Medicinal Chemistry: Insights into the Development of Novel H2S Donors

Abstract

Hydrogen sulfide (H2S) was traditionally considered as a toxic gas. However, recent studies have demonstrated H2S is an endogenously generated gaseous signaling molecule (gasotransmitter) with importance on par with that of two other well-known endogenous gasotransmitters, nitric oxide (NO) and carbon monoxide (CO). Although H2S's exact mechanisms of action are still under investigation, the production of endogenous H2S and the exogenous administration of H2S have been demonstrated to elicit a wide range of physiological responses including modulation of blood pressure and protection of ischemia reperfusion injury, exertion of anti-inflammatory effects, and reduction of metabolic rate. These results strongly suggest that modulation of H2S levels could have potential therapeutic values. In this regard, synthetic H2S-releasing agents (i.e., H2S donors) are not only important research tools, but also potential therapeutic agents. This chapter summarizes the knowledge of currently available H2S donors. Their preparation, H2S releasing mechanisms, and biological applications are discussed.

Exogenous Hydrogen Sulfide Ameliorates Diabetes-Associated Cognitive Decline by Regulating the Mitochondria-Mediated Apoptotic Pathway and IL-23/IL-17 Expression in db/db Mice

“…In our study, the expression levels of endogenous H 2 S in the db/db mice decreased, the levels of pro-apoptotic proteins were elevated, and the number of TUNEL-positive cells increased, indicating the modulatory effect of H 2 S on diabetes-associated dementia. The H 2 S donors include sulfide salts such as sodium sulfide (Na 2 S) and NaHS, garlic-derived compounds, and 1,2-dithiole-3-thiones [44]. Among these donors, NaHS has been widely used in neurodegenerative diseases such as Parkinson’s disease (PD) and AD, and the concentration used in this study was selected according to previous results and other references [45, 46].…”

Ammonium tetrathiomolybdate as a water-soluble and slow-release hydrogen sulfide donor

“…1–5 Because of this, the search for compounds that can release H 2 S and mimic the beneficiary activities of H 2 S has become an attractive area in medicinal chemistry. 6–10 So far, a number of H 2 S releasing compounds (also known as H 2 S donors), such as GYY4137, dithiothiones, N -mercapto-based donors, persulfide-based donors, gem-dithiol-based donors, etc., have been reported (Figure 1). 6–10 These compounds are normally small organic molecules which can be triggered by certain biologically relevant or compatible reactions to release H 2 S. Some of them have shown promising bioactivities.…”

“…6–10 So far, a number of H 2 S releasing compounds (also known as H 2 S donors), such as GYY4137, dithiothiones, N -mercapto-based donors, persulfide-based donors, gem-dithiol-based donors, etc., have been reported (Figure 1). 6–10 These compounds are normally small organic molecules which can be triggered by certain biologically relevant or compatible reactions to release H 2 S. Some of them have shown promising bioactivities. 6–10 On the other hand, inorganic molecule-based donors, especially metal complexes, which can slowly hydrolyze to release H 2 S have not been reported.…”

“…6–10 These compounds are normally small organic molecules which can be triggered by certain biologically relevant or compatible reactions to release H 2 S. Some of them have shown promising bioactivities. 6–10 On the other hand, inorganic molecule-based donors, especially metal complexes, which can slowly hydrolyze to release H 2 S have not been reported. Inspired by the fact that sodium nitroprusside (SNP), with the formula Na 2 [Fe(CN) 5 NO], is a widely used NO donor, 11–13 we suspected that certain sulfide-containing inorganic compounds might be able to serve as interesting H 2 S donors in aqueous solutions.…”

Estudo dos efeitos de compostos doadores de sulfeto de hidrogênio (H₂S) sobre o prurido agudo induzido pela ativação dos receptores ativados por proteases do tipo 2 (PAR-2) em camundongos.

“…Com base nos mecanismos e velocidade de liberação de H 2 S, os doadores de H 2 S podem ser divididos em três grupos: 1) substâncias inorgânicas ou sais de sulfeto, tais como hidrossulfeto de sódio (NaHS) e sulfeto de sódio (Na 2 S); em hidrolise a pH 7,4 ambas substancias podem gerar H 2 S rapidamente, e são assim chamados de "liberadores rápidos" ou "liberadores espontâneos"; 2) doadores de liberação lenta, são compostos de natureza orgânica representados por GYY4137; comparados com as sais de sulfeto a liberação de H 2 S é muito mais lenta e sustentada; 3) drogas híbridas H 2 S/anti-inflamatórios não esteroides; geralmente conjugados com DTT (1,2-Ditiol-3-tiona) como os compostos ATB337 (SDiclofenaco) e ACS14 (S-Aspirina; Wang, 2012;Zhao et al, 2015;Zheng et al, 2015).…”