A Dinuclear Persulfide-Bridged Ruthenium Compound is a Hypoxia-Selective Hydrogen Sulfide (H2S) Donor

Article abstract of DOI:10.1002/anie.202012620

Hydrogen sulfide (H₂S) is a gaseous molecule that has received attention for its role in biological processes and therapeutic potential in diseases, such as ischemic reperfusion injury. Despite its clinical relevance, delivery of H₂S to biological systems is hampered by its toxicity at high concentrations. Herein, we report the first metal-based H₂S donor that delivers this gas selectively to hypoxic cells. We further show that H₂S release from this compound protects H9c2 rat cardiomyoblasts from an in vitro model of ischemic reperfusion injury. These results validate the utility of redox-activated metal complexes as hypoxia-selective H₂S-releasing agents for use as tools to study the role of this gaseous molecule in complex biological systems.

Full text of DOI:10.1002/anie.202012620

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Accepted Article
Title: A Dinuclear Persulfide-Bridged Ruthenium Compound is a
Hypoxia-Selective Hydrogen Sulfide (H2S) Donor.
Authors: Joshua J. Woods and Justin J. Wilson
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A Dinuclear Persulfide-Bridged Ruthenium Compound is a
Hypoxia-Selective Hydrogen Sulfide (H2S) Donor.
Joshua J. Woods,[a,b] and Justin J. Wilson*[a]
[a]
J. J. Woods, Prof. J. J. Wilson
Department of Chemistry and Chemical Biology
Cornell University
Ithaca, NY 14853
E-mail: jjw275@cornell.edu
J. J. Woods
[b]
Robert F. Smith School for Chemical and Biomolecular Engineering
Cornell University
Ithaca, NY 14853
Supporting information and the ORCID identification number(s) for the authors of this article can be found under:
Abstract: Hydrogen sulfide (H2S) is a gaseous molecule that has
received attention for its role in biological processes and therapeutic
potential in diseases such as ischemic reperfusion injury. Despite its
clinical relevance, delivery of H2S to biological systems is hampered
by its toxicity at high concentrations. Herein, we report the first metal
based H2S donor that delivers this gas selectively to hypoxic cells. We
further show that H2S release from this compound protects H9c2 rat
cardiomyoblasts from an in vitro model of ischemic reperfusion injury.
These results validate the utility of redox-activated metal complexes
as hypoxia-selective H2S-releasing agents for use as tools to study
the role of this gaseous molecule in complex biological systems.
chemistry of Cu, Pt, Co, Fe, Ru, Os and Ir has been used to
develop prodrugs that are specifically activated in hypoxic cells to
produce reactive anticancer compounds.[27–31] Our strategy to
develop a redox-activated H2S donor invoked the dinuclear
ruthenium persulfide (µ-S22-) core [RuIIISSRuIII]. This moiety is
labile towards reduction in protic solvents, producing H2S and the
related RuII species.[32–34] In this report, we describe our initial
evaluation of a ruthenium persulfide complex as a platform for
hypoxia-activated delivery of H2S in cultured cells and
demonstrate the ability of this complex to protect against an in
vitro model of ischemic reperfusion injury. These results highlight
the value of metal-based H2S donors as tools for understanding
the therapeutic utility of this gasotransmitter.
Hydrogen sulfide (H2S) has long been known to be a highly
toxic gas with a noxious odor. In 1996, this perception was
changed by the discovery that this gas is produced endogenously
in mammals and functions as a modulator for neurological
activity.[1] Since this discovery, further work has revealed that H2S
is an important signaling molecule involved in angiogenesis and
the prevention of oxidative stress.[2] Furthermore, H2S has
promising therapeutic potential for the treatment of Alzheimer’s
disease, Parkinson’s disease, ischemic reperfusion injury (IRI),
stroke, and cancer.[3] The implementation of H2S in medicine,
however, is limited by its gaseous nature, flammability, and
toxicity at high concentrations. As such, significant research
efforts have focused on developing easily handled prodrugs for
this gaseous molecule.[4–12] Simple sulfide salts such as Na2S or
NaSH rapidly release H2S upon dissolution in aqueous solution.
Although these complexes are more practical for the delivery of
H2S than its direct administration as a gas, their rapid release
profiles do not mimic endogenous H2S production and often elicit
toxic side effects.[13] To circumvent these challenges, several
groups have developed synthetic compounds that release H2S
upon activation by external stimuli such as light,[14–21] pH,[22,23] and
reactive oxygen species.[24,25] These compounds allow localized
and controllable delivery of H2S in complex biological systems,
making them promising therapeutic candidates.
The compound [(H2O)Ru(NH3)4(µ-S2)Ru(NH3)4(OH2)]4+
([1]4+, Figure 1) was obtained as the chloride salt ([1]Cl4) by
treatment of trans-[Ru(NH3)4(SO2)Cl]+ with amalgamated zinc in
0.1
M HCl followed by purification with cation-exchange
chromatography.[32] This complex was characterized by NMR,
UV/vis, and resonance Raman spectroscopies in addition to
reverse-phase high-performance liquid chromatography (HPLC),
elemental analysis, and x-ray crystallography (Figures 1 and S1-
S5, Supporting Information, SI).
X-ray diffraction-quality crystals of [1](SiF6)2 were obtained
by vapor diffusion of acetone into a solution of [1](SbF6)4 in 0.1 M
DCl (Figure 1). Relevant details are included in the SI (Tables S2
and S3). The complex crystallizes such that the asymmetric unit
consists of one half of the molecule, with a center of inversion
located in the middle of the persulfide bond. Overall, the Ru–S
and S–S interatomic distances agree well with previously
explored Ru persulfide complexes (Table S1, SI). The S–S
interatomic distance is the longest reported for a persulfide-
bridged diruthenium complex (Table S1, SI) and falls between the
value expected for a sulfur-sulfur single (2.03 Å for Me2S2)[35] and
double bond (1.887 Å for S2).[36–38] This intermediate bond order
has been observed in other persulfide-bridged diruthenium
In this study, we sought to develop H2S donors that could
be selectively activated for therapeutic intervention in conditions
such as cancer, IRI, or stroke. Under these pathological
conditions, cells and tissue exist in a state of hypoxia, causing
them to lose the ability to maintain redox balance and the cellular
environment becomes reducing.[26] In this context, the redox
1
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complexes and is attributed to highly delocalized π-bonding within
the persulfide core.[34]
that the presence of Ru(III) in solution interferes with the
commonly used methylene blue assay for H2S detection (Figure
S6-S9, SI). As such, the turn-on fluorescent probe SF4 was used
to monitor release of H2S from [1]Cl4 (Figures 3 and S10-S11, SI).
No increase in emission intensity was detected when [1]Cl4 was
incubated at 37 °C, indicating that the complex does not release
H2S under these conditions (Figure 3). This result is consistent
with UV/vis spectroscopic studies that show this compound to
remain >95% intact after incubation in pH 7.4 PBS at 37 °C for 24
h and >75% intact after 72 h (Figure S12, SI). When [1]Cl4 is
–
treated with a 10-fold excess of the reducing agents HSO3 ,
cysteine, glutathione (GSH), and ascorbate, the emission of the
H2S sensor SF4 increases gradually over the course of 190 min,
confirming that reductive activation of [1]Cl4 triggers H2S release.
Notably the H2S yield scales directly with the reducing power of
the species and incubation with other biologically relevant species,
such as anionic nucleophiles (OH–, Cl–, aspartate) and oxidants
2-
Figure 1. (A) Chemical and (B) X-ray crystal structure of [1](SiF6)2. The SiF6
counterions have been omitted for clarity. Thermal ellipsoids are depicted at the
50% probability level. Selected geometric parameters (Å,°): S(1)–S(#1)
2.0186(13), Ru–S( 1) 2.1659(7), Ru–O(1) 2.177(2), Ru–S(1)–S(#1) 111.63(5).
t
(GSSG, H2O2, NaNO2, NaHClO, BuOOH) does not trigger H2S
To assess the suitability of [1]Cl4 for hypoxia activation, we
analyzed the redox activity of this compound using cyclic
voltammetry (CV; Figure 2). In pH 7.4 PBS, the CV of [1]Cl4
displays an irreversible reduction peak with an onset potential of
–716 mV vs. SCE (feature II, Figure 2). The irreversibility of this
feature may arise from dissociation of the complex upon reduction.
Importantly, the onset of the irreversible reduction for [1]Cl4 lies
within the required range (–0.75 to –0.35 V vs. SCE)[39,40] for
hypoxia selectivity. Another feature, an irreversible oxidation,
occurs with an onset potential of 490 mV, a potential that is
unlikely to be accessible under biological conditions (feature IV,
Figure 2). Following oxidation, a weak feature at 150 mV vs. SCE
(features III/V, Figure 2) appears, which possibly corresponds to
oxidation products of [1]4+ obtained after sweeping these higher
potentials.
release (Figure S11, SI). These results suggest that this
compound will be a useful agent for hypoxia-activated delivery of
this gas.
Figure 3. Top: H2S-release profile from [1]Cl4 (20 µM) in pH 7.4 PBS at 37 °C
in the presence of biologically relevant reducing agents (200 µM unless
indicated). Bottom: Quantification of [H2S] produced by [1]Cl4 after incubation in
pH 7.4 PBS with relevant biological species (200 µM) [1]Cl4 for 190 min at 37 °C.
Results are reported as mean ± SD (ns = not significant; n = 3–4).
Figure 2. Top: Cyclic voltammogram of [1]Cl4 in PBS (pH 7.4, 23 °C). Bottom:
Cyclic voltammogram of PBS. Conditions: glassy carbon working electrode, Pt
wire counter electrode, Ag/AgCl quasi-reference electrode, and 0.1 V s-1 scan
rate.
Following these initial studies, we sought to further elucidate
the pathway of H2S release from [1]Cl4. Two possible
mechanisms were considered (Figure S13). The first mechanism
(Type I) progresses via reduction of the Ru3+ centers. The labile
Ru2+ would undergo aquation to release H2S2, which would then
disproportionate to form H2S and higher order polysulfides. The
For [1]Cl4 to be useful as a biological delivery vehicle for H2S
that does not give rise to acute toxicity, the release of this gas
molecule should be gradual rather than instantaneous. We
examined the potential of [1]Cl4 to release H2S upon treatment
with a panel of biologically relevant reducing agents. We found
2
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second mechanism (Type 2) considered involves initial reduction
of the persulfide bond to yield RuIII-SH type complexes, which
undergo further reduction and ligand substitution to produce H2S
and a RuII species.
we observed no increase in fluorescence intensity with incubation
under normoxic or hypoxic conditions (Figure S20, SI). This result
confirms that the fluorescence enhancement observed for cells
treated with [1]Cl4 under hypoxic conditions arises from H2S
produced by the complex.
To probe these mechanisms, we first treated [1]Cl4 with 40-
fold excess GSH or 10-fold excess ascorbate in the presence of
the polysulfide-selective fluorescent probe DSP-3 (Figure S14-
S15, SI).[41] No change in DSP-3 fluorescence after 40 min of
treatment was observed, suggesting that polysulfide species are
not produced during the reduction of [1]Cl4 To further confirm
these results, we monitored the reaction between [1]Cl4 and 10-
fold excess GSH by UV/vis spectroscopy in the presence of 0.5
M isonicotinamide (isn), a technique previously employed to study
the reduction reaction between GSH and RuIII ammine complexes
(Figure S16, SI).[42] Upon addition of GSH to a solution containing
[1]Cl4 and 0.5 M isonicotinamide (isn), a peak rapidly appears at
427 nm, which is characteristic of trans-[isn(NH3)4Ru(SH)]2+.[43]
Taken together, these results suggest that decomposition of [1]Cl4
upon reduction proceeds through a mechanism similar to Type 2
(Figure S13, SI) to selectively release H2S without initial
production of polysulfide species. This reactivity pattern contrasts
that of many organic H2S donors that contain polysulfide bonds
H2S has therapeutic properties for preventing the damaging
effects of IRI in heart disease and stroke.[51–55] We therefore
investigated the ability of [1]Cl4 to protect H9c2 rat cardiomyoblast
cells from this condition using an in vitro model for IRI. hen cells
were pretreated with [1]Cl4 prior to hypoxia, a dose-dependent
increase in cell viability relative to the untreated cells was
observed, indicating that this compound gives rise to
cytoprotective effects (Figure 5). One the major mechanisms of
the therapeutic effect of H2S for the treatment of IRI is the
activation of the mitochondrial KATP channel,[56–59] an energy-
dependent transporter of mitochondrial K+ ions. H2S will activate
this channel, causing the mitochondria to expunge K+ ions to
decrease the mitochondrial membrane potential (MMP). The
decreased MMP will lead to diminished uptake of Ca2+ ions,
preventing mitochondrial calcium overload, the primary cause of
the cytotoxicity of IRI. To confirm that H2S mediates the protective
effects of [1]Cl4, the H9c2 cells were incubated with the KATP
channel inhibitor glibenclamide[60] (10 µM) prior to subjecting them
to IRI. In the presence of glibenclamide, [1]Cl4 fails to protect the
cells from death due to IRI (Figure 5). This result indicates that
the cytoprotective effects of [1]Cl4 arise from its ability to release
H2S, which acts directly on the mitochondrial KATP channel.
Furthermore, treatment with the spent solution described above
did not give rise to any of the observed protective effects,
confirming that the cytoprotective effects of [1]Cl4 arise from its
ability to produce H2S in hypoxic cells (Figure S21, SI).
produce reactive polysulfide species as intermediate products.[44–
49]
Figure 4. (A) Representative images of H2S-release from [1]Cl4 in vitro. HeLa
cells were loaded with 5 µM SF7-AM for 30 min, washed, and loaded with 0 or
50 µM [1]Cl4 for 1 h. Cells were then incubated in GBSS under either hypoxic
(95:5 N2/CO2) or normoxic (95:5 Air/CO2) conditions for 3 h. (B) Corrected total
fluorescence of HeLa cells incubated in the conditions described (see SI for
details). Results are reported as mean ± SD (***p<0.001, n = 3-4).
Given the promising H2S-release profile and selectivity of
[1]Cl4, we investigated the biological activity of this complex. The
complex is effectively nontoxic at concentrations up to 200 µM in
cervical cancer (HeLa) and rat cardiomyoblast (H9c2) cells
(Figure S17, SI). Additionally, [1]Cl4 is taken up by cells effectively
(Figure S18, SI), as determined by graphite furnace atomic
absorption spectroscopy. Based on its cell permeability and low
toxicity, we next investigated the ability of [1]Cl4 to selectively
release H2S in hypoxic cells using the cell-trappable, H2S-
responsive fluorescent probe, SF7-AM.[50] Cells that were only
treated with [1]Cl4 or subjected to hypoxic conditions in the
absence of the complex showed no significant increase in
fluorescence intensity compared to control cells. In contrast, we
observe a significant increase in fluorescence intensity in cells
treated with both [1]Cl4 and hypoxic conditions, indicating that
both components are required for intracellular release of H2S
(Figure 4). Additionally, when HeLa cells were treated with a spent
solution of the complex (See SI for details, Figure S19-S20, SI),
Figure 5. Protective effects of [1]Cl4 at various concentrations in H9c2 cells
exposed to hypoxia-reoxygenation injury after preincubation with 0 or 10 µM
glibenclamide. Results are reported as mean ± SD (ns = not significant;
**p<0.01; ***p<0.001; n = 3).
In summary, by applying the “activation by reduction”
principle that has been leveraged for the design of metal-based
anticancer agents, we have been able to use [1]Cl4 as the first
H2S donor that is activated selectively by reduction in hypoxic
cells. This work demonstrates that Ru persulfide complexes are
viable platforms for H2S delivery. Furthermore, it highlights how
transition metal compounds, in general, may serve as viable
candidates for releasing H2S and other reactive-sulfur species,
3
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adding to their prior roles as delivery agents for the more well-
known gasotransmitters CO and NO.[61–67]
Deng, Y.-N. Liu, Chem. Commun. 2015, 51, 9193–9196.
[17]
N. Fukushima, N. Ieda, K. Sasakura, T. Nagano, K. Hanaoka, T.
Suzuki, N. Miyata, H. Nakagawa, Chem. Commun. 2014, 50, 587–
589.
Acknowledgements
[18]
[19]
[20]
A. K. Sharma, M. Nair, P. Chauhan, K. Gupta, D. K. Saini, H.
Chakrapani, Org. Lett. 2017, 19, 4822–4825.
S. Y. Yi, Y. K. Moon, S. Kim, S. Kim, G. Park, J. J. Kim, Y. You,
Chem. Commun. 2017, 53, 11830–11833.
This work was supported by the National Science Foundation
(NSF-GRFP for J. J. Woods DGE-1650441 and NSF CAREER for
J. J. Wilson CHE-1750295) and the American Heart Association
(predoctoral fellowship for J. J. Woods, 20PRE35120390). This
work made use of the Cornell University NMR facility, which is
supported in part by the NSF (CHE-1531632), and the Cornell
Institute of Biotechnology Imaging Facility, which is supported in
part by the NIH (NIH S10RR025502). Dr. Weiwei An and
Professor Alexander R. Lippert (Southern Methodist University)
are thanked for supplying SF4. Ida DiMucci and Professor Kyle
Lancaster (Cornell University) are thanked for assistance with
Resonance Raman spectroscopy. Professor Jeremey Baskin is
thanked for use of his confocal fluorescence microscope.
Z. Xiao, T. Bonnard, A. Shakouri-Motlagh, R. A. L. Wylie, J. Collins,
J. White, D. E. Heath, C. E. Hagemeyer, L. A. Connal, Chem. Eur.
J. 2017, 23, 11294–11300.
[21]
[22]
Y. Zhao, S. G. Bolton, M. D. Pluth, Org. Lett. 2017, 19, 2278–2281.
J. Kang, Z. Li, C. L. Organ, C.-M. Park, C. Yang, A. Pacheco, D.
Wang, D. J. Lefer, M. Xian, J. Am. Chem. Soc. 2016, 138, 6336–
6339.
[23]
[24]
[25]
A. K. Gilbert, Y. Zhao, C. E. Otteson, M. D. Pluth, J. Org. Chem.
2019, 84, 14469–14475.
Y. Zhao, M. D. Pluth, Angew. Chem. Int. Ed. 2016, 55, 14638–
14642.
C. R. Powell, K. M. Dillon, Y. Wang, R. J. Carrazzone, J. B. Matson,
Angew. Chemie 2018, 130, 6432–6436.
Conflict of Interest
[26]
[27]
W. R. Wilson, M. P. Hay, Nat. Rev. Cancer 2011, 11, 393–410.
I. Romero-Canelón, P. J. Sadler, Inorg. Chem. 2013, 52, 12276–
12291.
None reported.
[28]
U. Jungwirth, C. R. Kowol, B. K. Keppler, C. G. Hartinger, W.
Berger, P. Heffeter, Antioxidants Redox Signal. 2011, 15, 1085–
1127.
Keywords: ruthenium complexes • hydrogen sulfide • hypoxia •
persulfide complex • reduction-activated
[29]
[30]
A. Sharma, J. F. Arambula, S. Koo, R. Kumar, H. Singh, J. L.
Sessler, J. S. Kim, Chem. Soc. Rev. 2019, 48, 771–813.
E. Reisner, V. B. Arion, B. K. Keppler, A. J. L. Pombeiro, Inorg.
Chim. Acta. 2008, 361, 1569–1583.
[1]
[2]
K. Abe, H. Kimura, J. Neurosci. 1996, 16, 1066–1071.
H. Liu, M. N. Radford, C. Yang, W. Chen, M. Xian, Br. J. Pharmacol.
2019, 176, 616–627.
[3]
[4]
J. L. Wallace, R. Wang, Nat. Rev. Drug Discov. 2015, 14, 329–345.
J. C. Foster, S. C. Radzinski, X. Zou, C. V Finkielstein, J. B. Matson,
Mol. Pharm. 2017, 14, 1300–1306.
[31]
[32]
N. Graf, S. J. Lippard, Adv. Drug Deliv. Rev. 2012, 64, 993–1004.
C. R. Brulet, S. S. Isied, H. Taube, J. Am. Chem. Soc. 1973, 95,
4758–4759.
[5]
M. Whiteman, A. Perry, Z. Zhou, M. Bucci, A. Papapetropoulos, G.
Cirino, M. E. Wood, in Handb. Exp. Pharmacol., 2015, pp. 337–363.
C. R. Powell, K. M. Dillon, J. B. Matson, Biochem. Pharmacol. 2018,
149, 110–123.
[33]
[34]
J. Amarasekera, T. B. Rauchfuss, Inorg. Chem. 1989, 28, 3875–
3883.
[6]
J. Amarasekera, T. B. Rauchfuss, S. R. Wilson, Inorg. Chem. 1987,
26, 3328–3332.
[7]
P. Rose, B. W. Dymock, P. K. Moore, Methods Enzymol. 2015, 554,
143–167.
[35]
[36]
[37]
R. Steudel, Angew. Chem. Int. Ed. 1975, 14, 655–664.
B. Meyer, Chem. Rev. 1976, 76, 367–388.
[8]
Y. Zhao, A. K. Steiger, M. D. Pluth, J. Am. Chem. Soc. 2019, 141,
13610–13618.
L. R. Maxwell, V. M. Mosley, S. B. Hendricks, Phys. Rev. 1936, 50,
41–45.
[9]
M. M. Cerda, Y. Zhao, M. D. Pluth, J. Am. Chem. Soc. 2018, 140,
12574–12579.
[38]
[39]
A. Mueller, W. Jaegermann, Inorg. Chem. 1979, 18, 2631–2633.
W. R. Wilson, R. F. Anderson, W. A. Denny, J. Med. Chem. 1989,
32, 23–30.
[10]
[11]
C.-M. Park, Y. Zhao, Z. Zhu, A. Pacheco, B. Peng, N. O. Devarie-
Baez, P. Bagdon, H. Zhang, M. Xian, Mol. Biosyst. 2013, 9, 2430.
Y. Zhao, S. Bhushan, C. Yang, H. Otsuka, J. D. Stein, A. Pacheco,
B. Peng, N. O. Devarie-Baez, H. C. Aguilar, D. J. Lefer, et al., ACS
Chem. Biol. 2013, 8, 1283–1290.
[40]
[41]
[42]
A. P. King, H. A. Gellineau, J. E. Ahn, S. N. MacMillan, J. J. Wilson,
Inorg. Chem. 2017, 56, 6609–6623.
C. Liu, W. Chen, W. Shi, B. Peng, Y. Zhao, H. Ma, M. Xian, J. Am.
Chem. Soc. 2014, 136, 7257–7260.
[12]
[13]
[14]
[15]
[16]
K. M. Dillon, R. J. Carrazzone, Y. Wang, C. R. Powell, J. B. Matson,
ACS Macro Lett. 2020, 9, 606–612.
D. R. Frasca, M. J. Clarke, J. Am. Chem. Soc. 1999, 121, 8523–
8532.
Y. Zheng, X. Ji, K. Ji, B. Wang, Acta Pharm. Sin. B 2016, 5, 367–
377.
[43]
[44]
C. G. Kuehn, H. Taube, J. Am. Chem. Soc. 1976, 98, 689–702.
S. Xu, Y. Wang, Z. Parent, M. Xian, Bioorg. Med. Chem. Lett. 2020,
30, 126903.
J. J. Woods, J. Cao, A. R. Lippert, J. J. Wilson, J. Am. Chem. Soc.
2018, 140, 12383–12387.
[45]
[46]
D. Liang, H. Wu, M. W. Wong, D. Huang, Org. Lett. 2015, 17, 4196–
4199.
N. O. Devarie-Baez, P. E. Bagdon, B. Peng, Y. Zhao, C.-M. Park,
M. Xian, Org. Lett. 2013, 15, 2786–2789.
M. M. Cerda, M. D. Hammers, M. S. Earp, L. N. Zakharov, M. D.
W. Chen, M. Chen, Q. Zang, L. Wang, F. Tang, Y. Han, C. Yang, L.
4
This article is protected by copyright. All rights reserved.

10.1002/anie.202012620
Angewandte Chemie International Edition
COMMUNICATION
Pluth, Org. Lett. 2017, 19, 2314–2317.
[47]
[48]
[49]
S. G. Bolton, M. M. Cerda, A. K. Gilbert, M. D. Pluth, Free Radic.
Biol. Med. 2019, 131, 393–398.
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. 2018, 140, 30–33.
A. Chaudhuri, Y. Venkatesh, B. C. Jena, K. K. Behara, M. Mandal,
N. D. P. Singh, Org. Biomol. Chem. 2019, 17, 8800–8805.
V. S. Lin, A. R. Lippert, C. J. Chang, PNAS 2013, 110, 7131–7135.
C. Szabó, Nat. Rev. Drug Discov. 2007, 6, 917–935.
Y. Zhao, C. Yang, C. Organ, Z. Li, S. Bhushan, H. Otsuka, A.
Pacheco, J. Kang, H. C. Aguilar, D. J. Lefer, et al., J. Med. Chem.
2015, 58, 7501–7511.
[50]
[51]
[52]
[53]
[54]
Z. Zhang, H. Huang, P. Liu, C. Tang, J. Wang, Can. J. Physiol.
Pharmacol. 2007, 85, 1248–1253.
J. W. Elrod, J. W. Calvert, J. Morrison, J. E. Doeller, D. W. Kraus, L.
Tao, X. Jiao, R. Scalia, L. Kiss, C. Szabo, et al., PNAS 2007, 104,
15560–15565.
[55]
J. W. Calvert, S. Jha, S. Gundewar, J. W. Elrod, A. Ramachandran,
C. B. Pattillo, C. G. Kevil, D. J. Lefer, Circ. Res. 2009, 105, 365–
374.
[56]
[57]
[58]
[59]
[60]
[61]
W. Liang, J. Chen, L. Mo, X. Ke, W. Zhang, D. Zheng, W. Pan, S.
Wu, J. Feng, M. Song, et al., Int. J. Mol. Med. 2016, 37, 763–772.
D. Johansen, K. Ytrehus, G. F. Baxter, Basic Res. Cardiol. 2006,
101, 53–60.
G. Tang, L. Wu, W. Liang, R. Wang, Mol. Pharmacol. 2005, 68,
1757–1764.
B. Jiang, G. Tang, K. Cao, L. Wu, R. Wang, Antiox. Redox Signal.
2010, 12, 1167–1178.
C. Ripoll, W. J. Lederer, C. G. Nichols, J Cardiovasc. Electrophysiol.
1993, 4, 38–47.
H. J. Xiang, M. Guo, J. G. Liu, Eur. J. Inorg. Chem. 2017, 1586–
1595.
[62]
[63]
R. Alberto, R. Motterlini, Dalton Trans. 2007, 1651–1660.
R. D. Rimmer, A. E. Pierri, P. C. Ford, Coord. Chem. Rev. 2012,
256, 1509–1519.
[64]
[65]
[66]
N. L. Fry, P. K. Mascharak, Acc. Chem. Res. 2011, 44, 289–298.
P. C. Ford, Coord. Chem. Rev. 2018, 376, 548–564.
M. J. Rose, P. K. Mascharak, Coord. Chem. Rev. 2008, 252, 2093–
2114.
[67]
F. Zobi, Future Med. Chem. 2013, 5, 175–188.
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10.1002/anie.202012620
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Targeting hypoxia with H2S Donors: Exploration of the biological activity of a dinuclear persulfide-bridged ruthenium persulfide
complex identifies an exciting class of compounds for delivery of H2S to hypoxic cells.
Institute and/or researcher Twitter usernames: @CornellChem @JWilsonLab
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