Synthesis and Evaluation of Sulfoxide-Functionalized BODIPYs as Chemosensors for Thiols

Article abstract of DOI:10.1002/cjoc.201500271

BODIPY-based fluorescent chemosensors bearing sulfoxide function were designed and evaluated. Thiols triggered sulfoxide→sulfide transduction in these probes leads to an obvious red-shift in absorption and dramatic fluorescence enhancement with distinctly

Full text of DOI:10.1002/cjoc.201500271

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DOI: 10.1002/cjoc. 201500271
Synthesis and Evaluation of Sulfoxide-Functionalized
BODIPYs as Chemosensors for Thiols
Chunchang Zhao* and Haifeng Jiang
Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science &
Technology, Shanghai 200237, China
BODIPY-based fluorescent chemosensors bearing sulfoxide function were designed and evaluated. Thiols trig-
gered sulfoxide→sulfide transduction in these probes leads to an obvious red-shift in absorption and dramatic fluo-
rescence enhancement with distinctly ratiometric features, enabling the accurate assay of thiols in living cells.
Keywords sulfoxide→sulfide transfer, Cysteine, ratiometric, living cells, reduction
Introduction
transfered to BODIPY-based thioether by benzenethiols,
accompanied with drastic ratiometric photophysical
changes.[12] However, these compounds show no
photophysical responses to Cys, Hcy and GSH. We
reason that the steric effects mainly influence such
sulfoxide→sulfide transduction. To test this hypothesis,
we herein report the design, synthesis, and biological
evaluations of two new sulfoxide-functionalized
BODIPYs. Detailed studies show that Cys can selec-
tively induce sulfoxide→sulfide transduction in these
probes, while there is no obvious interference from Hcy
and GSH. These probes are aslo proved the capability in
ratiometric measurement of Cys in living cells.
Biological thiols, including cysteine (Cys), homo-
cysteine (Hcy) and glutathione (GSH), play a prominent
role in variations of physical and pathological proc-
esses.[1] Importantly, these thiols exert anti-oxidation
protection in cells.[2] Nevertheless, abnormal levels of
thiols lead to a variety of pathologies.[3] It has been
known that aberrant levels of these sulfhydryl com-
pounds produce serious diseases, such as cancer, Alz-
heimer and even cardiovascular diseases.[4] Phenome-
non of interesting is that Cys, Hcy and GSH perform
somehow completely different functions even though
they have similar chemical structures.[5] Although Cys
and Hcy differ by a single methylene unit in their side
chains, Cys is one of the most important biothiols as
basic building block for proteins, while high levels of
Hcy are associated with an increased risk of stroke and
heart disease.[6] Therefore, it is of significant importance
to develop novel probes for discriminating these impor-
tant biothiols.
Generally, the sulfhydryl group in thiols bears strong
nucleophilicity, which has been employed for rational
design of diverse probes for thiol sensing, including
Michael addition,[7] cyclization with aldehydes,[8]
conjugate addition–cyclization reactions,[9] cleavage of
sulfonamide and sulfonate esters,[10] and thiol–halogen
nucleophilic substitution.[11] Furthermore, the sulfhydryl
group endows thiols a reductive feature, which is
mainly invovled in biological systems. Nevertheless,
few design strategies have been adopted to construct
probes via such promising character. Thus, we decide to
develop new fluorescence probes for biothiols utilizing
their intrinsic reducibility. We have previously reported
BODIPY-based sulfoxide, which can be selectively
Experimental
Synthesis of BSFI-1
The reaction mixture of 1 (0.358 g, 1 mmol), methyl
thioglycolate (0.127 g, 1.2 mmol) and DMAP (0.122 g,
1 mmol) in 20 mL CH3CN was stirred overnight at 25
℃. Then CH3CN was removed under vacuum. The re-
sulted crude product was purified by flash chromatog-
1
raphy (silica gel) to afford BSFI-1 (0.315 g, 73%). H
NMR (400 MHz, CDCl3) δ: 7.49－7.44 (m, 3H), 7.32－
7.27 (m, 2H), 6.34 (d, J＝4 Hz, 1H), 6.28 (d, J＝4 Hz,
1H), 3.77 (s, 2H), 3.74 (s, 3H), 2.61 (s, 3H), 2.34 (q, J＝
8 Hz, 2H), 1.42 (s, 3H), 1.01 (t, J＝8 Hz, 3H).
Synthesis of BSFO-1
0.99 equivalents of 75% m-CPBA (0.115 g, 0.49
mmol) was added to a solution of BSFI-1 (0.216 g, 0.5
mmol) in 20 mL dichloromethane and stirred for 2 h at 0
℃. Excessive acids were neutralized by Na2CO3 and the
reaction mixture was extracted with CH2Cl2, washed
with water, dried over Na2SO4 and evaporated in vacuo.
*
E-mail: zhaocchang@ecust.edu.cn
Received April 1, 2015; accepted May 5, 2015; published online June 2, 2015.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201500271 or from the author.
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The crude product was further purified by flash chro-
tion with m-CPBA furnished the final BODIPY-based
sulfoxides. Particularly, the oxidation of BSFI-2 bearing
formaldehyde moiety at the nearest 4-position led to the
production of aromatic fused BODIPY, which can be an
alternative strategy to the classical method for obtaining
aromatic ring-fused BODIPYs. All the chemical struc-
tures were analyzed by 1H NMR, 13C NMR and HRMS.
With these compounds in hand, we then evaluated
the photophysical responses to biothiols. As expected,
upon incubation of Cys, Hcy and GSH with BSFO in
acetonitrile/PBS buffer (1∶1, V/V, 25 mmol•L−1, pH
7.4, Figure S1), minimal changes in absorption and flu-
orescence spectra were observed. We reason that the
steric effects mainly influence the sulfhydryl group
triggered reduction of sulfoxide to sulfide. Generally,
such sulfoxide→sulfide transfer results in the changing
in the electronic nature of the substituents on the core,
which would lead to red/blue optical transition in ab-
sorption and emission wavelengths. All these features
enable the design of ratiometric probes based on sul-
foxide→sulfide transfer in case of feasible reduction by
thiols. On the base of these considerations, BSFO-1
with a flexible chain (Scheme 1) to reduce the steric
effect was then employed to testify the reaction proper-
ties with biothiols.
matography (silica gel) to afford BSFO-1 (0.154 g,
1
69%). H NMR (400 MHz, CDCl3) δ: 7.54－7.49 (m,
3H), 7.36－7.33 (m, 2H), 6.96 (d, J＝4 Hz, 1H), 6.35 (d,
J＝4 Hz, 1H), 4.23 (d, J＝12 Hz, 1H), 3.92 (d, J＝16
Hz, 1H), 3.81 (s, 3H), 2.64 (s, 3H), 2.37 (q, J＝8 Hz,
2H), 1.48 (s, 3H), 1.03 (t, J＝8 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ: 167.19, 165.43, 148.65, 143.96, 141.54,
138.11, 136.97, 135.12, 133.28, 129.73, 128.76, 128.73,
128.65, 128.61, 124.04, 114.82, 60.45, 52.83, 29.70,
17.16, 14.03, 12.55; HRMS (ESI＋) calcd for C22H23N2-
BF2SO3Na [M＋Na]＋: 467.1388; found 467.1387.
Synthesis of BSFI-2
A mixture of DMF (3 mL) and POCl3 (3 mL) was
stirred for 10 min at 0 ℃ and for another 30 min at
room temperature, then a solution of BSFI-1 (0.428 g, 1
mmol) in 20 mL dichloroethane was added to the mix-
ture. The resulting reaction mixture was stirred for 3 h at
50 ℃. POCl3 was then neutralized with saturated
aqueous NaHCO3 under ice-cold conditions and the re-
action mixture was extracted with CH2Cl2, washed with
water and dried by anhydrous Na2SO4. The solvents
were evaporated in vacuo. The crude product was fur-
ther purified using column chromatography to give
BSFI-2 (0.298 g, 65%). 1H NMR (400 MHz, CDCl3) δ:
11.01 (s, 1H), 7.55－7.49 (m, 3H), 7.35－7.31 (m, 2H),
6.68 (s, 1H), 3.79 (s, 2H), 3.66 (s, 3H), 2.71 (s, 3H),
2.39 (q, J＝8 Hz, 2H), 1.49 (s, 3H), 1.05 (t, J＝8 Hz,
3H).
We first evaluated the photophysical response of
BSFO-1 to Cys in a PBS buffer solution (pH 7.4, 50%
acetonitrile as co-solvent). As can be seen in Figure 1,
time-dependent absorption and fluorescence spectra
changes were collected in the presence of Cys. In the
absence of cysteine, BSFO-1 showed an intense absorp-
tion band at 480 nm with a corresponding emission
Synthesis of BSFO-2
0.99 equivalents of 75% m-CPBA (0.115 g, 0.49
mmol) was added to a solution of BSFI-2 (0.229 g, 0.5
mmol) in 20 mL dichloromethane and stirred for 2 h at 0
℃. Excessive acids were neutralized with Na2CO3 and
extracted with CH2Cl2, washed with water, dried over
Na2SO4. The solvents were evaporated in vacuo. The
crude product was further purified by flash chromatog-
1
raphy (silica gel) to afford BSFO-2 (0.169 g, 74%). H
NMR (400 MHz, CDCl3) δ: 7.69 (s, 1H), 7.56－7.51 (m,
3H), 7.34－7.31 (m, 2H), 6.21 (s, 1H), 3.91 (s, 3H),
2.72 (s, 3H), 2.39 (q, J＝8 Hz, 2H), 1.48 (s, 3H), 1.05 (t,
J＝8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 169.98,
162.00, 152.29, 144.56, 141.79, 140.79, 140.75, 139.10,
137.80, 136.25, 132.88, 129.96, 129.43, 128.98, 128.88,
128.58, 128.55, 116.55, 52.63, 29.70, 17.22, 13.91,
12.68; HRMS (ESI＋) calcd for C23H22N2BF2SO3 [M＋
H]＋: 455.1412; found 455.1410.
Results and Discussion
The preparation of the target probes BSFO-1 and
BSFO-2, together with the model compound BSFO was
depicted in Scheme 1. Nucleophilic aromatic substitu-
tion reaction (SNAr) proceeded readily with methyl
thioglycolate or p-thiocresol to generate the corre-
sponding sulfide compounds.[13] The follow-up oxida-
Figure 1 Time-dependent (a) absorption and (b) fluorescence
responses of BSFO-1 (10 µmol•L－1) to 1 mmol•L－1 Cys. Spectra
were recorded 0, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120
min after Cys addition at 37 ℃ in acetonitrile/PBS buffer (1∶1,
V/V, 25 mmol•L－1, pH 7.4), λex ＝480 nm.
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Synthesis and Evaluation of Sulfoxide-Functionalized BODIPYs as Chemosensors for Thiols
Scheme 1 Synthesis of target probes BSFO-1, BSFO-2 and the model BSFO
O
H
N
N
.
H
BF3 Et2O
Cl
POCl3
Toluene, Et3N
N
N
B
Cl
F
F
1
SH
m-CPBA, 0.99 equiv., CH2Cl2
1
N
N
N
N
B
B
CH3CN, DMAP
S
S O
F
F
F
F
BSFI
BSFO
O
HS
O
m-CPBA, 0.99 equiv., CH2Cl2
N
N
N
N
1
B
B
CH3CN, DMAP
Cys
S
S O
F
F
F
F
O
O
O
O
BSFI-1
BSFO-1
POCl3
DMF
m-CPBA, 0.99 equiv., CH2Cl2
CHO
N
F
N
B
N
B
N
S
F
O
S
F
F
O
O
O
O
BSFI-2
BSFO-2
maximum at 528 nm. Upon addition of Cys, a distinct
reduction of the absorption band at 480 nm was ob-
served, along with an increase of the absorption at 535
nm and occurrence of the obvious isosbestic point at
495 nm. Importantly, the fluorescence spectra also en-
dowed ratiometric changes in the presence of Cys. The
fluorescence intensity at 528 nm decreased gradually,
and that at 556 nm enhanced simultaneously, resulting
in a distinct ratio change of I556/I528 from 0.8 to 2.4
(Figure 2), indicative of the capability of accurate
analysis of Cys. The ratiometric change of fluorescence
is time-dependent and the observed rate constant was
determined to be 0.0158 min−1 under the pseudo-first-
order conditions. Also, Cys triggered distinct color
changes of the solution (Figure S2).
The response behavior of BSFO-1 toward other
thiol-containing amino acids was further determined. It
was found that Hcy and GSH elicited minimal photo-
physical responses under the same physiological condi-
tions (Figure S3). This distinct selectivity was contrib-
uted to the dynamics of reactions between probe and
thiols. From the experimental data, the pseudo-first-
order reaction rate was determined to be 0.0033 min−1
for Hcy, and that of GSH was 2.9×10−4 min−1 (Figure
S3). Obviously, these rates are much slower than that
for Cys, indicative of the high selectivity of BSFO-1
toward Cys over Hcy and GSH. The selectivity of
BSFO-1 towards Cys over relevant thiol-lacking amino
acids and hydrogen sulfide was then evaluated by
measuring the changes in the fluorescence spectra upon
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Figure 2 (a) Time-dependent fluorescence intensity ratio
(I556/I528) changes of BSFO-1 (10 µmol•L−1) toward 1 mmol•L−1
Cys at 37 ℃, in acetonitrile/PBS buffer (1∶1, V/V, 25 mmol•L−1,
pH 7.4), λex ＝480 nm; (b) Pseudo first-order kinetic plots of the
reaction of BSFO-1 (10 μmol•L−1) with 1 mmol•L−1 Cys at 37
℃.
Figure 3 (a) Fluorescence responses of BSFO-2 (10 µmol•L−1)
to 1 mmol•L－1 Cys. Spectra were acquired 0, 1, 3, 5, 7, 9, 11, 13
min after the addition of Cys in 25 mmol•L−1 sodium phosphate
at 37 ℃, pH 7.4, λex＝500 nm. Inset is pseudo first-order kinetic
plots of BSFO-2 (10 µmol•L−1) with 1 mmol•L−1 Cys at 37 ℃,
F0 represents the emission intensity at 564 nm in the absence of
Cys, Ft represents time-dependent emission intensity at 564 nm in
the presence of Cys. (b) Fluorescence responses of BSFO-2 (10
µmol•L−1) to 1 mmol•L Hcy. Spectra were acquired 0, 10, 20,
30, 40, 50, 60, 70, 80, 90 min after the addition of Hcy. Inset is
pseudo first-order kinetic plots of BSFO-2 (10 µmol•L−1) with 1
mmol•L−1 Hcy at 37 ℃, F0 represents the emission intensity at
564 nm in the absence of Hcy, Ft represents time-dependent
emission intensity at 564 nm in the presence of Hcy.
addition of excess amount of various amino acids within
the analytical time of 2 h. The ratiometric fluorescent
change can only be introduced by Cys (Figure S3). By
contrast, other relevant analytes led to no obvious rati-
ometric change, indicating that BSFO-1 is a highly se-
lective probe and can monitor Cys with minimum inter-
ference from other relevant analytes.
The reaction mechanism of BSFO-1 with Cys was
then studied. When BSFO-1 (5 mmol•L−1) and cysteine
(500 mmol•L−1) were stirred for 2 h in acetonitrile/PBS
buffer (1∶1, V/V, 25 mmol•L−1, pH 7.4) at 37 ℃, an
obvious color change of the solution from yellow to red
was noted and a stable fluorescent product was observed
clearly on the TLC plate. The reaction product was pu-
rified and identified by NMR and mass spectra. HRMS
manifested a peak at m/z＝451.1437, which is identical
－
1
Collectively, a ratiometric probe for thiols was ob-
tained via simply regulating the reactivity of sulfoxide
susceptible to reduction by sulfhydryl group in thiols.
Obviously, diminishing the steric effect is a suitable
design strategy to furnish the sulfoxide→sulfide trans-
fer.
To further demonstrate this trend, another BODIPY-
based sulfoxide, BSFO-2 was explored to evaluate the
responses to these thiols. BSFO-2 bears rigid conjugate
plane which makes sulfoxide exposure to reducing
agents. Furthermore, the rigidity of the aromatic ring
should accelerate the reduction by thiols. As expected,
1
to that of BSFI-1. H NMR spectra also matched well
with that of BSFI-1 (Figure S4). All these data suggest
that the sulfoxide function was eventually reduced to
sulfide by sulfhydryl group in Cys.
The linear relationship between the fluorescence re-
sponse[14] and concentration of Cys is important for ac-
curate measurement of Cys. In the titration experiments,
it was clear that the fluorescence response is Cys con-
centration dependent with Cys concentrations from 0 to
500 µmol•L−1. The detection limit was then calculated
to be 5.62×10−6 mol•L−1 (Figure S5).
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Synthesis and Evaluation of Sulfoxide-Functionalized BODIPYs as Chemosensors for Thiols
BSFO-2 showed much faster reaction toward Cys. Un-
der the pseudo-first-order conditions, the observed rate
constant was found to be 0.18 min−1 (Figure 3), which is
10 times that for BSFO-1. Since the elevating reactivity,
BSFO-2 showed poor selectivity toward thiol-contain-
ing amino acids. BSFO-2 also gave distinct fluores-
cence turn-on response to Hcy with an observed rate
constant of 0.05 min−1. Other related amino acids in-
duced minimal fluorescence variations (Figure S6).
BODIPY-based sulfoxides were designed and evaluated.
These probes showed thiol-triggered sulfoxide→sulfide
transfer, accompanied by ratiometric absorption and
fluorescence changes. These features were further suc-
cessfully used for imaging Cys in living cells.
Acknowledgement
We gratefully acknowledge the financial support by
the National Natural Science Foundation of China (Nos.
21172071, 21190033 and 21372083).
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Figure 4 Fluorescent confocal images of HeLa cells (a－c)
pretreated with 500 μmol•L−1 N-methylmaleimide for 20 min,
further incubated with BSFO-1 (5 μmol•L−1) for 1 h, the excita-
tion wavelength was 488 nm: (a) green channel at 500－530 nm,
(b) red channel at 550－580 nm, (c) overlay image generated
from (a) and (b); (d－f) cells pretreated with 500 μmol•L−1
N-methylmaleimide for 20 min, further incubated with Cys (500
μmol•L−1) for 20 min, then loaded with BSFO-1 (5 μmol•L−1) for
1 h, the excitation wavelength was 488 nm: (d) green channel at
500－530 nm, (e) red channel at 550－580 nm, (f) overlay image
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periments, HeLa cells were pretreated with N-methyl-
maleimide (500 μmol•L−1, a trapping reagent of thiols)
for 20 min, then incubated with BSFO-1 (5 μmol•L−1)
for 1 h. Bright fluorescence signals were observed in
green channel (500－530 nm), while the red channel
(550－580 nm) is dark. The ratio from red channel to
green channel can be defined to be 1.0. In sharp contrast,
pronounced fluorescence signals were observed in red
channel when pretreated cells were loaded with Cys
(500 μmol•L−1) for 20 min before incubation with
BSFO-1 (5 μmol•L−1) for 1 h, and the ratio was finally
improved to be around 2.0, resulting in nearly 2-fold
enhancement. These results indicated that BSFO-1 is
cell-permeable and can be a promising probe for rati-
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Conclusions
In summary, a new design strategy utilizing the in-
trinsic reductive characteristic of the sulfhydryl group in
thiols was explored to generate fluorescent probes. Thus,
Chin. J. Chem. 2015, 33, 711—716
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