Development and Application of Carbonyl Sulfide-Based Donors for H₂S Delivery

Abstract

In addition to nitric oxide and carbon monoxide, hydrogen sulfide (H 2 S) has been recently recognized as an important biological signaling molecule with implications in a wide variety of processes including vasodilation, cytoprotection, and neuromodulation. In parallel to the growing number of reports highlighting the biological impact of H 2 S, interest in developing H 2 S donors as both research tools and potential therapeutics has led to the growth of different H 2 S-releasing strategies. Many H 2 S investigations in model systems use direct inhalation of H 2 S gas or aqueous solutions of NaSH or Na 2 S, however such systems do not mimic endogenous H 2 S production. This stark contrast drives the need to develop better sources of caged H 2 S to be used in biological systems. To address these limitations, different small organosulfur donor compounds have been prepared that release H 2 S in the presence of specific activators or triggers. Such compounds, however, often lack suitable H 2 S-depeleted control compounds, which limits the use of these compounds in probing the effects of H 2 S directly. To address these needs, our group has pioneered the development of carbonyl sulfide (COS) releasing compounds as a new class of H 2 S donor motifs. Inspired by a commonly-used carbamate prodrug scaffold, our approach utilizes selfimmolative thiocarbamates to access controlled release of COS, which is rapidly converted to H 2 S by the ubiquitous enzyme carbonic anhydrase (CA). In addition, this design enables access to key control compounds that release CO 2 /H 2 O rather than COS/H 2 S, which enables delineation of the effects of COS/H 2 S from the organic donor byproducts.In this Account, we highlight a library of first-generation COS/H 2 S donors based on selfimmolative thiocarbamates developed in our lab and also highlight challenges related to H 2 S donor development. We showcase the release of COS in the presence of specific triggers and activators including biological thiols and bioorthogonal reactants for targeted applications. We also demonstrate the design and development of a series of H 2 O 2 / reactive oxygen species (ROS)triggered donors and show that such compounds can be activated by endogenous levels of ROS production. Utilizing approaches in bio-orthogonal activation, we establish that donors functionalized with an o-nitrobenzyl photocage can enable access to light-activated donors.Similar to endogenous production by cysteine catabolism, we also prepared a cysteine-selective COS donor activated by a Strongin-ligation mechanism. In efforts to help delineate potential differences in the chemical biology of COS and H 2 S, we also report a simple esterase-activated *

Visible-to-NIR-Light Activated Release: From Small Molecules to Nanomaterials

“…The first H 2 S-releasing systems activatable by UV light were reported only recently. 1343 The o -nitrobenzyl caged geminal dithiol 362 ( Figure 59 ) was prepared by the TiCl 4 -catalyzed condensation of the corresponding thiol with acetone. Upon irradiation of this compound at 365 nm in the presence of water, the free gem -dithiol is released and then hydrolyzed to liberate H 2 S. 1344 The ketoprofenate-based donor 363 also releases H 2 S with simultaneous decarboxylation upon irradiation at 300–350 nm, 1345 while its xanthone analog 364 liberates H 2 S under UVA irradiation (325–385 nm).…”

H2S and reactive sulfur signaling at the host-bacterial pathogen interface

“…Last, COS-based donors have been designed with various release mechanisms and rely on an endogenous carbonic anhydrase to produce H 2 S in high catalytic yields from probe-dependent release of COS (Fig. 6A) (162). The use of these compounds, like other enzyme-activated H 2 S donors (26), obviously relies on broad cell permeability and constitutive expression of a carbonic anhydrase (163), neither of which has been systematically investigated in bacteria.…”

Use of Dithiasuccinoyl‐Caged Amines Enables COS/H2S Release Lacking Electrophilic Byproducts

“…Recently, an alternative approach to H 2 S generation has utilized the hydrolysis of carbonyl sulfide (COS) by carbonic anhydrase (CA), a ubiquitous metalloenzyme . Existing in Nature as the most abundant sulfur‐containing gas in the atmosphere, COS is rapidly converted to H 2 S and carbon dioxide (CO 2 ) in the presence of bovine carbonic anhydrase II ( k cat / K M =2.2×10 4 m −1 s −1 ) .…”