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

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (30 May 2023) | Viewed by 8968

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Prof. Dr. Giuseppe Caliendo

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Department of Pharmacy, School of Medicine, University of Naples Federico II, Via D. Montesano 49, 80131 Napoli, Italy
Interests: drug discovery; medicinal chemistry; green chemistry; small molecules; peptides; peptidomimetics; heterocyclic compounds

Dr. Angela Corvino

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Guest Editor

Department of Pharmacy, School of Medicine, University of Naples Federico II, Via D. Montesano 49, 80131 Napoli, Italy
Interests: medicinal chemistry; drug design; synthesis; small-molecules; peptides; peptido-mimetics

Special Issue Information

Dear Colleagues,

Hydrogen sulfide (H₂S) has been recognized as the third endogenous pleiotropic gasotransmitter, along with nitric oxide and carbon monoxide, playing a significant role in many biological processes. Since endogenous concentrations of this gaseous signaling molecule are generally low, to better define its physio–pathological functions, exogenous sources of H₂S are needed. On this basis, the challenge for many research groups is the development of H₂S-donor molecules that are able to release H₂S in a tightly controlled way, mimicking the physiological production of this gas. Thus, the identification of novel chemical tools could be useful to further investigate the involvement of H₂S both in health and disease states.

The aim of this Special Issue is to collect novel research regarding H₂S-releasing compounds as innovative pharmacological tools and to provide further evidence of the crucial role of H₂S in physiological and pathological processes.

Prof. Dr. Giuseppe Caliendo
Dr. Angela Corvino
Guest Editors

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Keywords

hydrogen sulfide (H2S)
H2S-donors
hybrids
pharmacological tools
cell signaling

Published Papers (5 papers)

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Research

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15 pages, 3415 KiB

Open AccessArticle

Characterization of Glutathione Dithiophosphates as Long-Acting H₂S Donors

by Rezeda A. Ishkaeva, Nail N. Khaertdinov, Aleksey V. Yakovlev, Marina V. Esmeteva, Diana V. Salakhieva, Ilyas S. Nizamov, Guzel F. Sitdikova and Timur I. Abdullin

Int. J. Mol. Sci. 2023, 24(13), 11063; https://doi.org/10.3390/ijms241311063 - 4 Jul 2023

Viewed by 1403

Abstract

Considering the important cytoprotective and signaling roles but relatively narrow therapeutic index of hydrogen sulfide (H₂S), advanced H₂S donors are required to achieve a therapeutic effect. In this study, we proposed glutathione dithiophosphates as new combination donors of H₂S and glutathione. The kinetics of H₂S formation in dithiophosphate solutions suggested a continuous H₂S release by the donors, which was higher for the dithiophosphate of reduced glutathione than oxidized glutathione. The compounds, unlike NaHS, inhibited the proliferation of C2C12 myoblasts at submillimolar concentrations due to an efficient increase in intracellular H₂S. The H₂S donors more profoundly affected reactive oxygen species and reduced glutathione levels in C2C12 myocytes, in which these parameters were elevated compared to myoblasts. Oxidized glutathione dithiophosphate as well as control donors exerted antioxidant action toward myocytes, whereas the effect of reduced glutathione dithiophosphate at (sub-)micromolar concentrations was rather modulating. This dithiophosphate showed an enhanced negative inotropic effect mediated by H₂S upon contraction of the atrial myocardium, furthermore, its activity was prolonged and reluctant for washing. These findings identify glutathione dithiophosphates as redox-modulating H₂S donors with long-acting profile, which are of interest for further pharmacological investigation. Full article

(This article belongs to the Special Issue Hydrogen Sulfide (H2S)-Donor Molecules: Chemical, Biological, and Therapeutical Tools)

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11 pages, 2479 KiB

Open AccessArticle

Erucin, an H₂S-Releasing Isothiocyanate, Exerts Anticancer Effects in Human Triple-Negative Breast Cancer Cells Triggering Autophagy-Dependent Apoptotic Cell Death

by Ivana Bello, Martina Smimmo, Roberta d’Emmanuele di Villa Bianca, Mariarosaria Bucci, Giuseppe Cirino, Elisabetta Panza and Vincenzo Brancaleone

Int. J. Mol. Sci. 2023, 24(7), 6764; https://doi.org/10.3390/ijms24076764 - 5 Apr 2023

Cited by 8 | Viewed by 2226

Abstract

Breast cancer is the most frequent form of cancer occurring in women of any age. Among the different types, the triple-negative breast cancer (TNBC) subtype is recognized as the most severe form, being associated with the highest mortality rate. Currently, there are no effective treatments for TNBC. For this reason, the research of novel therapeutics is urgently needed. Natural products and their analogs have historically made a major contribution to pharmacotherapy and the treatment of various human diseases, including cancer. In this study, we explored the potential anti-cancer effects of erucin, the most abundant H₂S-releasing isothiocyanate present in arugula (Eruca sativa) in MDA-MB-231 cells, a validated in vitro model of TNBC. We found that erucin, in a concentration-dependent manner, significantly inhibited MDA-MB-231 cell proliferation by inducing apoptosis and autophagy. Additionally, erucin prevented intracellular ROS generation promoting the expression of key antioxidant genes and halted MDA-MB-231 cell migration, invasion, and colony formation. In conclusion, using a cellular and molecular biology approach, we show that the consumption of erucin could represent a novel and promising strategy for intervention against TNBC. Full article

(This article belongs to the Special Issue Hydrogen Sulfide (H2S)-Donor Molecules: Chemical, Biological, and Therapeutical Tools)

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22 pages, 6260 KiB

Open AccessArticle

Design, Synthesis and Evaluation of Novel Molecular Hybrids between Antiglaucoma Drugs and H₂S Donors

by Rosa Sparaco, Valentina Citi, Elisa Magli, Alma Martelli, Eugenia Piragine, Vincenzo Calderone, Giorgia Andreozzi, Elisa Perissutti, Francesco Frecentese, Vincenzo Santagada, Giuseppe Caliendo, Beatrice Severino, Angela Corvino and Ferdinando Fiorino

Int. J. Mol. Sci. 2022, 23(22), 13804; https://doi.org/10.3390/ijms232213804 - 9 Nov 2022

Cited by 4 | Viewed by 1636

Abstract

Glaucoma is a group of eye diseases consisting of optic nerve damage with corresponding loss of field vision and blindness. Hydrogen sulfide (H₂S) is a gaseous neurotransmitter implicated in various pathophysiological processes. It is involved in the pathological mechanism of glaucomatous neuropathy and exerts promising effects in the treatment of this disease. In this work, we designed and synthetized new molecular hybrids between antiglaucoma drugs and H₂S donors to combine the pharmacological effect of both moieties, providing a heightened therapy. Brinzolamide, betaxolol and brimonidine were linked to different H₂S donors. The H₂S-releasing properties of the new compounds were evaluated in a phosphate buffer solution by the amperometric approach, and evaluated in human primary corneal epithelial cells (HCEs) by spectrofluorometric measurements. Experimental data showed that compounds 1c, 1d and 3d were the hybrids with the best properties, characterized by a significant and long-lasting production of the gasotransmitter both in the aqueous solution (in the presence of L-cysteine) and in the intracellular environment. Because, to date, the donation of H₂S by antiglaucoma H₂S donor hybrids using non-immortalized corneal cells has never been reported, these results pave the way to further investigation of the potential efficacy of the newly synthesized compounds. Full article

(This article belongs to the Special Issue Hydrogen Sulfide (H2S)-Donor Molecules: Chemical, Biological, and Therapeutical Tools)

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23 pages, 4542 KiB

Open AccessArticle

Vasoactive Effects of Chronic Treatment with Fructose and Slow-Releasing H₂S Donor GYY-4137 in Spontaneously Hypertensive Rats: The Role of Nitroso and Sulfide Signalization

by Andrea Berenyiova, Martina Cebova, Basak Gunes Aydemir, Samuel Golas, Miroslava Majzunova and Sona Cacanyiova

Int. J. Mol. Sci. 2022, 23(16), 9215; https://doi.org/10.3390/ijms23169215 - 16 Aug 2022

Cited by 3 | Viewed by 1393

Abstract

Increased fructose consumption induces metabolic-syndrome-like pathologies and modulates vasoactivity and the participation of nitric oxide (NO) and hydrogen sulfide (H₂S). We investigated whether a slow-releasing H₂S donor, GYY-4137, could exert beneficial activity in these conditions. We examined the effect of eight weeks of fructose intake on the blood pressure, biometric parameters, vasoactive responses, and NO and H₂S pathways in fructose-fed spontaneously hypertensive rats with or without three weeks of GYY-4137 i.p. application. GYY-4137 reduced triacylglycerol levels and blood pressure, but not adiposity, and all were increased by fructose intake. Fructose intake generally enhanced endothelium-dependent vasorelaxation, decreased adrenergic contraction, and increased protein expression of interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα), and concentration of conjugated dienes in the left ventricle (LV). Although GYY-4137 administration did not affect vasorelaxant responses, it restored disturbed contractility, LV oxidative damage and decreased protein expression of TNFα in fructose-fed rats. While the participation of endogenous H₂S in vasoactive responses was not affected by fructose treatment, the expression of H₂S-producing enzyme cystathionine β-synthase in the LV was increased, and the stimulation of the NO signaling pathway improved endothelial function in the mesenteric artery. On the other hand, chronic treatment with GYY-4137 increased the expression of H₂S-producing enzyme cystathionine γ-lyase in the LV and stimulated the beneficial pro-relaxant and anti-contractile activity of endogenous H₂S in thoracic aorta. Our results suggest that sulfide and nitroso signaling pathways could trigger compensatory vasoactive responses in hypertensive rats with metabolic disorder. A slow H₂S-releasing donor could partially amend metabolic-related changes and trigger beneficial activity of endogenous H₂S. Full article

(This article belongs to the Special Issue Hydrogen Sulfide (H2S)-Donor Molecules: Chemical, Biological, and Therapeutical Tools)

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Review

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16 pages, 1502 KiB

Open AccessReview

Plants and Mushrooms as Possible New Sources of H₂S Releasing Sulfur Compounds

by Valentina Citi, Marco Passerini, Vincenzo Calderone and Lara Testai

Int. J. Mol. Sci. 2023, 24(15), 11886; https://doi.org/10.3390/ijms241511886 - 25 Jul 2023

Cited by 2 | Viewed by 1546

Abstract

Hydrogen sulfide (H₂S), known for many decades exclusively for its toxicity and the smell of rotten eggs, has been re-discovered for its pleiotropic effects at the cardiovascular and non-cardiovascular level. Therefore, great attention is being paid to the discovery of molecules able to release H₂S in a smart manner, i.e., slowly and for a long time, thus ensuring the maintenance of its physiological levels and preventing “H₂S-poor” diseases. Despite the development of numerous synthetically derived molecules, the observation that plants containing sulfur compounds share the same pharmacological properties as H₂S led to the characterization of naturally derived compounds as H₂S donors. In this regard, polysulfuric compounds occurring in plants belonging to the Alliaceae family were the first characterized as H₂S donors, followed by isothiocyanates derived from vegetables belonging to the Brassicaceae family, and this led us to consider these plants as nutraceutical tools and their daily consumption has been demonstrated to prevent the onset of several diseases. Interestingly, sulfur compounds are also contained in many fungi. In this review, we speculate about the possibility that they may be novel sources of H₂S-donors, furnishing new data on the release of H₂S from several selected extracts from fungi. Full article

(This article belongs to the Special Issue Hydrogen Sulfide (H2S)-Donor Molecules: Chemical, Biological, and Therapeutical Tools)

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