A simple excited-state intramolecular proton transfer probe based on a new strategy of thiol-azide reaction for the selective sensing of cysteine and glutathione

Article abstract of DOI:10.1039/c5cc07298k

A simple azido-substituted fluorescent sensor AHBO showing a selective turn-on response to cysteine (Cys) and glutathione (GSH) over homocysteine (Hcy), sulfide and other amino acids has been constructed, which is based on the mechanism of selective nucle

Full text of DOI:10.1039/c5cc07298k

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A simple excited-state intramolecular proton transfer probe
based on a new strategy of thiol-azide reaction for the selective
sensing of cysteine and glutathione
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Dan Zhang, Zihao Yang, Hongjuan Li, Zhichao Pei, Shiguo Sun and Yongqian Xu*
www.rsc.org/
A simple azido-substituted fluorescence sensor AHBO showing The Yoon group developed
a cyanine-based near infrared
2
2
selective turn-on response to cysteine (Cys) and glutathione (GSH) fluorescent probes that can selectively detect GSH in living cells.
over homocysteine (Hcy), sulfide and other amino acids has been Recently, Guo and co-workers showed a sensor for simultaneous
constructed, which is based on the mechanism of selective fluorescence sensing of Cys and GSH from different emission
2
0
nucleophilic substitution-rearrangement reactions.
channels. These sensors are manly reaction-based and depend on
the strong of nucleophilicity of the thiol group. The types of
reaction include cyclization reaction, Michael addition, cleavage
Intracellular thiols, such as cysteine (Cys), homocysteine (Hcy) and
1
9
-10,19
glutathione (GSH), play pivotal roles in biological processes. For
reaction, disulfide exchange reaction and others.
These
instance, GSH is the most abundant cellular thiol that maintains the
reduced state of proteins and protecting the cells against reactive
developments greatly advanced the research on the fluorescent
detection of biothiols. However, many of these sensors suffer from
relatively low sensitivity, long response time and a complicated
2
oxygen species (ROS), drugs or heavy metal ions. Cys is involved in
1
9
many important biological functions including protein synthesis,
synthesis process. In addition, considering that these biothiols
have similar structures and reactivity but are associated with
different diseases, the design of a highly selective detection system
that discriminates them is still a significant challenge for clinic
diagnosis.
3
detoxification and metabolism. Hcy is a risk factor for Alzheimer’s,
4
-5
cardiovascular diseases and neutral tube defects. Abnormal thiols
concentration has been implicated with the development of many
kinds of diseases. For example, elevated levels of Cys are
considered to be linked with neurotoxicity, and its deficiency is
involved in slow growth in children, hair depigmentation, loss of
Azido-substituted fluorescent dyes have been widely
designed to selectively turn-on detect hydrogen sulphide
because azide can be easily converted into amine upon
treatment with hydrogen sulphide to lose its quenching
3
muscle and fat, skin lesion, liver damage and edema. Glutathione
deficiency is associated with various diseases such as leukocyte loss,
6
2
6-28
cancer, AIDS and neurodegenerative diseases. Therefore, the
property.
Herein, we present an azido-substituted
rapid, convenient, selective and sensitive detection of these
biothiols is of great importance for clinical diagnosis.
hydroxyphenylbenzoxazole derivative AHBO (Scheme 1). In
comparison with the reported azido-substituted fluorescent
sensors for detection of hydrogen sulphide, AHBO shows no
obvious fluorescence response to sulphide but selective turn-
on fluorescence response to Cys and GSH. The exceptional and
interesting response derived from thiol-azide reaction provides
a new strategy for biothiols detection. To the best of our
knowledge, AHBO is the first fluorescent sensor based on
azide recognition for selective sensing of Cys and GSH without
interference by sulphide.
Among various detection methods, fluorescence detection is
more attractive as it offers several advantages including high
7
-8
sensitivity, simplicity of operation and non-invasiveness. In the
past decade, significant efforts have been devoted to the
9
-25
development of fluorescent sensors for biothiols.
group provided the first turn-on fluorescent chemodosimeter for
The Peng
1
2
discrimination of Cys over Hcy and GSH. The Strongin group
reported the first example of simultaneous fluorescent detection of
Cys and Hcy based on the different relative rates in an
Probe AHBO was prepared by the synthetic route outlined
in Supporting Information. Briefly, 2-aminophenol was first
readily reacted with 5-aminosalicylic acid under the catalysis of
polyphosphoric acid (PPA) to form 2-(2’-hydroxy-4’-
1
3
intramolecular cyclization reaction. Yang and his co-workers
showed a BODIPY-based probe to produce a selective and
18
ratiometric fluorescence change with GSH relative to Cys and Hcy.
aminephenyl)benzoxazole (
resulting compound was further converted to diazo by
common diazo-reaction in acid media in the presence of
1). Then the amine group in the
1
a.
College of Science, Northwest A&F University, Yangling, Shaanxi, P.R. China,
712100, xuyq@nwsuaf.edu.cn
Electronic Supplementary Information (ESI) available: [detailed experimental sodium nitrite and sodium azide, producing AHBO with 72%
procedures and additional figures]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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isolated yield. In addition, for comparison a referenced
compound ABO was synthesized through the acetylation of
AHBO with acetic anhydride. All these compounds were fully
1
1
25 b)
00
2
R
=0.99358
1
13
characterized by H NMR, C NMR and MS spectra.
7
5
5
0
40
2
2
eqGSH
eqCys
30
HO
20
10
0
AcO
O
HO
O
O
N
N
N
N
N
2
25
0
2eqHcy-
2eqHS
N
3
N
N
S
NH
S
ABO
s
0
2
4
6
8
10
y
C
H
2
N
Time/min
HO
2
H N
O
N
O
OH
0
1
2
3
4
5
6
7
8
O
OH
HO
N
3
2
b
3b
[GSH]/µM
O
N
AHBO
HO
N
N
N
2
O
N
HO
N
S
O
N
N
2
N
Fig. 1. a) The fluorescence spectra change of AHBO (10 μM) upon addition of GSH,
λex=325 nm. The inset shows the photo of AHBO in the presence and absence of 1
equivalent of GSH, which is excited by hand-held UV lamp (365 nm). b) The
fluorescence intensity change of AHBO (10 µM) at 488 nm upon addition of GSH,
indicative of good linear relationship. Inset: time dependent fluorescence intensity (488
nm) of AHBO (10 µM) in the presence of 2 equivalents of GSH, Cys, Hcy and sulphide,
indicating that the reaction with GSH or Cys can be done within 10 min. All the solution
N
N
S
NH
S
H
2
N
H
N
O
NH2
H
O
2
N
COOH
NH
S
HO
O
O
2c
O
HN
O
O
NH
O
O
NH
HO
COO
-
N
HO
4
HO
NH
2
HO
2a
1
3a
is in CH
3
CN/HEPES Buffer (1:1, v/v, pH 7.4).
Scheme
1 Chemical structures of AHBO and ABO, and the plausible reaction
mechanism
.
3
In CH CN/HEPES buffer (1:1, v/v, pH 7.4), AHBO exhibited two
amino acids
absorption peaks at 344 and 420 nm. Upon addition of GSH, the
absorption intensity at 344 nm decreased, while the intensity at 420
nm increased with a well-defined isosbestic point at 365 nm (Fig.
S1). Accordingly, upon excitation at 325 nm, the fluorescence
intensity at 488 nm evidently increased upon successive addition of
GSH (Fig. 1a). The fluorescence intensities at 488 nm linearly
gradually increased with addition of GSH (0-7 μmol/L) (Fig. 1b). As
high as 28-fold fluorescence enhancement at 488 nm was observed
as 1 equivalent of GSH was added. The Job’s plot revealed 1:1
stoichiometry between AHBO and GSH (Fig. S2). The detection limit
amino acids+GSH
32
24
16
8
0
Cyst Gln Met Trp Thr His Leu Pro Lys Gly Ala Hcy Na S Cys GSH
2
-8
was calculated to be 9.0×10 M. AHBO is a typical excited-stated
intramolecular proton transfer (ESIPT) molecule, which should
exhibit normal emission (N*) and tautomer emission (T*) (Scheme Fig. 2. The relative fluorescence intensity of AHBO (10 μM) at 488 nm upon addition of
various amino acids (20 μM) in CH CN/HEPES Buffer (1:1, v/v, pH 7.4), λex=325 nm
S1). If the hydroxyl was substituted, ESIPT molecules mainly show
3
2
9
(blank bar). Red bars represent the intensity with subsequent addition of GSH (20 µM).
normal emission (N*). As expected, the acetyl-substituted ABO
reveals a main and shorter fluorescence band at 366 nm after
addition of 2 equivalents of GSH (Fig. S4). From these results, we
can propose that the 488 nm emission of AHBO treated with GSH
should come from the tautomer emission. As far as we know, the
product that AHBO reacts with GSH is the first small ESIPT molecule
The selectivity of AHBO to various amino acids and sulfide was
further examined. As shown in Fig. 2, only GSH and Cys promote
significant fluorescence intensity enhancement at 488 nm, whereas
other amino acids cause no detectable spectra change. To explore
the possible utility of AHBO as fluorescent sensor for GSH,
competitive experiments were carried out in the presence of 2
equivalents of GSH and 2 equivalents of various other amino acids.
AHBO can still turn-on fluorescence response to GSH without
interference by other amino acids. It should be noted that azido-
3
0
that only affords tautomer emission in polar aqueous media. The
fluorescence intensities of AHBO in the absence and presence of
GSH are pH independent in the range of 7-8, demonstrating that
AHBO can detect GSH in biological environment (Fig. S5).
substituted fluorescent dyes universally showed good fluorescence
488 nm
24,26-28
a)
response to sulfide.
But interestingly, AHBO affords no
120
0 eq GSH
0
0
.1 eq
.2 eq
obvious fluoresce change even upon addition of 10 equivalents of
sulfide and can efficiently detect GSH in the presence of sulfide (Fig.
S7), which is possibly due to the unique molecular structure of
AHBO. In addition, other possible reducing species in biological
9
6
3
0
0
0
0
0.3 eq
0
0
.4 eq
.5 eq
0.6 eq
2
+
0
0
.7 eq
.8 eq
samples, such as Fe and ascorbate showed no reactivity with
AHBO (Fig. S7). These results suggested that AHBO shows excellent
selectivity for GSH and Cys detection. The reaction times of AHBO
to thiols were also studies. AHBO shows fast fluorescence response
to GSH and Cys within 10 min no matter 2 or 10 equivalents of
1.0 eq
.3 eq
1
4
00
450
500
550
600
Wavelength (nm)
2
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these thiols were added (Inset in Fig. 1b and Fig. S8). Interestingly, because the intramolecular cyclic rearrangement reaction is
we found that no absorption spectra change of AHBO in the inhibited (Fig. 3). Furthermore, AHBO showed identical
presence of sulfide was observed within 10 min (Fig. S8a and b). fluorescence response to Cys and N-acetylcysteine. These results
Although AHBO can react with sulfide to produce non-fluorescent suggested that the selective fluorescence response of AHBO to GSH
1, the reaction rate is very slow, which efficiently avoids the and Cys over Hcy should be attributed to the inhibition of cyclic
interference of sulfide with detection of GSH or Cys. transition states/intermediates reactions, which has been used to
To evaluate the possibility in biological system, AHBO was explain the mechanisms of other Cys- or Hcy-selective probes.
applied to detect GSH in human blood samples. In diluted (10%)
deproteinized fetal bovine serum (FBS), turn-on fluorescence
response of AHBO was obviously observed upon addition of GSH
2
1
1
00
50
00
(Fig. S9). More importantly, the fluorescence intensity changes at
488 nm linearly depend on the added concentration of GSH,
AHBO
eq Hcy
2 eq NꢀacetylꢀHcy
2
suggesting the potential application of AHBO in serum.
2
2
eq NꢀacetylꢀCys
eq 1
AHBO shows remarkable and selective fluorescence turn-on
response to GSH and Cys over Hcy and sulfide. We were interested
in achieving an understanding of the difference between these
biothiols. AHBO showed no fluorescence and its fluorescence
quantum yield (Φ) was very low (as small as 0.0007) because of the
quenching property of azide. Upon treatment with sulfide, it is
possible that AHBO would be transformed to 1 hanging with amino
group. In fact, the product of AHBO that reacts with sulfide is
undoubtedly confirmed to be 1 through TLC, NMR and MS spectra.
50
0
4
00
450
500
550
600
Wavelength (nm)
However, like AHBO, 1 also has very low fluorescence quantum Fig. 3. The fluorescence spectra change of AHBO (10 μM) upon addition of 2
yield (0.002) due to the photo-induced electron transfer (PET) equivalents of Hcy, N-acetylhomocyeteine, N-acetylcyeteine and 1 in CH
3
CN/HEPES
Buffer (1:1, v/v, pH 7.4), λex=325 nm.
effect, which should be interpreted that AHBO showed no obvious
fluorescence change upon addition of sulfide. Compared to Cys, Hcy
has one extra methylene group, which makes Hcy to be more
conducive to experience nucleophilic substitution-rearrangement
(
or S
N
Ar substitution) reaction. This property has been widely used
14,18-
to design fluorescent sensors for discrimination of Cys and Hcy.
1
9,21,25
Inspired by this, we propose the plausible reaction
mechanism between AHBO and these thiols. As shown in Scheme 1,
initial nucleophilic attack by sulfhydryl froup of thiols leads to the
formation of an intermediate 2. The intermediate 2 then release N
2
to provide the S-N product 3. In the case of Hcy, the amino group
then attacks the sulfur to form the non-fluorescent product 1, and
at the same time to yield a five-membered ring product 4, which is
confirmed by MS spectrum (Fig. S17). In the case of Cys and GSH, a
similar intramolecular attack would lead to a strained four
membered ring and a nine membered ring, respectively, which
would be unstable and thus unfavorable. In fact, their final products
should be the S-N compounds 3a and 3b. These compounds are
fluorescent with the fluorescence quantum yields of 0.017 and
0
.016, respectively. The S-N compounds 3a and 3b were also
confirmed by MS spectra (Fig. S10-11). The corresponding peaks of
a and 3b with exact molecular weight were also observed in LC-MS
3
Fig. 4. Fluorescence images of HeLa cells. (a-c) HeLa cells incubated with probe AHBO
(20 µM) for 30 min; (d-f) images of cells pretreated N-ethylmaleimide (NEM) for 30 min
and then incubated with AHBO for 30 min; (g-i) images of cells pretreated N-
ethylmaleimide (NEM) for 30 min and then incubated with AHBO and GSH (100 µM) for
spectra (Fig. S15-16). Similar to GSH, the 1:1 stoichiometry between
1
AHBO and Cys was obtained from Job’s plot (Fig. S3). The H NMR
spectra titration of AHBO with GSH was studied (Fig. S13). Upon
addition of GSH, no substitution on aromatic ring was observed, but 30 min; (a, d and g) Bright-field images of the HeLa cells in samples; (b, e and h) images
up-field shifts for the aromatic protons of the benzoxazole core taken in blue field; (c, f and i) are the overlap of brightfield and fluorescence. Images
were acquired by using excitation and emission windows of λex = 405 nm and λem = 420-
were found due to the displacement of azido by S-N bond. To
4
75 nm, respectively. Scare bar: 20 µm.
further confirm the mechanism including substitution-
rearrangement reaction, the control reaction of AHBO with N-
acetylhomocysteine, a molecule that structurally similar to Hcy but
lacks an amino group, was carried out. As expected, turn-on
fluorescence response similar to that added with Cys was obtained
To further investigate the biological application of AHBO, the
fluorescence microscopy experiment in living cells was carried out.
When HeLa cells were incubated with 20 μM AHBO in culture
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1
1
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4
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2
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2
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substitution-rearrangement reactions that take place in the case of
Hcy but not in the case of GSH and Cys. Finally, AHBO can be served
as a fluorescent sensor to visualize Cys and Hcy in living cells.
Although the excited wavelength of the sensor is in ultraviolet
region, the thiol-azide reaction provides a new strategy to design
fluorescent sensors for detection of thiols. Further work along
exploration of this kind of sensors with longer wavelength
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