Design of fluorescent probes with optimized responsiveness and selectivity to GSH

Article abstract of DOI:10.1016/j.tetlet.2019.03.051

We designed and synthesized a series of BODIPY based probes with fast and distinct ratiometric responsiveness for discriminative detection of GSH from Cys and Hcy. The discriminative detection is based on the different products obtained by the S_NAr between probes and thiol-containing amino acids. The amino group of the obtained thioether from the reaction with Cys or Hcy but not GSH would trigger an intramolecular nucleophilic substitution through five- or six-membered cyclic transition state, finally yielding an amino substituted derivative. To achieve highly discriminative detection and fast response, a series of structure modifications and improvements have been made by elongating the π-conjugation and introducing electron withdrawing groups, finally affording probe BOD-DBNPF with optimized responsiveness and selectivity. Importantly, BOD-DBNPF was successfully used for the selective detection of GSH from Cys with distinct fluorescent ratiometric responses in living HeLa cells.

Full text of DOI:10.1016/j.tetlet.2019.03.051

Accepted Manuscript
Design of fluorescent probes with optimized responsiveness and selectivity to
GSH
Ji-An Chen, Zhen-Yu Zhang, Jie Gao, Jia-Hui Tan, Xian-Feng Gu
PII:
S0040-4039(19)30266-7
https://doi.org/10.1016/j.tetlet.2019.03.051
TETL 50692
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
24 January 2019
21 February 2019
19 March 2019
Please cite this article as: Chen, J-A., Zhang, Z-Y., Gao, J., Tan, J-H., Gu, X-F., Design of fluorescent probes with
optimized responsiveness and selectivity to GSH, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.
2
019.03.051
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Design of fluorescent probes with optimized
responsiveness and selectivity to GSH
Ji-An Chen, Zhen-Yu Zhang, Jie Gao, Jia-Hui Tan and Xian-Feng Gu
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Tetrahedron Letters
Design of fluorescent probes with optimized responsiveness and selectivity to GSH
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Ji-An Chen, Zhen-Yu Zhang, Jie Gao, Jia-Hui Tan and Xian-Feng Gu
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Department of Medicinal Chemistry, Fudan University, 826 Zhangheng, Shanghai, China
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ARTICLE INFO
ABSTRACT
Article history:
Received
We designed and synthesized a series of BODIPY based probes with fast and distinct ratiometric
responsiveness for discriminative detection of GSH from Cys and Hcy. The discriminative
Received in revised form
Accepted
Available online
N
detection is based on the different products obtained by the S Ar between probes and thiol-
containing amino acids. The amino group of the obtained thioether from the reaction with Cys or
Hcy but not GSH would trigger an intramolecular nucleophilic substitution through five- or six-
membered cyclic transition state, finally yielding an amino substituted derivative. To achieve
highly discriminative detection and fast response, a series of structure modifications and
improvements have been made by elongating the π-conjugation and introducing electron
withdrawing groups, finally affording probe BOD-DBNPF with optimized responsiveness and
selectivity. Importantly, BOD-DBNPF was successfully used for the selective detection of GSH
from Cys with distinct fluorescent ratiometric responses in living HeLa cells.
Keywords:
Fluorescent probe
GSH
Ratiometric response
BODIPY
2
009 Elsevier Ltd. All rights reserved.
—
——

Corresponding author. Tel.: +86-021-51980112; fax: +0-000-000-0000; e-mail: xfgu@fudan.edu.cn

2
Tetrahedron
Scheme 1. The syntheses of BOD-204 and BOD-234. Reagents and
Introduction
conditions: (i) AcOH, HCl, Tin, 2.5 h; (ii) POCl
POCl , DCM, Et N, BF , 3 h.
3
, DMF, DCM, 5 h; (iii)
Glutathione (GSH) is the most abundant intracellular biothiol
3
3
3
in biological systems [1]. As an important antioxidant,
Glutathione is capable of protecting cells and organs against the
damages caused by ROS such as free radicals, peroxides, lipid
peroxides, and heavy metals [2]. It also has other biological
functions including maintenance of intracellular redox activity,
xenobiotic metabolism, intracellular signal transduction, and
gene regulation, which enable it to play crucial roles in many
physiological processes [3]. Therefore, it is of great significance
to develop highly selective methods to monitor and quantitate
GSH under physiological conditions.
Results and discussion
In order to achieve the highly selective detection of GSH over
other biothiols especially for Cys and Hcy, two probes BOD-234
and BOD-204 were first designed by introducing a chlorine at the
3
-position of BODIPY dyes as a leaving group (Figure 1), which
is expected to react with thiols via nucleophilic aromatic
substitution (S Ar) to produce thioethers. Once the thioether
N
forming, the amino group of Cys or Hcy but not GSH would
trigger an intramolecular nucleophilic substitution as they could
go through five- or six-membered cyclic transition state, finally
to yield an amino substituted derivative. The distinct
photophysical properties between thio- and amino-substituted
BODIPYs enabled the selective detection of GSH over Cys and
Hcy. BOD-204 and BOD-234 were prepared via the
condensation of 1,3-dimethyl-pyrrole or 1,3-dimethyl-2-ethyl-
In spite of the remarkable advance in the development of
fluorescent probes toward biothiols including Cys [4] and Hcy
[
5] over the past decade, the discriminative detection of GSH
from Cys and Hcy still remains a tough task due to their similar
structures and reactivity [6]. To achieve accurate and selective
detection GSH from other biothiols, the ratiometric fluorescent
chemosensor for responsive differences between GSH and other
biothiols should be developed, that could exhibit a spectral
fluorescent signal shift upon reacting with GSH and thus
eliminate most or all ambiguities by self-calibration of two
emission bands [7].
pyrrole with compound 2, followed by boron insertion with BF
Et O (Scheme 1).
3
-
2
Initially, the spectroscopic responses of BOD-234 to GSH,
Cys and Hcy were investigated (Figure S14). We evaluated the
time-dependent absorption and fluorescence response of BOD-
Herein, we designed (Figure 1) and synthesized two BODIPY
based probes, BOD-204 and BOD-234, consisting of a chlorine
as the reaction site which is expected to react with thiols via
nucleophilic aromatic substitution (S Ar) to produce thioether.
N
The discriminative detection of GSH from other biothiols,
especially from Cys and Hcy, is based on the different products
234 to these three analytes. Upon addition of GSH, the
absorption at 572 nm decreased gradually, and an increase of a
new band at 588 nm were observed with a distinct isosbestic
point at 579 nm. Concomitantly, a remarkable fluorescence
change was also observed upon addition of GSH with the
excitation wavelength at 450 nm. The emission maximum at 581
nm continuously red-shifted to 598 nm with time. The whole
process of spectroscopic changes lasted for 270 minutes.
N
obtained by the S Ar between probes and thiol-containing amino
acids. The amino group of the obtained thioether from the
reaction with Cys or Hcy but not GSH would trigger an
intramolecular nucleophilic substitution through five- or six-
membered cyclic transition state, finally yielding an amino
substituted derivative. As sulfenyl-substituted (thioether)
BODIPYs showed markedly different optical properties from
amino-substituted BODIPYs [8], thus selective detection of GSH
could be furnished by monitoring fluorescence changes.
However, BOD-204 and BOD-234 still suffered from the
drawbacks of relatively low selectivity and slow response in
aqueous system. In view of these problems, we further made a
series of structure modifications and improvements to the
fluorescent dyes. More significant fluorescent ratio changes were
attained by elongating the -conjugation, and faster response
towards GSH was achieved by introduction of electron
withdrawing groups. Importantly, the optimized probe BOD-
DBNPF was successfully used for the selective detection of GSH
from Cys with unique fluorescent ratiometric responses in living
HeLa cells.
In the case of Cys and Hcy, the absorption at 572 nm
decreased gradually upon addition of analytes. Meanwhile, the
fluorescence was increased gradually around 570 nm for Cys and
Hcy, reaching a plateau in 75 min for Cys and 360 min for Hcy,
respectively.
BOD-204, no ethyl substitution at 2-position when compared
to BOD-234, exhibited very similar photophysical properties as
those of BOD-234 (Figure S15). However, more discriminative
fluorescent ratio change caused by GSH (λem with and without
analyte is from 565 nm shifted to 584 mn) and faster fluorescent
response to thiols (GSH: 85 min; Cys: 40 min and Hcy: 240 min)
was observed. It was deducted that the activation of BOD-204
towards thiols might because it was more apt to be attacked by
nucleophile as there is no ethyl substitution at 2-position that led
to less electron cloud density at 3-position of BOD-204.
To achieve an optimized probe for GSH, we further
incorporated an ethylene phenyl group into BODIPY dye to
afford the probe BOD-DBP via Witting reaction (Scheme 2). We
expected to achieve more significant fluorescent ratio changes by
elongating the -conjugation. During the primary detection, a
colorimetric response of BOD-DBP to GSH was observed. The
absorption maximum at 550 nm continuously red-shifted to 610
nm with time (Figure S16). However, the vital drawbacks includ-
Figure 1. The design of the probes for detection of GSH.

3
high selectivity of BODIPY-Cl type of probe to GSH by
monitoring the change of fluorescent ratio.
Scheme 2. The synthesis of BOD-DBP. Reagents and conditions: (i) NaH,
Boc) O, THF, 2 h; (ii) NaH, THF, Benzyltriphenylphosphonium bromide, 14
h; (iii) THF, CH OH, EtONa, 12 h; (iv) morpholine, Et N, DCM, 4 h; (v)
pyrrole, POCl , DCM, overnight; (vi) CuCl , CH CN, 48 h; (vii) POCl
DCE, overnight; (viii) BF , Et N, DCM, 12 h.
(
2
3
3
Figure 2. The response time of the probes to GSH, Cys and Hcy.
3
2
3
3
,
3
3
The spectroscopic responses of above probes toward thiols
further verified our proposed the reaction mechanism as
illustrated in Scheme 4. Once added Cys or Hcy, the chloro
group in the probe is replaced by the thiols, and subsequently the
rearrangement reaction takes place by a five- or six-membered
cyclic transition state to yield amino substituted products which
resulted in a blue-shift in the UV absorption of the probes. In
case of GSH, only thiol substituted products produced and the
electron-donating effect of the thiols lead to a red-shift of UV
absorption for all the probes. The production of BOD-DBNPF-
GSH was also identified by the HRMS analysis (Figure S20).
ing long response time (48 hour) and poor solubility in aqueous
system limited its further applications. The further optimization
was inspired by BOD-204, a probe with more sensitivity to GSH
after removing the electron donating ethyl group of BOD-234.
So, we tried to introduce some electron withdrawing groups, such
as cyano or/and trifluoromethyl groups in the structure of BOD-
DBP and to afford the probes BOD-DBPN and BOD-DBPNF
(Scheme 3). As expected, the fastest response towards GSH and
the most significant fluorescent ratio change were attained by
using BOD-DBNPF, a probe with large conjugating group and
two electron withdrawing groups.
Scheme 3. The synthesis of BOD-DBNP and BOD-DBNPF. Reagents and
conditions: (i) NaOH, EtOH, 4 h; (ii) compound 8, POCl
iii) BF , Et N, DCM, 12 h.
3
, DCE, overnight;
(
3
3
BOD-DBPNF exhibit extremely fast response to GSH, Cys
and Hcy, as evidenced by the time dependent changes of UV
absorption and fluorescence (within 15 min for GSH and Hcy,
and 5 min for Cys, Figure S18). Upon addition of GSH, the
absorption of at 574 nm decreased gradually with time, and an
increase of a new band at 609 nm were observed with a distinct
isosbestic point at 550 nm. Concomitantly, a remarkable
fluorescence change was also observed upon addition of GSH
with the excitation wavelength at 550 nm. The emission
maximum at 590 nm continuously red-shifted to 621 nm with
time. The whole process of spectroscopic changes lasted for 15
minutes. In the case of Cys and Hcy, upon addition of Cys or
Hcy, the absorption at 574 nm decreased gradually with time, and
subsequently blue shifted. Meanwhile, the fluorescence turns off
gradually at 590 nm and the whole process was all over in 5 min
for Cys and 15 min for Hcy. For comparison, the response time
of all above probes to three analytes (GSH, Cys and Hcy) was
outlined in Figure 2.
Figure 3. The selectivity of the probes by monitoring the fluorescent
intensity ratio. The amino acids concentrations were kept as 1 mM.
The selective detections of GSH and Cys in living HeLa cells
were carried out by using confocal fluorescence imaging. Before
bioimaging by probe BOD-DBNPF, the pH interference and
photostability of probe BOD-DBNPF were also tested (Figure
S23 and S24) which indicated it is suitable for imaging in living
cells. Since BOD-DBNPF is able to serve as a ratiometric
fluorescence probe for monitoring GSH, we investigated the
feasibility of this probe to detect HeLa cells in a dual-color
manner. Although both green emission (500-530 nm) and red
emission (600-640 nm) was observed in all groups (blank, Cys
group and GSH group), the stronger fluorescence signals in red
channel and relatively low fluorescence signals in green channel
were collected in GSH group. In contrast, relatively strong green
emission and weak red emission were observed in blank and Cys
group. Therefore, the fluorescence ratios of red to green channels
were utilized for the discrimination between GSH and Cys in
In view of the distinct ratiometric response behaviors of above
probes to GSH, we evaluated the selectivity of all the probes (5
μM) toward GSH (1 mM) over various amino acids (1 mM) by
monitoring the fluorescent ratio change at λem with and without
analyte, except for BOD-DBP as its slow response. As shown in
Figure 3, only GSH was able to trigger obvious changes of the
fluorescent ratio at λem with and without analyte for all the
probes. The most significant fluorescent ratio change (about ten
times) was observed when BOD-DBNPF as the GSH probe.
Otherwise, the response of BOD-DBNPF to competing anions
was also investigated (Figure S22). The results confirmed the
living HeLa cells. In the GSH group, the fluorescence ratio (Ired
/
I
green) was calculated to be around 1.8, In comparison, the
fluorescence ratio reduced to about 0.4 in blank and around 0.6 in
Cys group. The results demonstrated that BOD-DBNPF could be
applied for imaging of GSH in living cells (Figure 4). In addition,
in vitro cytotoxicity of the probe was valuated with HeLa cells

4
Tetrahedron
using CCK8 assay. No obvious adverse effect of BOD-DBNPF
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In summary, we have designed and synthesized several
fluorescent probes for discriminative detection of GSH from Cys
and Hcy. The discriminative detection is based on the different
products obtained by the reaction between probes and GSH,
Cys/Hcy. GSH induced the formation of sulfenyl-substituted
BODIPYs while Cys/Hcy afforded amino-substituted BODIPYs.
The two initial probes BOD-204 and BOD-234 showed relatively
low selectivity and slow response in aqueous system. To achieve
optimized fluorescent probes, structure modification was
explored by elongation of -conjugation and introduction of
electron-withdrawing units. As expected, the obtained probe
BOD-DBNPF showed highly discriminative detection and fast
response. Furthermore, BOD-DBNPF was capable of selective
detection of GSH from Cys with distinct fluorescent ratiometric
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A. Supplementary data
(
(
Supplementary data associated with this article can be found,
in the online version, at
(
(

6
Tetrahedron
Highlights
1
2
3
. The fluorescent probe for selective detection of GSH
with ratiometric response.
. The optimized probe with highly selective detection
and fast response to GSH.
. Selective bioimaging GSH in Living cells.