Synthesis of 3,5-bis(acrylaldehyde) boron-dipyrromethene and application in detection of cysteine and homocysteine in living cells

Article abstract of DOI:10.1021/jo4004597

Synthesis, characterization, and spectral and electrochemical properties of 3,5-bis(acrylaldehyde) BODIPY are described. The compound exhibited higher selectivity toward cysteine/homocysteine than toward other amino acids and thiol-containing compounds as

Full text of DOI:10.1021/jo4004597

Note
pubs.acs.org/joc
Synthesis of 3,5-Bis(acrylaldehyde) Boron-dipyrromethene and
Application in Detection of Cysteine and Homocysteine in Living
Cells
Sheri Madhu,† Rajesh Gonnade,‡ and Mangalampalli Ravikanth*,†
†Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400076, India
‡Center for Materials Characterization, National Chemical Laboratory, Pune 411008, India
S
* Supporting Information
ABSTRACT: Synthesis, characterization, and spectral and
electrochemical properties of 3,5-bis(acrylaldehyde) BODIPY
are described. The compound exhibited higher selectivity
toward cysteine/homocysteine than toward other amino acids
and thiol-containing compounds as shown by absorption and
emission titration experiments and by experiments in living
cells.
Chart 1. Structure of BODIPY Compounds 1, 2, and 5
oron-dipyrromethenes (BODIPYs) are excellent fluores-
Bcent dyes and have been used in various research fields as
labeling reagents, fluorescent switches, chemosensors, light-
harvesting systems, and dye-sensitized solar cells because of
their advantageous photophysical properties, such as photo-
stability, high absorption coefficients, and high fluorescence
quantum yields.1 BODIPY dyes are amenable to modifications,
which allow fine-tuning of properties by introduction of suitable
substituents at appropriate positions of the dipyrromethene
framework.2 Because BODIPY dyes can be easily function-
alized, it is convenient to introduce the desired substituents at
the BODIPY core by carrying out suitable reactions on
functionalized BODIPYs.3 For example, we and others have
shown that BODIPYs can be halogenated at different positions
and that the halogenated BODIPYs can be used as synthons to
synthesize different types of substituted BODIPYs.4 We
recently reported the synthesis of 3,5-diformyl BODIPYs
under simple reaction conditions and demonstrated their use
as pH-based optical sensors and for cyanide sensing
applications.5 Because fluorophores appended with aldehyde
group(s) have been shown to be useful for the detection of
thiols such as cysteine6 (Cys) and homocysteine7 (Hcy) based
on the cyclization reaction between aldehyde and thiols to form
thiazolidines and thiazinanes,8 we thought of using 3,5-diformyl
BODIPY 1 (Chart 1) for sensing Cys/Hcy by this chemo-
dosimetric approach. Interestingly, there are very few reports
on fluorescent off−on molecular probes based on BODIPY for
the specific detection of thiols.9 However, we realized that 3,5-
diformyl BODIPY 1 cannot be used for sensing thiols because
the formyl groups are directly on the BODIPY core, and their
reaction with thiols to form cyclized thiozolidine product is not
stable enough to follow using any spectroscopic techniques. We
anticipated that if we use acrylaldehyde in place of formyl
groups, the reaction of acrylaldehyde with Cys/Hcy would form
stable hexahydro-1,4-thiazepine heterocycles and thus can be
used for sensing specific detection of thiols.10 In this paper, we
report synthesis, characterization, and spectral and electro-
chemical properties of 3,5-bis(acrylaldehyde) BODIPY 2
(Chart 1) and its use as a chemodosimetric probe for specific
detection of Cys and Hcy over other amino acids including
glutathione (GSH) under physiological conditions. Further-
more, confocal laser scanning fluorescence microscopy experi-
ments demonstrated that BODIPY 2 can permeate cell
membranes and could be used for ratiometric fluorescence
imaging in living cells. Although several probes for the
detection of Cys/Hcy are available in the literature,6 the
probe reported here absorbs and emits in a higher wavelength
region compared to that of the earlier probes and shows
ratiometric fluorescence response and good selectivity for Cys/
Hcy over other amino acids.
The desired target BODIPY 2 was prepared in two steps
starting from meso-(tolyl) dipyrromethane 3 as shown in
Scheme 1. The dipyrromethane 3 in 1,2-dichloroethane was
added dropwise to the reagent generated in situ by treating 3-
Received: March 5, 2013
© XXXX American Chemical Society
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Note
Scheme 1. Synthesis of BODIPY 2
dimethylaminoacrolein with POCl3 at −10 °C. The reaction
mixture was slowly brought to room temperature and was
subsequently refluxed at 60 °C for 30 min. The reaction was
quenched by aqueous NaHCO3, and the resultant crude
compound was subjected to silica gel column chromatography
that afforded pure compound 4 as a brown solid in 87% yield.
Compound 4 was confirmed by HRMS and elemental analysis
and was characterized in detail by NMR spectroscopy (Figures
S1−S3 in the Supporting Information). Compound 4 was
treated first with DDQ in CHCl3/THF (2:1) for 30 min at
room temperature, neutralized with triethylamine, and reacted
with BF3·OEt2 for an additional 30 min. The crude compound
was purified by silica gel column chromatography and afforded
pure BODIPY 2 as a golden-green solid in 32% yield (Figures
S4−S8 in the Supporting Information). In 1H NMR of
BODIPY 2, the aldehyde proton appeared as a doublet at
9.85 ppm; the alkene protons appeared as a doublet and a
quartet at 8.12 and 6.83 ppm, respectively (Figure S5 in the
Supporting Information). In 19F NMR, a quartet appeared at
high field (−137 ppm) compared to normal BODIPY
chromophores, such as meso-(tolyl) BODIPY 5 (−146 ppm),
because of hydrogen bonding with adjacent alkene proton. An
expected triplet was observed in BODIPY 2 at 1.1 ppm in 11B
NMR which was downfield shifted compared to BODIPY 5
(0.5 ppm) because of the presence of strong electron-
withdrawing formyl groups. The crystal structure solved for 2
has a planar BODIPY framework comprised of two pyrrole
rings and the central six-membered boron ring (Figure 1). The
plane defined by F−B−F atoms was perpendicular to the
BODIPY core. The dihedral angle between the meso-aryl ring
and the BODIPY core was 51°. The acrylaldehyde function-
alities at 3,5-positions and indacene plane were nearly planar,
indicating significant electronic conjugation between acrylalde-
hyde and BODIPY core.
The absorption spectrum of BODIPY 2 showed a sharp S0 →
S1 band at 602 nm that was bathochromically shifted by ∼55
nm (Figure S9 in the Supporting Information) compared to
BODIPY 1 because of an increase in the π-electron
delocalization. BODIPY 2 exhibited a bathochromically shifted
emission band at 615 nm (Figure S9 in the Supporting
Information) and increased quantum yield (Φ = 0.4) and
singlet state lifetime (τ = 6.5 ns) compared to those of
BODIPY 1 (λem = 556 nm, Φ = 0.3, τ = 5.5 ns). Thus, BODIPY
1 is green fluorescent, and BODIPY 2 is red fluorescent under a
UV lamp. The absorption and emission bands of BODIPY 2
were shifted hypsochromically with a decrease in quantum yield
and singlet state lifetime as the solvent polarity increases, which
is in agreement with the general behavior of BODIPY
chromophores (Table S1 in the Supporting Information).
BODIPY 2 exhibited two reversible reductions but no oxidation
like BODIPY 1 (Figure S12 in the Supporting Information).
However, compared to that of BODIPY 1, the first reduction
potential was shifted negatively by 100 mV, indicating that
BODIPY 2 was relatively less electron deficient (Figure S13 in
the Supporting Information).
As mentioned above, aldehydes are known to react with
thiols such as Cys/Hcy to form thiazolidine or thiazinane
derivatives, and the aldehydes present directly on the
fluorophores on reaction with thiols are expected to produce
significant changes in the electronic properties of the
fluorophore that are clearly reflected in their absorption and
emission properties. Thus, we investigated the recognition of
thiols by BODIPY 2 and monitored the changes in the
absorption and emission spectra of BODIPY 2 upon formation
of hexahydro-1,4-thiazepine derivatives. The systematic changes
in the absorption spectra of BODIPY 2 on titration with Cys in
pH 7.4 PBS/CH3CN (9:1, v/v) media are shown in Figure 2a,
and the same study on the fluorescence spectra is shown in
Figure 2b. Upon addition of increasing amounts of Cys to a
solution of BODIPY 2 in buffer media, the absorption band at
596 nm was decreased gradually, and at the same time a new
band at 552 nm increased with a clear isosbestic point at 568
nm, supporting the formation of a hexahydro-1,4-thiazepine
derivative. This is also clearly evident in the fluorescence
studies. Upon addition of Cys, the fluorescence band at 612 nm
decreased slowly, and a new band appeared at 567 nm with an
isoemissive point at 598 nm. Similar observations were also
made on systematic addition of Hcy to BODIPY 2 (Figure S14
in the Supporting Information). These changes were also
associated with a visually detectable change in solution color
from red to fluorescent green under a UV lamp, indicating that
BODIPY 2 can be used as a possible colorimetric sensor for the
detection of Cys and Hcy (Figure S19 in the Supporting
Information). To investigate the selectivity, the studies were
Figure 1. ORTEP diagram (left) top view, (right) side view (50%
probability) of BODIPY 2. Hydrogen atoms and solvent molecules are
omitted for clarity.
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Figure 2. (a) Absorption and (b) emission spectral changes of BODIPY 2 (5 μM) upon titration with Cys (0−35 equiv) in pH 7.4 PBS/CH3CN
(9:1, v/v). The spectra were recorded after incubation of the probe with Cys for 30 min (λex = 510 nm). (Inset: Fluorescence color change of
BODIPY 2 upon titration with Cys).
also carried with other amino acids such as Arg, GSH, Lys, Phe,
Thr, Trp, His, Asp, Gln, Glu, Leu, Ser, Val, Pro, and Tyr and
the proteins bovine serum albumin (BSA) and HepG2 cell total
protein (Figure 3), and we did not observe significant changes
other biospecies, including GSH (Figures S15−S18 in the
Supporting Information).
A possible sensing mechanism of BODIPY 2 based on the
reaction between α,β-unsaturated aldehydes and Cys to form a
stable hexahydro-1,4-thiazepine ring is shown in Scheme 2.
Initially, the amino group of Cys reacts with the aldehyde group
to afford imine intermediate, which could then undergo ring
closure to form perhydrothiazepine derivative 6.
Finally, in the presence of excess equivalents of Cys, the
hexahydro-1,4-thiazepine 7 is expected to form. To gain insight
into the above proposed mechanism, we monitored the
progress of the reaction of BODIPY 2 with Cys by mass
spectrometry. After treatment of BODIPY 2 with Cys for 30
min, an intense peak at m/z 621.4 corresponding to [6 + Na]+
was present in an ESI-MS spectrum (Figure S20 in the
Supporting Information). However, after addition of excess
equivalents of Cys to the solution, an intense peak was
observed at m/z 819.5 (Figure S21 in the Supporting
Information), corresponding to the formation of [7 − F]+.
Thus, the mass spectral study supports the proposed sensing
mechanism.
To examine the function of the probe for its application in
biological imaging, the living HepG2 cells were incubated with
BODIPY 2 (10 μM) at 37 °C for 30 min. Upon excitation at
543 nm, HepG2 cells exhibited bright intracellular red
fluorescence (Figure 4I). However, the cells that were
pretreated with Cys followed by incubation with BODIPY 2
Figure 3. Histogram showing the fluorescence enhancement (567 nm
band) during the titration of BODIPY 2 (5 μM) with different amino
acids (excess of equivalents) in PBS/CH3CN (9:1, v/v; pH 7.4)
solution.
in absorption and fluorescence spectra, suggesting that
BODIPY 2 is a specific sensor for detection of Cys/Hcy over
Scheme 2. Proposed Mechanism for the Reaction of BODIPY 2 with Cys
C
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The Journal of Organic Chemistry
Note
Preparation of the Test Solution. A stock solution of BODIPY 2
(5 × 10−4 M) was prepared in CH3CN. The test solution of BODIPY
2 (5 μM) in pH 7.4 PBS (containing PBS/CH3CN, 9:1, v/v) was
prepared by placing 0.03 mL of the probe stock solution in CH3CN
(0.27 mL of CH3CN, 2.70 mL of pH 7.4 PBS). The solutions of
various testing species were prepared from Cys, Arg, Hcy, Phe, Pro,
Tyr, Val, Ala, Gly, Lys, Leu, Glu, Ser, and GSH. The resulting solution
was shaken well and incubated for 30 min at room temperature before
recording the spectra.
Materials. Dulbecco’s modified Eagle’s medium (DMEM), fetal
calf serum (FCS), trypsin-EDTA, L-glutamine, penicillin (50 units/
mL), and streptomycin (50 μg/mL) were obtained from a commercial
source.
Cell Culture and Fluorescence Imaging. HepG2 cells were
cultured in complete medium at 37 °C under 5% CO2 in an incubator.
The complete medium comprised of DMEM supplemented with 10%
FCS, 2 mM L-glutamine, penicillin (50 units/mL), and streptomycin
(50 μg/mL). Before imaging, the cells were washed with PBS (pH 7.4)
three times and then incubated with BODIPY 2 (10 μM) in PBS
(containing 1% CH3CN as a cosolvent) for 30 min in an atmosphere
of 5% CO2 and 95% air at 37 °C. After the sample had been washed
with PBS three times to remove the remaining probe, the fluorescence
images were visualized under a laser scanning confocal microscope.
Red and green emissions were observed after excitation at 543 and 514
nm, respectively.
Figure 4. Confocal laser scanning fluorescence images of living HepG2
cells before (I) and after (II) incubation with BODIPY 2 (10 μM)
with Cys. The left panel represents the fluorescence, the center panel
the bright-field transmission images, and the right panel respective
bright-field and overlay images; incubation was performed at 37 °C for
30 min. Scale 50 μm.
for 30 min exhibited bright yellow-green fluorescence (Figure
4II). Further bright-field measurements confirmed that the cells
treated with BODIPY 2 were viable throughout the imaging
experiments (Figure 4Ia,IIb). The overlay of fluorescence and
bright-field images revealed that the fluorescence signals are
localized in the full area of the cell, indicating a cellular
distribution of Cys and good permeation of the cell membrane
by BODIPY 2 (Figure 4Ic,IIc). These results demonstrate the
practical applicability of BODIPY 2 for imaging Cys in living
cells.
In conclusion, we have synthesized 3,5-bis(acrylaldehyde)
BODIPY 2 in 32% yield from meso-aryl dipyrromethane under
simple reaction conditions. The compound absorbs and emits
at higher wavelengths compared to those of our earlier reported
3,5-diformyl BODIPY 1. However, 3,5-diformyl BODIPY 1
cannot be used for sensing thiols such as Cys/Hcy because of
the instability of the resulting thiazolidinine derivatives. 3,5-
Bis(acrylaldehyde) BODIPY can be used for selective sensing
of Cys/Hcy over other amino acids and thiols at physiological
pH. The probe displays a 45 nm blue-shift in emission with
associated visually detectable fluorescent color change from red
to fluorescent green upon addition of Cys/Hcy. Furthermore,
confocal laser fluorescence scanning microscopic experiments
demonstrated that the probe can permeate cell membranes and
can readily be used to detect the intracellular Cys/Hcy in living
HepG2 cells.
1,9-Bis(3-oxo-1-propenyl)-meso-(tolyl)-dipyrromethane (4).
3-(Dimethylamino) acrolein (1.26 g, 4.20 mmol) was added to a
100 mL three-neck round-bottom flask that was then cooled to 5−10
°C and flushed with nitrogen for 5 min. POCl3 (1.94g, 4.23 mmol)
was added dropwise over 15 min with stirring. Dry dichloroethane (10
mL) was then added, and the mixture was stirred at room temperature
for 15 min. The mixture was cooled to 0 °C, and meso-(tolyl)-
dipyrromethane 3 (1g, 1.40 mmol) in dry dichloroethane (20 mL) was
added dropwise over 1 h; the solution turned a deep purple color. The
solution was warmed to 60 °C for 30 min and then allowed to cool to
room temperature. Saturated sodium carbonate solution (50 mL) was
added, and the reaction mixture was stirred vigorously at room
temperature for 2 h. The mixture was extracted with ethylacetate (3 ×
100 mL), and the combined organic layers were dried over Na2SO4,
filtered, and evaporated. The crude compound was subjected to silica
gel column chromatography eluting with petroleum ether/ethylacetate
(30:70) and afforded pure 1,9-bis(3-oxo-1-propenyl)-meso-(tolyl)
1
dipyrromethane 4 as a brown solid in 87% yield (1.26 g). H NMR
(400 MHz, DMSO-d6): δ 2.28 (s, 3H, −CH3), 5.46 (s, 1H, meso-CH),
5.84−5.85 (d, 3J (H, H) = 3.68 Hz, 2H, Py), 6.39−6.45 (dd, 3J (H, H)
= 15.57 Hz, 2H, −CH), 6.58−6.59 (d, 3J (H, H) = 3.68 Hz, 2H, Py),
7.07−7.09 (d, 3J (H, H) = 8.16 Hz, 2H, Ar), 7.13−7.15 (d, 3J (H, H) =
3
7.92 Hz, 2H, Ar), 7.37−7.41 (d, J (H, H) = 15.57 Hz, 2H, −CH),
3
9.41−9.43 (d, J (H, H) = 8.04 Hz, 2H, −CHO), 11.61 (br s, 2H,
−NH). 13C NMR (100 MHz, DMSO-d6): δ 20.8, 43.2, 107.2, 110.4,
117.3, 121.4, 128.1, 128.3, 129.1, 136.1, 138.3, 140.4, 142.8, 193.1.
HRMS calcd [M + 1]+ for C22H20N2O2 345.1715, found 345.1691.
Anal. Calcd for C22H20N2O2: C, 76.72; H, 5.85; N, 8.13. Found: C,
76.68; H, 5.80; N, 8.20.
3,5-Bis(3-oxo-1-propenyl)-meso-(tolyl)-4-bora-3a,4a-diaza-s-
indacene (2). 1,9-bis(3-oxo-1-propenyl)-meso-(tolyl) dipyrromethane
4 (0.5 g, 1.46 mmol) was dissolved in CHCl3/THF (2:1; 100 mL) and
oxidized with DDQ (0.4 g, 1.75 mmol) at room temperature. The
reaction mixture was allowed to stir at room temperature for 30 min.
Triethylamine (5.88 g, 58.4 mmol) and then BF3·OEt2 (10.3g, 73
mmol) were added to the reaction mixture successively without any
time delay, and the reaction mixture was stirred at room temperature
for an additional 30 min. The reaction mixture was evaporated, and the
crude product was purified using silica gel column chromatography
with petroleum ether/ethylacetate (75:25) and afforded pure 3,5-
bis(3-oxo-1-propenyl)-meso-(tolyl) BODIPY 2 as a golden-green solid
EXPERIMENTAL SECTION
■
General. The NMR experiments were performed with a 400 MHz
spectrometer, and chemical shifts are expressed in parts per million
with TMS as an internal reference. Cyclic voltammetric (CV) studies
were carried out with an electrochemical system utilizing a three-
electrode configuration consisting of a glassy carbon (working)
electrode, a platinum wire (auxiliary) electrode, and a saturated
calomel (reference) electrode. The experiments were performed in dry
CH2Cl2 with 0.1 M TBAP as the supporting electrolyte. All potentials
were calibrated versus the saturated calomel electrode by the addition
of ferrocene as an internal standard, taking E1/2 (Fc/Fc+) = 0.42 V
versus SCE.15 The quantum yields were calculated using Rhodamine
6G (Φf = 0.88 in ethanol).16 All Φ values are corrected for changes in
refractive index. HRMS (ESI/TOF) data were recorded with a mass
spectrometer.
1
in 32% yield (0.182 g). H NMR (400 MHz, CDCl3): δ 2.50 (s, 3H,
−CH3), 6.78−6.83 (dd, 3J (H, H) = 16.05 Hz, 2H, −CH), 6.99−7.02
(dd, 3J (H, H) = 4.48 Hz, 4H, Py), 7.37−7.39 (d, 3J (H, H) = 8.0 Hz,
2H, Ar), 7.45−7.47 (d, 3J (H, H) = 8.0 Hz, 2H, Ar), 7.98−8.03 (d, 3J
D
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The Journal of Organic Chemistry
Note
(H, H) = 16.1 Hz, 2H, −CH), 9.84−9.86 (d, 3J (H, H) = 7.76 Hz, 2H,
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1
−CHO). 11B NMR (128.3 MHz, CDCl3): δ 1.07 (t, J (B−F), 1B).
1
19F NMR (376.4 MHz, CDCl3): δ −137.2 (q, J (F−B), 2F). 13C
NMR (100 MHz, CDCl3): δ 21.7, 29.9, 119.3, 129.7, 130.6, 130.8,
131.9, 133.9, 138.4, 139.8, 142.3, 146.2, 152.2, 193.3. HRMS calcd [M
− F]+ for C22H17BF2N2O2 371.1367, found 371.1378. Anal. Calcd for
C22H17BF2N2O2: C, 67.72; H, 4.39; N, 7.18. Found: C, 67.79; H, 4.30;
N, 7.25.
X-ray Crystallography. X-ray intensity data measurements of
BODIPY 2 were carried out on a SMART APEX II CCD
diffractometer with graphite-monochromatized (Mo Kα = 0.71073
Å) radiation at 297(2) K. Data were collected with an ω scan width of
0.5° at different settings of φ and 2θ with a frame time of 10 s, keeping
the sample-to-detector distance fixed at 50 mm. The X-ray data
collection was monitored by the APEX2 program.11 The data were
corrected for Lorentzian, polarization, and absorption effects using the
SAINT12 and SADABS13 programs. SHELX-97 was used for structure
solution and full matrix least-squares refinement on F2.14 All the H
atoms were placed in geometrically idealized position and constrained
to ride on their parent atoms. The asymmetric unit contained two
molecules of acetonitrile along with one molecule of BODIPY 2; thus
the host to guest ratio was 1:2.
Crystal Data of BODIPY 2. (CCDC 913899) C22H17BF2N2O2·2-
(CH3CN), M = 472.29, colorless plate, 0.31 × 0.24 × 0.12 mm3,
triclinic, space group P1, a = 6.7710(4) Å, b = 12.0890(7) Å, c =
̅
14.8586(9) Å, α = 99.663(3)°, β = 93.799(3)°, γ = 91.628(3)°, V =
1195.39(12) Å3, Z = 2, T = 90(2) K, 2θmax = 60.00°, Dcalc (g cm−3) =
1.312, F(000) = 492, μ (mm−1) = 0.095, 30409 reflections collected,
6940 unique reflections (Rint = 0.0276), 6254 observed (I > 2σ(I))
reflections, multiscan absorption correction, Tmin = 0.971, Tmax
=
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(11) APEX2; Bruker AXS Inc.: Madison, WI, 2006.
(12) SAINT; Bruker AXS Inc.: Madison, WI, 2006.
0.989, 319 refined parameters, S = 1.024, R1 = 0.0374, wR2 = 0.1008
(all data R = 0.0414, wR2 = 0.1054), maximum and minimum residual
electron densities; Δρmax = 0.23, Δρmin = −0.26 (e Å−3).
ASSOCIATED CONTENT
* Supporting Information
■
S
All NMR spectra of compounds 2 and 4, fluorescence and
absorption spectral traces, and photophysical data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(13) SADABS;. Bruker AXS Inc.: Madison, WI, 2006.
(14) Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112.
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(16) Qin, W.; Leen, V.; Rohand, T.; Dehaen, W.; Dedecker, P.; Van
der Auweraer, M.; Robeyns, K.; Van Meervelt, L.; Beljonne, D.; Van
Averbeke, B.; Clifford, J. N.; Driesen, K.; Binnemans, K.; Boens, N. J.
Phys. Chem. A 2009, 113, 439−447.
AUTHOR INFORMATION
Corresponding Author
*ravikanth@chem.iitb.ac.in
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
M.R. is thankful for the financial support from BRNS and DST,
Government of India. S.M. thanks IIT Bombay for a fellowship.
We also acknowledge SAIF, IIT Bombay, Mumbai, India, for
the confocal laser scanning microscopy facility.
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