A Persulfide Donor Responsive to Reactive Oxygen Species: Insights into Reactivity and Therapeutic Potential

Article abstract of DOI:10.1002/anie.201803087

Persulfides (RSSH) have been hypothesized as critical components in sulfur-mediated redox cycles and as potential signaling compounds, similar to hydrogen sulfide (H₂S). Hindering the study of persulfides is a lack of persulfide-donor compounds

Full text of DOI:10.1002/anie.201803087

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International Edition: DOI: 10.1002/anie.201803087
German Edition: DOI: 10.1002/ange.201803087
Reactive Oxygen Species
A Persulfide Donor Responsive to Reactive Oxygen Species: Insights
into Reactivity and Therapeutic Potential
Chadwick R. Powell, Kearsley M. Dillon, Yin Wang, Ryan J. Carrazzone, and John B. Matson*
Abstract: Persulfides (RSSH) have been hypothesized as
critical components in sulfur-mediated redox cycles and as
potential signaling compounds, similar to hydrogen sulfide
(H2S). Hindering the study of persulfides is a lack of
persulfide-donor compounds with selective triggers that release
discrete persulfide species. Reported here is the synthesis and
characterization of a ROS-responsive (ROS = reactive oxygen
species), self-immolative persulfide donor. The donor, termed
BDP-NAC, showed selectivity towards H2O2 over other
potential oxidative or nucleophilic triggers, resulting in the
sustained release of the persulfide of N-acetyl cysteine (NAC)
over the course of 2 h, as measured by LCMS. Exposure of
H9C2 cardiomyocytes to H2O2 revealed that BDP-NAC
mitigated the effects of a highly oxidative environment in
a dose-dependent manner over relevant controls and to
a greater degree than common H2S donors sodium sulfide
(Na2S) and GYY4137. BDP-NAC also rescued cells more
effectively than a non-persulfide-releasing control compound
in concert with common H2S donors and thiols.
redox chemistry in a biological context will allow further
development of therapeutics that exploit pathways involved
in H2S signaling.
Dean and co-workers first identified persulfides in
a biological context in their 1994 report on a protein
persulfide intermediate of the cysteine desulfurase NifS.[10]
Persulfides are prevalent in mammalian biology, generated by
À
reaction of an oxidized thiol (e.g., a sulfenic acid, R SOH)
with H2S in a process called S-persulfidation.[11] More
nucleophilic than thiols, persulfides have pKa values a few
units lower than their corresponding thiols,[12] as well as
greater reduction potentials,[13] making them highly reactive,
transiently stable species. In a biological context, persulfides
protect thiols from irreversible oxidation, serve as reactive
intermediates in sulfur shuttling,[14] and alter enzymatic
activity.[15] Some examples of protein persulfidation and the
resulting changes in protein activity include: an increased
parkin activity upon S-persulfidation, resulting in a decrease
in Parkinsonꢀs symptoms,[16] an increase in activity of
GAPDH, protecting cells from apoptosis,[17] and H-Ras
activation in cardiac tissue, regulating cellular redox signal-
ing.[18] More recently, studies have confirmed the presence of
endogenously produced small-molecule persulfides (e.g.,
cysteine persulfide and glutathione persulfide) with reported
concentrations as high as 150 mm in human and mouse
tissue.[9a] Small-molecule persulfides likely play a role in
regulating cellular redox balance and mediating cellular
signaling.[9c] A major barrier in the study of the biological
roles of persulfides is a lack of chemical tools capable of
generating well-defined persulfide species in response to
specific, biologically relevant triggers. Our understanding of
H2S biology has been aided immensely by the synthesis of
organic H2S donors. Analogous to H2S, persulfide donors will
be vital tools for understanding how persulfides fit into the
overall web of redox signaling.
H
ydrogen sulfide (H2S) plays a key signaling role in
mammalian biology and has been under investigation as
a potential therapeutic by exogenous delivery.[1] To help
elucidate its biological roles, chemists have synthesized
several types of H2S-releasing compounds (termed H2S
donors) with a variety of biologically relevant triggers,
including water,[2] nucleophiles (e.g., thiols, amines),[3]
enzymes,[4] and light.[5] Additionally, compounds that release
carbonyl sulfide (COS),[6] and sulfur dioxide (SO2),[7] have
recently been reported, thus allowing the study of other small-
molecule sulfur species as potential signaling compounds.
These donors aid in our understanding of the physiological
roles of H2S and related compounds and hold potential
therapeutic value by exogenous H2S delivery.[8] Interestingly,
recent studies into the redox chemistry of sulfur species in the
body indicate that persulfides (R-SSH) may have physiolog-
ical roles similar to H2S, insinuating that some of the
physiological effects ascribed to delivery of H2S may actually
be derived from persulfides.[9] Further study of persulfides is
needed to differentiate between the roles of H2S itself and its
biological products. Moreover, a clear description of sulfur
Polysulfides (RS-(S)n-SR), such as naturally occurring
diallyl trisulfide (DATS), are perhaps the best known type of
persulfide donor, but their reactivity in biological systems is
complex, leading to the generation of other redox-active
species, including H2S.[19] As a result, polysulfides are not ideal
persulfide donors for use in studying persulfide biology, and
the complex product mixture may limit their therapeutic
À
potential. Free persulfides (i.e., R SSH) have been isolated,
[*] C. R. Powell, K. M. Dillon, Y. Wang, R. J. Carrazzone, J. B. Matson
Department of Chemistry, Virginia Tech Center for Drug Discovery,
and Macromolecules Innovation Institute, Virginia Tech
Blacksburg, VA 24061 (USA)
but they suffer from poor stability under storage conditions
and poor water solubility, and thus have relatively low utility
in a practical sense.[19c] Persulfides are also proposed inter-
mediates in several types of H2S donors,[3] but these com-
pounds all require conditions that cause rapid conversion of
the persulfide into H2S. To date there exist only two families
of compounds capable of generating discrete persulfides:
E-mail: jbmatson@vt.edu
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201803087.
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Wang and co-workers developed esterase-triggered persulfide
prodrugs capable of releasing either a persulfide or hydrogen
persulfide (HSSH), and Galardon and co-workers developed
a
pH-triggered persulfide analogue of the nitrosothiol
SNAP.[20] These donors generate persulfides without concom-
itant generation of H2S and can be viewed as spontaneous
persulfide donors as a result of the ubiquity of esterases
in vitro and in vivo.
We sought to synthesize a discrete persulfide-donor
scaffold, which would be inert under normal physiological
conditions but capable of self-immolation in response to
a specific trigger to release a discrete persulfide species
(Figure 1). As the triggering moiety and persulfide could be
Scheme 1. A) Synthetic route to BDP-NAC. Reaction conditions:
i) MgSO4, Et2O, RT, 16 h; ii) AIBN, C6H12, reflux, 16 h; iii) 1) EtOH, RT,
4 h; iv) 1n NaOH, reflux, 45 min; v) NEt3, CHCl3, RT, 3 h. B) Synthetic
route to BDP-Fluor. Reaction conditions: vi) CHCl3/MeOH (1:1 v/v),
RT, 40 h. AIBN=2,2’-azobis(2-methylpropionitrile).
Figure 1. Cartoon schematic representing the proposed release of
a discrete persulfide species from a generalized self-immolative
prodrug (PG=protecting group) in the presence of a trigger (H2O2
shown here).
immolation moiety. Our choice of N-acetyl cysteine (NAC)
was motivated by its biocompatibility as well as its ability to
protect cells in vitro in highly oxidative environments.[22]
The ability of BDP-NAC to mediate the release of the
desired NAC persulfide (NAC-SSH) in response to ROS was
analyzed by LCMS (Figure 2). Aliquots of the reaction
mixture of BDP-NAC with H2O2 were injected at various
time points until the peak attributed to BDP-NAC (2.9 min)
had subsided, showing near complete decomposition of BDP-
NAC within 2 hours. A peak corresponding to NAC-SSH
(3.4 min) increased in intensity over the course of the
reaction, and is consistent with our proposed mechanism of
persulfide generation. Mass spectrometry evidence also
confirmed the presence of the other byproduct, 4-hydrox-
ybenzyl alcohol (a result of addition of water to the quinone
methide), of the reaction but the chromatogram peak was of
low intensity, probably because of the low absorbance at the
wavelength used for monitoring.
readily tuned, this system would enable persulfide generation
in response to many types of triggers, thus providing
a valuable set of laboratory tools similar to the self-
immolative COS donors recently reported by Pluth and co-
workers.[21] In addition to their use as biological tools to study
persulfide reactivity, persulfide prodrugs are exciting from
a therapeutic standpoint because the reduction potential of
persulfides is greater than that of thiols or H2S, making them
prime candidates for scavenging and reducing the harmful
effects resulting from high levels of reactive oxygen species
(ROS). Therefore, we aimed to synthesize a ROS-responsive
persulfide prodrug as a proof of concept. This approach would
allow a two-stage quenching of ROS: the initial reaction of
the ROS with the prodrug to trigger release, followed by
release of the persulfide. We envisioned that such an ROS-
triggered persulfide prodrug would be ideal for cytoprotec-
tion against harmful levels of ROS.
Aryl boronic esters are relatively easy to synthesize,
generally biocompatible, and react selectively with ROS in
In addition to LCMS, we also investigated the reaction of
BDP-NAC with H2O2 utilizing 1H NMR spectroscopy.
Experiments were conducted in [D6]DMSO/D2O (9:1 v/v)
because of the hydrophobic nature of BDP-NAC and the
increased concentration required in NMR spectroscopy
compared with LCMS. Shortly after the addition of H2O2 to
the BDP-NAC solution, two new sets of peaks in the aryl
À
a B C bond-cleavage reaction to release the corresponding
phenolate. Therefore, we set out to synthesize a self-immo-
lative persulfide donor containing an aryl boronic ester as an
ROS-sensitive trigger.
The desired persulfide donor (termed BDP-NAC for
Bpin-disulfide prodrug-N-acetyl cysteine) was synthesized
from commercially available 4-tolylboronic acid in four steps
(Scheme 1A). Theoretically, any thiol may be installed on the
distal end of the disulfide bond from the trigger/self-
1
region of the H NMR spectrum appeared. One was consis-
tent with 4-hydroxybenzyl alcohol, and the other was
attributed to the slow hydrolysis of the Bpin moiety of
BDP-NAC, yielding a boronic acid. Boronic acids react with
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Figure 3A, we expected self-immolation to trigger release of
a discrete persulfide, which would then cyclize to form a five-
membered benzodithiolone species, resulting in the release of
7-hydroxycoumarin. Because BDP-Fluor itself is not fluores-
cent, an increase in fluorescence at the characteristic emission
wavelength of 7-hydroxycoumarin should only result from
persulfide release and subsequent intramolecular cyclization,
thus providing secondary confirmation of persulfide release
from these self-immolative prodrug systems.
We tested this design by exposing BDP-Fluor to a variety
of potential triggers. BDP-Fluor showed no evidence of self-
immolative behavior (i.e., no fluorescence signal) in the
absence of a trigger, but addition of H2O2 (100-fold excess)
led to a 90-fold increase in fluorescence intensity at the
characteristic wavelength of 7-hydroxycoumarin after incu-
bation for 5 hours in PBS buffer (Figures 3B and C). When
BDP-Fluor was treated with other potential triggers, includ-
ing sodium hypochlorite (NaOCl), cysteine (Cys), glutathione
(GSH), lysine (Lys), and potassium superoxide (KO2), the
response was significantly lower, with H2O2 showing a greater
than 20-fold response over that of all other potential triggers
tested, and a greater than 90-fold response over Lys and KO2.
As the increase in fluorescence response to thiols was
unexpected, further investigation indicated that the fluores-
cence increase may be attributed to nucleophilic attack by
cysteine at the aryl ester position, resulting in the release of 7-
hydroxycoumarin. For more discussion on the probe response
to thiols and relevant controls see Figure S22. Taken together,
these results confirm release of the desired persulfide species
and demonstrate the selectivity of H2O2 as a trigger.
Figure 2. A) Proposed reaction of BDP-NAC in the presence of H2O2
leading to the release of NAC-SSH. B) LC chromatograms highlighting
the conversion of BDP-NAC into NAC persulfide (NAC-SSH) in the
presence of H2O2. Timepoints are noted above each LC chromatogram.
The peak eluting at 2.9 min corresponds to BDP-NAC, and the peak at
3.4 min corresponds to NAC-SSH (see Figure S20 for corresponding
mass spectrometry data).
We next aimed to analyze BDP-NAC in a biological
context. In vitro cytotoxicity studies on H9C2 cardiomyocytes
showed that BDP-NAC is nontoxic up to 200 mm (see
Figure S27). As mentioned previously, persulfides have
greater reducing potential than their corresponding thiols as
H2O2 in a similar fashion as pinacol
boronic esters.[23] The reaction was con-
siderably slower under these reaction
conditions than in the LCMS experiments.
This retardation in reaction rate is likely
a result of the high organic solvent content
in the reaction.[24] Further insights into the
stability of BDP-NAC as a persulfide
prodrug as well as pertinent controls with-
out the Bpin-triggering moiety can be
found in the Supporting Information (Fig-
ures S25 and S26).
To further evaluate the reactivity and
trigger selectivity of BDP-NAC, a pro-
fluorophore (BDP-Fluor; Scheme 1B)
was synthesized. Drawing inspiration
from Xian and co-worker’s turn-on fluo-
rescence probe (7) used for detection of
sulfane sulfur species [HSSH, RS-(S)n-SR,
or S8], the self-immolative BDP-Fluor has
the same general structure as BDP-NAC,
but with a coumarin-based fluorophore as
the distal thiol species.[25] As shown in
Figure 3. A) Proposed reaction mechanism for the release of 7-hydroxycoumarin from BDP-
Fluor in the presence of H2O2. B) Representative overlay of the fluorescence spectra of BDP-
Fluor in the presence of 100-fold excess H2O2 resulting from the release of 7-hydroxycou-
marin over the course of 5 h. C) Relative response of BDP-Fluor (3.3 mm) to each potential
trigger (330 mm) or control (no trigger added) represented as the ratio of the final
fluorescence (If) intensity after 5 h to the initial fluorescence intensity (I0), showing an
increased selectivity for H2O2 over other potential triggers.
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well as H2S. Thus, we envisioned that BDP-NAC might be
effective in rescuing cells under oxidative stress, either by
direct reduction of H2O2 or by upregulation of antioxidant
pathways mediated by persulfide signaling.[9a,15a] To this end,
we evaluated the protective effects of BDP-NAC on H9C2
cells in culture by exogenous delivery of H2O2, which stresses
the cells and promotes apoptosis (Figure 4). In the absence of
BDP-NAC, cell viability drastically decreased after exposure
(see Figure S28). These data provides further evidence that
persulfides may serve to maintain redox homeostasis in cells
to a greater extent than H2S. NAC, a potential thiol byproduct
after reaction of BDP-NAC, also had no effect on viability. To
confirm that BDP-NAC derives its activity from ROS-
triggered persulfide release, the cardiomyocytes were treated
with BDP-Control, which has an identical structure to BDP-
NAC, but without the Bpin triggering moiety. BDP-Control
also did not rescue cells exposed to H2O2 under identical
conditions to the previous experiments.
Finally, to recreate the synergistic effects of the Bpin
moiety of BDP-NAC and the resultant persulfide release,
cells were treated simultaneously with Bpin-OH and either
NAC, GYY4137 or Na2S (Figure 4). Each of these combina-
tions mitigated the effects of H2O2 on cell viability, but not to
the same degree as BDP-NAC, with the exception of Bpin-
OH + Na2S. We suspect that simultaneous treatment of the
cardiomyocytes with Bpin-OH and Na2S gives a greater
instantaneous concentration of potential antioxidants than
BDP-NAC, considering its sustained release. In a system with
continuous generation of ROS, delivery of Bpin-OH and
Na2S would likely have a diminished ability to rescue cells
compared to sustained release from BDP-NAC.
In summary, we have synthesized a self-immolative
prodrug (BDP-NAC) that releases a discrete persulfide
species in the presence of H2O2. Persulfide release and trigger
specificity were characterized by LCMS and fluorescence
spectroscopy, respectively, demonstrating that sustained
release of persulfide is selectively triggered by H2O2. In
vitro studies using H9C2 cardiomyocytes under oxidative
stress showed that BDP-NAC mitigates the harmful effects of
highly oxidative environments with greater potency than the
commonly used H2S-donors Na2S and GYY4137, as well as
relevant controls. BDP-NAC not only shows promise ther-
apeutically, but it also provides a modular system for
persulfide donors that may be triggered under a variety of
conditions. We envision that a library of persulfide donors
based on the BDP-NAC template will enable the study of
persulfide biology in greater depth than is currently possible,
providing insight into sulfur redox cycles and sulfur-mediated
cell signaling.
Figure 4. Viability of H9C2 cardiomyoctyes treated with BDP-NAC or
various controls and related compounds concurrent with exposure to
H2O2 (100 mm) for 1 h. Each control compound was applied at
a concentration of 200 mm (except for Na2S (100 mm) in the Bpin-OH
+ Na2S treatment group). Quantification of viability was carried out
using Cell Counting Kit-8 (CCK-8). Results are expressed as the mean
Æ SEM (n=10–15 for each treatment group) with 2–3 independent
experiments. *P<0.01 for comparisons with the H2O2 treatment
group and #P<0.01 for comparisons with the BDP-NAC (200 mm)
treatment group. Group comparisons are indicated as determined by
a one-way analysis of variance (ANOVA) with a Student-Newman-Keuls
comparisons post-hoc test.
to H2O2 (100 mm) for 1 h. However, simultaneous application
of BDP-NAC (100–200 mm) with H2O2 showed a dose-depen-
dent increase in cell viability, with no cytotoxicity observed
after treatment with 200 mm BDP-NAC. At longer treatment
times (2 h), BDP-NAC rescued a similar percentage of cells
compared to H2O2-only controls (see Figure S29). These
results indicate that BDP-NAC can successfully mitigate the
deleterious effects of a hyperoxidative environment in
culture.
Acknowledgements
To further ensure that persulfide release imparts protec-
tion to the cardiomyocytes in the presence of H2O2, several
control studies were carried out (Figure 4). Exposure of the
cells to H2O2 with added 4-(hydroxymethyl)benzeneboronic
acid pinacol ester (Bpin-OH), a non-persulfide-releasing
compound with a Bpin moiety, showed an increase in viability
compared to H2O2 alone, but did not rescue cells to the same
extent as BDP-NAC. We also compared BDP-NAC to sodium
sulfide (Na2S), a fast-releasing H2S donor, and GYY4137,
a slow-releasing H2S donor, under the same experimental
conditions. Na2S had a limited ability to rescue cells while
GYY4137 had no effect on viability. Interestingly, BDP-NAC
was more effective at rescuing cells than Na2S, even while
Na2S enhanced H9C2 proliferation in the absence of H2O2
This work was supported by the National Science Foundation
(DMR-1454754) and the National Institutes of Health
(R01GM123508). We also thank 3M for support of this
work through a Non-Tenured Faculty Award to J.B.M. We
thank Dr. Tijana Grove and Dr. Webster Santos and their
students for experimental assistance as well as Dr. Mehdi
Ashraf-Khorassani for help with LCMS.
Conflict of interest
The authors declare no conflict of interest.
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Arch. Biochem. Biophys. 2017, 617, 9 – 25; d) M. R. Filipovic, J.
Keywords: drug delivery · hydrogen sulfide · fluoresence ·
Zivanovic, B. Alvarez, R. Banerjee, Chem. Rev. 2018, 118, 1253 –
1337.
persulfide · reactive oxygen species
[10] L. Zheng, R. H. White, V. L. Cash, D. R. Dean, Biochemistry
1994, 33, 4714 – 4720.
[11] M. R. Filipovic in Chemistry, Biochemistry and Pharmacology of
Hydrogen Sulfide (Eds.: P. K. Moore, M. Whiteman), Springer
International Publishing, Cham, 2015, pp. 29 – 59.
[12] Y.-R. Cai, C.-H. Hu, J. Phys. Chem. B 2017, 121, 6359 – 6366.
[13] N. E. Francoleon, S. J. Carrington, J. M. Fukuto, Arch. Biochem.
Biophys. 2011, 516, 146 – 153.
[14] D. H. Flint, J. Biol. Chem. 1996, 271, 16068 – 16074.
[15] a) R. Millikin, C. L. Bianco, C. White, S. S. Saund, S. Henriquez,
V. Sosa, T. Akaike, Y. Kumagai, S. Soeda, J. P. Toscano, J. Lin,
J. M. Fukuto, Free Radic. Biol. Med. 2016, 97, 136 – 147; b) E. G.
Mueller, Nat. Chem. Biol. 2006, 2, 185 – 194.
[16] M. S. Vandiver, B. D. Paul, R. Xu, S. Karuppagounder, F. Rao,
A. M. Snowman, H. S. Ko, Y. I. Lee, V. L. Dawson, T. M.
Dawson, N. Sen, S. H. Snyder, Nat. Commun. 2013, 4, 1626.
[17] A. K. Mustafa, M. M. Gadalla, N. Sen, S. Kim, W. Mu, S. K. Gazi,
R. K. Barrow, G. Yang, R. Wang, S. H. Snyder, Sci. Signal 2009,
2, ra72 – ra72.
[1] a) R. Wang, FASEB J. 2002, 16, 1792 – 1798; b) A. Papapetro-
poulos, A. Pyriochou, Z. Altaany, G. Yang, A. Marazioti, Z.
Zhou, M. G. Jeschke, L. K. Branski, D. N. Herndon, R. Wang, C.
Szabꢁ, Proc. Natl. Acad. Sci. USA 2009, 106, 21972 – 21977;
c) A. K. Mustafa, M. M. Gadalla, S. H. Snyder, Sci. Signal 2009,
2, re2 – re2; d) B. L. Predmore, D. J. Lefer, G. Gojon, Antioxid.
Redox Signal 2012, 17, 119 – 140.
[2] a) W. Zhao, J. Zhang, Y. Lu, R. Wang, EMBO J. 2001, 20, 6008 –
6016; b) L. A. D. Nicolau, R. O. Silva, S. R. B. Damasceno, N. S.
Carvalho, N. R. D. Costa, K. S. Arag¼o, A. L. R. Barbosa,
P. M. G. Soares, M. H. L. P. Souza, J. V. R. Medeiros, Braz. J.
Med. Biol. Res. 2013, 46, 708 – 714; c) L. Li, M. Whiteman, Y. Y.
Guan, K. L. Neo, Y. Cheng, S. W. Lee, Y. Zhao, R. Baskar, C.-H.
Tan, P. K. Moore, Circulation 2008, 117, 2351 – 2360; d) S. D.
Zanatta, B. Jarrott, S. J. Williams, Aust. J. Chem. 2010, 63, 946 –
957.
[18] M. Nishida, T. Sawa, N. Kitajima, K. Ono, H. Inoue, H. Ihara, H.
Motohashi, M. Yamamoto, M. Suematsu, H. Kurose, A.
van der Vliet, B. A. Freeman, T. Shibata, K. Uchida, Y. Kuma-
gai, T. Akaike, Nat. Chem. Biol. 2012, 8, 714 – 724.
[19] a) G. A. Benavides, G. L. Squadrito, R. W. Mills, H. D. Patel,
T. S. Isbell, R. P. Patel, V. M. Darley-Usmar, J. E. Doeller, D. W.
Kraus, Proc. Natl. Acad. Sci. USA 2007, 104, 17977 – 17982;
b) M. M. Cerda, M. D. Hammers, M. S. Earp, L. N. Zakharov,
M. D. Pluth, Org. Lett. 2017, 19, 2314 – 2317; c) C.-M. Park, L.
Weerasinghe, J. J. Day, J. M. Fukuto, M. Xian, Mol. Biosyst.
2015, 11, 1775 – 1785.
[20] a) Y. Zheng, B. Yu, Z. Li, Z. Yuan, C. L. Organ, R. K. Trivedi, S.
Wang, D. J. Lefer, B. Wang, Angew. Chem. Int. Ed. 2017, 56,
11749 – 11753; b) B. Yu, Y. Zheng, Z. Yuan, S. Li, H. Zhu, L. K.
De La Cruz, J. Zhang, K. Ji, S. Wang, B. Wang, J. Am. Chem. Soc.
2017, 0, 0; c) I. Artaud, E. Galardon, ChemBioChem 2014, 15,
2361 – 2364.
[21] Y. Zhao, H. A. Henthorn, M. D. Pluth, J. Am. Chem. Soc. 2017,
139, 16365 – 16376.
[22] a) M. Zafarullah, W. Li, J. Sylvester, M. Ahmad, Cell. Mol. Life
Sci. 2003, 60, 6 – 20; b) N. P. Murphy, K. J. Lampe, Biotechnol.
Bioeng. 2018, 115, 246 – 256.
[23] H. G. Kuivila, J. Am. Chem. Soc. 1954, 76, 870 – 874.
[24] K. M. Schmid, L. Jensen, S. T. Phillips, J. Org. Chem. 2012, 77,
4363 – 4374.
[25] W. Chen, C. Liu, B. Peng, Y. Zhao, A. Pacheco, M. Xian, Chem.
Sci. 2013, 4, 2892 – 2896.
[3] a) Y. Zhao, H. Wang, M. Xian, J. Am. Chem. Soc. 2011, 133, 15 –
17; b) J. C. Foster, C. R. Powell, S. C. Radzinski, J. B. Matson,
Org. Lett. 2014, 16, 1558 – 1561.
[4] a) Y. Zheng, B. Yu, K. Ji, Z. Pan, V. Chittavong, B. Wang, Angew.
Chem. Int. Ed. 2016, 55, 4514 – 4518; b) Z. Li, C. L. Organ, Y.
Zheng, B. Wang, D. J. Lefer, Circulation 2016, 134, A17903 –
A17903; c) P. Chauhan, P. Bora, G. Ravikumar, S. Jos, H.
Chakrapani, Org. Lett. 2017, 19, 62 – 65.
[5] a) N. O. Devarie-Baez, P. E. Bagdon, B. Peng, Y. Zhao, C.-M.
Park, M. Xian, Org. Lett. 2013, 15, 2786 – 2789; b) N. Fukushima,
N. Ieda, K. Sasakura, T. Nagano, K. Hanaoka, T. Suzuki, N.
Miyata, H. Nakagawa, Chem. Commun. 2014, 50, 587 – 589.
[6] a) C. R. Powell, J. C. Foster, B. Okyere, M. H. Theus, J. B.
Matson, J. Am. Chem. Soc. 2016, 138, 13477 – 13480; b) A. K.
Steiger, S. Pardue, C. G. Kevil, M. D. Pluth, J. Am. Chem. Soc.
2016, 138, 7256 – 7259.
[7] a) W. Wang, X. Ji, Z. Du, B. Wang, Chem. Commun. 2017, 53,
1370 – 1373; b) J. J. Day, Z. Yang, W. Chen, A. Pacheco, M. Xian,
ACS Chem. Biol. 2016, 11, 1647 – 1651.
[8] a) Y. Zheng, B. Yu, L. K. De La Cruz, M. Roy Choudhury, A.
Anifowose, B. Wang, Med. Res. Rev. 2018, 38, 57 – 100; b) C. R.
Powell, K. M. Dillon, J. B. Matson, Biochem. Pharmacol. 2017, 0,
0; c) Y. Zhao, T. D. Biggs, M. Xian, Chem. Commun. 2014, 50,
11788 – 11805.
[9] a) T. Ida, T. Sawa, H. Ihara, Y. Tsuchiya, Y. Watanabe, Y.
Kumagai, M. Suematsu, H. Motohashi, S. Fujii, T. Matsunaga, M.
Yamamoto, K. Ono, N. O. Devarie-Baez, M. Xian, J. M. Fukuto,
T. Akaike, Proc. Natl. Acad. Sci. USA 2014, 111, 7606 – 7611;
b) P. K. Yadav, M. Martinov, V. Vitvitsky, J. Seravalli, R.
Wedmann, M. R. Filipovic, R. Banerjee, J. Am. Chem. Soc.
2016, 138, 289 – 299; c) E. Cuevasanta, M. N. Mçller, B. Alvarez,
Manuscript received: March 13, 2018
Version of record online: && &&, &&&&
Angew. Chem. Int. Ed. 2018, 57, 1 – 6
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Reactive Oxygen Species
C. R. Powell, K. M. Dillon, Y. Wang,
R. J. Carrazzone,
J. B. Matson*
&&&& — &&&&
BDP-NAC to the rescue! Reported here is
the synthesis and characterization of the
redox-responsive, self-immolative persul-
fide-donor BDP-NAC. BDP-NAC shows
selectivity towards H2O2 over other
potential oxidative or nucleophilic trig-
gers, resulting in the sustained release of
the persulfide of N-acetyl cysteine (NAC).
Exposure of H9C2 cardiomyocytes to
H2O2 revealed that BDP-NAC mitigates
the effects of a highly oxidative environ-
ment in a dose-dependent manner. BDP-
NAC also rescued cells more effectively
than a non-persulfide-releasing control
system.
A Persulfide Donor Responsive to
Reactive Oxygen Species: Insights into
Reactivity and Therapeutic Potential
6
www.angewandte.org
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2018, 57, 1 – 6
These are not the final page numbers!