A Vinyl-Boronate Ester-Based Persulfide Donor Controllable by Hydrogen Peroxide, a Reactive Oxygen Species (ROS)

Article abstract of DOI:10.1021/acs.orglett.8b03471

A vinyl boronate ester-based persulfidating agent that is selectively activated by hydrogen peroxide, which is a reactive oxygen species (ROS), and efficiently generated a persulfide by a hitherto unexplored 1,4-O,S-relay mechanism is reported. This donor was found to protect cells from cytotoxicity induced by oxidants, and the major byproduct is cinnamaldehyde, which is widely used in the food industry as an additive.

Full text of DOI:10.1021/acs.orglett.8b03471

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
A Vinyl-Boronate Ester-Based Persulfide Donor Controllable by
Hydrogen Peroxide, a Reactive Oxygen Species (ROS)
Prerona Bora, Preeti Chauhan, Suman Manna, and Harinath Chakrapani*
Department of Chemistry, Indian Institute of Science Education and Research Pune, Pune 411 008, Maharashtra, India
S
* Supporting Information
ABSTRACT: A vinyl boronate ester-based persulfidating
agent that is selectively activated by hydrogen peroxide,
which is a reactive oxygen species (ROS), and efficiently
generated a persulfide by a hitherto unexplored 1,4-O,S-relay
mechanism is reported. This donor was found to protect cells
from cytotoxicity induced by oxidants, and the major
byproduct is cinnamaldehyde, which is widely used in the food industry as an additive.
ydrogen sulfide (H2S) has emerged as an important
mediator of redox cellular processes, especially in the
H
context of cellular responses associated with oxidative
stress.1−3 During several disease-like conditions, cells are
exposed to increased reactive oxygen species (ROS), which
contribute to neurodegenerative disorders, inflammation,
diabetes, tumor progression, and aging.4−8A mechanism by
which H2S exerts its effects is protein persulfidation (or S-
sulfhydration),3 which is an oxidative post-translational
modification where a cysteine (Cys-SH) residue is modified
to Cys-SSH group.1 Ambient protein persulfidation in cells is
symptomatic of normal functioning in certain cells;4 a corollary
to this observation is that diminished persulfidation is
associated with stressed or diseased states. For example,
diminished persulfidation of parkin, an E3 ubiquitin ligase that
contains a reactive cysteine residue, is correlated with
decreased rescue of damaged neurons. Increasing parkin
persulfidation appears to protect neurons by removing
damaged proteins. This finding has tremendous implications
in the treatment of neurodegenerative diseases such as
Parkinson’s disease.9 However, this correlation does not hold
for other proteins, underscoring the importance of developing
new tools to interrogate the chemical biology of persulfidation
under disease-relevant conditions.1 Furthermore, since persul-
fides (RSS−) are superior reductants, compared with RS−,
these species have gained traction as important intermediates
in countering oxidative stress.10,11 However, since persulfides
are unstable in biological milieu, it is challenging to generate
these reactive sulfur species in a controllable manner,10,11
hence the growing interest in small-molecule persulfidating
agents as tools to interrogate redox chemical biology of this
reactive sulfur species.
Figure 1. (a) Design of a triggerable protein S-sulfhydrating agent.
(b) Key intermediates of some reported triggerable persulfide donors
that operate via a 1,2- or a 1,6-O,S-relay mechanism. (c) An example
of a retro Michael reaction: the first step is presumably the generation
of an enol(ate), which generates a thiol by a 1,4-O,S-relay mechanism.
(d) Design of a ROS-triggered persulfide donor that is expected to
operate by a 1,4-O,S-relay mechanism.
inflammatory conditions, the donor would ideally need to be
triggered by hydrogen peroxide, which is a stable ROS.14 The
first major class of persulfidating agents are based on a 1,2-O,S-
relay mechanism, where the oxygen and sulfur are placed
adjacent to each other (Figure 1b).15 These donors respond to
An ideal donor would respond to elevated ROS to produce a
protein persulfidating agent. The general strategy to generate a
persulfide in situ involves stimuli responsive deprotection,
followed by electronic rearrangement or a relay mechanism to
release a persulfide.12,13 Subsequent exchange of the sulfhydryl
group between the persulfidating agent and a protein occurs to
induce protein persulfidation (Figure 1a). To closely mimic
Received: October 31, 2018
© XXXX American Chemical Society
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Letter
a nucleophile,15,16 enzyme,17−19 or fluoride.20 These donors,
while useful, have limited selectivity toward oxidative stress
conditions. The next class of persulfidating agents involves a
1,6-O,S-relay mechanism, where the oxygen is masked in the
form of a boronate ester, which is a substrate for oxidation by
ROS such as hydrogen peroxide.21 As a testament to its
therapeutic utility, this donor was shown to protect cells from
oxidative stress. The formation of a quinone-methide22 during
persulfide delivery is possibly a limitation of this method.
To address these major gaps, we considered an alternate
design for a ROS-triggerable persulfide donor, which was based
on a hitherto unexplored 1,4-O,S-relay mechanism.12 Formally,
this type of rearrangement is a retro Michael reaction involving
a thiol as a leaving group (Figure 1c).23,24 Here, the enol
undergoes a 1,4-O,S-relay mechanism to generate a thiol and
an α,β-unsaturated carbonyl compound. Since the pKa of R-
SSH (6.2) is somewhat lower than a thiol (7−9), it was
envisaged that this group might depart under these
conditions.11 The carbonyl was masked as a vinyl boronate
ester 1, which is known to undergo oxidation in the presence
of hydrogen peroxide to generate an aldehyde (Figure 1d).25,26
The byproduct of decomposition of 1 is cinnamaldehyde,
which is a constituent of cinnamon oil, and has been classified
as Generally Recognized As Safe (GRAS). Together, 1 should
respond to oxidative stress to generate a persulfide and
relatively innocuous byproducts.
First, to ascertain the reactivity of 1 toward ROS, 1 was
incubated with H2O2 (10 equiv) in pH 7.4 buffer at 37 °C.
HPLC analysis of the reaction mixture revealed the complete
disappearance of this compound in 90 min (Figure S1a in the
Supporting Information). A time course of this decomposition
was obtained, and curve fitting to a first-order equation gave a
rate constant k1 of 5.3 × 10−2 min−1 (Figure 2a). The
Figure 2. (a) Decomposition of 1, as monitored by HPLC analysis.
Curve fitting to first-order decomposition gave a rate constant (k1) of
5.3 × 10−2 min−1. (b) HPLC analysis of the reaction of 1 with
hydrogen peroxide in the presence of monobromobimane (mBBr) at
37 °C in pH 7.4 buffer (containing 20% CH3CN).
estimated half-life of 1 under these conditions is 13 min. This
value is comparable with arylboronate ester decomposition
(0.09 min−1), suggesting no significant difference in the
mechanism of hydrogen peroxide-mediated oxidation. To
study the potential for 1 to generate a persulfide, we used a
method developed by Binghe Wang and co-workers, where
they used 1-fluoro-2,4-dinitrobenzene (7, FDNB) to trap the
persulfide.17 The resulting compound 8 (Figure 3) can be
detected by HPLC analysis.
To synthesize 1 (Scheme 1a), benzaldehyde and TMS-
acetylene were reacted in the presence of n-butyllithium to
Scheme 1. (a) Synthesis of Thiol 5; (b) Reaction of
Benzylthiol (6) with 5 Affords the Desired Compound 1
a
Figure 3. Structures of key tools and compounds used in this study.
Compound 8 was synthesized using a reported procedure
and HPLC analysis showed a distinct peak at 11.3 min (Figure
S3a in the Supporting Information). When 1 (retention time
(RT) = 16.3 min) was coincubated with FDNB in the presence
of H2O2, we found nearly complete decomposition in 90 min
with a concomitant formation of 8 (Figure S3b in the
Supporting Information). Because of the susceptibility of
persulfides to decompose, this experiment was performed at
room temperature. In the absence of hydrogen peroxide, we
did not observe the formation of 8 (Figure S3d in the
Supporting Information). These data support the generation of
a persulfide when 1 was reacted with H2O2. The rate constant
for the formation of 8 (k3) was 0.15 min−1 and is a proxy to the
persulfide formation rate (Scheme 2).
An independent assay based on monobromobimane (mBBr)
was next used for detecting persulfides (Figure 2b). Reaction
of mBBr with a persulfide is expected to produce the disulfide
9 (Figure 3). When 1 was reacted with hydrogen peroxide at
37 °C in the presence of mBBr, we find a distinct peak that is
attributable to the formation of 9 (m/z = 369.07; observed,
a
BtCl = 1-chlorobenzotriazole and BtH = benzotriazole.
produce the secondary alcohol 2.27 Under Mitsunobu reaction
conditions, 2 was converted to the thioacetate 3a in 65%
yield.28 Hydroboration of 3a gave 4 as the trans isomer (vicinal
olefinic, J = 17.2 Hz). Deprotection of the thioacetate in the
presence of acetyl chloride afforded the thiol 5 in 52% crude
yield. Next, using a reported protocol, the reaction of benzyl
thiol 6 with 5 afforded the desired product 1 in 31% yield.29
B
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Letter
agent, to prevent the decomposition of H2O2 and the
subsequent radical-based oxidation of persulfides, the possi-
bility of polysulfide formation cannot be ruled out.
Furthermore, in cells, we would expect cinnamaldehyde to
react with other thiols such as glutathione, which typically
occurs in millimolar concentrations. When cinnamaldehyde
was reacted with glutathione, the pseudo-first-order rate
constant for this reaction was found as 2.3 × 10−2 min−1,
which translates to a half-life of ∼30 min (Figure S5 in the
Supporting Information). Previously, cinnamaldehyde was
found to react with thiols as well as bovine serum albumin;31
the half-life of the latter reaction was in the range of 3−8 min.
These data suggested the possibility of cellular thiols
competitively reacting with cinnamaldehyde and possibly
sparing the persulfide to conduct protein persulfidation.
We next estimated the selectivity of 1 toward activation by
H2O2. We tested 1 against a variety of oxidants in the presence
of FDNB and tested if the persulfide adduct 8 was produced.
We find no evidence for decomposition of 1 or the formation
of 8 under these conditions (Figure S6a in the Supporting
Information). In a separate assay with 10, we found no
evidence for the formation of cinnamaldehyde, except when 10
was treated with H2O2 (Figure S6c in the Supporting
Information). Together, these data support the excellent
selectivity of the vinyl boronate ester functional group toward
oxidation by hydrogen peroxide.
The proposed mechanism for the reaction of 1 with
hydrogen peroxide involves the oxidation of the vinyl boronate
ester (likely the boronic acid in pH 7.4 buffer) to produce an
enolate intermediate, which decomposes to produce the
persulfide and cinnamaldehyde. Since the value of kcinn was
comparable in magnitude with that of k3 and k4, it is likely that
the formation of the persulfide and cinnamaldehyde is
concerted. Previously, retro Michael reactions involving
thioethers of N-ethylmaleimide have been reported.23,24
These reactions are extremely slow (half-lives ranging from
∼1−7 days). Hence, the present method appears to be distinct
from the previous reports due to the direct generation of an
enolate II that rapidly rearranges to produce a persulfide. The
equilibrium constant for tautomerism (Ktaut), which is defined
as [keto]/[enol] for aliphatic aldehydes, is in the range of
10−3−10−4.32
These data suggest that, once formed, III would likely
equilibrate to the aldehyde IV (Scheme 2). If the aldehyde
(keto form) is indeed produced, it is likely that the generation
of the persulfide might be extremely slow. Our attempts to
detect this aldehyde IV were unsuccessful. Since the yields of
products are in excess of 70%, we reasoned that tautomerism
may not be a major competitive process. Thus, it is likely that
the enolate II, once formed, would rapidly rearrange to
generate the persulfide. The estimated pKa for the enol is 9−
10, likely to be deprotonated in pH 7.4.33 Previously, in basic
solution, the enolate was found to be the dominant form for
certain aldehydes.33 Although the operating pH is 7.4, it
appears to stabilize the enolate sufficiently to promote the 1,4-
O,S-relay.
Lastly, since persulfides are reported to mitigate oxidative
stress, we tested the ability of 1 to protect colon carcinoma
DLD-1 cells from cytotoxicity induced by elevated ROS. Colon
cells are constantly exposed to xenobiotics and stress induced
by pathogens. It has been reported that hydrogen sulfide is an
important mediator of stress response in the gut.34−36 Using
DLD-1 colon carcinoma cells, a cell viability assay was first
Scheme 2. Mechanism of Persulfide Formation during the
Oxidation of 1
a
a
The rate constant for decomposition of 1 was k1 = 5.3 × 10−2 min−1,
whereas that for the decomposition of 10 was k2 = 4.8 × 10−2 min−1.
The rate constant for the formation of cinnamaldehyde during the
decomposition of 1 in the presence of FDNB was kcinn = 12.8 × 10−2
min−1. The rate constants for the formation of 8 (k3 = 0.15 min−1)
and 9 (k4 = 0.12 min−1) were comparable.
369.25; see Figure S4 in the Supporting Information). The
time course for formation of this compound was monitored,
and a rate constant of k4 of 0.12 min−1 was obtained. This rate
constant is comparable with k1. Furthermore, the value of k3
was determined at 25 °C, and considering rate effects on
temperature, we suggest that the values of k1, k3, and k4 are
similar.
Next, the silylated derivative 10 was synthesized in two steps
from the propargyl alcohol 2 (Scheme S1 in the Supporting
Information). Compound 10 should undergo decomposition
in the presence of hydrogen peroxide but does not generate a
persulfide. When 10 was incubated in the presence of H2O2,
indeed, we find evidence for the formation of cinnamaldehyde
(Figure S2 in the Supporting Information).
Curve fitting yielded a rate constant (k2) of 4.8 × 10−2 min−1
that was comparable in value with the rate of decomposition of
1 (Scheme 2). The yield of cinnamaldehyde under these
conditions was 73%, which is comparable with the yield of 8
during incubation of 1 with hydrogen peroxide and FDNB
(Figure S3b in the Supporting Information). Phillips and co-
workers have previously demonstrated the use of vinyl
boronate esters in the deprotection of alcohols with pKa
values of >11.26 Since the estimated pKa value of tert-
butyldimethylsilanol is 15, this result supports the use of such
vinylboronate esters for the release of poorly acidic alcohols as
well.
When 1 was incubated in the presence of hydrogen
peroxide, we similarly observed the formation of cinnamalde-
hyde, but with diminished yield (Figure S1a in the Supporting
Information). This diminished yield could be due to the
collateral consumption of cinnamaldehyde by the persulfide.
To test this possibility, we incubated 1 in the presence of H2O2
and mBBr, and we found that the yield of cinnamaldehyde was
significantly better (∼70%; Figure 2b). The rate constant for
the formation of cinnamaldehyde (kcinn) was 12.8 × 10−2
min−1 (Scheme 2). Persulfides, being good one-electron
reductants, have a high propensity to undergo oxidation to
form tetrasulfides (RSSSSR) and polysulfides (RSnR).30
Although all assays were performed in the presence of
diethylenetriaminepentaacetic acid (DTPA) as a chelating
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conducted with increasing doses of 1, and no significant
inhibition up to 100 μM was observed (Figure S7a in the
Supporting Information). Next, using menadione, which is a
known redox cycling agent and inducer of oxidative stress, we
evaluated the protective effects of 1.37,38 DLD-1 cells were
treated with menadione and viable cells were measured (Figure
S7b in the Supporting Information). We found significant cell
killing at 50 μM (30% viable cells); this concentration was
chosen to study possible cytoprotective effects of 1. When 1
was cotreated with menadione, a dose-dependent cytoprotec-
tion was observed (Figure 4a). A cell viability assay conducted
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03471.
■
S
Synthesis and characterization data, analytical data, and
protocols (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: harinath@iiserpune.ac.in.
ORCID
Harinath Chakrapani: 0000-0002-7267-0906
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the Department of Science and Technology
(DST, Grant No. EMR/2015/000668), Department of
Biotechnology, India (No. BT/PR15848/MED/29/1025/
2016) for financial support for our research. Council for
Scientific and Industrial Research (CSIR) and the Department
of Science and Technology−Innovation in Science Pursuit for
Inspired Research (DST-INSPIRE) for fellowships.
Figure 4. (a) Cytoprotective effects of compound 1 against
menadione (50 μM). Results are expressed as mean
SEM (n =
3). [Legend: (**) p < 0.01, (***) p < 0.001, (****) p < 0.0001 vs
menadione.] A similar assay was conducted with 10. No significant
effect on the percentage of viable cells during incubation of 10 with
menadione was observed. (b) Cytoprotective effects of compound 1
against JCHD (50 μM). Results are expressed as mean SEM (n =
3). [Legend: (*) p < 0.05, (**) p < 0.01, (***) p < 0.001, vs JCHD.]
A similar assay was conducted with 10, and no significant effect was
observed.
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