A NIR BODIPY dye bearing 3,4,4a-trihydroxanthene moieties

Article abstract of DOI:10.1039/c2ob26218e

A novel 3,4,4a-trihydroxanthene-fused pyrrole 2 was synthesized by the reaction of 2,3,4,4a-tetrahydro-1H-xanthen-1-one with 3-phenyl-2H-azirine in the presence of LDA. Utilizing this pyrrole 2, a NIR BODIPY 1 (λ _abs = 732 nm, λ_em = 747 nm) has been prepared. The new BODIPY 1 was stable, non-cytotoxic, and suited to labeling living cells for imaging assay in the NIR region.

Full text of DOI:10.1039/c2ob26218e

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A NIR BODIPY dye bearing 3,4,4a-trihydroxanthene moieties†
Xin-Dong Jiang,*a Ruina Gao,a Yi Yue,a Guo-Tao Sunc and Weili Zhao*a,b
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
5
A novel 3,4,4a-trihydroxanthene-fused pyrrole 2 was synthesized by the reaction of 2,3,4,4a-tetrahydro-
1H-xanthen-1-one with 3-phenyl-2H-azirine in the presence of LDA. Utilizing this pyrrole 2, a NIR
BODIPY 1 (λabs = 732 nm, λem = 747 nm) has been prepared. The new BODIPY 1 was stable, non-
cytotoxic, and suited to label living cells for imaging assay in the NIR region.
Introduction
10 Near-infrared (NIR) fluorescent dyes can greatly reduce
background absorption, fluorescence, light scattering, and
improve the sensitivity and selectivity of the fluorescent probes
and sensors.1 More importantly, NIR fluorescent dyes have deep
penetration in tissues to allow in vivo imaging and photodynamic
15 therapy (PDT).2 The safe, non-invasive nature of NIR fluorescent
imaging has attracted great interests in the design and synthesis of
novel NIR fluorescent dyes.3 NIR dyes such as azo dyes,3a
cyanine dyes,3b quinone dyes,3c,d and phthalocyanine dyes3e have
been developed so far, however insufficient photo-stability and/or
20 difficult modification obstructed their applications. Most NIR
fluorescent dyes possess highly conjugated systems which lead to
significantly reduced fluorescence due to increased internal
conversion.3 BODIPY dyes are well-known to be highly
fluorescent, very stable, and exceptionally insensitive to the
25 polarity of solvents as well as to pH.4 To develop NIR responsive
BODIPY dyes, recent developments focused on the extension of
π-conjugation, or rigidification of rotatable moieties in pyrroles
(Fig. 1, A−F).5,6 For BODIPY dyes, to extend the
absorption/emission of the fluorescent dyes over 700 nm requires
30 judicious design. Our previous work on rigidified pyrrole (F)
derived restricted aza-BODIPYs paved the way to discover NIR
fluorescent dyes absorbed and emitted over 700 nm.7 Herein, we
utilized the combinations of extended conjugation and
rigidification strategies and discovered a novel NIR BODIPY dye
35 1 (λabs = 732 nm) derived from 3,4,4a-trihydroxanthene-fused
pyrrole 2 (Fig. 1).
40
Fig. 1 Pyrrole skeletons used for NIR BODIPY (aza-BODIPY) dyes.
Results and discussion
Synthesis of the NIR compound 1
45
For the preparation of the novel 3,4,4a-trihydroxanthene-fused
pyrrole 2, 2,3,4,4a-tetrahydro-1H-xanthen-1-one8 was employed
to react with 3-phenyl-2H-azirine to give 2 in 14% yield in the
presence of LDA (Scheme 1).7 BODIPY 1 was successfully
synthesized from 2 in 80% combined yields by condensation with
50 trimethyl orthoformate in the presence of 0.5 equiv. of TsOH,
followed by complexation with BF3⋅Et2O/Et3N.9
Scheme 1 Synthetic route to the novel pyrrole 2 and BODIPY 1.
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35 maximum of 3 (λabs = 564 nm), merely rigidificaiton (cf 4) or
extended conjugation (cf 5) leads to about 70 nm of bathochromic
shift; However, the combined effect of restricting the phenyl
substituent and extending the π-conjugation in 1 is dramatic
wherein 168 nm of bathochromic shift was accomplished in
Pale green crystals for 2 suitable for X-ray crystallography
were obtained by recrystallization form n-hexane/CH2Cl2 (Fig.
1).10 Due to the torsional rigidity, the angles of H12-C13-O1,
H12-C13-C12, and H12-C13-C14 are all 107.1° which distorts
from the ideal value of 109.2° in sp3 hybridized structure.
Moreover, the dihedral angel of C3-C11-C12-C13 of the
restricted bond was 43.4°.
5
40 comparison with 3. The fluorescence quantum yield (
Φ f) of the
NIR BODIPY 1 was measured to be 0.06 which was bright
enough for the staining experiments.
Stability and toxicity of 1
Stability and toxicity of a probe is very important to biological
45 labeling. The stability measurements of BODIPY 1 in acidic and
basic solutions12 were carried out by monitoring the transmission
at absorption maxima (Fig. 4). Dye 1 was found to be reasonably
stable in a range of the pH from 2 to 14 by monitoring the change
of transimission in a solution of dye 1 in H2O/DMSO (95:5, v/v)
50 after 2 h. The light stability of 1 was evaluated by monitoring the
intensity changes of the emission with time of irradiation in
comparison with a typical visible fluorescent BODIPY dye,
10 Fig. 2 Molecular structure and conformation for 2. Carbon, nitrogen
and oxygen atoms are depicted with thermal ellipsoids set at the 30%
probability level. Selected bond lengths (Å) and angles (deg) for R-2:
C3-C11, 1.513(5); C11-C12, 1.480(6); C12-C13, 1.501(6); C13-O1,
1.438(5); O1-C21, 1.363(5); C3-C11-C12, 112.0(3); C11-C12-C13,
15 114.0(4); C12-C13-O1, 109.0(4); C13-O1-C21, 119.4(3).
namely
1,3,5,7-tetramethyl-4-difluorobora-3a,4a-diaza-s-
indacene (TM-BDP) (Fig. 5). As expected, the NIR BODIPY 1
55 was found to slightly inferior to the visible TM-BDP.
Photophysical properties of 1
To our delight, the combinations of extended conjugation and
rigidification result in the NIR absorption and emission of dye 1.
20 The absorption and emission spectra of 1 in CHCl3 (λabs = 732
nm; λem = 747 nm) were illustrated in Fig 3. Dye 1 exhibited
moderate extinction coefficients (29000 M−1 cm−1) and a narrow
full width at half maximum (32 nm).
Fig. 4 The normalized transmission (A/A0) of 1 in response to pH
range from 1−14 in H2O/DMSO (95:5, v/v) after 2 h at room
60 temperature.
25
Fig. 3 Absorption (solid curve) and emission (dashed curve) spectra
of 1 in CHCl3 at 298 K.
Table 1 Effect of extended conjugation and rigidification on
30 photophysical properties.
Fig. 5 Intensity variations of TM-DBP (red) and 1 (blue) under
continuous irradiation with light (470 and 700 nm, respectively) in
65 toluene.
As for the toxicity studies, MTT assays carried out on HepG2
cell indicated non-cytotoxic nature of 1, which is quite similar to
that of TM-BDP (Fig. 6).
The spectral characteristics of 1 were compared to those of the
known dyes 3−5 (Table 1).11 In comparison with the absorption
2
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standard. Infrared spectra were recorded on an AVA TAR 360
using KBr pellets. Mass spectrometric measurements were
performed by the mass spectrometry service of the ETHZ on a
Bruker Reflex MALDI as matrix (20 kV).
45 Fluorescence spectra were recorded on FluoroSENS
spectrophotometer and are reported as cm−1. UV/Vis spectra were
recorded on Perkin-Elmer Lambda 35 UV/Vis spectrophotometer
at room temperature.
The fluorescence quantum yields (Φf) of the BODIPY systems
50 were calculated using the following relationship (equation 1):
Φf = Φref Fsampl Aref n2sampl/Fref Asampl n2
(1)
Fig. 6 Comparison of the cytotoxic effects of TM-BDP (blue) and 1
ref
(red) on HepG2 cells.
Here, F denotes the integral of the corrected fluorescence
spectrum, A is the absorbance at the excitation wavelength, and n
is the refractive index of the medium, ref and sampl denote
55 parameters from the reference and unknown experimental
samples, respectively. The reference systems used was
boronazadipyrromethene compound aza-BODIPY (Φf = 0.36 in
chloroform)6d as references.
The pH-dependence experiments were carried out by monitoring
60 the change of absorbance at 732 nm of 5 ꢀM the dye 1 in
DMSO/H2O (95:5, v/v) in the pH range from 1-14 after 2 h at
room temperature.
The photostability experiments were carried out using a 5 ꢀM
solution of the dye (TM-BDP or 1) in toluene. After initial 10
65 minutes irradiation, the fluorescence change was recorded for 1 h
at 540 or 750 nm under continuous excitation at 470 or 700 nm,
respectively. The slit width was 8.0 nm for excitation, and 1 nm
for emission.
5
Cell-staining experiment of 1
For the cell-staining experiment, 2 × 10−5 M of dye 1 in PBS
containing 0.5% (v/v) DMSO was incubated with HepG2 cells
for 20 min. at 37 °C and the excess dye was removed by washing
with PBS prior to visualization. An ArrayScan® VTI HCS
10 Reader inverted fluorescence microscope was employed for the
fluorescence image, with the excitation wavelength of the laser at
700 nm. The obtained images indicated that 1 was efficiently
internalised by living cells. Dye 1 was memberane-permittable
and was found to localize exclusively to the cytoplasm (red color)
15 with nuclear intact (dark area) (Fig. 7).
70 Preparation of 3-phenyl-1,4,5,5a-tetrahydrochromeno[2,3-
g]indole 2.
Under N2, LDA (4.78 mmol) in THF (5 mL) was added to
2,3,4,4a-tetrahydro-1H-xanthen-1-one (0.902 g, 4.50 mmol) in
THF (20 mL) at −78 °C. Then, 3-phenyl-2H-azirine (0.746 g,
75 0.636 mmol) in THF (2 mL) was added and the resulting mixture
was stirred for 2 h at the same temperature. The reaction was
allowed to warm up to room temperature slowly. It was quenched
with water, neutralized with dilute HCl to a pH about 7. The
mixture was extracted with CH2Cl2 (2 × 60 mL), and the organic
80 layer was washed with brine (2 × 50 mL) and dried over
anhydrous MgSO4. After removal of the solvents by evaporation,
the resulting crude mixture was separated by column
chromatography (n-hexane : CH2Cl2 = 1 : 1) to afford 2 as a plae
green solid (190.6 mg, 0.636 mmol, 14%). Pale green crystals of
Fig.
7 Fluorescence microscope imaging of HepG2 cells
following incubation with 2 × 10−5 M of 1 in PBS + 0.5% (v/v)
20 DMSO (red color) for 20 min. at 37 °C; dark area represents the
cell nuclei. Scale bar: (a) 40 ꢀm; (b) 20 ꢀm; (c) 10 ꢀm.
Conclusions
A novel 3,4,4a-trihydroxanthene-fused pyrrole 2 was prepared.
The structure of 2 was confirmed by single crystal X-ray analysis.
25 BODIPY 1 (λabs = 732 nm, λem = 747 nm, Φ f = 0.06 in CHCl3)
prepared from pyrrole 2 absorbed and emitted in NIR region as a
result of combined extension of conjugation and restriction. Dye
1 was fairly stable, non-cytotoxic, and suitable for labeling of
living cells in the NIR region. Efforts are currently under way to
85
2
suitable for the X-ray analysis were obtained by
recrystallization from n-hexane/CH2Cl2. M.p.: 103-104 °C. 1H
30 develop
nonsymmetrically
substituted,
water-soluble
BODIPY/aza-BODIPY to allow conjugation for biosensing
experiments.
NMR (400 MHz, CDCl3) δ (TMS, ppm): 8.27 (s, 1H), 7.44 (d,
3
3
3
2H, J = 8.0 Hz), 7.37 (t, 2H, J = 8.0 Hz), 7.24 (t, 2H, J = 8.0
Hz), 7.07 (td, 1H, 3J = 8.0 Hz, 4J = 1.2 Hz), 7.02 (dd, 1H, 3J = 8.0
90 Hz, 4J = 1.2 Hz), 7.01 (s, 1H), 6.89 (td, 1H, J = 8.0 Hz, 4J = 1.2
3
Experimental
3
Hz), 6.85 (d, 1H, J = 8.0 Hz), 5.14−5.10 (m, 1H), 2.99−2.89(m,
General
2H), 2.55-2.51 (m, 1H), 2.22−2.11 (m, 1H). 13C NMR (75 MHz,
CDCl3), δ (TMS, ppm): 153.5, 135.2, 128.6, 127.6, 127.0, 126.3,
126.2, 125.9, 125.8, 124.3, 124.1, 121.7, 120.9, 118.4, 115.6,
95 108.2, 30.8, 21.0. IR (KBr) cm−1: 2930, 2360, 2340, 1640, 1470,
1450, 1116, 1010, 760. HRMS-MALDI (m/z): [M]+ Calcd. For
C21H17NO: 299.1305; found 299.1305.
35 1H NMR spectra were recorded on a VARIAN Mercury 300 MHz
spectrometer. 1H NMR chemical shifts (
δ) are given in ppm
downfield from Me4Si, determined by residual chloroform (δ =
7.26 ppm). 13C NMR spectra were recorded on a VARIAN
Mercury 75 MHz spectrometer in CDCl3, all signals are reported
40 in ppm with the internal chloroform signal at
δ 77.0 ppm as
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Preparation of BODIPY dye 1.
Under N2, a solution of pyrrole 2 (46.1 mg, 0.153 mmol) and
toluene-4-sulfonic acid (13.5 mg, 0.078 mmol) in triethyl
orthoformate (2 mL) was stirred for 15 min at room temperature.
The solution was diluted with ethyl acetate (10 mL), filtered, and
the precipitated solid was washed with ethyl acetate and n-
hexane. After removing the solvents by evaporation, the crude
compound was obtained. Then, triethylamine (40 mg, 0.39 mmol)
was added to this crude in BF3·OEt2 (3 mL) and the reaction
X-ray crystal structure determinations of compound 2
Crystals suitable for the X-ray structural determination were
60 mounted on a Mac Science DIP2030 imaging plate diffractometer
and irradiated with graphite monochromated Mo-Kα radiation (
= 0.71073 Å) for the data collection. The unit cell parameters
were determined by separately autoindexing several images in
each data set using the DENZO program (MAC Science).13 For
65 each data set, the rotation images were collected in 3° increments
5
λ
10 mixture was stirred for 15 min at room temperature. The mixture
was extracted with CH2Cl2 (2 × 80 mL), and the organic layer
was washed with brine (2 × 60 mL), then dried over anhydrous
MgSO4. The solvents evaporated to afford a dark green solid 1
(40.2 mg, 0.0612 mmol, 80%). M.p.: 270-271 °C (decomp.). λabs
15 = 732 nm, λem = 747 nm of 1 in CHCl3. The log P value of 1 is
4.110, when the solvent is DMSO. 1H NMR (400 MHz, CDCl3) δ
(TMS, ppm): 8.26 (s, 1H), 7.54−7.27 (m, 14H), 7.25−7.20 (dd,
with a total rotation of 180° about the
φ axis. The data were
processed using SCALEPACK. The structures were solved by a
direct method with the SHELX-97 program.14 Refinement on F2
was carried out using the full-matrix least-squares by the
70 SHELX-97 program.14 All non-hydrogen atoms were refined
using the anisotropic thermal parameters. The hydrogen atoms
were included in the refinement along with the isotropic thermal
parameters.
3
4
3
4
2H, J = 8.0 Hz, J = 1.6 Hz), 7.02 (td, 2H, J = 8.0 Hz, J = 1.6
Hz), 6.88 (d, 2H, 3J = 8.0 Hz), 5.17−5.12 (m, 2H), 2.89−2.68 (m,
20 4H), 2.64−2.48 (m, 4H). Compound 1 was too insoluble to record
CCDC reference number 878978 for
2
contains the
75 supplementary crystallographic data. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or
from the Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-336033; or
deposit@ccdc.cam.uk).
a
13C NMR spectrum. IR (KBr) cm−1: 3400, 2930, 1590, 1525,
1407, 1226, 1205, 1116, 1072, 1045, 756. HRMS-MALDI (m/z):
[M]+ calcd for C43H31BF2N2O2: 656.2441; found 656.2447.
80 Acknowledgements
25 In vitro cytotoxicity studies
This work was supported by the National Natural Science
Foundation of China (20872026), National Basic Research
Program of China (973 Program) No. 2010CB912600, Shanghai
Pujiang Talent Plan Project (09PJD008), and Sino Swiss Science
85 and Technology Cooperation (SSSTC, EG 30-032010).
HepG2
cells
were
used
to
compare
the
cytotoxicity/biocompatibility of the dye (1 or TM-BDP) via a
MTT test. HepG2 cells were incubated in DMEM with 10% (v/v)
fetal bovine serum, 1% penicillin/streptomycin at 37 °C in 5%
30 CO2. HepG2 cells were seeded at a density of 5 × 104 cells/well
(200 ꢀL) in a 96-well plate. After 24 h, Different concentrations
including 0.375, 0.75, 1.25, 2.5, 5, 10, 20, 40 ꢀM the dye (1 or
TM-BDP) were added into the wells as 200 ꢀL quantities (n = 8),
respectively. Blank wells contained 200 ꢀL of medium with the
35 equivalent quantity of DMSO. After 24 h, a MTT solution (1
mg/mL, 20 ꢀL) was added into each well and incubated for 4 h at
37 °C in 5% CO2. Media was removed and the formazan was
dissolved in 150 ꢀL of DMSO. OD was measured at 570 nm
using a microplate reader. The cytotoxicity of samples was
40 investigated by relative cell survival rates (%). The absorbance of
the blank wells was considered as that corresponding to 100%
survival and the relative cell survival rates in the treated wells
were calculated. The relative percent survival rates were
statistically compared using the student's t-test.
Notes and references
aThe Key Laboratory for Special Functional Materials, Ministry of
Education, Henan University, Kaifeng, Henan 475004, China, Tel./fax:
+86 0378 3881358, E-mail: xdjiang@henu.edu.cn; zhaow@henu.edu.cn
90 bSchool of Pharmacy, Fudan University, Shanghai, 201203, China
cDepartment of Biochemistry and Molecular Biology, Institute of
Molecular Medicine, Medical School, Henan University, Kaifeng, Henan
475004, China
†Electronic Supplementary Information (ESI) available: Experimental
95 details, spectra crystallographic data, and 1H, 13C NMR. See DOI:
10.1039/b000000x/
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10 Crystal data for 2. C21H17NO, M = 299.36, orthorhombic, a =
7.6581(1), b = 8.0433(2), c = 50.1404(7) Å,
α = 90, β = 90, γ = 90°, V
45
50
55
= 3088.47(10) Å3, T = 298(2) K, space group Pbca, Z = 8,
Data/restraints/parameters = 2728/0/208, R1 = 0.0937 (I > 2σ(I)), wR2
(all data) = 0.2160, GOF = 1.152. CCDC reference number 878978 for
2.
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