Hydrogen Sulfide Donors Activated by Reactive Oxygen Species

Article abstract of DOI:10.1002/anie.201608052

Hydrogen sulfide (H₂S) exhibits promising protective effects in many (patho)physiological processes, as evidenced by recent reports using synthetic H₂S donors in different biological models. Herein, we report the design and evaluation of compounds denoted PeroxyTCM, which are the first class of reactive oxygen species (ROS)-triggered H₂S donors. These donors are engineered to release carbonyl sulfide (COS) upon activation, which is quickly hydrolyzed to H₂S by the ubiquitous enzyme carbonic anhydrase (CA). The donors are stable in aqueous solution and do not release H₂S until triggered by ROS, such as hydrogen peroxide (H₂O₂), superoxide (O₂^?), and peroxynitrite (ONOO^?). We demonstrate ROS-triggered H₂S donation in live cells and also demonstrate that PeroxyTCM-1 provides protection against H₂O₂-induced oxidative damage, suggesting potential future applications of PeroxyTCM and similar scaffolds in H₂S-related therapies.

Full text of DOI:10.1002/anie.201608052

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International Edition: DOI: 10.1002/anie.201608052
German Edition: DOI: 10.1002/ange.201608052
H2S Donors
Hydrogen Sulfide Donors Activated by Reactive Oxygen Species
Yu Zhao and Michael D. Pluth*
Abstract: Hydrogen sulfide (H2S) exhibits promising protec-
tive effects in many (patho)physiological processes, as evi-
denced by recent reports using synthetic H2S donors in
different biological models. Herein, we report the design and
evaluation of compounds denoted PeroxyTCM, which are the
first class of reactive oxygen species (ROS)-triggered H2S
donors. These donors are engineered to release carbonyl
sulfide (COS) upon activation, which is quickly hydrolyzed to
H2S by the ubiquitous enzyme carbonic anhydrase (CA). The
donors are stable in aqueous solution and do not release H2S
until triggered by ROS, such as hydrogen peroxide (H2O2),
À
superoxide (O2 ), and peroxynitrite (ONOOÀ). We demon-
strate ROS-triggered H2S donation in live cells and also
Figure 1. Selected H2S donating molecules and motifs.
demonstrate that PeroxyTCM-1 provides protection against
H2O2-induced oxidative damage, suggesting potential future
applications of PeroxyTCM and similar scaffolds in H2S-
related therapies.
instantaneous and uncontrollable H2S release from these salts
does not mimic endogenous generation and often result in
acute side effects and contradictory results (i.e. pro- and anti-
inflammatory effects).[9] Two of the most commonly used H2S
donor classes include polysulfides derived from natural
products, such as diallyl trisulfide (DATS),[10] and hydroly-
sis-based donors, such as GYY4137,[11] derived from Law-
essonꢀs reagent, both of which exhibit H2S-related protective
effects in a wide array of systems.[8b–e] Additionally, dithiole-
thione (ADT) and its derivative ADT-OH have been used to
develop a series of H2S-hybrid nonsteroidal anti-inflamma-
tion drugs, which greatly reduce GI damage while maintain-
ing NSAID activity.[12] Synthetic thiol-activated H2S donors
have also been developed based on protected disulfides, with
some exhibiting promising protective effects in animal
models.[13] More recently, donors based on esterase-activa-
tion[14] and pH-modulation[15] have been reported, and
demonstrated to influence inflammatory response factors
and provide protection in oxidative stress models, respec-
tively. In addition, other H2S-donating motifs, such as
thioamino acids,[16] caged gem-dithiols,[17] and caged keto-
profenate,[18] are also being investigated for different appli-
cations. Despite the diverse palette of available donor motifs,
two main challenges remain. First, many synthetic donors lack
appropriate, H2S-depleted control compounds, which compli-
cates conclusions drawn from use of these donors. Second,
few donors can be triggered by specific cellular species or
events, thus limiting the tunability of available platforms.
Based on these needs, H2S donors that respond to specific
stimuli and have suitable control compounds would provide
a significant advance.
H
ydrogen sulfide (H2S) is now recognized as an important
cellular signaling molecule owing to its important functions in
various aspects of human health and disease, and also as
a member of the gasotransmitter family along with nitric
oxide (NO) and carbon monoxide (CO).[1] Biological H2S is
generated primarily from Cys and/or Hcy by cystathionine g-
lyase (CSE), cystathionine b-synthase (CBS), cysteine amino-
transferase (CAT), and 3-mercaptopyruvate sulfur transfer-
ase (3-MST), which work either individually or in concert.[2]
In many cases, both endogenous H2S production, as well as
exogenous H2S administration, has been demonstrated to
protect cells, tissues, and organs against damage associated
with different (patho)physiological processes.[3,4] For example,
H2S shows potent anti-inflammation effects in animal
models[5] and exhibits antioxidant properties and protective
effects against reactive oxygen species (ROS).[6] Additionally,
H2S provides protection against myocardial ischemia reper-
fusion (MI/R) injury by consuming ROS generated by
dysfunctional mitochondria and thus preserving cardiac
activity.[7]
Many researchers use H2S-releasing small molecules
(“H2S donors”) as primary tools to modulate cellular H2S
levels (Figure 1).[8] Although exogenous administration of
Na2S or NaHS provides a convenient source of H2S, the
[*] Dr. Y. Zhao, Prof. Dr. M. D. Pluth
Department of Chemistry and Biochemistry, Institute of Molecular
Biology, and Materials Science Institute
University of Oregon
A viable platform to access such responsive H2S donors
stems from related H2S sensing work recently report by us, in
which a new class of analyte-replacement fluorescent probes
was developed using the engineered release of carbonyl
sulfide (COS) from thiocarbamates.[19] Importantly, probe
Eugene, OR 97403 (USA)
E-mail: pluth@uoregon.edu
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201608052.
activation generated
a fluorescence response and also
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released COS, which is quickly hydrolyzed to H2S by carbonic
anhydrase (CA), a ubiquitous enzyme in plants and mammals.
Recognizing the potential utility that similar platforms could
provide for triggered COS/H2S release, we envisioned that
caged-thiocarbamates could also serve as a new and diverse
class of H2S donors that could be engineered to release H2S in
response to specific stimuli. Importantly, these donors would
operate by mechanisms dissimilar to currently available H2S
donors, and would enable access to viable H2S-depleted
control compounds absent from most donor constructs, thus
addressing major limitations in the field. Herein we report the
use of caged thiocarbamates, in combination with ROS-
responsive arylboronate triggers, to access the first class of
triggerable COS/H2S donors activated by cellular ROS
(Scheme 1a).
Figure 2. a) H2S release from PeroxyTCM-1 (50 mm) in the presence of
H2O2 (50–1000 mm) in PBS (pH 7.4, 10 mm) containing CA
(25 mgmLÀ1). b) H2S release from thiocarbamates (50 mm) in the
presence of H2O2 (500 mm) in PBS (pH 7.4, 10 mm) containing CA
(25 mgmLÀ1).
respectively, which are consistent with increased H2O2
scavenging by H2S at higher ROS concentrations. We next
evaluated PeroxyTCM-2 and PeroxyTCM-3 and demon-
strated that the rate of H2S release can be tuned by electronic
modulation of the thiocarbamate (Figure 2b). In contrast,
TCM-1 and TCM-2, which lack the H2O2-reactive arylboro-
nate trigger, failed to release H2S upon treatment with H2O2
(Figure 2b). Taken together, these studies demonstrate that
arylboronate-functionalized thiocarbamates provide a func-
tional platform to access H2O2-mediated H2S donors.
We investigated whether CAwas essential to convert COS
into H2S by incubating PeroxyTCM-1 with H2O2 (10 equiv) in
the absence of CA. Although COS can be hydrolyzed to H2S
under both acidic and basic conditions, this hydrolysis is much
slower at physiological pH.[20] Unexpectedly, a positive H2S
release response was observed, indicating that COS could
react directly with H2O2 to generate H2S in a CA-independent
pathway (Figure S2a). To further investigate these observa-
tions, we treated an aqueous solution (10 mm PBS, pH 7.4) of
COS gas with H2O2. No H2S was detected prior to H2O2
addition, whereas H2O2 addition resulted in rapid H2S
generation (Figure S2b). Notably, these studies demonstrate
that H2O2 alone can convert COS into H2S directly, although
this process was significantly slower than CA-catalyzed COS
hydrolysis.
Scheme 1. Design (a) and synthesis (b) of ROS-triggered H2S donors.
To test our hypothesis that thiocarbamate functionalized
arylboronates could function as ROS-triggered H2S donors,
we prepared three thiocarbamate donors (peroxythiocarba-
mate: PeroxyTCM-1, PeroxyTCM-2, and PeroxyTCM-3) and
two carbamate control compounds (thiocarbamates: TCM-
1 and TCM-2). The PeroxyTCM compounds are stable in
aqueous buffer (pH 5–9) and are not hydrolyzed by esterases.
We also prepared the parent carbamate (peroxycarbamate-1,
PeroxyCM-1), which can also be activated by ROS, but
releases CO2/H2O instead of COS/H2S. Access to these simple
control compounds provides useful tools to determine
whether observed biological activities of the donors are
H2S-related or merely a product of the organic scaffold and/or
byproducts.
To evaluate the H2S release from the donor constructs in
the presence of ROS, we used an H2S-selective electrode to
monitor H2S release from PeroxyTCM-1 (50 mm) upon treat-
ment with H2O2 (50–1000 mm) in PBS buffer (pH 7.4, 10 mm)
containing CA (25 mgmLÀ1). Consistent with our hypothesis,
we observed H2O2-dependent H2S release from PeroxyTCM-
We next evaluated which specific reactive sulfur, oxygen,
and nitrogen species (RSONS) resulted in donor activation by
measuring H2S release from PeroxyTCM-1 after incubation
with different RSONS (Figure 3). We found that incubation
with H2O2, O2À, or ONOOÀ resulted in H2S release, with
H2O2 being the most active trigger. Other RSONS, such as
hypochlorite (ClOÀ), hydroxyl radical (HO·), singlet oxygen
(1O2), tert-butyl hydroperoxide (TBHP), tert-butoxy radical
(tBuO·) cysteine (Cys), reduced glutathione (GSH), oxidized
glutathione (GSSG), S-nitrosoglutathione (GSNO), nitrite
À
(NO2 ), sulfate (SO42À), thiosulfate (S2O32À), NO, or nitroxyl
(HNO) failed to release H2S.[21] Taken together, this selectiv-
ity screening demonstrates that only specific ROS (H2O2,
O2À, and ONOOÀ) activate PeroxyTCM-1 to release H2S.
Before investigating different potential biological appli-
cations of the PeroxyTCM compounds, we first investigated
to cytotoxicity of PeroxyTCM-1, PeroxyCM-1 and TCM-
1
with corresponding second-order rate constant of
1.44mÀ1 sÀ1 (Figure 2a, Figure S1 in the Supporting Informa-
tion). Quantification of H2S release, 50 mm PeroxyTCM-
1 using electrode data demonstrated a H2S release efficiencies
of 80% and 60% in the presence of 250 mm and 500 mm H2O2,
2
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Having demonstrated activation by exogenous ROS, we
next investigated the response of PeroxyTCM-1 to endoge-
nous ROS generation. RAW 264.7 cells were incubated with
phorbol 12-myristate 13-acetate (PMA), which is a well-
established method to induce ROS and H2O2 production in
macrophages.[23] ROS generation was confirmed using 2’,7’-
dichlorofluorescin diacetate (DCFDA; Figure S6). Perox-
yTCM-1-treated cells were stimulated by PMA, and H2S
release was monitored using HSN2. In the absence of PMA,
no fluorescent signal from HSN2 was observed. By contrast,
addition of 500 nm PMA resulted in a significant increase in
signal from HSN2 corresponding to the released H2S
(Figure 5). These studies confirm that PeroxyTCM-1 is sensi-
tive enough to be activated by endogenous ROS, suggesting
that it may provide a viable platform for ROS-related H2S
investigations.
Figure 3. H2S release response of PeroxyTCM-1 (50 mm) to various
RSONS (5 mm for GSH, 500 mm for all other RSONS) in PBS buffer
(pH 7.4, 10 mm; 100 mm for GHS and ONOOÀ). Experiments were
performed at room temperature for 20 min. The response is expressed
as meanÆSD (n=3).
1 (10–100 mm) in HeLa cells. No significant decrease in cell
viability was observed after a 2 h incubation, indicating that
none of the three compounds exhibited appreciable cytotox-
icity at the tested concentrations (Figure S3). We next
investigated whether exogenous H2O2 could be used to
release H2S in cellular environments by incubating HeLa
cells with PeroxyTCM-1 (50 mm) followed by treatment with
H2O2 (25 mm or 50 mm). We used HSN2, a reaction-based H2S
fluorescent probe, to monitor H2S accumulation by fluores-
cence microscopy.[22] In the absence of H2O2, no HSN2
fluorescence was observed, confirming that PeroxyTCM-
1 was stable and did not release H2S in a normal cellular
environment. By contrast, addition of H2O2 resulted in a H2O2
dose-dependent increase in HSN2 fluorescence (Figures 4
and Figure S5), confirming that PeroxyTCM-1 can be acti-
vated by exogenous ROS in a cellular environment to release
H2S.
Figure 5. H2S release from PeroxyTCM-1 in RAW 264.7 cells. Cells were
co-incubated with PeroxyTCM-1 (50 mm), HSN2 (5 mm), and NucBlue
dye for 30 min. After washing, cells were incubated in FBS-free DMEM
in the absence (Top row) or presence (Bottom row) of PMA (500 nm)
for 3 h.
In addition to cellular imaging experiments, we also
investigated whether the developed ROS-activated donors
could provide protection against ROS-related oxidative stress
in simple cell culture models. Recent studies suggest that ROS
play deleterious roles in various physiological and patholog-
ical systems ranging from aging to cardiovascular damage. In
many cases, H2S administration can provide partial protection
or rescue from these different disease states. For example,
ROS generated during mitochondrial dysfunction are respon-
sible for a wide range of damage in the cardiovascular system,
including MI/R injury, and that exogenous H2S significantly
preserved cardiac activity through a ROS scavenging path-
ways.[7b,24] On the basis of this H2S/ ROS relationship, we
envisioned that PeroxyTCM compounds would exhibit sim-
ilar cytoprotective effects toward ROS-induced damage due
to H2S release.
Figure 4. H2S release from PeroxyTCM-1 in HeLa cells. HeLa cells
were co-incubated with PeroxyTCM-1 (50 mm), HSN2 (5 mm), and
NucBlue nuclear dye for 30 min. After removal of extracellular Perox-
yTCM-1 and HSN2, cells were incubated in FBS-free DMEM in the
absence (Top row) or presence (Bottom row) of H2O2 (50 mm) for
30 min.
To simulate increased cellular oxidative stress, we incu-
bated HeLa cells with H2O2 (50–400 mm) for 1 h and observed
a dose-dependent reduction of cell viability (Figure 6a). Since
100 mm of H2O2 led to approximately 70% cell death, this
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related COS-related H2S donors triggered by other mecha-
nisms are ongoing.
Acknowledgements
Research reported in this publication was supported by Sloan
Foundation and Dreyfus Foundation. Applications on H2S
sensing were supported by the NIH (R01GM113030). NMR
spectroscopy and microscopy capabilities in the UO
CAMCOR facility are supported by the NSF (CHE-
1427987, CHE-1531189).
Keywords: carbonyl sulfide · hydrogen sulfide · oxidative stress ·
reactive oxygen species · thiocarbamate
Figure 6. a) Cytotoxicity of H2O2 (50–400 mm) in HeLa cells. Cytopro-
tections of b) PeroxyTCM-1, c) PeroxyCM-1, and d) TCM-1 against
H2O2-induced (100 mm) oxidative stress in HeLa cells. Results were
expressed by mean Æ SEM (n=5). ****P<0.0001 vs. VEH group;
##P<0.01, ###P<0.001, and ####P<0.0001 vs. H2O2-treated group,
respectively.
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Received: August 17, 2016
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Revised: September 21, 2016
Published online: && &&, &&&&
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Communications
H2S Donors
Y. Zhao, M. D. Pluth*
&&&& — &&&&
Hydrogen Sulfide Donors Activated by
Reactive Oxygen Species
Release and protection: H2S is an
triggered to release H2S on exposure to
reactive oxygen species (ROS), such as
hydrogen peroxide. It also provides live
cells protection against H2O2-induced
oxidative damage.
important biomolecule and H2S donors
are valuable research and pharmacolog-
ical tools. An H2S donor is prepared that
is stable in aqueous solution and is
6
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