Near-IR absorbing BODIPY derivatives as glutathione-activated photosensitizers for selective photodynamic action

Article abstract of DOI:10.1002/chem.201405450

Enhanced spatiotemporal selectivity in photonic sensitization of dissolved molecular oxygen is an important target for improving the potential and the practical applications of photodynamic therapy. Considering the high intracellular glutathione concentrations within cancer cells, a series of BODIPY-based sensitizers that can generate cytotoxic singlet oxygen only after glutathione-mediated cleavage of the electron-sink module were designed and synthesized. Cell culture studies not only validate our design, but also suggest an additional role for the relatively hydrophobic quencher module in the internalization of the photosensitizer.

Full text of DOI:10.1002/chem.201405450

DOI: 10.1002/chem.201405450
Communication
&
Photosensitizers
Near-IR Absorbing BODIPY Derivatives as Glutathione-Activated
Photosensitizers for Selective Photodynamic Action
Ilke Simsek Turan,[a] Fatma Pir Cakmak,[b] Deniz Cansen Yildirim,[c] Rengul Cetin-Atalay,[c] and
Engin U. Akkaya*[a, b]
tosensitivity is still an issue, often leading to painful edema for
Abstract: Enhanced spatiotemporal selectivity in photonic
sensitization of dissolved molecular oxygen is an impor-
patients undergoing PDT treatment.[4] Thus, more selective
PDT sensitizers are needed to remove any chance of off-target
tant target for improving the potential and the practical
sensitization. In principle, this can be done in a number of
applications of photodynamic therapy. Considering the
ways.[5] Previously, we reported a photosensitizer, the activity
high intracellular glutathione concentrations within cancer
of which is dependent on the pH and ion concentrations.
cells, a series of BODIPY-based sensitizers that can gener-
Other groups have reported quenched photosensitizers, by co-
ate cytotoxic singlet oxygen only after glutathione-medi-
valent attachments to carbon nanotubes, carotenoids, and the
ated cleavage of the electron-sink module were designed
commercial quencher BHQ3. Self-quenching of the photosensi-
and synthesized. Cell culture studies not only validate our
tizer is another route for activity control.
design, but also suggest an additional role for the relative-
The removal of quencher module can be accomplished en-
ly hydrophobic quencher module in the internalization of
zymatically (by caspase 3, cathepsin B, b-galactosidase, b-lacta-
the photosensitizer.
mase or trypsin, among others). Unfortunately, in most cases,
More than one hundred years
after the initial observation of
photodynamic action,[1] genera-
tion of cytotoxic singlet oxygen
by photosensitization of molecu-
lar oxygen through the interme-
diacy of a dye continues to at-
tract considerable attention.[2]
This is mostly due to its medical
applications, which is the photo-
dynamic therapy (PDT) of vari-
ous cancers and non-cancerous
indications.[3] One attractive fea-
ture of photodynamic therapy is
in its built-in selectivity, which
results from the fact that the ex-
citing light can be targeted to
Figure 1. Mode of operation for the GSH-mediated activation of caged photosensitizers.
the tumor region, thus minimiz-
ing accidental excitation of the
sensitizer dye at undesired locations. In practice, however, pho-
the change in photosensitizer activity was less than tenfold.
Our goal was to design a quenched photosensitizer, which is
only capable of singlet oxygen generation after a glutathione
(GSH)-mediated reaction that results in the removal of the
quencher moiety (Figure 1). Such compounds could aptly be
called “caged photosensitizers”. It should also be noted here
that cancer cells reportedly have much higher concentration of
GSH (up to 1000-fold) compared with normal cells.[6]
[a] I. S. Turan, Prof. Dr. E. U. Akkaya
UNAM-Institute of Material Science and Nanotechnology
Bilkent University, Ankara, 06800 (Turkey)
E-mail: eua@fen.bilkent.edu.tr
[b] F. P. Cakmak, Prof. Dr. E. U. Akkaya
Department of Chemistry, Bilkent University, Ankara, 06800 (Turkey)
[c] D. C. Yildirim, R. Cetin-Atalay
To realize this goal, we set out to synthesize the target com-
pounds depicted in Scheme 1 as caged sensitizers, to be re-
leased on a triggering GSH reaction. The design includes a 2,4-
dinitrobenzenesulfonate group, which was previously shown
Department of Molecular Biology and Genetics
Bilkent University, Ankara, 06800 (Turkey)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201405450.
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characterized analytically. Once
the synthesis and characteriza-
tion were completed, we first
studied the reaction with GSH
spectroscopically.
Under physiological condi-
tions, all three sulfonates can be
cleaved at reasonable rates,
a process that can be followed
by spectral shifts in the electron-
ic absorption spectra. In the
cleavage reaction of PS1, the
major band in the visible region
shows a 35 nm blueshift (Fig-
ure 2A). Other photosensitizers
also show such changes in the
absorption. The cleavage of the
quencher moiety can also be fol-
lowed by the changes in the
emission spectra. In 30 min,
more than 80% of the PS1 can
be uncaged (see the Supporting
Information). For the halogenat-
ed derivatives, intersystem cross-
ing competes very effectively
with the fluorescence emission
process, resulting in low emis-
sion quantum yields.
Nevertheless, the quenching
due to ISC is less than the essen-
tially total quenching generated
by the 2,4-dinitrobenzenesulfon-
yl moiety; thus, the emission en-
hanced at 683 nm is reported as
another indication of the prog-
Scheme 1. Synthesis of the caged photosensitizers (PS1–3) and the control compounds (6–8). TFA=trifluoroacetic
acid, TEA=triethylamine, DMAP=4-dimethylaminopyridine.
to be susceptible to thiol mediated cleavage.[7] The design can
be abbreviated as PS-Q, Q being the electron sink 2,4-dinitro-
benzenesulfonyl moiety, which quenches the excited state of
the photosensitizer (PS) by providing an alternative, non-radia-
tive relaxation path.
ress of the cleavage reaction (Figure 2B). As expected, the sin-
glet oxygen generation capacity is nil when the quencher
module Q is intact. But, when it is removed by the reaction
with GSH, the residual BODIPY moieties are very effective in
singlet oxygen generation (Figure 3). The change in the singlet
oxygen generation capacity looks like an “off–on” process,
demonstrating the effectiveness of the 2,4-dinitrophenyl
moiety in quenching, and hence the “uncaging” process. So, it
is clear that GSH at physiologically relevant concentrations is
capable of transforming an ineffective chromophore into
a very effective sensitizer that generates singlet oxygen when
excited within the therapeutic window (in this case at 660 nm).
Next, we wanted to demonstrate the effectiveness of intra-
cellular GSH in activating our “caged” photosensitizers. To that
end, a number of human epithelial cancer cells in culture
(Huh7, MCF7, and HCT116) were tested with the photosensitiz-
ers, and as a control, photosensitizers with no quencher group
(in other words, the active photosensitizers obtained when the
Q group is removed) were also included.
The core photosensitizer was based on the BODIPY chromo-
phore, bromo or iodo-substituted derivatives of which have
been shown on many occasions to be good candidates for
photodynamic photosensitizers.[8] The synthesis work was
straightforward; hydroxyphenyl-BODIPY derivatives were syn-
thesized, sulfonylated, and chromatographically purified. It is
important to functionalize the dyes with heavy atoms to
ensure an enhanced spin-orbit coupling, and thus faster rates
of intersystem crossing (ISC), which in turn translates into
more efficient singlet oxygen generation. BODIPY dyes without
such modifications are known to be very poor photosensitizers
unless they are arranged as orthogonal dimers.[8b,9] Oligo-
ethyleneglycol moieties were added to improve the water sol-
ubility. Non-sulfonated BODIPY dyes 6–8 (meso-hydroxyphenyl-
BODIPY derivatives) were utilized as control compounds for
studying the change in activity in response to the removal of
the dinitrobenzenesulfonate groups. All new compounds were
Based on our results with chemical trap studies of singlet
oxygen generation, we expected higher photocytotoxic activity
on cancer cells with the control series. The cell culture studies
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Table 1. IC50 values of sensitizers with the HCT116 cell line.[a]
Sensitizers
Red LED irradiation for 4 h, IC50 [mm]
No light, IC50 [mm]
BODIPY-6
BODIPY-7
BODIPY-8
BODIPY-11
PS1
0.35Æ0.10
0.64Æ0.11
0.43Æ0.12
0.04Æ0.02
0.02Æ0.003
0.02Æ0.004
<0.06
0.35Æ0.16
0.42Æ0.27
0.75Æ0.04
0.20Æ0.03
4.38Æ0.03
0.29Æ0.11
0.36Æ0.10
no inhibition
no inhibition
PS2
PS3
NC[b]
no inhibition
no inhibition
PS1[c]
[a] IC50 values of sensitizers with the HCT116 cell line after 72 h of incuba-
tion with indicated sensitizers. [b] NC: Negative control compound,
1,3,5,7-tetramethyl-BODIPY. [c] The effect of PS1 on MRC-5 human fetal
lung fibroblast cells. The experiments were performed in triplicate.
It is both surprising and noteworthy that when control com-
pounds (6–8) were introduced, we observed that their photo-
cytotoxicity is significantly lower. This may be due to reduced
cell permeability and lipid solubility. To investigate this matter
further, we synthesized a putative positive control, compound
11, where R1 =OCH3 and R2 =R3 =H. Control compound 11 is
effective as a photosensitizer as predicted as it is unionizable
and expected to be cell-permeable. Cellular uptake is an essen-
tial parameter for controlling the photocytotoxicity and even
changes in the substitution pattern have an effect on intracel-
lular availability.[10]
Figure 2. (A) Absorption spectra of PS1 (20.0 mm), and (B) emission spectra
of PS1 (4.0 mm) upon addition of 50 equivalents of GSH in DMSO/1X PBS
buffer (50:50, v/v, pH 7.4), inscribed for 120 min. Excitation (lex) is at 655 nm.
Corresponding data for PS2 and PS3 are available in the Supporting
Information.
However, it is clear that since the photosensitizers are in the
caged form (PS-Q), they are not capable of producing singlet
oxygen, but once the photosensitizers are inside the cells, in-
tracellular GSH apparently cleaves the quencher module, and
thus releases the active photosensitizer. Using fluorescence mi-
croscopy, (Figure 4) fluorescent-labeled Annexin-V and
Hoechst-33258 co-staining show that cells clearly undergo
apoptosis on irradiation in the presence of 20 nm of caged
sensitizer PS1. This is demonstrated by the dense incorpora-
tion of the nuclear stain Hoechst-33258, and FITC-Annexin-V la-
Figure 3. Absorbance values of the trap molecule (2,2’-(anthracene-9,10-
diyl)bis(methylene)dimalonic acid) in DMSO/1X PBS (50:50, v/v, pH: 7.4).
BODIPY-6, or PS1 were introduced at 4 mm concentration, except for the
&
control run. Irradiation at 660 nm was initiated at t=30 min ( trap mole-
!
*
cule alone, BODIPY-6, PS1). The light source was an LED array at
0.2 mW fluence rate.
were all done in triplicate with most of our caged photosensi-
tizers were found to be effective. Some had relatively high
dark toxicity, which was checked by additional experiments to
isolate the contribution of photocytotoxicity.
The BODIPY dyes were tested both in the dark and under ir-
radiation with red LED light. The results are presented in
Table 1. In one particular colon cancer cell line, HCT116, we ob-
tained a remarkable IC50 value of 20.0 nm under irradiation for
PS1. The IC50 value without light is much higher, suggesting
that much lower concentrations will be effective under the
photodynamic regime.
Figure 4. Fluorescence microscope images of Annexin-V-fluos stained
HCT116 cells in the presence of 40 nm sensitizer 1. Cells were either subject-
ed to red LED irradiation at 660 nm for 4 h, followed by 20 h incubation in
the dark, or 24 h of incubation in dark. Hoechst-33258 stains nuclear DNA in
all conditions. Arrows point to the apoptotic cells with fragmented chroma-
tin (bright blue) and Annexin V positive membrane (green) corroborating
apoptosis in the presence of light and PS1. Images were captured at 100ꢁ
magnification.
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(100 unitsmLÀ1), and streptomycin (100 gmLÀ1). MRC-5 human
fetal lung fibroblast cells (ATCC) were maintained in Mininum Es-
sential Medium (MEM) (Invitrogen GIBCO), with 10% FBS (Invitro-
gen GIBCO), glutamine (2 mmL), penicillin (100 unitsmLÀ1), and
streptomycin (100 gmLÀ1) at 378C in a humidified incubator under
5% CO2.
beling of the exposed phosphatidylserines on the outer cyto-
plasmic membrane. Without red light irradiation, cells show no
such changes, keeping their usual appearance.
The response to the varying concentrations of the best per-
forming sensitizers is also shown in the form of a bar graph
(Figure 5).
Sulforhodamine B assay
Cells were plated in 96-well plates (2000 cell/well in 150 mL) and
grown for 24 h at 378C prior to treatment with different concentra-
tions of sensitizers and negative control (0.25–0.0005 mm for sensi-
tizers 1, 2, and 3; 5.0–0.06 mm for BODIPYs dissolved in DMSO).
After 72 h of incubation, the medium was aspirated, washed once
with 1X PBS (Gibco, Invitrogen), followed by addition of 50 mL of
a cold (48C) solution of 10% (v/v) trichloroacetic acid (MERCK) for
fixation. Then the plates were washed five times with dd-H2O and
were left to air-dry. A solution of sulforhodamine (50 mL, 0.4%,
m/v; Sigma–Aldrich) in 1% acetic acid solution was then added to
each well and left at room temperature for 10 min. The sulforhod-
amine B (SRB) solution was removed and the plates were washed
five times with 1% acetic acid and left for air-drying. Protein-
bound sulforhodamine B was solubilized in a Tris-base solution
(200 mL, 10 mm) and the plates were shaken for 10 min on a plate
shaker before the measurement of absorbance. The absorbance
was read in a 96-well plate reader at 515 nm. Cells incubated in
DMSO alone were used as controls for percent inhibition and IC50
calculations either in irradiated plates (for 4 h) or the plates kept in
dark. Percent inhibition (%) values were calculated with the given
formula: 1À[average (OD of treated wells)/average (OD of DMSO
treated cells)]ꢁ100.
Figure 5. Percent viability of HCT116 cells was determined by NCI-SRB assay.
Various concentrations of sensitizer PS1 (1–250 nm) were used to determine
cell death. Red bars show cell viability after 4 h irradiation with red LED, fol-
lowed by 20 h incubation in the dark, black bars indicate cell viability follow-
ing 24 h incubation in the dark.
Additional support for PS1 inducing apoptosis in the
HCT116 cell line was obtained by a fluorescence-activated cell
sorting (FACS) analysis. The analysis shows that when the cells
are treated with PS1 and red light, the percentage of cells with
fractional (sub-G1) DNA content increase significantly
compared with the control (Figure S20 in the Supporting
Information).
Detection of apoptosis
Cells were seeded onto coverslips in 6-well plates. After 24 h in cul-
ture, cells were treated with sensitizer 1 (40 nm/well). One group
was irradiated with red LED at 625 nm for 4 h and kept 20 h in the
dark. Another group was incubated in the dark for 24 h. Apoptosis
was determined with Annexin-V-Fluos (Roche) staining together
with Hoechst-33258 (Sigma–Aldrich) counterstaining that shows
the nuclear condensation. Cells were washed twice with ice-cold
1X PBS. Hoechts-33258 staining was performed with 1 mgmLÀ1
(final concentration) in each well followed by incubation for
10 min in the dark. Cells were destained with 1X PBS for 5 min.
Then, Annexin-V-Fluos staining was carried out according to the
manufacturer’s recommendations (Roche). Slides were then ana-
lyzed under the fluorescence microscope (Nikon Eclipse 50i).
Finally, we are very pleased that PS1 showed no apparent
photocytotoxicity (or dark toxicity) on the MRC-5 (human fetal
lung fibroblast cells) cell line, which is a normal cell line.
In conclusion, improved selectivity in any therapeutic agent
is highly desirable. In this work, we took advantage of the acti-
vation (uncaging) of a photosensitizer by a cancer-related cel-
lular parameter, glutathione concentration. Before the uncag-
ing reaction, the PS-Q conjugate has low to negligible toxic ac-
tivity on the selected cell cultures. GSH-mediated intracellular
uncaging results in a highly active photodynamic agent. We
are confident that as the stumbling blocks hindering the
broader applicability of photodynamic therapy are removed,
the methodology will be more effective competitor of the cur-
rent established treatment protocols. We shall continue to do
our part in providing chemical/photophysical avenues towards
that end.
Acknowledgements
The authors gratefully acknowledge support from TUBITAK in
the form of a grant (112T480).
Keywords: BODIPY dyes · photochemistry · photodynamic
action · photosensitizers · singlet oxygen
Experimental Section
[1] a) O. Raab, Z. Biol. 1900, 39, 524–546; b) A. Jesionek, H. von Tappeiner,
MMW Muench. Med. Wochenschr. 1903, 47, 2042–2044; c) H. von Tap-
peiner, A. Jodlbauer, Dtsch. Arch. Klin. Med. 1904, 80, 427–487.
Cell culture
HCT116 human colon carcinoma cells (ATCC) were maintained in
Dulbecco’s Modified Eagle’s Medium (DMEM) (Invitrogen GIBCO),
with 10% fetal bovine serum (FBS) (Invitrogen GIBCO), glutamine
(2 mmL), nonessential amino acids (0.1 mm), penicillin
[2] a) A. Kamkaew, S. H. Lim, H. B. Lee, L. V. Kiew, L. Y. Chung, K. Burgess,
Chem. Soc. Rev. 2013, 42, 77–88; b) A. B. Ormond, H. S. Freeman, Materi-
als 2013, 6, 817–840; c) O. J. Stacey, S. J. A. Pope, RSC Adv. 2013, 3,
25550–25564; d) S. G. Awuah, Y. You, RSC Adv. 2012, 2, 11169–11183.
&
&
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www.chemeurj.org
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[3] a) W. M. Gallagher, L. T. Allen, C. O’Shea, T. Kenna, M. Hall, A. Gorman, J.
Killoran, D. F. O’Shea, Br. J. Cancer 2005, 92, 1702–1710; b) S. G. Rock-
son, P. Kramer, M. Razavi, A. Szuba, S. Filardo, P. Fitzgerald, J. P. Cooke,
S. Yousuf, A. R. DeVault, M. F. Renschler, D. C. Adelman, Circulation 2000,
102, 2322–2324; c) D. E. J. G. J. Dolmans, D. Fukurama, R. K. Jain, Nat.
Rev. Cancer 2003, 3, 380–387; d) R. Waksman, P. E. McEwan, T. I. M.
Moore, R. Pakala, F. D. Kolodgie, D. G. Hellinga, R. C. Seabron, S. J. Rych-
novsky, J. Vasek, R. W. Scott, R. Virmani, J. Am. Coll. Cardiol. 2008, 52,
1024–1032; e) Y. Choi, R. Weissleder, C.-H. Tung, Cancer Res. 2006, 66,
7225–7229; f) T. J. Dougherty, C. J. Gomer, B. W. Henderson, G. Jori, D.
Kessel, M. Korbelik, J. Moan, Q. Peng, J. Natl. Cancer Inst. 1998, 90, 889–
905; g) T. J. Dougherty, J. E. Kaufman, A. Goldfarb, K. R. Weishaupt, D.
Boyle, A. Mittleman, Cancer Res. 1978, 38, 2628–2635.
Morgenstern, Anal. Biochem. 2009, 390, 52–56; d) A. Shibata, K. Furuka-
wa, H. Abe, S. Tsuneda, Y. Ito, Bioorg. Med. Chem. Lett. 2008, 18, 2246–
2248; e) H. Maeda, H. Matsuno, M. Ushida, K. Katayama, K. Saeki, N.
Itoh, Angew. Chem. 2005, 117, 2982–2985; Angew. Chem. Int. Ed. 2005,
44, 2922–2925; f) W. Jiang, Q. Fu, H. Fan, J. Ho, W. Wang, Angew. Chem.
2007, 119, 8597–8600; Angew. Chem. Int. Ed. 2007, 46, 8445–8448;
g) X. Li, S. Qian, Q. He, B. Yang, J. Li, Y. Hu, Org. Biomol. Chem. 2010, 8,
3627–3630; h) Z. Dai, L. Tian, Z. Ye, B. Song, R. Zang, J. Yuan, Anal.
Chem. 2013, 85, 11658–11664; i) K. Cui, Z. Chen, Z. Wang, G. Zhang, D.
Zhang, Analyst 2011, 136, 191–195; j) S.-Q. Wang, Q.-H. Wu, H.-Y. Wang,
X.-X. Zheng, S.-L. Shen, Y.-R. Zhang, J.-Y. Miao, B.-X. Zhao, Analyst 2013,
138, 7169–7174; k) H. Guo, Y. Jing, X. Yuan, S. Ji, J. Zhao, X. Li, Y. Kan,
Org. Biomol. Chem. 2011, 9, 3844–3853; l) H. He, P.-C. Lo, D. K. P. Ng,
Chem. Eur. J. 2014, 20, 6241–6245.
´
[4] a) J. Gołab, D. Olszewska, P. Mrꢂz, K. Kozar, R. Kaminski, A. Jalili, M. Jakꢂ-
bisiak, Clin. Cancer Res. 2002, 8, 1265–1270; b) H. Hirschberg, F. A. Uzal,
D. Chighvinadze, M. J. Zhang, Q. Peng, S. J. Madsen, Lasers Surg. Med.
2008, 40, 535–542; c) M. S. Mathews, D. Chighvinadze, H. M. Gach, F. A.
Uzal, S. J. Madsen, H. Hirschberg, Lasers Surg. Med. 2011, 43, 892–900.
[5] a) S. Ozlem, E. U. Akkaya, J. Am. Chem. Soc. 2009, 131, 48–49; b) S.
Erbas, A. Gorgulu, M. Kocakusakogulları, E. U. Akkaya, Chem. Commun.
2009, 4956–4958; c) S. O. Mcdonnell, M. J. Hall, L. T. Allen, A. Byrne,
W. M. Gallagher, D. F. O’Shea, J. Am. Chem. Soc. 2005, 127, 16360–
16361; d) J. Chen, K. Stefflova, M. J. Niedre, B. C. Wilson, B. Chance, J. D.
Glickson, G. Zheng, J. Am. Chem. Soc. 2004, 126, 11450–11451; e) G.
Zheng, J. Chen, K. Stefflova, M. Jarvi, H. Li, B. C. Wilson, Proc. Natl. Acad.
Sci. USA 2007, 104, 8989–8994; f) T. Yogo, Y. Urano, A. Mizusmus, H. Su-
nahara, T. Inoue, K. Hirose, M. Lino, K. Kikuchi, T. Nagano, Proc. Natl.
Acad. Sci. USA 2008, 105, 28–32.
[6] a) Z.-B. Zheng, G. Zhu, H. Tak, E. Joseph, J. L. Eiseman, D. J. Creighton,
Bioconjugate Chem. 2005, 16, 598–607; b) H. S. Jung, X. Chen, K. Seung,
J. Yoon, Chem. Soc. Rev. 2013, 42, 6019–6031; c) C.-C. Yeh, M.-F. Hou, S.-
H. Wu, S.-M. Tsai, S.-K. Lin, L. A. Hou, H. Ma, L. Y. Tsai, Cell Biochem.
Funct. 2006, 24, 555–559; d) S. C. Barranco, R. R. Perry, M. E. Durm, M.
Quarishi, A. L. Werner, S. G. Gregorcyk, P. Kolm, Dis. Colon Rectum 2000,
43, 1133–1140.
[8] a) S. Atilgan, Z. Ekmekci, A. L. Dogan, D. Guc, E. U. Akkaya, Chem.
Commun. 2006, 4398–4400; b) Y. Cakmak, S. Kolemen, S. Duman, Y.
Dede, Y. Dolen, B. Kilic, Z. Kostereli, L. T. Yildirim, A. L. Dogan, D. Guc,
E. U. Akkaya, Angew. Chem. 2011, 123, 12143–12147; Angew. Chem. Int.
Ed. 2011, 50, 11937–11941; c) M. Isik, T. Ozdemir, I. S. Turan, S. Kolemen,
E. U. Akkaya, Org. Lett. 2013, 15, 216–219; d) T. Yogo, Y. Urano, Y. Ishit-
suka, F. Maniwa, T. Nagano, J. Am. Chem. Soc. 2005, 127, 12162–12163;
e) X. Zhang, Y. Xiao, J. Qi, J. Qu, B. Kim, X. Yue, K. D. Belfield, J. Org.
Chem. 2013, 78, 9153–9160; f) H. Yu, Y. Dai, H. Lib, Y. Xiao, New J. Chem.
2013, 37, 1688–1691; g) S. Kou, H. N. L. Lee, D. van Noort, K. M. K.
Swamy, S. H. Kim, J. H. Soh, K.-M. Lee, S.-W. Nam, J. Yoon, S. Park,
Angew. Chem. 2008, 120, 886–890; Angew. Chem. Int. Ed. 2008, 47,
872–876; h) L. Li, J. Han, B. Nguyen, K. Burgess, J. Org. Chem. 2008, 73,
1963–1970; i) G. Ulrich, R. Ziessel, A. Harriman, Angew. Chem. 2008, 120,
1202–1219; Angew. Chem. Int. Ed. 2008, 47, 1184–1201.
[9] a) W. Pang, X.-F. Zhang, J. Zhou, C. Yu, E. Hao, L. Jiao, Chem. Commun.
2012, 48, 5437–5439; b) X.-F. Zhang, X. Yang, J. Phys. Chem. B 2013,
117, 9050–9055.
[10] Y. You, S. L. Gibson, R. Hilf, S. R. Davies, A. R. Oseroff, I. Roy, T. Y. Ohul-
chanskyy, E. J. Bergy, M. E. Detty, J. Med. Chem. 2003, 46, 3734–3747.
[7] a) S. Ji, H. Guo, X. Yuan, X. Li, H. Ding, P. Gao, C. Zhao, W. Wu, W. Wu, J.
Zhao, Org. Lett. 2010, 12, 2876–2879; b) J. Shao, H. Guo, S. Ji, J. Zhao,
Biosens. Bioelectron. 2011, 26, 3012–3017; c) J. ꢃlander, K. Johansson,
V. D. Heuser, H. Farebo, J. Jꢄrvliden, H. Abe, A. Shibata, M. Ito, Y. Ito, R.
Received: September 28, 2014
Published online on && &&, 0000
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These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
Power with a control switch: Enhanced
spatiotemporal selectivity in photonic
sensitization of dissolved molecular
oxygen is an important target for im-
proving the potential and practice of
photodynamic therapy. Considering the
high glutathione (GSH) concentrations
in cancer cells, a series of BODIPY-based
“caged” sensitizers have been designed
and synthesized. The sensitizers can
generate cytotoxic singlet oxygen only
after glutathione-mediated cleavage of
the electron-sink module.
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Photosensitizers
I. S. Turan, F. P. Cakmak, D. C. Yildirim,
R. Cetin-Atalay, E. U. Akkaya*
&& – &&
Near-IR Absorbing BODIPY Derivatives
as Glutathione-Activated
Photosensitizers for Selective
Photodynamic Action
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Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!