Investigation of thiolysis of 4-substituted SBD derivatives and rational design of a GSH-selective fluorescent probe

Article abstract of DOI:10.1039/d1ob01114f

In order to evaluate 7-sulfonamide benzoxadiazole (SBD) derivatives for the development of fluorescent probes, herein we investigated the thiolysis reactivity and selectivity of a series of SBD compounds with different atoms (N/O/S/Se) at the 4-position.

Full text of DOI:10.1039/d1ob01114f

Organic &
Biomolecular Chemistry
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Investigation of thiolysis of 4-substituted SBD
derivatives and rational design of a GSH-selective
fluorescent probe†
Cite this: Org. Biomol. Chem., 2021,
19, 6527
c
Chao Yang,a Xiaoqiang Tu,b Xiuru Ji,c Haishun Ye,b Shan Li,b Lu Sun,
Long Yi *b and Zhen Xi*a
In order to evaluate 7-sulfonamide benzoxadiazole (SBD) derivatives for the development of fluorescent
probes, herein we investigated the thiolysis reactivity and selectivity of a series of SBD compounds with
different atoms (N/O/S/Se) at the 4-position. Both SBD-amine and SBD-ether are stable toward biothiols
in buffer (pH 7.4), while SBD-selenoether can react efficiently with biothiols GSH/Hcy, Cys, and H2S to
produce SBD-SG/S-Hcy, SBD-NH-Cys, and SBD-SH, respectively, with three different sets of spectral
signals. Therefore, the SBD-selenoether compounds should be useful platforms for the differentiation of
these biothiols. Though SBD-alkylthioether shows much lower reactivity than SBD-selenoether, SBD-
arylthioether is a tunable motif and structural modifications at the aryl moiety enable the rate of thiol-
mediated thiolysis to be modified. To this end, an ER-targeted GSH-selective fluorescent probe 7 was
rationally designed via thiolysis of SBD-arylthioether. Compared with control probe SBD-Cl, probe 7 exhi-
bits improved GSH selectivity and better biocompatibility. In total, this study highlights that the modifi-
cation at the 4-position of SBD is an efficient strategy for the development of new fluorescent probes
with tunable reactivity and selectivity.
Received 9th June 2021,
Accepted 6th July 2021
DOI: 10.1039/d1ob01114f
rsc.li/obc
is found to be much higher than that in normal tissues.4
Therefore, chemical tools that enable the in situ detection and
Introduction
Biothiols, including glutathione (GSH), cysteine (Cys), homo- differentiation of GSH have potential applications in the treat-
cysteine (Hcy), and hydrogen sulfide (H2S), are potent nucleo- ment of various disease states. To this end, significant pro-
philes and play diverse and important roles in living biosys- gress has been made in the development of fluorescent probes
tems. GSH is the most abundant intracellular biothiol, and for selective detection of GSH among other biothiols.5–16
normally, the endogenous level of GSH (∼1–10 mM) is much
Many of the reported GSH-selective probes are based on the
higher than that of Cys (<200 μM), Hcy (<15 μM), and H2S initial reactions toward all sulfhydryl nucleophiles and then,
(<1 μM).1 GSH provides protection against oxidative stress the resultant products undergo an additional intermolecular
through its reversible oxidation to GSSG.2 A decrease in GSH interaction or reaction (e.g., the Smiles rearrangement for Cys/
levels can be related to different diseases, including neurode- Hcy but not for GSH), producing different photophysical pro-
generative diseases, liver damage, schizophrenia, and perties for the differentiation of GSH from Cys and Hcy.6–11
cancers.3 However, the concentration of GSH in some tumors Another relatively minor group of probes with relatively low
reactivity toward sulfhydryl nucleophiles can selectively detect
GSH over Cys/Hcy due to higher concentration of endogenous
aState Key Laboratory of Elemento-Organic Chemistry and Department of Chemical
GSH,12–16 which is more preferable if one only needs to detect
Biology, College of Chemistry, National Pesticide Engineering Research Center,
GSH without probe-consuming from other thiols. For example,
Yin and coworkers developed the thiolysis of sulfonamide-con-
Collaborative Innovation Center of Chemical Science and Engineering, Nankai
University, Tianjin, 300071, China. E-mail: zhenxi@nankai.edu.cn
bState Key Laboratory of Organic-Inorganic Composites and Beijing Key Lab of
Bioprocess, Beijing University of Chemical Technology (BUCT), Beijing 100029,
China. E-mail: yilong@mail.buct.edu.cn
cTianjin Key Laboratory on Technologies Enabling Development of Clinical
Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical
University, Tianjin 300070, China
taining naphthalimides for selectively tracking mitochondrial
GSH.13 The Wang group and the Yoon group employed revers-
ible thiol-Michael addition for quantitatively monitoring cellu-
lar GSH.14 Li, Zang, and coworkers developed naphthalimide–
sulfoxide based probes for revealing the functions of GSH in
chemotherapy resistance and in developing neurons.15 Many
of these GSH fluorescent probes have been successfully used
†Electronic supplementary information (ESI) available: Experimental details and
additional figures. See DOI: 10.1039/d1ob01114f
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for predicting disease evolution, differentiation of cancer cells, sion of NBD-based probes with sulfonamide substituents at the
and tumor imaging.5–16 Building from these broad bioapplica- 7-position is an additional area of likely investigation.5f For
tions, the development of GSH-selective probes is still in its example, SBD-Cl derivatives have been developed for the differ-
infancy.
entiation of Cys and Hcy/GSH, and unlike NBD-SG, the SBD
We have been interested in compounds with a nitrobenzo- thioethers are fluorescent with a different emission wavelength
dioxzole (NBD) skeleton for the detection and scavenging of from that of SBD amines (Scheme 1a).22 In addition, SBD con-
biothiols (including H2S) for several years.5f,17,18 For example, we tains two sites for the facile development of multi-functional
as well as others found that NBD derivatives show high reactivity probes.23 Therefore, SBD should be a useful dye platform for the
toward biothiols and amines, resulting in distinct colorimetric development of new fluorescent probes with tunable properties.
and fluorescence changes.5f Pluth and coworkers revealed that
On the other hand, chemical modifications at the 4-posi-
after the initial SNAr reaction between Cys/Hcy and the NBD elec- tion of SBD are considered to impact the reactivity and selecti-
trophile, the resultant NBD-thioether undergoes an inter- vity of the probes, but such studies are understudied in detail.
molecular Smiles rearrangement to generate fluorescent Herein, we prepared a series of SBD derivatives (Scheme 1b)
NBD-NHR compounds.19a,b The strong emission of NBD-NHR and studied their thiolysis reactions in aqueous buffer (pH
derives from intramolecular charge transfer (ICT) transitions, 7.4). We demonstrate that the thiolysis reactivity of SBD deriva-
where the amino group and the nitro group are the ICT donor tives increases with 4-substituted atoms varing from N, O, S to
and acceptor, respectively. GSH only generates a non-fluorescent Se. SBD selenoether can react with all biothiols efficiently and
thioether product (NBD-SG). To this end, Ma and coworkers can be a useful receptor motif for sensing and differentiating
combined NBD-ether with resorufin to differentiate between biothiols. Moreover, SBD arylthioethers are found to be
GSH and Cys based on the formation of NBD-NH-Cys.19c In tunable motifs and structural modifications at the aryl group
addition, Kim and coworkers compared the thiolysis reactivity lead to a new GSH-selective receptor for the development of
and selectivity of several NBD ethers with different aromatic sub- improved fluorescent probes.
stituents at the 4-position and developed a Cys-selective probe
(Scheme 1a).20 Yoon, Yin, and coworkers reported that the differ-
entiation of Cys over Hcy/GSH at pH 6.0 can be achieved by an
Results and discussion
NBD derivative with sulfur replacement of oxygen at the oxazole
group.21 To further obtain different reactivities and selectivities One major challenge in the development of GSH probes is the
with distinct photophysical properties, we note that the expan- discovery of a chemical reaction to effectively separate the reac-
Scheme 1 (a) NBD-Cl can react with biothiols to give fluorescent products NBD-NH-Cys/Hcy and non-fluorescent NBD-SG; NBD-OR can selec-
tively react with Cys to give NBD-NH-Cys; SBD-Cl can react with biothiols to give two kinds of fluorescent products SBD-NH-Cys and SBD-S-G/
Hcy. In this design, we hope to tune the thiolysis reactivities of SBD-XR derivatives for the selective detection of GSH. (b) Chemical structures of SBD
compounds 1–7.
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tivity of GSH and other biothiols. To address this challenge, we the NBD-piperazinyl moiety discovered by our group has been
intend to investigate the chemistry of SBD derivatives. Probes widely employed as a fast receptor for the development of H2S
1–4 contain an SBD fluorophore with a water-soluble group probes,5f,18 but probe 1 cannot react with H2S under similar
and different atoms at the 4-position, while probes 5–7 conditions (Fig. S3†). The reaction of probe 3 and 10 mM GSH
contain an endoplasmic reticulum (ER)-targeting group and a could not reach completion after 1 h, but the thiolysis rate of
thiol recognition group or Cl atom as a control (Scheme 1).24 NBD thioether with GSH could reach 80.7 M−1 s−1 17d
It was
.
These probes can be facilely prepared from commercially avail- noted that the reaction of 4 and GSH could lead to a signifi-
able reagents. The structures of these probes were confirmed cant fluorescence increase at 520 nm, which was employed to
by 1H NMR and 13C NMR spectroscopy and HRMS (see the determine the pseudo-first-order rate, kobs. The linear fitting
ESI† for details).
between kobs and GSH concentrations gives the reaction rate
With these probes in hand, we first performed the time- (k2) of 5.16 M−1 s−1 for SBD selenoether (Fig. S4†), which is
dependent HPLC of the probes in the presence of 10 mM GSH also much lower than that of NBD thioether. In total, SBD
in PBS buffer (pH 7.4, containing 30% DMSO). As shown in probes show much lower reactivities than NBD probe analogs.
Fig. 1, probes 1 and 2 were stable toward 10 mM GSH within
Now that probe 4 can react with GSH efficiently, we further
5 hours, and this stability lasted for at least 72 hours examined the absorbance and fluorescence spectra of 4 toward
(Fig. S1†), while probe 3 exhibited a certain thiolysis reactivity different biothiols (Fig. 2). Probe 4 showed quite weak fluo-
over time. A small amount of 3 could still be detected in HPLC rescence due to the fluorescence-quenching ability of the
traces after 5 h of incubation with GSH, suggesting that the heavy atom Se. Upon the thiolysis reaction with GSH or Hcy, a
thiol-exchange thiolysis may be reversible. The thiolysis rate of large fluorescence turn-on at 520 nm was observed because of
4 is much faster than that of 3, since more than 95% of 4 was the formation of fluorescent SBD-SR.22 However, Cys triggered
consumed within 3 min of reaction with 1 mM GSH. Time- fluorescence at 580 nm, which is because the resultant SBD-
dependent UV-Vis spectra of 1–4 in the presence of GSH thioether can further undergo an intermolecular Smiles
(Fig. S2†) supported the results from HPLC analysis. rearrangement to generate SBD-NHR. These sensing mecha-
Therefore, the thiolysis reactivities of 1–4 increase with substi- nisms of SBD selenoether are similar to those of SBD-Cl
tuted atoms varing from N, O, and S to Se (Fig. 1e).
probes.22a Though H2S cannot trigger fluorescence turn-on of
Compared with these SBD probes, the stronger electron- 4, a ratiometric UV-Vis absorption spectrum was observed for
withdrawing nitro group in NBD increases the electrophilicity the time-dependent reaction of 4 and H2S (Fig. 2b). Such a
of the carbon at the 4-position, resulting in more efficient thio- ratiometric response is based on H2S-mediated cleavage of the
lysis of NBD probes. For example, the H2S-specific thiolysis of selenoether bond, which is similar to that of an NBD sele-
noether probe.25 However, the stronger electron-withdrawing
nitro group increases the maximum absorbance peak from
490 nm (SBD-SH) to 530 nm (NBD-SH). The above results
suggest that SBD selenoethers may be used as a new robust
tool to differentiate H2S, Cys, and GSH/Hcy simultaneously via
the different photochromic and fluorescence properties in the
future.
Because the SBD alkylthioether 3 is slow reactive towards
GSH, we further considered SBD arylthioethers as tunable
motifs because structural modifications at the aryl group
should enable the rate of thiol-mediated thiolysis to be modi-
fied. To this end, we designed 6 and 7 with strong electron-
Fig. 1 (a–d) Time-dependent HPLC traces for probes 1–4 (200 µM) in
the presence of GSH in PBS buffer (pH 7.4, containing 30% DMSO),
respectively. (e) Illustration of the relative reactivities of these probes
with GSH.
Fig. 2 (a) Fluorescence spectra of 4 (10 µM) and its reaction with 1 mM
biothiols for 1 h. Excitation = 400 nm for 4, 4 + Hcy, and 4 + GSH; exci-
tation = 440 nm for 4 + Cys. (b) Time-dependent UV-vis spectra of 4
(10 µM) and H2S (0.25 mM).
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withdrawing and strong electron-donating groups at the aryl reaction (Fig. S7†). All these results imply that probe 7 is GSH-
moiety, respectively. SBD-Cl 5 was used as a control probe. As selective, with higher selectivity than that of probe 5.
shown in Fig. 3, probes 5 and 7 showed quite weak fluo-
Moreover, the reaction kinetics for probes 5 and 7 were
rescence within 1 h in PBS buffer, while probe 6 exhibited monitored by obtaining emission data at 520 nm. The kobs was
increasing fluorescence over time due to its water instability. determined by fitting the intensity data with single exponen-
The strong electron-withdrawing nitro group increases the tial function (Fig. S8 and S9†). The linear fitting between kobs
electrophilicity of the carbon at the 4-position of SBD, result- and GSH concentrations gives a k2 of 0.29 and 0.03 M−1 s−1 for
ing in the possible hydrolysis of probe 6. Subsequently, we 5 and 7, respectively (Fig. 5), both of which are lower than that
only employed probe 7 for the following studies.
of 4 (5.16 M−1 s−1). Comparing the chemical structures of
We further examined the fluorescence spectra of 7 in the these probes, we surmise that 4-(dimethylamino)benze-
presence of different thiols. Because the GSH and Cys levels nethioether at the 4-position decreases the reactivity of the
normally remain in the range of millimolar and micromolar electrophilic SBD in 7, providing a better GSH-selective recep-
concentrations, respectively, we tested the reaction between tor. Therefore, probe 7 was chosen and employed for the selec-
the probe and 2 mM GSH or 100 μM Cys/Hcy. The results tive detection of GSH in the following studies.
showed that probe 7 displayed a selective response to GSH and
Next, we conducted the concentration titration of GSH
led to a strong enhancement of emission at 520 nm, while toward probe
7
for the investigation of its sensitivity
only a slight fluorescence response was detected when it was (Fig. S10†). The fluorescence intensity at 520 nm was linearly
incubated with Cys/Hcy (Fig. 4a and S5†). We further investi- related to the concentration of GSH in the 0.1–1.0 mM range.
gated the time-dependent emission changes of the probe with The detection limit of probe 7 for GSH was calculated to be
biothiols in PBS buffer. Compared with SBD-Cl 5, probe 7 2.1 µM, indicating that probe 7 has high sensitivity for GSH.
worked better in the selective detection of GSH (Fig. 4b and To reveal the sensing mechanism, we further analysed the
S6†). In addition, we can easily distinguish GSH from other reaction of probe 7 with biothiols by HPLC and HRMS
biothiols under a 365 nm UV lamp by the naked eye since Hcy (Fig. S11 and S12†). Time-course HPLC traces indicated that
and Cys do not show green fluorescence even after overnight probe 7 reacted with GSH more efficiently than with Hcy and
Cys. The product (7-GSH) was further identified by HRMS
(Fig. S11c†). The studies were consistent with the fluorescence
tests showing that 7 selectively reacted with GSH.
The high selectivity of probe 7 to GSH is an important para-
meter to examine its biological applicability. To this end, the
fluorescence response of probe 7 to diverse interfering species
including various amino acids and thiols was further studied.
As shown in Fig. 6, only the samples containing GSH showed
an obvious fluorescence enhancement, suggesting that probe 7
could selectively detect GSH over amino acids and other
biothiols. Furthermore, we carried out competition selectivity
studies via the addition of GSH and other analytes at the same
time. All the samples showed a significant fluorescence
enhancement, which means that other biologically relevant
species show no obvious interference with GSH detection. The
results suggested that probe 7 was highly selective to GSH.
Encouraged by the good performances of probe 7, we
further evaluated the biological applications of probe 7. To
Fig. 3 Time-dependent emission intensities at 520 nm of the probes
5–7 (10 μM) in PBS buffer (pH 7.4).
Fig. 4 (a) Fluorescence spectra of 10 μM probe 7 and its reaction with
Cys (100 μM), Hcy (100 μM) or GSH (2 mM) for 1 h. (b) Time-dependent
emission intensities at 520 nm of 10 μM 7 toward these biothiols.
Fig. 5 The linear relationships between the concentration of GSH and
kobs values to produce the reaction rate k2 values for probes 5 (a) and 7
(b).
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Fig. 6 Emission response at 520 nm of probe 7 (10 μM) toward various
biologically relevant species (100 μM) with or without GSH (1 mM) in
PBS buffer (pH 7.4).
Fig. 8 Fluorescence images of intracellular GSH with probe 7 and
ER-Tracker Red. Scale bar, 20 µm.
Red, while the control cells were pre-treated with the thiol
blocking reagent N-ethylmaleimide (NEM, 1 mM) for 30 min,
and then incubated with probe 7. The cells were then exam-
ined using a confocal microscope. As shown in Fig. 8, the
green fluorescence was hardly detected in the NEM-treated
cells, while the fluorescence signal produced by the reaction of
endogenous GSH and 7 was observed. In addition, the red
fluorescence signal from ER-Tracker merged well with the
green fluorescence of 7 in the cells, with a Pearson’s corre-
lation coefficient of 0.598. These preliminary data implied that
probe 7 could be a promising tool for imaging of GSH in the
ER.
start with, the cytotoxicity of probes 5 and 7 was evaluated via
a standard MTT assay with non-cancerous FHC (human fetal
normal colonic mucosa) cells (Fig. 7). The result indicated that
compared to probe 5, probe 7 had no obvious inhibitory effect
on cell growth after 24 hours of incubation. Even if the concen-
tration of probe 7 reached 75 µM, the cell viability was still
higher than 90%. However, probe 5 displayed obvious cyto-
toxicity to cells when its concentration was greater than 25 µM.
These results implied that probe 7 was more biocompatible for
live cell imaging than probe 5.
Encouraged by these positive results, we next used HeLa
cells as the model biological system to evaluate the potential
of probe 7 for the imaging of endogenous GSH in the ER.
HeLa cells were co-incubated with probe 7 and ER-Tracker
Conclusions
In summary, a series of SBD derivatives were synthesized and
characterized for the evaluation of their thiolysis reactivity in
PBS buffer (pH 7.4). Both SBD-amine and SBD-ether are stable
toward biothiols in buffer, while SBD-selenoether can react
with all biothiols with three different sets of spectral signals,
suggesting that SBD-selenoether should be an efficient motif
for differentiated detection of biothiols. In addition, SBD-
arylthioethers are tunable motifs because structural modifi-
cations at the aryl group enable the rate of thiol-mediated thio-
lysis to be modified. For example, the reaction rates of probes
5 and 7 toward GSH are 0.29 and 0.03 M−1 s−1, respectively. In
addition, probe 7 displayed good selectivity and sensitivity to
GSH, excellent biocompatibility, and ER-targeting ability for
imaging of GSH in the ER in live cells. We propose that the
expansion of BD-based probes with different substituents at
the 4-position and/or electron-withdrawing groups at the
7-position is an efficient strategy to obtain different reactivities
and selectivities and is an additional area of likely future
investigation.5f
Fig. 7 Cell viability studies of probes 5 and 7 with FHC cells for 24 h of
incubation by the MTT assay.
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Conflicts of interest
The authors declare no competing financial interests.
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Acknowledgements
We acknowledge the support of the National Key R&D Program
of China (2017YFD0200501), NSFC (21877008, 21837001), and
the Beijing Natural Science Foundation (2192038).
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