Hydrogen Sulfide (H₂S)-Donor Molecules: Chemical, Biological, and Therapeutical Tools

This Special Issue aims to gather new research on hydrogen sulfide (H₂S)-releasing compounds (Figure 1) as cutting-edge pharmacological tools and to advance the understanding of the critical role that H₂S plays in physiological and pathological processes.

Over the past two decades, H₂S has emerged as the third recognized endogenous gasotransmitter [1,2] with several positive effects in different physiological and pathophysiological processes, such as inflammation, hypertension, oxidation, metabolic disorders, neuromodulation, and tumor progression [3,4,5].

Among the natural sources of H₂S, there are polysulfides, which include garlic-derived compounds, and isothiocyanates, derived from vegetables belonging to the Brassicaceae family [6,7].

In addition to plants from the Alliaceae and Brassicaceae families, Citi and colleagues (contribution 1) performed a qualitative and quantitative analysis of the organosulfur compounds contained in mushroom extracts using an amperometric approach. Their studies confirmed the H₂S-releasing capabilities of fungus extracts.

Moreover, the authors reported the pharmacological effects of natural H₂S-donating compounds, including antioxidant properties, anti-inflammatory effects, regulation of the immune system, cardioprotection, and systemic metabolism’s regulation.

Interestingly, it has been demonstrated that natural isothiocyanates, including sulforaphane and erucin, significantly prevent and reduce the onset and spread of cancer [8]. In particular, several studies have proven the anti-tumor action of erucin (4-(methylthio)butyl isothiocyanate) [9].

Brancaleone et al., 2023 (contribution 2), investigate the anti-cancer properties of erucin in an in vitro model of triple-negative breast cancer. Erucin was found to significantly inhibit MDA-MB-231 cell proliferation by inducing apoptosis and autophagy in a concentration-dependent manner. Furthermore, the authors proved that erucin reduced intracellular ROS generation, boosting the activation of critical antioxidant genes and stopping MDA-MB-231 cell movement, invasion, and colony formation.

Moreover, to further define the physio-pathological functions of H₂S, synthetic H₂S-donating compounds have been developed.

In this regard, 4-methoxy-phenyl(morpholino)phosphinodithioate morpholinium salt, named GYY4137, is the earliest synthesized and characterized H₂S donor molecule [10]. Due to its capability to gradually release H₂S, it is the most widely studied H₂S donor to elucidate the involvement of H₂S signaling pathway in specific physio-pathological conditions [11,12,13,14].

More recently, Berenyiova and colleagues (contribution 3), through the intraperitoneal application of GYY-4137, investigated the involvement of NO and H₂S pathways in fructose-fed spontaneously hypertensive rats with metabolic disorders. They found that the slow H₂S-releasing donor activated the endogenous sulfide pathway in the thoracic aorta, with a consequent positive pro-relaxant and anti-contractile effect.

Ishkaeva et al., 2023 (contribution 4), develop novel synthetic H₂S donating molecules. These compounds are derived from the combination of glutathione with different H₂S donors, dithiophosphates.

The kinetics of H₂S generation from the new compounds indicated that the donors were continuously releasing H₂S, with the dithiophosphate of reduced glutathione releasing more H₂S than oxidized glutathione. The compounds that effectively increased intracellular H₂S prevented C2C12 myoblasts from proliferating at submillimolar doses, in contrast to NaHS. Overall, these studies revealed glutathione dithiophosphates as redox-modulating H₂S donors with a long-acting profile.

As well as being used as pharmacological tools for further studies on the functions of H₂S in the body, some of the H₂S-releasing moieties have been largely combined with different drugs already used in the clinic to obtain novel multi-target molecular hybrids [15].

In the study by Sparaco et al., 2022 (contribution 5), new molecular hybrids between antiglaucoma drugs, such as brinzolamide, betaxolol, and brimonidine, and H₂S donors were designed and synthesized.

All new compounds were proven to release H₂S both in aqueous solutions and in the intracellular environment of human primary corneal epithelial cells. Moreover, their findings indicated two brinzolamide derivatives and one brimonidine H₂S donor as the best hybrids, characterized by a significant and long-lasting production of the gasotransmitter. Their findings allow for more intensive glaucoma therapy to be provided.