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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2016, Vol. 10 Issue (1) : 18-27     DOI: 10.1007/s11684-015-0427-6
REVIEW |
Therapeutic application of hydrogen sulfide donors: the potential and challenges
Dan Wu1,2,Qingxun Hu1,Yizhun Zhu1,*()
1. Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China
2. Department of Pharmacy, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
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Abstract  

Hydrogen sulfide (H2S), a colorless gas smelling of rotten egg, has long been considered a toxic gas and environment hazard. However, evidences show that H2S plays a great role in many physiological and pathological activities, and it exhibits different effects when applied at various doses. In this review, we summarize the chemistry and biomedical applications of H2S-releasing compounds, including inorganic salts, phosphorodithioate derivatives, derivatives of Allium sativum extracts, derivatives of thioaminoacids, and derivatives of anti-inflammatory drugs.

Keywords hydrogen sulfide      cardiovascular      cancer      hypertension     
Corresponding Authors: Yizhun Zhu   
Just Accepted Date: 09 November 2015   Online First Date: 23 November 2015    Issue Date: 31 March 2016
URL:  
http://academic.hep.com.cn/fmd/EN/10.1007/s11684-015-0427-6     OR     http://academic.hep.com.cn/fmd/EN/Y2016/V10/I1/18
Fig.1  Production and metabolism of H2S. In mammalian cells, endogenous H2S is produced from desulfhydration of cysteine catalyzed by two enzymes, cystathionine b-synthase (CBS) and cystathionine g-lyase (CSE). Cysteine is catalyzed by the tandem enzymes cysteine aminotransferase (CAT) and 3-mercaptopyruvate sulfurtransferase (3-MST) to form H2S in mitochondria. Sulfide is first oxidized into thiosulfate and then thiosulfate is reduced into sulfite by thiosulfate reductase (TSR) and thiosulfate sulfurtransferase (TST). Sulfite is oxidized into sulfate in the presence of glutathione.
Fig.2  Inhibitors of CSE and CBS. Propargylglycine (PAG) is an irreversibly selective inhibitor of CSE, and b-cyanoalanine (BCA) is a reversible inhibitor of CSE. Minooxy-acetic acid (AOAA) and hydroxylamine (HA) inhibit the activities of both CBS and CSE.
H2S donors Pathway of H2S generation Potential therapeutic effects Development stage
Inorganic salts Hydrolytic action Ischemia reperfusion injury Phase I
GYY4137 Hydrolytic action Cancer/hypertension/ischemia reperfusion injury Preclinical
SPRC H2S generation enzyme Cancer/ inflammation /ischemia reperfusion injury Preclinical
SAC H2S generation enzyme Hypertension Phase II
DADS Glutathione Cancer/coronary artery disease Preclinical
Thioglycine Mild alkaline pH values Hypertension Preclinical
H2S-releasing NSAIDs Glutathione Cancer/inflammation Preclinical
N-(Benzoylthio) benzamides Cysteine No effects were reported to date Preclinical
Ketoprofenate-caged compound Light No effects were reported to date Preclinical
Tab.1  H2S donors in development
Fig.3  H2S donating compounds (I). (A) Morpholin-4-ium 4 methoxyphenyl (morpholino) phosphinodithioate (GYY4137) is a water-soluble and slowly released H2S donor. (B, C) S-allycysteine (SAC) and S-propargyl- cysteine (SPRC) are derivatives of Allium sativum extracts. (D) LEO is obtained as a combination of SPRC and leonurine.
Fig.4  H2S donating compounds (II). (A, B) The chemical structure and mechanism of H2S release of derivatives of the Allium sativum extracts diallyl sulfide (DAS), diallyl disulfide (DADS), diallyl trisulfide (DATS), and ajoene. (C) The chemical structure and mechanism of H2S release of derivatives of the thioaminoacids thioglycine and thiovaline.
Fig.5  H2S-releasing non-steroidal anti-inflammatory drugs (NSAIDs) that prevent gastrointestinal side effects and increase anti-inflammatory effects.
Fig.6  Chemical structure of NOSH-aspirin, which can release both H2S and NO.
Fig.7  H2S donating compounds (III). The chemical structure and H2S generation pathway of (A) N-(benzoylthio)benzamides and (B) the light-activated donor propane-2,2-diylbis((1-(4,5-dimethoxy-2-nitro-phenyl)ethyl)sulfane).
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