A new ESIPT-based fluorescent probe for highly selective and sensitive detection of hydrogen sulfide and its application in live-cell imaging

Article abstract of DOI:10.1039/c6nj03355e

A new excited-state intramolecular proton transfer (ESIPT) based fluorescent probe for the detection of hydrogen sulfide has been reasonably designed and developed. The probe operates by H₂S-mediated reduction of hydroxylamine to amine and exhibits high selectivity and sensitivity under mild conditions. Furthermore, the probe was successfully used for fluorescence imaging of H₂S in living cells.

Full text of DOI:10.1039/c6nj03355e

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PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
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A New ESIPT-Based Fluorescent Probe for Highly Selective and
Sensitive Detection of Hydrogen Sulfide and Its Application in
Live-Cell Imaging
Received 00th January 20xx,
Accepted 00th January 20xx
Bo Chen,a Jing Huang,a Huiqing Geng,a Lingli Xuan,a Tengfei Xu,a Xin Li,b and Yifeng Han*a
DOI: 10.1039/x0xx00000x
A new excited-state intramolecular proton transfer (ESIPT) based fluorescent probe for the detection of hydrogen sulfide
has been reasonably designed and developed. The probe operates by H2S-mediated reduction of hydroxylamine to amine
and exhibits high selectivity and sensitivity under mild conditions. Furthermore, the probe was successfully used for
fluorescence imaging of H2S in living cells.
www.rsc.org/
current research has been focused on fluorescent methods
and probes because of their noninvasive and real-time
detection capability in vivo.6
Introduction
Hydrogen sulfide (H2S), recently recognized as an important
redox-active signaling molecule,1 is generated predominantly
in the cytosols and mitochondria of mammalian cells from
cysteine or its derivatives by cystathionine-γ-lyase (CSE),
cystathionine-β-synthase (CBS), cysteine aminotransferase
(CAT), or 3-mercaptopyruvate sulfurtransferase (MST).2
Endogenous H2S has been recognized in a variety of significant
biochemical processes, including vasodilation, angiogenesis,
neurotransmission, insulin regulation, and anti-inflammation.3
Due to its vital roles in the physiological processes, production
and metabolism of H2S in biological systems is strictly
adjusted, with the imbalance of its homeostasis causing many
pathological states, such as Alzheimer’s disease, Down’s
syndrome, cardiovascular dysfunction, hypertension, diabetes,
and liver cirrhosis.4 Therefore, it is of great importance to
explore accurate tools for H2S detection and measurement in
its native environments to facilitate detailed biological
function studies.
In 2011, Chang’s group as well as Wang and colleagues
reported the first-generation of fluorescent probes for H2S
based on selective H2S-mediated reduction of azides and
sulfonylazides, respectively.7 Since then, a number of highly
innovative fluorescent H2S-probes have been developed based
on the selective H2S-mediated reduction of nitro or
hydroxylamine to amines, the nucleophilic attack of H2S to
Michael receptors, or even the precipitation of metal cations
(Fig. 1).8 Although these reported probes are highly selective,
many of them still have limitations such as low sensitivity, high
detection limits, and laborious synthesis processes with
expensive chemicals.9 On the other hand, now it is known that
the physiological concentrations of H2S in plasma is 20-80 μM
and it is low at sub-micromolar or nano-molar concentration
levels in living cells.10 Therefore, the development of simple
yet highly sensitive fluorescent probe for the accurate
detection of H2S is still in high demand.
3-Aminophthalimide,
a fragment of anticancer drug,
Whereas
conventional techniques,
including
gas
Pomalidomide,11 has been reported as a fluorophore which
exhibits a large Stokes shift upon excitation by excited state
intramolecular proton transfer (ESIPT) through the keto-enol
tautomerism (Scheme S1, ESI†). Furthermore, the fluorophore
also possesses many favorable properties such as good photo-
chromatography, electro-chemical methods, methylene blue
method, monobromobimane method, and colorimetric
methods, used for H2S detection often need expensive and
sophisticated
instrumentation,
complicated
sample
preparation, and/or tissue or cell destruction, and are
therefore not suitable for real-time and in situ analysis.5 Thus,
O
N
O
H
O
O
N
O
N
N
O
N3
O
N
O
N
Cu2+
TPE
TPE
O
N
O
O
O
O
NHOH
C. J. Chang 2011
W. Wang 2012
S. H. Liang 2014
O2N
NO2
Z. Xu and J. Cui 2013
Fig. 1 Some reported fluorescent H2S-probes.
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2-butyl-4-(hydroxyamino)isoindoline-1,3-dione (2, PHS1):
compound (500.0 mg, 2.0 mmol), NH4Cl (118.5 mg, 2.2
1
mmol) were dissolved in 60 oC water (8 mL), then zinc powder
(263.4 mg, 4.0 mmol) was added, and then the reaction
mixture was stirred for another 15 min. The insoluble zinc was
filtered, washed with hot water (10 mL). The water solution
was then extracted with ethyl acetated (3
× 10 mL). The
Scheme 1 Fluorescent turn-on sensing of H2S by PHS1.
extract was dried over sodium sulfate and then concentrated
under vacuum. The product was purified by flash
stability, relatively high fluorescent quantum, emission in
green spectral region, and facile preparation.
chromatography using hexane-EtOAc (4:1, v/v) as the eluant to
1
as a pale yellow powder (330.0 mg, 70%). H NMR (400
give
2
In this work, we report a new ESIPT-based fluorescent turn-
on probe, PHS1 (probe for hydrogen sulfide), which is a 3-
hydroxylamine derivative of phthalimide, for the detection of
H2S. Based on the specific reduction of hydroxylamine by H2S
to generate the corresponding amine, a hydroxylamine group
was selected as the reaction site. We envisioned that
protection of the 3-amine nitrogen as a hydroxylamine group
renders the fluorophore non-emissive by the prevention of
ESIPT process until the hydroxylamine is reduced to the amine
by H2S (Scheme 1). To the best of our knowledge, this is the
first example of an ESIPT-based fluorescent probe using H2S-
mediated hydroxylamine reduction for the selective H2S
detection.
MHz, Acetone-d6) δ 8.42 (brs, 1H), 8.36 (brs, 1H), 7.51 (m, 1H),
7.35 (m, 1H), 7.07 (m, 1H), 3.44 (m, 2H), 1.48 (m, 2H), 1.18 (m,
2H), 0.79 (m, 3H). 13C NMR (100 MHz, Acetone-d6) δ 169.87,
168.93, 149.83, 136.11, 133.30, 119.37, 114.22, 112.64, 37.75,
31.27, 20.58, 13.84.
N-butyl-3-aminophthalimide (3): compound
2 (20.0 mg, 0.085
mmol) and Na2S·9H2O (204 mg, 0.85 mmol) were dissolved in
EtOH (10 mL) and the solution was stirred at room
temperature for 3 h. The solvent was pumped off and then
water (10 mL) was added. The mixture was then extracted
with DCM (3 × 5 mL). The extract was washed with brine (15
mL), dried over sodium sulfate and then concentrated under
vacuum. The product was purified by flash chromatography
Experimental section
using hexane-EtOAc (4:1, v/v) as eluant to give 3 (14.2 mg,
1
76%) as a light yellow solid. H NMR (400 MHz, Chloroform-d)
δ 7.33 (dd, J = 8.4, 7.2, 1H), 7.07 (d, J = 6.8 Hz, 1H), 6.82 (d, J =
8.4 Hz, 1H), 5.32 (brs, 2H), 3.58 (t, J = 7.2 Hz, 2H), 1.59 (q, J =
7.4 Hz, 2H), 1.32 (q, J = 7.5 Hz, 2H), 0.90 (t, J = 7.4 Hz, 3H). 13C
NMR (100 MHz, Chloroform-d) δ 170.18, 168.62, 145.11,
134.91, 132.65, 121.14, 112.45, 111.07, 37.18, 30.58, 19.92,
13.64.
General methods
All the solvents were of analytic grade. NMR experiments were
carried out on a Bruker AV-400 NMR spectrometer with
chemical shifts reported in ppm (in CDCl3, d-Acetone, or TMS
as an internal standard). Mass spectra were measured on an
Agilent 1290 LC-MS spectrometer. All pH measurements were
made with a Sartorius basic pH-Meter PB-10. Fluorescence
spectra were determined on a PerkinElmer LS55 Fluorescence
spectrophotometer. Absorption spectra were collected on a
Shimadzu UV 2501(PC)S UV-Visible spectrophotometer. The
excitation and emission widths for measurements were all 3
nm. All the cation solutions were prepared from GSH, Cys.
NaHSO3, Na2S2O4, Na2S2O3, Na2SO3, NaClO, KI, FeCl3, NaF, NaCl,
NaBr, NaH2PO4, NaNO3, Na2CO3, and Na2S in distilled water,
with a concentration of 1 mM, respectively.
Cell culture and imaging
HeLa cells were cultured in DMEM (Invitrogen, Carlsbad, CA),
supplemented with 10% fetal bovine serum in a humidified
o
atmosphere of 5% CO2 at 37 C. For imaging experiments,
e
xponentially growing cells were seeded in 24-well plate. Cells
were cultured at 37 oC in a 5% CO2 atmosphere for 24 h before
they were exposed to reagents.
For labeling, the medium was removed and cells were rinsed
three times with PBS. Then HeLa cells were incubated with
PHS1 (10 μM) in PBS (containing 1% EtOH) at 37 oC for 30 min
as control. For H2S imaging, another set of HeLa cells was
preloaded with PHS1 (10 μM) in PBS (containing 1% EtOH) at
Synthesis
N-butyl-3-nitrophthalimide (1): 3-nitrophthalic acid anhydride
(5.0 g, 25.9 mmol) was dissolved in acetic acid (50 mL),
followed by n-butylamine (3.3 mL, 33.7 mmol), and then the
mixture solution was refluxed for 2 h until all the starting
material was consumed, which was monitored by TLC analysis.
Then water (100 mL) was added, the light yellow precipitate
formed was separated by filtration, washed thoroughly with
o
37 C for 30 min, rinsed three times with PBS and further
treated with different concentrations of H2S (100, 200, and 400
o
μM, respectively) in PBS at 37 C for additional 30 min. Cells
were rinsed three times with PBS and bathed in it, then
imaging was carried out. Images were acquired using an
inverted fluorescence microscope and fluorescence imaging
was performed in a blue channel.
water, and dried in vacuo to give
1 as a white solid (5.30 g,
1
83%). H NMR (400 MHz, Chloroform-d) δ 8.11 (m, 2H), 7.91
(dd, J = 8.0, 7.2 Hz, 1H), 3.73 (t, J = 7.3 Hz, 2H), 1.68 (m, 2H),
1.40 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H).
Results and discussion
2 | J. Name., 2012, 00, 1-3
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HO
NO2
O
NO2
O
NH
O
(a)
(b)
O
N
N
O
O
O
1
2 (PHS1)
NH2
O
(c)
N
O
3
Scheme 2 Synthesis of PHS1: (a) n-butylamine, AcOH, reflux, 2 h, 83%; (b)
Zn, NH4Cl, H2O, r.t., 70%; (c) H2S, EtOH, r.t., 3 h, 76%.
As shown in Scheme 2, PHS1 can be readily prepared in two
convenient steps under facile conditions with good yields
starting with commercially available 3-nitrophthalic anhydride.
Fig. 3 Fluorescence intensity of PHS1 (10.0 μM) at 486 nm as a function of
H2S concentration in PBS buffer (10.0 mM, pH 7.4, containing 50% EtOH).
(Data were collected after incubation of PHS1 with H2S for 1 h).
1
The probe (PHS1) was well characterized by H, and 13C NMR
(see ESI†).
= 0.993) (Fig. 2 and S2, ESI†) and further smoothly increased
until a maximum was reached up to 20.0 μM of H2S (Φ = 0.104,
Table S1, and Fig. 3 and S2, ESI†). Based on these results, the
detection limit of PHS1 for H2S was determined to be 8.87 nM
(Fig. S2, ESI†), which was sufficiently low for the detection of
H2S in biological samples.
UV-vis and fluorescence spectral responses of PHS1 to H2S
PHS1 alone showed a UV absorption band centered at 380 nm
1
(ε = 3.3
1
× =
103 M− cm− ) and was almost non-fluorescent (λex
393 nm, λem = 486 nm, Φ = 0.009, Table S1, ESI†) in PBS buffer
solution (10 mM, pH 7.4, containing 50% EtOH), indicating that
the ESIPT process was blocked efficiently (as shown in Scheme
1). However, upon progressive addition of hydrogen sulfide
(Na2S was used as a sulfide source in all experiments), an
emission band centered at 486 nm rapidly increased, which
was deduced to be attributed to the formation of the free
ESIPT active 3-amine phthalimide fluorophore by the H2S-
Response mechanism
A plausible mechanism of the H2S-induced fluorescence
response is proposed (Scheme 1 and S2, ESI†). To make further
confirmation, the fluorescent spectra of the PHS1-H2S system
and that of compound
be identical to each other (Fig. S3 and S4, ESI
the detection product was isolated and its structure was
3
was compared and they turned out to
†). Furthermore,
mediated reduction of hydroxylamine in PHS1
.
1
3
by H and 13C NMR spectra
Moreover, the fluorescence titration experiment revealed
that the fluorescence intensity of PHS1 at 486 nm increased
linearly with concentrations of H2S in the range of 0-2.0 μM (R2
confirmed to be just compound
analysis PHS1 (see ESI ).
†
Fig. 2 Fluorescence spectra of PHS1 (10.0 μM) in PBS buffer solution (10
mM, pH 7.4, containing 50% EtOH) in the presence of different
concentrations of H2S (0-8.0 equiv.) (λex = 393 nm) (Data were collected after
incubation of PHS1 with H2S for 1 h). Inset: cuvette images of probe PHS1
Fig. 4 Fluorescence spectra of PHS1 (10.0 μM) in PBS buffer solution (10
mM, pH 7.4, containing 50% EtOH) in the presence of 20.0 μM of H2S with
excitation at λex = 393 nm. Emission was collected between 425 and 625 nm.
Time points represent 0, 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 75, 90, 120, and
(red trace) 180 min after addition of 20.0 μM H2S.
before and after the addition of H2S taken under a hand-held UV lamp (λex
365 nm).
=
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Fig. 6 Fluorescence images of HeLa cells with PHS1 (10.0 μM) and different
concentration of H2S (0, 100, 200, 400 μM, respectively) for 30 min.
Fig. 5 Fluorescence responses of PHS1 (10.0 μM) to various reactive sulfur
-
species and coexisting ions (H2S at 20.0 μM, GSH at 1.0 mM, and Cys, HSO3 ,
-
-
2-
S2O42-, S2O32-, SO32-, ClO-, I-, Fe3+, F-, Cl-, Br-, H2PO4 , NO3 and CO3 at 100.0
PHS1 remained its desired ability to sense H2S in the range of
μM, respectively). Black bars represent the addition of the appropriate ions
to PHS1 (10.0 μM) (in PBS buffer solution, 10 mM, pH 7.4, containing 50% pH from 6.0 to 9.0, indicating that it could be used in living
EtOH). Red bars represent the addition of 2.0 equiv. of H2S to the solutions
containing PHS1 (10.0 μM) and the appropriated ions. (λex = 393 nm). (Data
were collected after incubation of PHS1 with analytes for 1 h).
cells.
Cell imaging
Due to the favorable properties of PHS1 in vitro, its potential
application in living cells was studied. For this purpose, HeLa
cells were first incubated with PHS1 (10.0 μM) for 30 min, then
H2S (0, 100, 200, and 400 μM, respectively) was added and
Kinetics
Subsequently, the time-dependence of the fluorescence was
also evaluated in the presence of H2S in PBS buffer solution (10
o
mM, pH 7.4, containing 50% EtOH) (Fig. 4, and S5, ESI†).The
incubated for another 30 min at 37 C, and the fluorescent
results showed that, within 1 h of reaction under these
images were taken. As shown in Fig. 6, cells without the
treatment of H2S showed weak blue fluorescence, whereas the
cells exposed to both PHS1 and H2S displayed strong blue
fluorescence and the intracellular fluorescence intensities
correlated with the concentration of H2S added (from 100 to
400 μM) (Fig. 6). These obvious changes indicated that PHS1
was cell membrane permeable and capable of imaging H2S in
living cells. Moreover, the series of bright field images shown
that cells were intact, healthy spread and adherent during and
after the labeling process with PHS1 indicated that the probe
has no cytotoxic effect.
conditions, PHS1 produced 40-fold response (Figure 4).
Selectivity of PHS1 toward H2S
Continuing on, the fluorescence response of PHS1 towards
various reactive sulfur species and coexisting ions was
conducted to examine the selectivity (Fig. 5, S6 and S7, ESI†).
Much to our delight, PHS1 exhibited high specificity towards
H2S. Reactive sulfur species (RSS) such as glutathione, cysteine,
-
HSO3 , S2O42-, S2O32-, SO32-, which are highly relevant to H2S,
cannot induce fluorescence change. In addition, other
biologically related species in a large excess amount (10 equiv.)
-
-
2-
such as ClO-, I-, Fe3+, F-, Cl-, Br-, H2PO4 , NO3 and CO3 also
caused no change to the fluorescence profile of PHS1. It
should be mentioned that PHS1 still responded to H2S
sensitively even in the presence of other relevant competing
ions (Fig. 5, and S7, ESI†). Taken together, the probe displayed
excellent selectivity over other biological species.
Conclusions
In conclusion, we have rationally developed a new and simple
ESIPT-based sensitive fluorescent probe for the selective
detection of H2S by H2S-mediated hydroxylamine reduction
reaction. The probe displayed a specific fluorescence response
towards H2S under mild conditions with a low detection limit.
Furthermore, fluorescence imaging of H2S in live cells indicated
that this probe might be favorable for biological applications.
pH effects
Moreover, the H2S-sensing ability of PHS1 at a wide range of
pH values was also investigated. As depicted in Fig. S8, ESI†,
PHS1 alone was inert to pH in the range of 4.0-9.0. But in the
presence of H2S, the fluorescence response scope of PHS1
decreased when the surrounding pH decreased, and vice versa
Acknowledgements
This work was supported by Zhejiang Provincial Top Key
Academic Discipline of Chemical Engineering and Technology,
Zhejiang Sci-Tech University (YR2015006), and the Project
Grants 521 Talents Cultivation of Zhejiang Sci-Tech University.
(Fig. S9 and S10, ESI†), which was due to that H2S (pKa1 = 7.02)
is less nucleophilic than HS-. These results are also consistent
with the proposed mechanism (Scheme S2, ESI†). Moreover,
4 | J. Name., 2012, 00, 1-3
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New Journal of Chemistry
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DOI: 10.1039/C6NJ03355E
A new ESIPT-based fluorescent probe for the sensitive detection of hydrogen sulfide has been
reasonably designed and developed.