Hydrogen sulfide, once considered as toxic gas, is now recognized as important biological mediator. The deficiency of hydrogen sulfide could lead to various pathological changes, such as arterial and pulmonary hypertension, Alzheimer's disease, gastric mucosal injury and liver cirrhosis. However, excessive production of hydrogen sulfide by using inorganic hydrogen sulfide donor such as NaHS, may contribute to the pathogenesis of inflammatory diseases, septic shock, cerebral stroke and mental retardation in patients with Down syndrome. So, an increasing interest of organic molecules that are capable of regulating the formation of hydrogen sulfide over extended in recent years. Allium vegetables, as one of natural resource of organic sulfur containing compounds, have been widely investigated about its therapeutic applications, and the ingredients of garlic, such as diallyl disulfide (DADS) and diallyl trisulfide (DATS) and S-ally cysteine (SAC) have been proved that act as hydrogen sulfide donors or mediators in the pharmaceutical studies. In addition, S-propargyl cysteine (ZYZ-802) and S-propyl cysteine (SPC), two synthetic cystein analogs, have been examined that they could used to treat ischemic heart disease via modulation of the hydrogen sulfide pathway. Besides, the drugs containing a H2S-releasing moiety have been also synthesized and widely reported in recent years, such as S-nonsteroidal anti-inflammatory drugs and the derivative of Lawesson's reagents which exhibit varied biological effects in experiments. As cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE) are the enzymes being able to catalyze the production of endogenous hydrogen sulfide from cysteine, their inhibitors, such as DL-propyl-argylglycine (PAG) and β-cyanoalanine (BCA) have been frequently used in the studies on the biological mechanism of hydrogen sulfide. All these hydrogen sulfide donors, mediators and inhibitors have provided us useful tools in the research of varied variety of the biological effects and promising drug candidates of hydrogen sulfide.
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Keywords: Hydrogen sulfide; Hydrogen sulfide donor; Hydrogen sulfide mediator
Toxic gas with foul odor of rotten eggs is the first impression hydrogen sulfide given, which is due to its chemical and physical characteristics. However, every sword has two edges. It is known that the body produces small amount of H2S to be used as a signaling molecule. In 1996, Abe and Kimura first reported the role of hydrogen sulfide in human neuromodulation, which had become a research prelude on biological signaling function of hydrogen sulfide . Since then, research on has unfolded all aspects the biological functions of hydrogen sulfide, such as cardioprotective [2-5], neuroprotective [6-8], gastroprotective effects , regulation of insulin release  and anti-inflammatory , which make it known that hydrogen sulfide also plays an important, probably even pivotal role in human and biological systems (Fig. 1).
Hydrogen sulfide has been identified as the third gasotransmitter together with nitric oxide (NO) and carbon monoxide (CO). More interestingly, they share many similarities. For examples, all of them, once considered solely as toxic gases, are now recognized as important biological mediators. And all of them are able to rapidly permeate cell membranes without using specific transporters. Moreover, all of them could be produced by mammalian cells-similar to nitric oxide and carbon monoxide synthesized from L-arginine by NO synthase and from heme by heme oxygenase respectively, hydrogen sulfide is synthesized from L-cysteine by some enzymes such as cystathionine β-synthase (CBS) or cystathionine γ-lyase (CSE) both using pyridoxal 5'-phosphate (vitamin B6) as a cofactor [12-15], and 3-mercaptopyruvate sulfurtransferase (3-MST) along with cysteine aminotransferase (CAT), a third pathway of hydrogen sulfide production being reported recently ; In addition, recent studies suggest that not only cysteine but also homocysteine may be the substrate for CSE (or CBS)-catalyzed H2S synthesis . Except these, all of them exert serials of biological effects on various biological targets, resulting in responses either cytotoxic or cytoprotective. However, unlike NO and CO, H2S does not activate soluble guanylate cyclase [18-19]. It should be noted that hydrogen sulfide has been extensively reported to play a role in the regulation of vascular tone, myocardial contractility, neurotransmission, and insulin secretion. The deficiency of H2S could lead to various pathological changes, such as arterial and pulmonary hypertension, Alzheimer's disease, gastric mucosal injury and liver cirrhosis. The beneficial effects of hydrogen sulfide in the cardiovascular system have been studied extensively [20-21]. For instance, exogenous hydrogen sulfide could ameliorate myocardial dysfunction associated with the ischemia-reperfusion injury . An additional area in which hydrogen sulfide has been shown to exert protective effects is the GI tract: it can reduce the damage of gastric mucosa induced by anti-inflammatory drugs . More interestingly, excessive H2S production was observed in certain types of inflammation, in which inorganic H2S donors such as NaHS have been used. However, recent studies with slowly-releasing donors such as GYY4137 strongly suggest that H2S is anti-inflammatory.
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Over the past years, the reagents being able to release hydrogen sulfide have been appreciated as useful research tools in studies of biological effects and drug development of hydrogen sulfide . To date, sodium hydrosulfide (NaHS) is the most frequently used hydrogen sulfide donor in biological experiments, but as it releases hydrogen sulfide instantaneously in aqueous solution, it may not mimic the biological functions of endogenous hydrogen sulfide, and so there exists an increasing need for organic molecules capable of releasing hydrogen sulfide. A number of independent groups have reported the beneficial effects of sulfide-donor compound both in vitro and in vivo models of disease [25-29]. In addition, modified drugs containing a H2S-releasing moiety has also emerged (Fig. 2), such as S-nonsteroidal anti-inflammatory drugs which were inspired by the discovery and clinical development of NO-anti-inflammatory drugs . Although there are several issues to be overcome in future studies, such as dose controlling, releasing controlling and issues about formulation of its releasing reagents and drug candidates, recent advances in hydrogen sulfide donors and mediators have provided the basis for future exploitations on hydrogen sulfide related reagents and drugs.
In this article, organosulfur compounds (Fig. 2), especially derived from Allium vegetables and natural amino acid, have been reviewed as potential donors of hydrogen sulfide or mediators of its signaling pathways. Besides, regarding the development of CSE or CBS inhibitors is another potential therapeutic area, Such as PAG, BCA and other inhibitors of CSE and CBS is being reported are also discussed in this review. Also considering that understanding of the mechanism of endogenous hydrogen sulfide-releasing is important for developing more and new potent drugs that are capable of producing hydrogen sulfide or targeting on hydrogen sulfide signaling pathway, the biochemical pathways and chemical reactions associated with hydrogen sulfide formation are also introduced in this article.
Biochemical pathway and chemical reaction associated with hydrogen sulfide formation
To develop more and new potent drugs that are capable of producing hydrogen sulfide or targeting on hydrogen sulfide signaling pathway, knowledge on the mechanisms of both endogenous and exogenous hydrogen sulfide formation is absolutely necessary. Thus the biochemical pathways and chemical reactions associated with hydrogen sulfide formation have been first discussed here.
Apart from the formation of hydrogen sulfide from cysteine catalyzed by CSE in the cardiovascular system and CBS in the brain, it could also be produced via several other pathways in different tissues and biological systems. For example, It has been reported recently that 3-mercaptopyruvate sulfur transferase (3-MST) along with cystein aminotransferase (CAT) produces hydrogen sulfide in the brain as well as in vascular endothelium [16,18]. Moreover, the bacteria in mammal intestines are able to ferment sulfur containing amino acid, reduce sulfate and sulfite and decompose sulomucin. Subsequently, large amounts of hydrogen sulfide could be produced, which then expulsed outside from gut or oxidized into sulfate and methyl sulfide . In plants, hydrogen sulfide is derived from cysteine by cysteine desulfhydrases, or sulfite by sulfite reductases . In addition, the generation of hydrogen sulfide in yeast is mainly due to the reduction of S2O32- by thiosulfate reductase in the presence of GSH . All in all, understanding these biological events and processes about hydrogen sulfide formation is essential for designing and exploring the drugs related hydrogen sulfide.
After at a glance of the bio-pathways on hydrogen sulfide formation, let's turn our attention to the chemical reactions of organosulfur compounds involved during hydrogen sulfide production. Releasing hydrogen sulfide from polysulfides ever occurs in nature. During the generation of hydrogen sulfide from these sulfur species, thiol/polysulfide exchange, C-S bond cleavage and reductive or oxidative reactions are the mostly occurring processes. For instance, once attacked by a nucleophile such as GSH, disulfide could release hydrogen sulfide through cleavage reaction at α- and/or olefinic carbon. In the case of trisulfides, hydrogen sulfide can be released via RSSH and RSSSH produced by exchange and C-S bond reactions. Monosulfides, such as SAC, possibly serve as hydrogen sulfide donor catalyzed by C-S lyases. On this subject, two reviews with more detail information were published by Jacob in 2007 and 2008 [34-35].
Organosulfur compound derived from Allium vegetables
The scientific investigation over the years has shown that allium vegetables and their active ingredients have been able to reduce the risk of cardiovascular disease and diabetes, stimulate immune system, protect against infection, and have anti-aging as well as anti-cancer effect [36-38]. Although allium vegetables, such as garlic and onion, are natural library of organic sulfur-containing compounds which could release hydrogen sulfide under particular chemical condition, It was not until 2006 that study had shown that the health benefits of allium vegetables are related with hydrogen sulfide releasing. In 2006, Kraus' group reported that the garlic-derived organic polysulfides could be converted into hydrogen sulfide in the presence of GSH, and their studies also suggested the vasoactivity of garlic compounds was synchronous with hydrogen sulfide production . Several months later, Kraus' group reported further evidence to support previous results about correlations between vasoactivity of organosulfur compounds in garlic and hydrogen sulfide release , which combing with the results published by Zhu's group about S-allyl-cysteine(SAC), an active component in garlic being able to mediates cardioprotection in an acute myocardial infarction rat model via a hydrogen sulfide mediated pathway , have brought great promise to the researchers in this area in order to develop organosulfur compounds in allium vegetables into novel endogenous hydrogen sulfide regulators.
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Although a great amount of sulfur-containing components in garlic and their pharmaceutical effects have been broadly reported, only γ-glutamylcysteines, S-alk(en)yl-cysteine sulphoxides, including alliin (S-allyl-cysteine sulphoxide), and small amounts of SAC can be found in intact garlic . Other active organosulfur components being reported actually formed during different process of garlic preparations such as extraction of garlic essential oil, and preparation of garlic powder or aged garlic extract (AGE). Water-soluble fractions, mainly containing SAC and S-allyl-mecaptocysteine (SAMC), are dominant in AGE, which have been heavily explored (more than 400 papers). They exhibit a wide variety of biological activities from hepatoprotective, neuroprotective, and antioxidative activities to anticancer effect. Lipid-soluble organosulfur components, including monosulfide and polysulfide such as diallyl sulfide (DAS), diallyl disulfide (DADS), diallyl-trisulfide (DATS) and ajoene, can be produced in the preparation process of garlic oil . All of these lipid-soluble ingredients are derived from allicin (diallyl thiosulfinate), a water-soluble compound in garlic, which is highly unstable and instantly decomposes to a lipid-soluble sulfur-containing molecule. To date, severial organosulfur compounds in garlic have been found and identified, but only three of them, SAC, DADS and DATS, have been validated that their pharmaceutical effects correlating with the hydrogen sulfide signaling pathway [39-41]. Most importantly, these results have offered people in these area new tools to explore mechanism of hydrogen sulfide signaling pathways, and enable us to develop novel hydrogen sulfide donors or inhibitors (Fig. 3).
Diallyl disulfide (DADS) and Diallyl trisulfide (DATS)
DADS and DATS are major components of garlic oil [42-43], which exhibit antiproliferative effects on human cancer cell lines from colon, lung, and skin. Other pharmacological effects, such as cardiovascular and anti-microbial effects have also been reported . In 2006, Benavides' group first reported experimental evidence about correlations between vasoactivity of organosulfur compounds and hydrogen sulfide releasing in garlic. They observed that DADS and DATS could be converted into hydrogen sulfide by human RBCs via glucose-supported and thiol-dependent cellular as well as glutathione (GSH)-dependent acellular reactions. Based on their observations, they speculated that the major beneficial effects of garlic-rich diets, specifically on cardiovascular disease and more broadly on overall health, are mediated by the biological production of hydrogen sulfide from garlic-derived organic polysulfides [39-40]. Recently, O'Brien's group observed that DADS was able to induce cytotoxic effectiveness towards hepatocytes, which was prevented by the hydrogen sulfide scavenger hydroxocobalamin, and they also found that cytotoxic effectiveness induced by DADS prevented cytochrome oxidase dependent mitochondrial respiration suggesting that inhibition of cytochrome oxidase by hydrogen sulfide contributed to DADS hepatocyte cytotoxicity . This result proved in another respect that the pharmaceutical effects of polysulfides, such as DADS and DATS, correlated with hydrogen sulfide formation.
SAC, the major component in AGE, is a reduced form of S-allyl-cysteine sulfoxide (alliin), which can also be obtained from cysteine hydrogen chloride salt and allyl bromide by chemical synthesis method under basic condition. Previous study of our group has shown that SAC mediated cardioprotection in an acute myocardial infarction rat model via a hydrogen sulfide mediated pathway. Recently, our group observed that SAC is cardioprotective in myocardial infarction (MI) by lowering mortality as well as a reduction in infarct size and ventricular hypertrophy. In addition to the antioxidative role of SAC as reported by other groups, we propose that this cardioprotection is also mediated by a novel hydrogen sulfide-related pathway, due to that SAC serves to upregulate CSE expression and activity in the infarcted myocardium and significantly increased plasma hydrogen sulfide concentration. This increase in left ventricular CSE expression and activity together with plasma hydrogen sulfide levels are abrogated when rats are treated concurrently with PAG. This finding serves to substantiate that SAC is beneficial to the ischemic myocardium and is promising as a therapeutic candidate in the treatment of MI .
Although we have already got some results about the correlations between cardioprotection attributed by SAC and hydrogen sulfide mediated pathway, there is no direct evidence shown by us and others that whether and how SAC may be a source of hydrogen sulfide. Most helpfully, Jacob and his colleagues proposed four possibilities for this question in their review about sulfur-containing agents, those are chemical release of cysteine from SAC, enzymatic release of cysteine, direct (or indirect) release of hydrogen sulfide from SAC and the possibility of an alliinase-like enzymatic chemistry in humans . They also gave some explanations about these possibilities based on organosulfur compound related chemistry and biology. Nevertheless, to answer this question, further evidence will be search for in our future studies.
Cysteine, a natural sulfur-containing amino acid, is found in all somatic cells and is indispensable for life. It can usually be synthesized by the human body under normal physiological conditions if a sufficient quantity of methionine is available. The side chain on cysteine is a thiol, which often participates in enzymatic reactions, serving as a nucleophile. The thiol is susceptible to oxidization to form disulfide bond between two cysteine residues, which plays an important structural role in many proteins. The other important role of cysteine in biological system is that it serves as an endogenous hydrogen sulfide donor catalyzed by cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS) which are pyridoxal phosphate (PLP)-dependent enzymes of sulfur-containing amino acid metabolism. It has been reported that PLP as a cofactor of cystathionine synthase or lyase-like enzymes, is able to form a Schiff base with the ε-amino group of the active site lysine. The Cβ-Sγ cleavage reaction of sulfur-containing amino acid is catalyzed by enzyme-PLP complex, and yield ammoia, pyruvate, hydrogen sulfide, homocysteine and cysteine persulfide, respectively [12-15].
Other sulfur-containing amino acids, especially cysteine analogues, have been broadly reported because of their health benefits ranging from cardioprotective and anti-cancer effect to delaying diabetic deterioration [45-51]. Analogues of cysteine are abundant in garlic products, especially in aged garlic extract which is mainly containing S-alk(en)yl-cysteine or S-alk(en)yl-mecaptocysteine such as S-allyl cysteine (SAC), S-allyl mecaptocysteine (SAMC), S-methyl cysteine (SMC), S-ethyl cysteine (SEC) and S-propyl cysteine (SPC). N-acetylcysteine (NAC) found in garlic products is another type of derivative of cysteine and is an intermediary in conversion of cysteine to GSH, which exhibits antioxidant effects in biological systems. In addition, some synthetic cysteine analogues, such as S-trityl cysteine has been reported to exert their anticancer effect . Among these cysteine analogues mentioned above, only S-allyl cysteine (SAC) has been reported to possibly act as the substrate of CSE, it is able to regulate CSE expression and endogenous hydrogen sulfide releasing, which we have already discussed in last topic . Based on previous studies of our group on SAC mediated cardioprotection in an acute myocardial infarction rat model via a hydrogen sulfide mediated pathway, we further designed and synthesized a structural analogue of SAC, S-propargyl cysteine (ZYZ-802), in which a allyl group is replaced by a propargyl group in the SAC molecule.
ZYZ-802 (S-propargyl cysteine , SPRC)
ZYZ-802, as reported by our group is a synthetic cysteine analogue with a propargyl group on the thiol side chain of cysteine molecule [53-54]. The idea on designing of ZYZ-802 is initiated by previous reports about SAC serving as a substrate of CSE that produces endogenous hydrogen sulfide and has cardioprotective effects. After comparation of all the molecular structures which have been reported as CSE substrates, we found that PAG, a good inhibitor of CSE, had a similar carbon back bone to SAC. In their structures, a terminal akynyl group in PAG and S-allyl group in SAC is the only disparity between two molecules, which offered us inspirations on ZYZ-802 designing. Therefore, we synthesized ZYZ-802 and SPC (S-propyl cysteine) from L-cysteine hydrochloride and propargyl or propyl bromide respectively. In the pharmacological studies of these compounds, we observed that SPC, ZYZ-802 and SAC were all able to enhance cellular antioxidant defenses in rats with MI, and ZYZ-802 might be more selective towards CSE. In order to obtain more confident evidence on the cardioprotective effects of ZYZ-802 whether or not via hydrogen sulfide pathway, we further investigated their cardioprotective effects compared to SAC in both a rat model of MI and isolated cardiomyocytes underwent hypoxic damage. In these studies, we observed ZYZ-802 had better cardioprotective effects than SAC. More importantly, we also found that the protective effects of ZYZ-802 were partly mediated by the CSE/hydrogen sulfide pathway because firstly, ZYZ-802 induced protein and mRNA expression of CSE and increased CSE activities, secondly, ZYZ-802 elevated hydrogen sulfide levels, and thirdly these protective effects could be abolished by administration of the CSE inhibitor PAG. All of these results demonstrated that ZYZ-802 represented a new, valuable SAC analog, which could possibly be used to treat ischemic heart disease via modulation of the hydrogen sulfide pathway.
Recently, the protective effects of ZYZ-802 on cognitive impairment and neuronal ultrastructure damage induced by Abeta in rats were reported by our group. These studies damonstrated that ZYZ-802 administration at the doses of 40, 80 mg/kg by intraperitoneal injection may inhibit cognitive impairment and neuronal ultrastructure damage induced by intracerebroventricular injection of 10 mug of Abeta(25-35) in rats. Subsequently, ZYZ-802 inhibited the expressions of tumor necrosis factor (TNF)-alpha, cyclooxygenase-2 (COX-2) mRNA, and protein in rat hippocampus. ZYZ-802 afforded a beneficial action on inhibitions of extracellular signal-regulated kinase (ERK1/2), as well as inhibitions of IkappaB-alpha degradation and activation of transcription factors of the nuclear factor kappaB (NF-kappaB) produced by Abeta. These findings suggested that ZYZ-802 might be a potential agent for treatment of AD [55-56].
CSE or CBS inhibitors
The cysteine analogues, such as DL-propyl-argylglycine (PAG), β-cyanoalanine (BCA), L-aminoethoxyvinylglycine (AVG) and trifluoromethyl alanine (F3C-Ala), has similar carbon backbone to cysteine, which could not directly or indirectly release hydrogen sulfide, but is able to act as CSE or CBS inhibitors to redeuce endogenous hydrogen sulfide formation [57-62]. PAG and AVG both are natural products elaborated by streptomycetes, but exhibit different mechanisms in enzymatic inhibition. Based on the studies of Clausen's group, AVG binds to the active site PLP cofactor by formation of a Schiff base bond, which results in a weak EI complex because the linkage can be readily resolved by reversion of the transaldimination reaction. The α-proton in AVG-enzyme complex is then extracted by the active site lysine and subsequently transfers to C4', which lead to a much more stable ketimine complex. The whole process of AVG binding on CSE is so-called slow binding inhibition [60-61]. Unlike the inhibition of CSE by AVG, a covalent enzyme-PAG complex can be formed through its activated γ-carbon atom, which is called suicide inhibition as it is irreversible. F3-Ala is also able to conduct suicide inhibition towards CSE. In contrast, F3-Ala does not provide a γ-carbon atom, whereas a fluorine atom on its β carbon is acts as a leaving group under the attack of active site lysine, thereafter a covalent bond formed between enzyme and F3-Ala . The compounds mentioned above, although have been used in several studies as tools to investigate the metabolism of sulfur-containing amino acid and endogenous hydrogen sulfide production; however, low potency, low selectivity and poor cell-membrane permeability are the limitations of these compounds which should always be kept in mind. Therefore, developing the inhibitors of hydrogen sulfide with high potency and selectivity has become of an increasing interest in recent years.
Hydrogen sulfide-releasing drugs
In light of the studies on NO-releasing drugs, such as NO-aspirin and NO-naproxen , hydrogen sulfide, the endogenous gaseous mediators like NO and CO has been considered as potential therapeutic agents in drug design, and some hydrogen sulfide-releasing drugs, such as S-diclofenac, S-aspirin and S-sulindac have been widely reported in recent years .
S-Nonsteroidal anti-inflammatory drugs
S-diclofenac is a novel molecule comprising a hydrogen sulfide-releasing dithiol-thione moiety attached by an ester linkage to diclofenac. Greater anti-inflammatory activities of S-diclofenac than diclofenac both in carrageenan-evoked hind-paw edema model and LPS-induced endotoxic shock model in the rat have been observed by Moore's group [64-66]. In addition, Moore and his colleagues also investigated the effects of S-diclofenac on cell survival, cell cycle alterations and proteins associated with cell growth and apoptosis in rat aortic vascular smooth muscle cells, and found that S-diclofenac inhibited smooth muscle cell proliferation and may act as an antimitotic agent . Besides, other pharmacological effects of S-diclofenac, such as anti-ischemic and anti-cancer activities, have been examined by several groups [68-69], which have opened up the way of S-diclofenac to a range of therapeutic applications also in cardiovascular disease and cancers.
In addition to S-diclofenac, other nonsteroidal anti-inflammatory drugs (NSAIDs) with dithiol-thione moiety have also been reported. For example, the anti-cancer effects of S-diclofenac, S-sulindac and anethole dithile thione-OH (ADT-OH) have been compared by Yeh's group . They found S-diclofenac and S-sulindac inhibit the activity and expression of carcinogen activating enzymes as well as cytochrome P450s. Furthermore, the studies of Moody's group indicated that S-diclofenac and S-valproate inhibit the proliferation of NSCLC cell both in vitro and in vivo . Recently, Mcgeer's group has also extended the therapeutic application of hydrogen sulfide-releasing NSAIDs to treat neuroinflammation . There is a significant neuroprotection of S-aspirin, S-diclofenac and ADT-OH, in LPS and γ-interfenon activated human microglia and THP-1 cells.
GYY4137 is one of a series of compounds synthesized by Moore's group on the basis of the structure of Lawesson's compound, which releases hydrogen sulfide in organic solvents. It has been utilized as a slow-releasing hydrogen sulfide compound to examine the effect of hydrogen sulfide in the cardiovascular system. The study has shown that GYY4137 has potential vasodilator and antihypertensive activities. Moreover, anti-inflammatory effects of this compound have also been investigated both in LPS-treated rat blood and murine RAW264.7 macrophages. All of these experiments prove GYY4137 is a useful tool in the study of varied variety of the biological effects of hydrogen sulfide and a promising drug candidate related to hydrogen sulfide [73-74].
Sulfur is an essential element for life and is found in two natural amino acids: cysteine and methionine which serves as endogenous hydrogen sulfide-donors. Hydrogen sulfide as the simplest sulfur compound in nature plays important roles in human and biological systems. In recent years, the reagents being able to release hydrogen sulfide have been appreciated as useful research tools for biological effects studies and drug development of hydrogen sulfide. Allium vegetables, as one of natural resource of organic sulfur containing compounds, have long been known that it possess beneficial effects in multiple models of diseases, such as diseases of cardiovascular and immune system, diabetes and cancers. Although the pharmaceutical effects of organosulfur compounds in allium vegetables have been widely reported, there was no clue about the correlations between the beneficial effects of allium vegetable and the formation of hydrogen sulfide from organosulfides. Until 2006, Kraus' group first reported experimental evidence about correlations between vasoactivity of organosulfur compounds in garlic (DADS and DATS) and hydrogen sulfide releasing, which brought great promise to the researchers in this area about developing organosulfur compounds in allium vegetables into novel endogenous hydrogen sulfide regulators. Subsequently, S-allyl-cysteine(SAC), another active component in garlic, was first reported as a CSE substrate in an acute myocardial infarction rat model by our group. These results have offered people in this area the new tools to explore mechanism of hydrogen sulfide signaling pathway, and enable us to develop novel hydrogen sulfide mediators or inhibitors. Excited by the findings on SAC, we further designed and synthesized two more cysteine analogs, S-propargyl cysteine and S-propyl cysteine, and the experiment data demonstrated that ZYZ-802 represented a new, valuable SAC analog, which could used to treat ischemic heart disease via modulation of the hydrogen sulfide pathway.
In recent years, the drugs containing a H2S-releasing moiety have emerged. For instance, some modified drugs with H2S-releasing moiety have been reported by several groups. These drugs are some S-nonsteroidal anti-inflammatory drugs, such as S-diclofenac, S-aspirin and S-sulindac, and the H2S-releasing moiety in these drugs is dithiol-thione that is a five member ring fragment having three sulfur atoms. In addition, GYY4137, a derivative of Lawesson's reagent, has been synthesized by Moore's group, which serves as a slow-releasing hydrogen sulfide compound to examine the effect of hydrogen sulfide in the cardiovascular system.
As the researches on the therapeutic applications of hydrogen sulfide have advanced, the studies of CSE or CBS inhibitors have become another potential therapeutic area. For instance, PAG, a compound having similar carbon backbone with cysteine, has become the most frequently used inhibitor of CSE in biological experiments in order to reduce endogenous hydrogen sulfide formation. Other inhibitors of this type of enzyme with different binding mechanisms, such as BCA, AVG and F3-Ala have also been reported by several groups. All of these compounds prove that act as useful tools during the investigations about the metabolism of sulfur-containing amino acid and endogenous hydrogen sulfide production.
As discussed previously, hydrogen sulfide or hydrogen sulfide donors or mediators exert beneficial effects in multiple models of diseases. The mechanisms that hydrogen sulfide involved range from inhibition of cellular metabolism (in the lethal hypoxia model) to vasodilation, KATP-channel activation, regulation of anti-inflammatory and inflammatory genes. The biological effects of hydrogen sulfide and its donors bring us broad space to explore and develop more new therapeutic targets associated with hydrogen sulfide, such as gene transcription, KATP channel, mammalian mitochondria, cytochrome c oxidase and 3-mercaptopyruvate sulfur transferase (3-MST) as well as cystein aminotransferase (CAT) [75-76]. However, the studies on hydrogen sulfide and its donors or mediators are still in preclinical stage, and several challenging issues about the therapeutic development of hydrogen sulfide donors or mediators have to be overcome. Firstly, for the therapeutic application of hydrogen sulfide related reagents, dose-controlling is a very important aspect to be considered. Controlling dose is difficult to be achieved when using inhaled hydrogen sulfide or its exogenous donors, such as sodium hydrosulfide. Endogenous hydrogen sulfide mediator, such as SAC and ZYZ-802, is ideal development candidate on this aspect, because they could adjust hydrogen sulfide production via cysteine metabolic pathways. Therefore, in five years, exploitation of more efficacious drugs, which are able to mediate the hydrogen sulfide formation by endogenous metabolic pathways, is a potential area. Secondly, slow-releasing is another issue to be surmounted for the candidate of this type of drug. Reasonable half-life in the body is the basic requirement for the drug candidate. However, in the case of sodium hydrosulfide, fast releasing hydrogen sulfide in aqueous is a possible hurdle in the way of its druggable studies. Thus, developing hydrogen sulfide-precursors or prodrugs is another area for us to explore in next five years. Finally, as hydrogen sulfide has an unpleasant odor and is liable to be oxidized, the issue on the formulation of hydrogen sulfide-releasing drug candidates is also a challenge we have to face. Moreover, the study on the inhibitors of hydrogen sulfide formation is another developing direction of therapeutics related to hydrogen sulfide. Although hydrogen sulfide formation inhibitors, such as PAG and BCA, have been extensively employed in the research on the biological functions of hydrogen sulfide and their beneficial effects on human diseases, low potency and poor selectivity are two major aspects still to be improved in future studies.
In 1996, Abe and Kimura first reported the role of hydrogen sulfide in human neuromodulation, which had become a research prelude on biological signaling function of hydrogen sulfide .
In 2005, a novel H2S-releasing derivative of diclofenac (S-diclofenac) has been synthesized, and it shows potent anti-inflammatory activity with less gastric intolerance that the parent compound, with a significant release of hydrogen sulfide [63-68,70-72].
In 2006, Kraus' group reported that the garlic-derived organic polysulfides could be converted into hydrogen sulfide in the presence of GSH, and their studies also suggested the vasoactivity of garlic compounds was synchronous with hydrogen sulfide production [39-40].
In 2007, Zhu's group reported that S-allyl-cysteine(SAC), an active component in garlic being able to mediates cardioprotection in an acute myocardial infarction rat model via a hydrogen sulfide mediated pathway .
In 2008, Wang's group reported direct evidence that H2S is a physiologic vasodilator and regulator of blood pressure .
In 2008, a novel slow-releasing H2S donor (GYY4137) was synthesized to examine the effect of hydrogen sulfide in the cardiovascular system by Moore's group [73-74].
In 2009, a novel cysteine analogs S-propargyl cysteine (ZYZ-802) has been synthesized by Zhu's group, and it shows better cardioprotective effects than SAC [53-54].
In 2010, Wang's group provided evidences about the correlations between cystathionine gamma-lyase deficiency and overproliferation of smooth muscle cells .
The author would like to thank Jinfang Wu, Chunhua Liu, Stefanie Maerz and Xueru Shi for helpful revise and discussion. The research program was funded by National Basic Research Program of China (973 Program) (No. 2010CB912600), National Natural Science Foundation of China (No. 30772565, No. 30888002) and New Teacher Foundation from Ministry of Education in China (No. 20090071120).
Abeta: amyloid beta peptide
ADT-OH: anethole dithile thione-OH
AGE: aged garlic extract
CAT: cystein aminotransferase
CBS: cystathionine β-synthase
CO: carbon monoxide
CSE: cystathionine γ-lyase
DAS: diallyl sulfide
DADS: diallyl disulfide
F3C-Ala: trifluoromethyl alanine
H2S: hydrogen sulfide
3-MST: 3-mercaptopyruvate sulfur transferase
NaHS: sodium hydrosulfide
NO: nitric oxide
NSAIDs: nonsteroidal anti-inflammatory drugs
PLP: pyridoxal 5′-phosphate
SEC: S-ethyl cysteine
SMC: S-methyl cysteine
SPC: S-propyl cysteine
SPRC: S-propargyl cysteine (ZYZ-802)