Kinetic Insights into Hydrogen Sulfide Delivery from Caged-Carbonyl Sulfide Isomeric Donor Platforms

Abstract

Hydrogen sulfide (H2S) is a biologically-important small gaseous molecule that exhibits promising protective effects against a variety of physiological and pathological processes. To investigate the expanding roles of H2S in biology, researchers often use H2S donors to mimic enzymatic H2S synthesis or to provide increased H2S levels under specific circumstances. Aligned with the need for new broad and easily-modifiable platforms for H2S donation, we report here the preparation and H2S release kinetics from a series of isomeric caged-carbonyl sulfide (COS) compounds, including thiocarbamates, thiocarbonates, and dithiocarbonates, all of which release COS that is quickly converted to H2S by the ubiquitous enzyme carbonic anhydrase. Each donor is designed to release COS/H2S after the activation of a trigger by activation by hydrogen peroxide (H2O2). In addition to providing a broad palette of new, H2O2-responsive donor motifs, we also demonstrate the H2O2 dose-dependent COS/H2S release from each donor core, establish that release profiles can be modified by structural modifications, and compare COS/H2S release rates and efficiencies from isomeric core structures. Supporting our experimental investigations, we also provide computational insights into the potential energy surfaces for COS/H2S release from each platform. In addition, we also report initial investigations into dithiocarbamate cores, which release H2S directly upon H2O2-mediated activation. As a whole, the insights on COS/H2S release gained from these investigations provide a foundation for the expansion of the emerging area of responsive COS/H2S donors systems.

The Role of Host-Generated H2S in Microbial Pathogenesis: New Perspectives on Tuberculosis

“…tested a series of arylboronate-functionalized thiocarbamate (PeroxyTCM) compounds. Upon exposure to H 2 O 2 , and to a lesser extent to superoxide and peroxynitrite, PeroxyTCM compounds release carbonyl sulfide (COS) which is quickly converted to H 2 S by ubiquitous carbonic anhydrase ( Zhao and Pluth, 2016 ; Zhao et al., 2017 ). In a similar approach, Hu and colleagues developed a ROI-triggered H 2 S donor, NAB, wherein COS release (and conversion to H 2 S by carbonic anhydrase) is accompanied by release of a strong fluorophore, allowing for real-time monitoring of H 2 S release ( Hu et al., 2019 ).…”

Self-amplified depolymerization of oligo(thiourethanes) for the release of COS/H2S

“…[32][33][34] Unfortunately, the S-alkyl thiocarbamate isomer is a less efficient COS donor than the Oalkyl isomer, likely stemming from an unfavorable Gibb's free energy (ΔG) for the COSreleasing reaction. 35 In contrast, the O-alkyl thiourethane isomer readily decomposes to form COS via the 1,6-benzyl elimination. Accordingly, synthesis of a depolymerizable Oalkyl thiourethane repeating unit would require a monomer containing both an aryl isothiocyanate (Ar-NCS) and a benzyl alcohol to facilitate efficient COS release.…”

Clopidogrel as a donor probe and thioenol derivatives as flexible promoieties for enabling H2S biomedicine

“…Although many synthetic donors have been reported, most of them undergo spontaneous hydrolysis to release H 2 S in an uncontrollable manner, which compromises their therapeutic potentials. In recent years, H 2 S promoieties such as acylated N–S 18 – 20 and S–S derivatives 21 , 22 , caged-carbonyl sulfides 23 – 28 , and iminothioethers 29 , 30 have been reported, and they require more specific bioactivation, e.g., thiol attack, for the H 2 S release. However, the chemical complexity of these precursors limits their versatility in assembly with different vehicle molecules.…”