the non-steroidal anti-inflammatory compound naproxen). For pharmacological inhibition of H2S synthesis, there are now several small molecule compounds targeting each of the three H2S-producing enzymes cystathionine-?-synthase (CBS), cystathionine-?-lyase, and 3-mercaptopyruvate sulfurtransferase. Although many of these compounds have their limitations (potency, selectivity), these molecules, especially in combination with genetic approaches, can be instrumental for the delineation of the biologic processes involving endogenous H2S production. Moreover, some of these compounds (e.g., cell-permeable prodrugs of the CBS inhibitor aminooxyacetate, or benserazide, a potentially repurposable CBS inhibitor) may serve as starting points for future clinical translation. The present article overviews the currently known H2S donors and H2S biosynthesis inhibitors, delineates their mode of action, and offers examples for their biologic effects and potential therapeutic utility.

Dataset Information

Development of Acid-Mediated H2S/COS Donors That Respond to a Specific pH Window.

Publications

Development of Acid-Mediated H<sub>2</sub>S/COS Donors That Respond to a Specific pH Window.

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