Current Trends and Future Perspectives of Hydrogen Sulfide Donors

Abstract

Hydrogen sulfide (H2S) gas is included to be the most critical endogenous gasotransmitters that has several pathophysiological effects in many human cells and organ tissues. The synthesis of endogenous H2S in cells via several pathways. Variant biological effects of H2S including ion channel regulation, redox regulation of protein, thiols, polysulfides, thiosulfate/sulfite, and anti-oxidant activities affecting many cellular and molecular reactions. Therefore, it is essential to review H2S chemical biology, methods of detection of H2S release and its effects on pathological and physiological functions along with their therapeutic uses, including cardiovascular protective activities, anti-inflammatory and anti-tumor activities of the H2S donors.

Full text

J. Adv. Biomed. & Pharm. Sci .
J. Adv. Biomed. & Pharm. Sci. 4 (2021) 231-245
Current Trends and Future Perspectives of Hydrogen Sulfide Donors
Aya H Shabib1, Mai E. M. Shoman1, El-Shimaa M. N. Abdelhafez1*, Gamal El-Din A Abuo-Rahma1,2
Minia, Egypt-Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519
1
Department of Pharmaceutical Medicinal Chemistry, Faculty of Pharmacy, Deraya University, New Minia, Minia, Egypt
2
Received: June 14, 2021; revised: July 20, 2021; accepted: July 29, 2021
Abstract
Hydrogen sulfide (H2S) gas is included to be the most critical endogenous gasotransmitters that has several pathophysiological
effects in many human cells and organ tissues. The synthesis of endogenous H2S in cells via several pathways. Variant biological
effects of H2S including ion channel regulation, redox regulation of protein, thiols, polysulfides, thiosulfate/sulfite, and anti-oxidant
activities affecting many cellular and molecular reactions. Therefore, it is essential to review H2S chemical biology, methods of
detection of H2S release and its effects on pathological and physiological functions along with their therapeutic uses, including
cardiovascular protective activities, anti-inflammatory and anti-tumor activities of the H2S donors.
Key words
Hydrogen sulfide (H2S), gasotransmitters, donors, anticancer, hybrids..
Introduction
As nitric oxide (NO) and carbon monoxide (CO),
hydrogen sulfide (H2S) is considered one of the most important
gasotransmitter [1–7]. Synthesis of endogenous H2S in cells of
mammalians through three enzymes: cystathionine ɤ-lyase
(CSE), cystathionine β-synthase (CBS), and 3-
mercaptopyruvate sulfur-transferase (MPST) (Figure 1), that
also regulate H2S levels in tissues [8–12].
H2S has potent reducing properties and is scavenged by
endogenous oxidizing molecules including hydrogen peroxide,
superoxide and peroxynitrite [14, 15]. Also, H2S is forming
sulfhemoglobin when reacts with methemoglobin [16] and
causing protein S-sulfhydration (formation of -S-SH) [17–19].
H2S can also interact with S-nitrosothiols forming thionitrous
acid (HSNO) which is metabolized forming NO, NO-, and NO+
that are with several physiological activities [17–19].
Journal of Advanced Biomedical and Pharmaceutical Sciences
Journal Homepage: http://jabps.journals.ekb.eg
* Correspondence: Elshimaa M. N. Abdelhafez
Tel.: (+02)(01021583335); Fax: +2086-236-90-75.
Email Address: shimaanaguib_80@mu.edu.eg,
Figure1. Endogenous Enzymatic Biosynthesis of H2S [13].

J. Adv. Biomed. & Pharm. Sci .
Shabib et al
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H2S exhibits various biological activities at concentrations
between 10 and 300 µM [3]. Whereas, it can modulate many
physiological responses including reducing oxidative stress
[21], anti-inflammatory [20], vasoregulation [23],
neuromodulation [22], inhibition of insulin resistance [25] and
protection against myocardial ischemia injury [24]. H2S at
concentrations of <100 ppm causes several toxic effects in
human such as nausea, dizziness, sore throat, eye irritation,
chest tightness and short breath [26, 27]. while severe adverse
effects of high exposure to >1000 ppm hydrogen sulfide
affecting the central nervous system causing loss of
consciousness to death [28] and also affecting the respiratory
system causing respiratory paralysis and pulmonary edema [29,
30].
1.Measurement of H2S release:
Several methods for sulfide detection have been developed
ranging from simple spectrophotometric and colorimetric
methods to other advanced techniques and methods [31].
1.1. Ion-selective (Sulfide-specific) electrodes (ISEs)
ISEs is usually used for measuring H2S levels in biological
fluids with a range of 1–10 µM. ISEs method detects the sulfide
S-2 form in an alkaline condition. ISEs is a readily, available and
easy method [32, 33].
1.2. Polarographic electrodes
H2S detection using the polarographic H2S electrodes for
measuring H2S gas in biological samples, in the nM detection
range. However the polarographic H2S sensor is a very sensitive
and accurate method, it can't detect other forms of sulfide [34].
1.3. Chromatographic methods
Chromatographic H2S detection methods are versatile including
ion-exchange chromatography, gas chromatography (GC), and
HPLC that can measure volatile sulfur compounds and different
sulfide forms in biological samples [35]. RP (reversed-phase)-
HPLC is used for measuring methylene blue, zinc acetate that is
used to trap H2S in brain tissue in acidic conditions [36]. The
thiol-sensitive fluorescent probe Monobromobimane (MBB)
could measure bioavailable H2S levels, whereas measuring the
H2S/HS- is by HPLC with fluorescence detection [37, 38].
1.4. Fluorescent probes based strategy for H2S detection
In this strategy measuring H2S in plasma via evaluating the
fluorescence of the formed benzodithiolone [39] [40].
Moreover, a novel dansyl azide (DNS-Az), which is reduction-
sensitive, nonfluorescent and upon reacting with sulfide
becomes fluorescent [41].
1.5. Methylene blue formation method
It is the usually known chemical method in measuring H2S as
H2S is firstly trapped with Zn(OAc)2 forming ZnS. The trapped
H2S is released after Sample acidification, H2S is reacted with
N,N-dimethyl-p-phenylenediamine 1 in presence of FeCl3 and
forming methylene blue 2 (Figure 2). The absorbance of
methylene blue is measured at 670 nm [31, 42].
NH2
Me2NH2S
FeCl3,
H2SO4
800C,6h N
S N+Me2
2
1
+
Me2N
1.6. Chemical properties based methods
Due to H2S physicochemical and reactive properties, it was
developed new H2S detection methods can be classified into
three types: (1) 1.6.1. Chemical reduction method (2)
Nucleophilic Attack method and (3) Methods depend on metal
precipitation.
1.6.1. Chemical reduction method
Due to H2S reducing properties it can reduce azide and nitro
groups [14, 15] [43] and this is used for H2S detection using
different fluorescent probes (Figure 3) [44–46].
1.6.2. Nucleophilic Attack method
H2S can go two sequential nucleophilic attacks, therefore upon
reaction with two equivalents monobromobimane that trapping
H2S forming the fluorescent thioether product (Figure 4)
followed by HPLC separation for detection of H2S [47, 48].
N N
O
OBr
H2SNN
O
OSN
NO
O
2
1.6.3. Methods depend on metal precipitation
H2S can precipitate metals including copper, magnesium and
zinc, therefore developing H2S detection method using the
Cu(II) gravimetric method in which precipitation of CuS by H2S
and using a fluorescein derivative (dipicolylamine) [49]. When
the fluorescein compound is complexed with Cu (II) that
causing quenching of the fluorescence. While the fluorescence
is restored after precipitation of CuS by the released H2S in the
sample [49] (Figure 5).
Figure 2. Methylene Blue (2) Formation Method for H2S Detection.
Figure 3. H2S Reducing Azide and Nitro Groups Forming Fluorescence
Amines.
Figure 4. Formation of A Fluorescent Bimane Thioether for H2S
Detection.
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NN
N
Cu
Not fluorescent
H2SNN
N+CuS
Fluorescent
+
2. Hydrogen sulfide releasing agents (H2S donors)
However, the endogenous or the exogenous H2S are showing
different useful effects in many pathophysiological conditions
[50, 51], H2S gas can not be considered as an ideal source for
H2S as it is difficult to reach controlled concentrations and
release of H2S and the toxic effects of high H2S concentrations
[52]. Therefore, novel H2S donors were established that
releasing H2S through different mechanisms such as:
2.1. Inorganic Salts Of Sulfide
Inorganic salts of sulfide are sodium hydrogen sulfide (NaHS)
and sodium sulfide (Na2S) and which are equivalents to H2S.
After the dealings of animal cells and tissues with inorganic
salts of sulfide, it could protect against many diseases [20, 53–
55]. Na2S can also diminish ischemia-induced heart failure and
decrease cardiac hypertrophy, and improving cardiac function
[56]. Na2S can also reduce oxidative stress-related heart failure
[57, 58]. Furthermore, sulfide salts could protect against many
diseases including inflammation [59]. Moreover, the release of
H2S release from sulfide salts is rapid but can lead to severe cell
and tissue damages [60].
2.2. Garlic and Related Sulfur Compounds
Recent studies revealed that many of the biological effects of
garlic were related to H2S release from garlic active constituents
such as Allicin (diallyl thiosulfinate) in aqueous solutions is
unstable and is rapidly decomposed to diallyl sulfide (DAS),
diallyl disulfide (DADS) and diallyl trisulfide (DATS) and also
in the presence of glutathione (GSH), H2S is released (figure 6),
(Figure 7) [61]. Also, garlic polysulfide derivatives can produce
H2S by Human blood cells (RBCs) [62].
SS+SSS
S
SS
SSS
O-
Diallyl Thiosulfinate
(Allicin) Dailllyl Sulfide
(DAS) Diallyl Disulfide
(DADS)
Diallyl Trisulfide
(DATS) Dipropyl Disulfide
(DPDS) Allyl Methyl Sulfide
(AMS)
SS
GS HS S
GS S
DADS GSH Allyl perthiol GSH H2S
R'SSSR GSH
R'SSG
RSSH GSH
GSSRH2S
2.3. Lawesson’s reagent and its analogs
(Lawesson’s reagent) is 2,4-bis(4-methoxyphenyl)-1,3,2,4-
dithiadiphosphetane-2,4-disulfide and is considered as
sulfurization substance used in synthesis [63]. Many biological
activities are related to H2S release including regulation of ion
channels and anti-inflammation showing reduction of ulceration
of the colon and reduced the severity of colitis [64].
lawesson's reagent
S
PSP
S
SO
O
Furthermore, Compound (GYY4137) is the derivative of
Lawesson’s reagent which is water-soluble and upon hydrolysis
releases H2S [65]. H2S released from GYY4137 was much
slower than inorganic sulfide salts which are pH- and
temperature-dependent [66].
GYY4137
H2N O
O
N
P S
S
O
Lately in GYY4137 substituting the phosphorus-carbon with
phosphorus-oxygen affording the phosphorodithioate H2S
donors [67].
NHPh
P
-S
OR
Phosphorodithioate-based H2S donors
R= Br
S
H3CO O2N
Moreover, phosphorodithioates hydrolysis is under acidic
conditions and releases H2S [68]. O-aryl substituted
phosphorodithioates donors exhibited protection against H2O2-
induced oxidative damage and marked enhanced cell viability
[69],[70]. Moreover, phosphorodithioate oligodeoxycytidine
showed activities against the human immunodeficiency virus
[71].
Figure 5. Complexation of Cu (II) With H2S and Precipitation of CuS
Releasing The Fluorescent Compound.
Figure 6. Garlic-Derived Sulfur Compounds.
Figure 7. Release of H2S from Garlic- Sulfur Compounds.
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2.4. 1, 2-Dithiole-3-Thiones:
H2S release from 1,2-Dithiole-3-Thiones (DTTs) is in aqueous
solutions [72–74] (Figure 8). and is measured by a sulfide-
sensitive electrode [75].
SS
S
O
O
R
H2OSS
O
O
O
RH2S
1,2-Dithiole-3-thiones
(DTTs)
+
2.5. Thiol activated H2S donors:
The release of H2S from H2S donors must be slowly and in
moderate amounts and stable compounds [76], Therefore it is
critical for developing new H2S donors with the controlled H2S
release and production.
2.5.1. N-mercapto-based H2S donors:
N-mercapto-based H2S donors were the first thiol-activated
donors of controlled release H2S donors that were stable in
aqueous solutions [77]. Many factors controlling H2S release
including pH, biomolecules and light. The thiol-activated N-
mercapto (N-SH) H2S donors is unstable, however the addition
of acyl groups to N-mercapto (N-SH) for protection of SH
groups could improve the stability [77].
R S H
NPh
O
O
N-SH-Based H2S donors
In the presence of cysteine or GSH, the N-mercapto-based
donors are decomposed releasing H2S (Figure 9). Moreover, the
structure-activity relationship studies revealed that adding of
electron-withdrawing groups caused more and rapid release of
H2S while electron-donating groups showed slower release of
H2S [77].
2.5.2 Perthiol-based H2S donors
Perthiol-based donors which in the presence of thiols (cysteine
or GSH) showed H2S release [78]. (figure 10).
PG SSRDeprotection HS SRH2S
PG= protecting group
thiols
(cysteine or GSH)
perthiols
Primary perthiol-based donors exhibited a marked decrease in
H2S release, The tertiary perthiol-based compounds were more
potent H2S donors. [78] and H2S release can be controlled as in
N-SH-based donors by structural modifications, also steric
effects exhibited slower or no H2S release [78].
The perthiol-based donors exhibited H2S-mediated cardiac
protection in MI/R injury [79–81].
2.5.3 Dithioperoxyanhydrides
Dithioperoxyanhydrides release H2S as perthiol-based donors
and N-mercapto-based H2S donors in both buffers and cellular
lysates [82].
RSSR
O
OR S
OS OCH3
O
dithiocarboxyanhydrides
Figure 8. H2S Release from DTTs.
R S H
N Ph
O
O
HS OH
NH2
O
R S
O
OH
O
NH2
s-acylated cysteine
HS N
Hph
O
N-mercapto benzamide
RH
NOH
O
SH
O
N-acylated cysteine
S to N
acyl transfer
H2NOH
O
SH
Ph NH2
O
benzamide
H2NOH
O
SSH
Cysteine perthiol
HO SSOH
O
NH2
NH2
O
H2NOH
O
HS
H2S
N-SH based H2S donors
Cystiene
+
cystine
Figure 9. Release of H2S from N-mercapto-based H2S Donors in The
Presence of Cysteine or GSH.
Figure 10. Release of H2S from Perthiol-Based H2S Donors.
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Additionally, CH3C(O)SSC(O)CH3 was reported to prompt
vasorelaxation of pre-contracted rat aortic rings [82] (Figure
11).
S
OS
OS
OSH RSH
RSAc
H2SRSSAc
AcSH
RS SH RSH H2S RSSR
(Cysteine or GSH)
RSH
RSH
+
+
2.5.4 Arylthioamides
The lead arylthioamide compound (p-hydroxybenzothioamide)
was followed by more arylthioamide compounds by structural
modifications [83] (Figure 12). However, arylthioamides release
small amounts of H2S but exhibit (3-21 mΜ) as maximum
concentrations [83].
S
NH2
HO
4-hydroxybenzothioamide
Thiol H2S
CN
R1R2
P4S10, EtOH
700C
R1
R2
NH2
S
Ar NH2
OLawesson's
reagent Ar NH2
S
In absence of cysteine release of H2S is very weak in buffers,
however When 4 mM cysteine or GSH (4 mM) with 1 mM of p-
hydroxybenzothioamide showed complete inhibition of
vasoconstriction and a decrease in blood pressure (89 ± 1%)
[83]
2.5.5. S-Aroylthiooximes (SATOs)
S-Aroylthiooximes (SATOs) are also thiol-triggered donors
[84]. Treatment of HCT116 colon cancer cells with 250 μM S-
Aroylthiooximes showed a great reduction of colon cancer cell
viability more than Na2S and GYY4137 [85].
R
O
SN R'
Y
S-Aroylthiooximes
2.5.6. 1,2,4-thiadiazolidine-3,5-dione scaffold
1,2,4-thiadiazolidine-3,5-dione are novel thiol-based H2S
donors aiming to obtain with more controllable H2S release and
is detected by an amperometric method. (1 mM). THIA 3 could
completely diminish any vasoconstriction (Emax > 94%) [86].
2.6. Dual Carbonyl Sulfide / H2S Donors
Compounds releasing carbonyl sulfide (COS)can be used as an
intermediate to generate H2S through the action of carbonic
anhydrase (CA) [87].
2.6.1. N-Thiocarboxyanhydrides
A carbonyl sulfide releasing compounds that in the presence of
glycine and carbonic anhydrase CA, convert carbonyl sulfide
COS into H2S that evaluated by the methylene blue method
[88].
2.6.2. Esterase Activated Carbonyl Sulfide/Hydrogen Sulfide
(H2S) Donors
These compounds are triggered by esterase and release carbonyl
sulfide (COS) followed by carbonyl sulfide (COS) is
hydrolyzed and release H2S [89].
2.6.3. Cyclic Sulfenyl Thiocarbamates
These compounds in presence of cellular thiols generate
carbonyl sulfide (COS) followed by the release of H2S by
carbonic anhydrase (CA) [90] (Figure 13).
S
N
SO
R
R'SH
Cystien,GSH
RNH
SSR'
COS CA H2S
Figure 13. Cyclic Sulfenyl Thiocarbamates Releasing H2S.
Figure 11. H2S Release from Dithioperoxyanhydrides.
Figure 12. Synthesis and Release of H2S from p-hydroxybenzothioamide.
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2.7. Photo-Induced H2S Donors:
2.7.1. Gem-dithiol-based- H2S Donors:
The stable-dithiol-based- H2S Donors are obtained by the
addition of a photolabile 2-nitrobenzyl group for protection of
SH group. Light irradiation liberates the free gem-dithiol
derivatives that are hydrolyzed to release H2S [91–93] (figure
14).
NO2
S S
R1R2
O2N
Light HS SH
R1R2
Hydrolysis H2S
gem-dithiols
Figure 14. Release of H2S from gem-dithiol-based H2S Donors.
2.7.2 Ketoprofenate-caged H2S donors
Lately to develop photolabile H2S donors, ketoprofenate-caged
donors were synthesized and released H2S after the irradiation at
300-350 nm [94, 95] (Figure 15).
Figure 15. H2S Release from The Ketoprofenate-Caged Donor.
2.8 Thioamino acids
Thioglycine and thiovaline are thioamino acids that can be
converted to their corresponding amino acid N-carboxy
anhydrides and releasing H2S in the presence of bicarbonate
[96] (figure 16). Also, the pharmacological benefits showed a
rise in cGMP levels (~ 10-fold increase) and vasorelaxation of
precontracted aortic rings[96].
RSH
O
NH2
HCO3-RSH
O
HN
O
OH HN O
O
O
RHS-
Amino acid
N-carboxyanhydriedes
Thioglycine, R = H
Thiovaline, R = Iso-propyl
Figure 16. Release of H2S from Thioamino Acids.
2.9. Other natural H2S releasing compounds:
Erucin (1‐isothiocyanato‐4‐(methylthio)butane) (ERU), a
natural isothiocyanates H2S‐releasing compounds exhibited
significant antiproliferative effects and at high concentrations
(30–100 μM) could inhibit AsPC‐1 cell viability. ERU could
also inhibit cell migration and showed proapoptotic effects in
pancreatic cancer [97].
SNCS
Erucin
Moreover, the hydrogen sulfide releasing evodiamine derivative
compound I exhibited effective inhibition of human leukemia
HL-60 and epithelial colorectal adenocarcinoma Caco-2 cells
with IC50 values of 0.58 and 2.02 mM, respectively. Also,
Compound I showed mitochondrial dysfunction in HL-60 cells
through induction of apoptosis and arrest the cell cycle at the
G2/M phase [98].
N
N
N
O
O
O
OS
S
S
I
3. Biological activities of Hydrogen sulfide:
H2S exhibits various biological activities at concentrations
between 10 and 300 µM [3]. Whereas, H2S can modulate many
physiological responses including reducing oxidative stress
[21], anti-inflammatory [20], neuromodulation [22], protection
against myocardial ischemia injury [24], vasoregulation [23]
and inhibition of insulin resistance [25].
3.1. Vasodilation and anti-hypertensive effects
Studies reported that H2S showed relaxation of blood vessels
similar to NO by altering K+ channel and increased cGMP
levels of vascular smooth muscles [99, 100]. It also reported
that the H2S donor (NaHS) causing reduction of hypertension
through rapid relaxation of aortic rings smooth muscles due to
opening KATP channels [65]. The genetic deletion of
cystathionine c-lyase (CSE) the H2S generating enzyme cause
hypertension [99].
3.2. Anti-inflammatory effects
As known that chronic and excessive administration of
nonsteroidal anti-inflammatory drugs induce gastroenteropathy,
and it was suggested that NSAIDs cause suppression of
cystathionine c-lyase (CSE) expression lead to a decrease of
endogenous H2S synthesis in gastric injury [101–103].
Therefore, the administration of exogenous H2S could reduce
gastric injury [104]. Also, the short-term treatment with NaHS
down-regulated expression of IL-6 and IL-8 and showed anti-
inflammatory effects against osteoarthritis OA [59]. Moreover,
GYY4137 could inhibit the production of pro-inflammatory
mediators such as nitric oxide, TNF-α, IL-1β, IL-6 and PGE2
and rise the anti-inflammatory IL-10 chemokine levels[75].
3.3. Anti-oxidant effects
As known that H2S has antioxidant properties via stimulation of
glutathione metabolism [105] and increasing the activity of
cysteine that increasing substrates for production of glutathione
(GSH) [106]. Also, H2S causes up-regulation of intracellular
antioxidants and protection from ischemia-reperfusion (I/R)
injury [107]. Moreover, H2S could reduce mitochondrial ROS
production through inhibition of cytochrome C oxidase [109].
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3.4. Fibrinolytic activity
Essential oils of garlic showed a significant reduction in the rise
in blood coagulation of hypercholesterolemic rabbits [110].
Furthermore, recent studies on garlic showed inhibition of
platelet aggregation and increased fibrinolytic activity [111].
3.5. Anti-platelet activation and aggregation effects
Observations indicated that garlic H2S releasing compounds
could be helpful in the prevention of thrombosis [112]. It was
found that treatment of rabbits with garlic extract could block
synthesis of thromboxane-B2 (TXB2) that protects from
thrombocytopenia [112]. Moreover, garlic aqueous extract
prevents platelet aggregation stimulated by collagen and
epinephrine in vitro [113]. Moreover, diallyl disulfide and
diallyl trisulfide in garlic could inhibit platelet thrombus
formation in stenosed coronary arteries [114].
3.6. Pro-angiogenic effects
Angiogenesis is a microvascular growth that revascularizes
ischemic tissues and has an important role in modifying and
developing chronic inflammation and tumorigenesis [115, 116].
It was reported that low micromolar concentrations of Na2S or
NaHS could modulate angiogenesis by increasing endothelial
cell growth and migration [115, 117, 118]. More studies showed
that H2S could improve blood flow and microvascular growth in
ischemic organs [119]. Additionally, H2S regulates angiogenesis
with other molecules, such as NO and CO [120] by increasing
cGMP in vascular smooth muscle cells that inhibiting
phosphodiesterase action [121].
3.7. Cardioprotective effects (MI and I/R)
Many studies showed that H2S has a cardioprotective effect in
vitro and in vivo [24, 57, 58, 122]. The CSE inhibitor DL-
propargylglycine (PAG) inhibiting endogenous H2S production
that inhibits the cardioprotective effect. It has been
demonstrated that at elevated plasma H2S concentrations a
decrease of infarct size and mortality after MI, while at
decreased H2S levels in the plasma the infarct size and mortality
are increased [123]. Also, H2S causes opening K-ATP channels
that protect the heart during I/R injury [122], [24, 123, 124].
Moreover, H2S could block cytochrome c oxidase that inhibits
cellular respiration and protect against myocardial ischemic
injury [125, 126]. H2S could also suppress Na+/H+ exchanger
and prevent Ca2+ overload of the ischemic heart that explains
the H2S cardioprotection effect [127].
3.8. Metabolic suppression
Literature reported that after administration of H2S the
metabolic oxygen demand is reduced through inhibition of the
cellular oxygen receptors [128–130]. Also, the metabolic rate is
reduced reversibly with decreased cardiovascular function
without affecting blood pressure in mice [131].
3.9. Anticancer activity
As reported that H2S could affect cell transporters [132] and ion
channels causing down-regulation of cellular activities [133,
134]. Also after the treatment of HEK293 cells with NaHS
caused inhibition of voltage-gated T-type Cav3.2 channels [135]
and increased anticancer effects and enhanced sensitivity of
cancer cells to drugs [136, 137]. Moreover, DAS and DATS
caused a decrease in tumor growth due to increased expressions
of heme oxygenase-1 (HO-1) [140, 141]. Also, NaHS treatment
enhances the release of NO and increased cytoprotective effects
in L1210 leukemia cells [142].
H2S Cancer suppressing activities:
3.9.1. H2S donor regulates immune responses
Treatment of glomerulus cells with NaHS could protect against
antibody-induced cell lysis and reducing antibody binding
ability lead to a reduction of apoptosis [143].
3.9.2. H2S donors regulating many transcription factors
H2S can affect various transcription factors including STAT-3
[139], NF-кB [144] and Nrf-2 [145] which are included in
apoptosis and inflammation. NaHS and GYY4137 showed
protection from inflammatory and apoptotic reactions through
sulfurating the p65 subunit of NF-кB at Cys-38 in
monocyte/macrophage [146, 147]. Moreover, the treatment with
NaHS, GYY4137 or DATS could enhance Nrf-2 antioxidant
pathway that improves antioxidant status [148].
3.9.3. H2S donor blocks cell cycle
It was reported that GYY4137 could induce arrest of cell cycle
at G1/S in HCC cells [139], and S-G2/M phases in colorectal
cancer [149] and breast cancer cells [66]. Also, NaHS could
trigger G0/G1 arrest that prevents cell cycle progression in
breast cancer [150]. Moreover, DATS could induce DNA
damage and arrest G2/M phase in thyroid and bladder cancer
[151, 152], and in prostate cancer[153]. Also, DATS enhanced
the intercellular cyclins (A2 and B1) expression, and increased
levels of apoptotic markers (Bax, p53, cleaved caspase 8, 9, and
cytochrome c) and phosphorylation of histone 3 in gastric
cancer [154, 155]. Additionally, DADS could induce arrest of
G2/M phase in pancreatic [156] and ovarian cancer [157].
3.9.4. H2S donor modulating cell proliferation and viability
H2S could interact with the cell cycle regulators that control cell
proliferation and viability by [155, 158]. As GYY4137 could
enhance cell cycle arrest and apoptosis that showed pro-
proliferation activities in colon and breast cancer [66, 149].
Moreover, DATS could decrease cell proliferation and viability
in gastric cancer [155], osteosarcoma [158]. Also, NaHS could
inhibit the growth of HepG2 cells [159] and breast cancer MCF-
7 cells [150].
3.9.5. H2S donor inhibiting cell migration and invasion
NaHS (600-1000 μM) could inhibit migration and invasion of
tumor cells due to regulation of EGFR/ERK/MMP-2 and
PTEN/AKT pathways in HCC cells [160]. Moreover, 200 μM
NaHS caused deactivation of the MAPK and PI3K/AKT/mTOR
pathways that inhibited migration activities in thyroid cancer
cells [161]. However, treatment of colon cancer HT29 cells with
DATS could decrease vascular endothelial growth factor, focal
adhesion kinase and inhibiting p38, MAPK and JNK signaling
cascades that prevented angiogenesis and migration [162].
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3.9.6. H2S donor induces apoptosis
H2S could interact with numerous apoptosis-inducing pathways
that cause the regulation of apoptosis [149, 163]. GYY4137
could increase the apoptotic markers caspase-9 expressions in
breast cancer MCF-7 cells, colorectal cancer Caco-2 cells [149],
and ovarian cancer A2780 cells [164], without affecting normal
cell lines [66]. Moreover, GYY4137 showed a significant
increase in apoptotic activities in HCC cells through the
prevention of phosphorylation of STAT-3 prompted by
interleukin-6 and JAK-2 [139]. In addition, NaHS causes
upregulation of apoptosis- genes caspase-3 expressions and
suppression of anti-apoptotic marker Bcl-2 through modulation
of p38, MAPK and p53 pathways [165]. Also, DATS could
induce apoptosis by enhancing mitochondria-mediated DNA
damage [151]. Moreover, DADS could suppress cancer
progression by enhancing DNA damage [156]. Furthermore,
HA-ADT (a hybrid formed from ADT-OH and hyaluronic acid)
showed a very great apoptotic index in breast cancer cells
compared to NaHS and GYY4137 [166].
3.9.7. H2S donor increase the sensitivity of cancer cells to
anticancer drug
In addition to H2S exhibited anti-cancer activities even in drug-
resistant cancer cells including cisplatin-resistant cells [167],
H2S donors could also increase the sensitivity and decrease the
resistance of cancer cells to anti-cancer agents [155, 168].
Treatment with DATS could improve the sensitivity of cancer
cells to docetaxel (anticancer drug) the anti-cancer drug and
increased the survival of gastric cancer patients through
elevation of the mRNA and MT2A protein levels [168].
Moreover, treatment of osteosarcoma cells with DATS could
suppress multidrug resistance protein 1 (P-gp1) and reduce drug
resistance [169]. Furthermore, treatment of breast cancer cells
with NaHS could increase tumor oxygen levels and enhance
radiosensitivity [170]. In addition, NaHS could decrease the
methotrexate (MTX) induced hepatotoxicity [171].
3.9.8. H2S donor decreasing in vivo tumor growth
The treatment of leukemia model with 100-300 mg/kg
GYY4137 showed a decrease in cancer growth and size [66]. It
was reported that (50 mg/kg/day) GYY4137 decreased
subcutaneous HepG2 cancer growth and size through regulation
of STAT-3 pathway [139]. Moreover, DADS/DATS cause
inhibition of cancer growth, size and weight [172]. Similarly,
treatment of HCC mice model with NaHS(0.8-1 mM ) leads to
suppression of cancer growth and development [160].
4. H2S donors hybrids:
As known that molecular hybridization is commonly used
in drug design and development depending on binding two or
more pharmacophoric groups having more biological activities
to obtain a novel hybrid with enhanced affinity, efficacy and/or
decreased side effects compared to the parent drugs[173]. Such
a strategy was used in many studies gathering an H2S donor
pharmacophore with another pharmacologically active moiety.
NSAIDs were the most used drug moieties in the design of such
hybrids.
4.1. HS/NSAIDs
O
S
S
NSAID
OS
HS/NSAIDS
NSAIDs were coupled with 1,2-Dithiole-3-thiones DTTs giving
HS-hybrid NSAIDs (HS-NSAIDs) exhibited a decrease of
gastrointestinal injury caused by the corresponding NSAIDs
[74, 174, 175] (Table 1). In addition, HS-SUL, HS-IBU, HS-
ASA and HS-NAP showed significant inhibition of several
human cancer cell growth such as leukemia, colon, breast, lung,
prostate and pancreas cancer cells [176].
ATB-346 a naproxen-hydroxybenzothioamide hybrid that
exhibited to promot apoptosis in melanoma cells [177]. ATB-
346 when compared to naproxen showed a decrease in
gastrointestinal tract damage with anticancer activity against
colorectal cancer [178]. ATB-346 could also induce cell death
through suppression of AKT and NF-кB signaling and reduction
of cyclooxygenase-2 (COX-2) effects in human melanoma cells
[177].
O
O
O
S
NH2
ATB-346
Moreover, the dual nitric oxide and hydrogen sulfide-releasing
hybrid NOSH-aspirin (NBS-1120), showed significant
anticancer activity with IC50s of 45.5 ± 2.5, 19.7 ± 3.3, and 7.7 ±
2.2 nM at 24, 48, and 72 h, respectively against HT-29 colon
cancer cells. Also, NOSH–aspirin could block could G0/G1 cell
cycle, induced apoptosis and inhibit cell proliferation, [179].
NOSH–aspirin exhibited anti-inflammatory by the decrease of
the interleukin-1 beta (IL-1b) production in carrageenan-
induced paw inflammation and reduced prostaglandin E2-
induced hyperalgesia and more potency than aspirin and
reduced inflammatory pain [180].
O
O
O
OONO2
SS
S
H2S
NO
NOSH-aspirin
(NBS-1120)
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J. Adv. Biomed. & Pharm. Sci .
NSAIDs
HS/NSAIDs Hybrid
NH
O
OH
Cl
Cl
diclofenac
NH
O
O
S
S
S
Cl
Cl
ATB-337
F
SO
HO
O
sulindac
O
OS
S
S
S
O
HS-SUL
F
O
OH
Ibuprofen
O
OS
S
S
HS-IBU
O OH
O
O
aspirin
O
O
O
O
S
S
S
HS-ASA
O
HO
O
naproxen
O
O
OS
S
S
HS-NAP
Table 1. Structures of HS-NSAIDs and Their Corresponding NSAIDs.
239
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J. Adv. Biomed. & Pharm. Sci .
Shabib et al
.
4.2. Other synthetic H2S hybrids
NON
O
O
O
NH
S
O
O
ZYZ-803
NCS
O
O
R
R
RR
R=OAc
II
ONCS
R
R
RR
III
R=OAc
CHOOO
OO
O
OS
S
S
O
IV
O
O
O
OH
O
R
O
O
O
O
SS
R=
V
Mo
SS-
S
-SNH4+
NH4+
Ammonium tetrathiomolybdate
(ATTM)
O N NSPt
S
Cl
P
F F
F
VI
NH2
S
O
O
O
n
S S
O
O
O
On
n=6,8 n=2,4
VII VIII
RO
O
OSS
S
IX R=CH3
X R=CH2OH
Figure17. Structures of Some Synthetic H2S Hybrids.
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Shabib et al
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J. Adv. Biomed. & Pharm. Sci .
The novel hydrogen sulfide-nitric oxide donor hybrid ZYZ-803
could stimulate STAT3/CaMKII pathway in angiogenesis
through H2S/NO-mediated mechanisms [181]. Moreover, HA-
ADT a novel hydrogen sulfide-releasing donor caused inhibition
of the Ras/Raf/MEK/ERK and PI3K/AKT/mTOR pathways that
decreased the breast cancer cells growth. Results showed that
HA-ADT could suppress breast cancer cells growth, migration
and invasion. Also, HA-ADT increased the apoptotic index of
breast cancer cells [166].
Compounds (II and III) are H2S‑Releasing Glycoconjugates
showed anticancer activities of pancreas adenocarcinoma
metastasis AsPC-1 and are effective in decreasing cell viability.
These compounds (II and III) produce H2S inside the AsPC-1
cells that modify the basal cell cycle [182].
A new series of hydrogen sulfide donating ent-kaurane and
spirolactone-type 6,7- seco-ent-kaurane derivatives with
anticancer activity against four human cancer cell lines (K562,
Bel-7402, SGC-7901 and A549) and two normal cell lines (L-
02 and PBMC) specially compound IV that was the most potent
with IC50 values of 1.01, 0.88, 4.36 and 5.21 mM, respectively
[183]. The antiproliferative activity of IV was through Bel-7402
cell cycle arrest at G1 phase and induction of apoptosis by
enhancing the Bax, cleaved caspase-3 and cytochrome c
expression and inhibition of procaspase-3, Bcl-2 and PARP
[184]. Furthermore, compound V one of enmein- diterpenoid
H2S releasing hybrids showed the most potent antiproliferative
activity and release of hydrogen sulfide due to α-thioctic acid
moiety and could induce apoptosis through mitochondria-
related pathways with anticancer activities against Bel-7402,
SGC-7901 and A549 cancer cells with IC50 of 2.16, 5.07 and
6.98 μM respectively. However, having little activity on normal
cell lines L-02 and PBMC with IC50 of 15.81 μM and 14.15 μM
respectively [185].
Ammonium tetrathiomolybdate (ATTM) is releasing H2S and is
commonly used for chelation of copper. As high levels of
copper stimulate tumor and cancer growth, it was found that at
high concentrations of ATTM cell growth was inhibited while
at low concentrations cell growth is enhanced in three lung
adenocarcinoma cell lines (A549, HCC827, and PC9).
Conversely, triethylenetetramine another chelator of copper not
producing H2S does not promote cell growth [186].
Furthermore, Platinum(II) dithiocarbamate H2S releasing
compound [Pt(S2CNR2)Cl(PAr3)] VI showed potent anticancer
activities which could cleave DNA double-helical structure that
inhibits tumor cells replication and growth [187].
The hydrogen sulfide donor oleanolic acid/ursolic
acid/glycyrrhetinic acid- and their 25–pentacyclic triterpene
hybrids showed anti-tumor activity especially VII and VIII
hybrids that revealed anticancer activity against K562 cell line.
[188].
The novel nitric oxide-hydrogen sulfide donor Chalcone hybrids
especially compound IX and X exhibited vasorelaxation in
Isolated Rat Aorta with pEC50 of 3.716 and 3.789 M,
respectively and produced significant activation and release of
cGMP [189].
Conclusion:
H2S releasing agents showing several biological activities with
many physiological effects. Besides the anti-inflammatory and
anti-cancer activities, H2S releasing agents also showed anti-
oxidant effects and regulation of cardiovascular functions via
ion channel alteration. Inorganic salts of sulfide are helpful to
study H2S biological importance, but the acute and rapid rate of
H2S release makes them not ideal H2S donors. Natural H2S
releasing agents are potent antioxidant, anti-inflammatory and
anti-tumor compounds. Based on the scope of H2S donors,
several new synthetic H2S releasing compounds with effective
moieties such as polysulfide, thioamide, disulfide and anethole
trithione have been evaluated for different pathophysiological
effects. These agents can be combined with specific scaffolds
for targeted therapy. Finally, it is critical for developing novel
H2S releasing drugs with a slow and consistent rate of H2S and
improved efficacy and decreased undesired side or toxic effects.
In addition, the solubility of these agents must be controlled to
obtain a good pharmacokinetic profile and the donor must be
with good aqueous stability. Finally, the importance of the
synthesis and development of H2S releasing agents with
enhanced properties will support moving these agents in the
direction of clinical trials.
Funding statement: no funding.
Author contributions: All authors are equal in contribution.
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