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Novel types of boronated chlorin e6 conjugates via Сclick chemistryТ.

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Full Paper
Received: 12 March 2009
Revised: 13 May 2009
Accepted: 13 May 2009
Published online in Wiley Interscience: 22 June 2009
(www.interscience.com) DOI 10.1002/aoc.1521
Novel types of boronated chlorin e6 conjugates
via ‘click chemistry’
Vladimir I. Bregadzea , Andrey A. Semioshkina , Julia N. Las’kovaa,
Maria Ya. Berzinaa,b , Irina A. Lobanovaa, Igor B. Sivaeva∗ , Mikhail A. Grinb ,
Rustam A. Titeevb , Dmitry I. Brittalb , Olga V. Ulybinab ,
Anastasija V. Chestnovab,c , Anastasija A. Ignatovac,d, Alexey V. Feofanovc,d
and Andrey F. Mironovb
Conjugates of chlorin e6 with closo-dodecaborate and cobalt bis(dicarbollide) anions were synthesized for the first time in high
yields using the advanced ‘click’ methodology. In vitro study on A549 human lung adenocarcinoma cells revealed that the
synthesized boronated conjugates are able to penetrate and accumulate in cancer cells, but their intracellular concentration is
c 2009 John Wiley & Sons,
not sufficient for effective photodynamic and boron neutron capture therapy of cancer. Copyright Ltd.
Keywords: chlorin e6 ; boronated conjugates; PDT; BNCT
Introduction
370
Over the last two decades, photodynamic therapy (PDT) of cancer
has received increasing attention as a viable and interesting
alternative to currently used methods for treatment of solid
tumors.[1] PDT is a relatively new binary modality of cancer
treatment whereby a relatively nontoxic drug (sensitizer) and
nonhazardous visible or near infrared light combine to generate
cytotoxic reactive oxygen species (primarily singlet oxygen) at
a selected treatment site. Because the average free path of
singlet oxygen is very short (<0.5 µm), the resultant apoptosis
and necrosis occur only in tumor cells that have accumulated
the sensitizer and not in surrounding normal cells. As a result,
PDT is a highly selective method of cancer treatment producing
minimum side effects in comparison to conventional radio- and
chemo- therapies. Selective accumulation of porphyrins in cancer
tumors was reported more than 60 years ago.[2] At present
various protoporphyrin and chlorin based photosensitizers are
approved for clinical use, and have been successfully employed
in PDT in many countries.[1,3] Despite the exact mechanism of
accumulation of porphyrins in tumor cells remaining unknown,
the low-density lipoprotein (LDL) receptor-mediated pathway has
been established to play a key role in the delivery of porphyrins to
tumor cells.[4]
Boron neutron capture therapy (BNCT) is another binary method
for the treatment of cancer, which is based on the nuclear reaction
of two essentially nontoxic species, nonradioactive 10 B and lowenergy thermal neutrons. The neutron capture reaction by 10 B
produces high-linear-energy transfer ions 4 He2+ and 7 Li3+ that
dissipate their kinetic energy during traveling one cell diameter
(5–9 µm) in biological tissues, giving them the potential for precise
cell-killing.[5 – 6] Efficient BNCT requires selective accumulation of
10 B atoms in cancer cells. This has caused growing interest in
synthesis of boronated porphyrins as potential BNCT agents
where porphyrin moiety acts as a tumor-targeting molecule.[7]
Appl. Organometal. Chem. 2009 , 23, 370–374
On other hand, some of the boron-containing porphyrins, for
example BOPP {disodium salt of 2,4-bis-[α, β-bis(1,2-dicarba-closododecaboranecarboxy)ethyl] deutero-porphyrin IX}, have been
found to demonstrate the proper photophysical and biological
characteristics and can be considered as potential PDT agents.[8]
Chlorins are photosensitizers that have high quantum yields of
singlet oxygen production and absorb light in the 640–690 nm
region, i.e. within the so-called ‘phototherapeutic window’
(630–900 nm), where light absorption and scattering in human
tissues are minimized and they are relatively transparent for activating light.[9] Syntheses of a few carborane-containing derivatives
of chlorin e6 have been reported recently.[10] In this contribution
we describe the synthesis of new conjugates of chlorin e6 with
closo-dodecaborate[11] and cobalt bis(dicarbollide)[12,13] anions using ‘click’ methodology and report their interactions with cancer
cells.
∗
Correspondence to: Igor B. Sivaev, A.N.Nesmeyanov Institute of Organoelement
Compounds, Vavilov Str. 28, 119991 Moscow, Russian Federation.
E-mail: sivaev@ineos.ac.ru
a A.N.Nesmeyanov Institute of Organoelement Compounds, Russian Academy
of Sciences, Vavilov Str. 28, 119991, Moscow, Russia
b M.V.Lomonosov Moscow State Academy of Fine Chemical Technology,
Vernadskii Prosp. 86, 119571, Moscow, Russia
c Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy
of Sciences, Miklukho-Maklay Str., 16/10, 117997 Moscow, Russia
d Biological Faculty, Lomonosov Moscow State University, Vorobyevi Gori 1,
Moscow, 119992, Russia
c 2009 John Wiley & Sons, Ltd.
Copyright Novel types of boronated chlorin e6 conjugates
N
1. R-[OCH2CH2]2-N3
CuI, base, MeCN
N
Zn
N
NH N
N
N HN
2. HCl/ H2O
MeOOC
MeOOC
O
NH
MeOOC
MeOOC
NH
O
N
1 - Zn
N
N
O R
2
2-
R=
BH (B)
-
R=
CH
4
Co
5
Scheme 1. Synthesis of boron-containing conjugates of chlorin e6 .
Results and Discussion
Appl. Organometal. Chem. 2009, 23, 370–374
Figure 1. Absorption (solid lines) and fluorescence (dotted lines) spectra
for conjugates 4 (circles) and 5 (triangles) in 1% Cremophor EL emulsion
(50 mM Na-phosphate buffer, pH 7).
Conjugates 4 and 5 are hydrophobic and insoluble in water.
Therefore nonionic solubilizer Cremophor EL (polyoxyethylenglyceroltriricinoleat 35, polyoxyl 35 castor oil) was used to prepare
water-soluble formulations. As shown previously, Cremophor
EL-based formulations provide stabilization of monomeric forms
of various hydrophobic tetrapyrrolic compounds.[20] The prepared
0.5 mM stock solutions of conjugates 4 and 5 were found to be
stable in the dark at 4 ◦ C for at least 3 months. The absorption
spectra of compounds 4 and 5 in 1% Cremophor EL aqueous
emulsion are identical [402 (1.00), 499 (0.10), 528 (0.03), 611 (0.04)
and 665 (0.36) nm] but differ slightly from their absorption spectra
in organic solvents (see Experimental section). The boronated
conjugates were found to maintain characteristic fluorescence of
the chlorin e6 chromophore. Both compounds have small Stokes
shifts (5 nm) and the same emission maximum (670 nm); however,
the fluorescence quantum yield for conjugate 5 is 25% lower than
for conjugate 4 (Fig. 1). Low degree of the fluorescence quenching
in the case of cobalt bis(dicarbollide) anion suggests rather weak
interaction between the excited state of the porphyrin core and
the appended metallocomplex. In general, replacement of cobalt
bis(dicarbollide) for closo-dodecaborate anion does not produce
a significant effect on absorption and fluorescence of the chlorin
e6 chromophore.
Interaction of conjugates 4 and 5 with A549 human lung
adenocarcinoma cells was studied using confocal laser scanning
microscopy. It was found that these compounds are able to
penetrate in the A549 cells and accumulate in cytoplasm.
Patterns of intracellular distribution of the both conjugates are
c 2009 John Wiley & Sons, Ltd.
Copyright www.interscience.wiley.com/journal/aoc
371
Recently reported conjugates of chlorin e6 with carboranes 1,2C2 B10 H12 and [CB11 H12 ]− were prepared using methylpheophorbide a as starting material. Nucleophilic opening of its exo-ring E
by 2-ethhanolamine or 1,2-diaminoethane followed by alkylation
of terminal hydroxyl/amino group with the corresponding carboranylmethyl triflate resulting in boronated derivatives of chlorin
e6 .[10] In the present work we decided to use ‘click’ methodology for
synthesis of boron-containing conjugates of chlorin e6 . The Cu(I)catalyzed 1,3-dipolar cycloaddition of alkyne and azide to form a
triazole, termed ‘‘click chemistry’, has been recently established
as a promising tool for chemical modification of biomolecules.
The 1,2,3-triazole is a rigid linking unit that mimics geometry and
electronic properties of a peptide bond and is more stable to hydrolytic cleavage. The reactants, alkyne and azide, are convenient
to introduce, independently stable and do not react with common
organic reagents or functional groups in biomolecules.[14] A few
examples of the synthesis of boron-containing nucleosides[15] and
carbohydrates[16] using the click chemistry approach have been
reported. Recently we described the synthesis of an acetylenic
derivative of chlorin e6 1 by reaction of methylpheophorbide a
with propargylamine.[17] Syntheses of azide derivatives of closododecaborate 2[18] and cobalt bis(dicarbollide) 3[15b] anions using
nucleophilic opening of their cyclic oxonium derivatives[19] have
been developed recently.
In the present work we found that both closo-dodecaborate (2)
and cobalt bis(dicarbollide) (3) based azides readily undergo click
reactions with terminal alkyne group in zinc complex 1–Zn in the
presence of copper(I) iodide. The standard removal procedure of
zinc metal resulted in novel conjugates of chlorin-e6 with closododecaborate (4) and cobalt bis(dicarbollide) (5), respectively
(Scheme 1).
The synthesized conjugates 4 and 5 were characterized by
UV–vis, IR and NMR spectroscopy. The UV–vis spectra of both
compounds contain typical absorption bands of chlorin unit at
402 (1.00), 526 (0.03), 609 (0.04) and 662 (0.30) nm. The 11 B NMR
spectra of conjugates 4 and 5 contain typical sets of signals
for monoalkoxy derivatives of closo-dodecaborate (1 : 5 : 5 : 1) and
cobalt bis(dicarbollide) (1 : 1 : 1 : 1 : 2 : 6 : 2 : 2 : 1 : 1), respectively. In
the 1 H NMR spectra of both compounds signals of the CH protons
of the triazole linker were observed at 8.81 and 8.80 ppm for 4 and
5, respectively.
V. I. Bregadze et al.
Figure 2. Intracellular distribution of conjugates 4 (A, C) and 5 (B, D) in
A549 cells. (A, B) Conventional light microscope images of the cells. (C,
D) Intracellular distributions of 4 and 5 as measured with confocal laser
scanning microscopy. Cells were incubated with 4 µM conjugate 4 or 5 for
3 h. Bar represents 10 µm. N marks nucleus.
similar: accumulation in granular cellular structures of submicron
size and diffuse cytoplasm staining (Fig. 2). Neither intranuclear
penetration nor accumulation in plasma membrane was detected
for conjugates 4 and 5.
The intracellular fluorescence spectra of 4 and 5 measured
using spectral imaging technique[18] coincide completely with the
spectra of the dyes in the lipid-like environment (1% Cremophor
EL emulsion, Triton X-100 micelles). These results allow one to
suppose that accumulation of conjugates 4 and 5 in cells occurs in
the monomeric form in a lipid environment. Most probably they
are bound to cytoplasmic membranous structures.
Compounds 4 and 5 do not cause the death of A549
cells at concentrations less than 16 µM and incubation time
6 h. Further increase in the conjugate concentration is limited
because of Cremophor EL cytotoxicity. Chlorin e6 is a wellknown photosensitizer. Accordingly, photoinduced cytotoxicity
of the conjugates 4 and 5 was studied to characterize their
photosensitizing properties. The irradiation of A549 cells after
incubation with conjugates 4 and 5 in the concentration range
0.5–16 µM during 3 h does not result in cell death. The absence
of photodynamic effect allows one to suppose that intracellular
concentration of the conjugates 4 and 5 was insufficient to provide
nonreparable photoinduced damage of cells.
In conclusion, the conjugates of chlorin e6 with closododecaborate and cobalt bis(dicarbollide) anions were
synthesized for the first time in high yields using the advanced
‘click’ methodology. As intended, the synthesized conjugates 4
and 5 were able to penetrate and accumulate in cancer cells,
but their intracellular concentration seemed to be insufficient
for effective PDT and BNCT of cancer. Accordingly, further
optimization of a structure of boron-containing derivatives of
chlorin e6 is in progress now.
Experimental
372
Chemicals were reagent-grade and were used as received from
commercial vendors. Compounds 1–Zn, (Bu4 N)2 (2) and [8O(CH2 CH2 )2 O-3, 3 -Co(1,2-C2 B9 H10 )(1 , 2 -C2 B9 H11 )] were prepared
according to the previously described procedures.[17,18,21] Ace-
www.interscience.wiley.com/journal/aoc
tonitrile was distilled from P2 O5 and then from CaH2 . Absorption
spectra were recorded on Jasco-UV 7800 spectrophotometer in
CHCl3 . 1 H and 11 B NMR spectra were recorded at 400.13 and
128.38 MHz, respectively, on a Bruker-Avance-400 spectrometer.
ESI-MS spectra were recorded on a Micromass Quattro micro spectrometer. IR spectra were recorded on Bruker Equinox 55 in KBr
pellets. Column chromatography was carried out on 40/60 silica
gel (Merk). Preparative TLC was performed on silica gel 60 (Merck)
using 20 × 20 × 1 mm plates. Analytical TLC was carried out on
Kieselgel 60 F245 plates (Merck).
The stock solutions of 4 and 5 were prepared by grinding
powders in a small quantity of 100% Cremophor EL followed by
20-fold dilution with Na-phosphate buffer (50 mM, pH 7.0) to 5%
CrEL. Concentrations of 4 and 5 were measured in the presence of
1% Cremophor EL using the extinction coefficient at the Q-band
maximum (665 nm) of 45200 M−1 cm−1 .
A549 human lung adenocarcinoma cells were cultured as
described elsewhere.[20] To study intracellular accumulation and
distribution, the cells were incubated with conjugates 4 and 5 at
4 µM concentration for 3 h.
The confocal microspectral measurements were carried out
with an installation on the basis of OMARS-89 spectrograph (Dilor,
France), Olympus BH-2 microscope (Japan), and a motorized
scanning stage (Märzhäuser, Wetzlar, Germany). An air-Peltier
cooled CCD camera (1024 × 256 pixels, Wright Instruments Ltd,
UK) was used as a detection system. Intracellular distribution was
studied using a LSM-510 META confocal laser scanning microscope
(Carl Zeiss AG, Germany). The confocal fluorescence images were
obtained with a 63× C-Apochromat water-immersion objective
(NA = 1.2, Carl Zeiss AG, Germany) at 0.3 µm lateral and 1.5 µm
axial resolution. The fluorescence was excited with an Ar+ -laser
with a wavelength of 514.5 nm and emission was registered with
the 650 nm long-wavelength barrier filter.
For the survival assays A549 cells were seeded into 96-well
plates. Twenty four hours later, conjugates 4 and 5 were added
into the wells to achieve concentrations ranging from 0.5 to 16 µM
with a two-fold increment. Cytotoxicity was determined after 6 h
incubation of cells with conjugates 4 and 5 in the dark. For the
control test cells were incubated with Cremophor EL emulsion
at the equivalent concentrations. Photoinduced cytotoxicity was
determined on the cells incubated with conjugates 4 and 5 for 3 h
and irradiated with a 500 W halogen lamp through a 5 cm water
filter and a band-pass filter (transmission 640–1000 nm, 4 mW
cm−2 , 10 J cm−2 ). After the irradiation the cells were incubated
for additional 3 h under standard conditions and subjected to
examination for viability. For evaluation of cell viability the
fluorescent dyes Hoechst 33342 (4 µM, stains all cells) and PI (6 µM,
stains dead cell) were added to cells for 15 min. The percentage
of dead cells was calculated using the inverted fluorescence
microscope Axio Observer (Carl Zeiss AG, Germany). At least 500
cells were examined in each well.
(Me3 NH)[(8-N3 (CH2 CH2 O)2 -3,
C2 B9 H11 )] (3)
3 -Co(1,2-C2 B9 H10 )(1 ,
2 -
To solution of 0.97 g (2.37 mmol) [8-O(CH2 CH2 )2 O-3, 3 -Co(1,2C2 B9 H10 )(1 , 2 -C2 B9 H11 )] in 70 ml of ethanol 0.38 g (5.90 mmol)
of NaN3 was added and stirred for 1 h at 60–70 ◦ C. The reaction
mixture was cooled to room temperature and filtered. The filtrate
was treated with excess aqueous Me3 NHCl. The precipitate formed
was filtered off, washed with ethanol and dried over P2 O5 to yield
0.63 g (68%) of the orange product. The 1 H and 11 B NMR spectra
c 2009 John Wiley & Sons, Ltd.
Copyright Appl. Organometal. Chem. 2009, 23, 370–374
Novel types of boronated chlorin e6 conjugates
of the product are similar to those reported earlier for the sodium
salt.[15b]
Synthesis of Conjugate (Bu4 N)2 (4)
The mixture of 10 mg (0.015 mmol) of zinc-complex 1–Zn, 8 mg
(0.016 mmol) of azide (Bu4 N)2 (2), one drop of triethylamine and
1 mg (0.005 mmol) of CuI were stirred in 2 ml of CH3 CN for 3 h.
The reaction mixture was poured into 100 ml of 6 M HCl, shaken
several times, neutralized by aqueous solution of NaHCO3 and
extracted by CH2 Cl2 (5 × 10 ml). The combined organic layers
were dried over Na2 SO4 and concentrated. Purification of the
product by preparative TLC (CHCl3 /MeOH) afforded 13 mg (60%)
of compound (Bu4 N)2 (4). ESI-MS (m/z): 1175 ([M2− X+ ]− ). UV–vis,
λmax , (nm): 402 (1.00), 526 (0.03), 609 (0.04) and 662 (0.30). IR
(cm−1 ): 2486 (B-H). 1 H NMR (CDCl3 , δ, ppm): 9.67 (1H, s, 5-H); 9.62
(1H, s, 10-H); 8.81 (1H, s, CH of triazole); 8.40 (H, s, 20-H); 8.07 (1H,
dd, J = 18 Hz, 12 Hz, 31 -H); 7.42 (1H, broad s, 132 -NH), 6.33 (1H, dd,
J = 18 Hz, 1.5 Hz, E-32 -H); 6.12 (1H, dd, J = 12 Hz, 1.5 Hz, Z-32 -H);
5.39 (2H, m, 15-CH2 ); 5.03 (2H, dd, 133 -CH2 ); 4.71 (2H, t, J = 4.5 Hz,
137 -CH2 ); 4.47 (1H, d, 18-H); 4.39 (1H, d, 17-H); 3.99 (2H, t, J = 4.5
Hz, 138 -CH2 ); 3.79 (2H, t, J = 8 Hz, 1310 -CH2 ); 3.75 (2H, t, J = 8 Hz,
1311 -CH2 ); 3.72 (3H, s, 152 -COOCH3 ); 3.70 (2H, m, 81 -CH2 ); 3.63 (3H,
s, 12-CH3 ); 3.51 (3H, s, 173 -COOCH3 ); 3.49 (3H, c, 2-CH3 ); 3.31 (3H,
s, 7-CH3 ); 3.04(16H, m, N+ CH2 CH2 CH2 CH3 ), 2.55 (H, m, 171 -CH2 );
2.20 (3H, m, 171 -CH2 , 172 -CH2 ); 1.72 (3H, d, 18-CH3 ); 1.71 (3H, t,
J = 8 Hz, 82 -CH3 ); 1.46 (16H, m, N+ CH2 CH2 CH2 CH3 ); 1,29 (16H,
m, N+ CH2 CH2 CH2 CH3 ); 0.88 (24H, m, N+ CH2 CH2 CH2 CH3 ); 1.9–0.1
(11H, broad m, BH); −1.64 (1H, broad s, NH); −1.90 (1H, broad s,
NH). 11 B NMR (CDCl3 , δ, ppm): 6.3 [1B, s, B(1)]; −16.8 [5B, d, B(2–6)];
−18.2 (5B, d, B(7–11)]; −22.5 [1B, d, B(12)]. Chemical analysis and
13 C NMR study were not collected due to insufficient amount of
the compound.
Synthesis of Conjugate (Me3 NH) (5)
Appl. Organometal. Chem. 2009, 23, 370–374
This work was supported in part by programs of the Presidium of
the Russian Academy of Sciences on Molecular and Cell Biology, the
Russian Federation Agency for Science and Innovations (‘Leading
Scientific School’, SS-1061.2008.4), the Russian Federation Agency
for Education (‘Development of Scientific Potential of High School’
2.1.1/2889), and by the Russian Foundation for Basic Research
(07-03-00712 and 09-03-00701).
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Copyright www.interscience.wiley.com/journal/aoc
373
The mixture of 10 mg (0.015 mmol) of zinc-complex 1–Zn, 7 mg
(0.014 mmol) of azide (Me3 NH) (3), one drop of diisopropylethylamine, and 1 mg (0.005 mmol) of CuI was stirred in 2 ml of CH3 CN
for 3.5 h. The reaction mixture was poured into 100 ml of 6 M HCl,
shaken several times, neutralized by aqueous solution of NaHCO3
and extracted by CHCl3 (5 × 10 ml). The combined organic layers
were dried over Na2 SO4 and concentrated. Purification of the product by preparative TLC (CHCl3 –MeOH) afforded 10.5 mg (68%) of
(Me3 NH) (5). ESI-MS (m/z): 1115 [M]− . UV–vis (λmax , nm): 402 (1.00),
526 (0.03), 609 (0.04) and 662 (0.30). IR (cm−1 ): 2550 (B-H). 1 H-NMR
(CDCl3 , δ, ppm): 9.60 (1H, s, 5-H); 9.58 (1H, s, 10-H); 8.80 (1H, s,
of triazole), 8.35 [1H, broad s, (CH3 )3 NH]; 8.05 (1H, dd, J = 18 Hz,
12 Hz, 31 -H); 7.99 (1H, s, 20-H); 7.70 (1H, broad t, 132 -NH); 6.34
(H, dd, J = 18 Hz, 1.5 Hz, E-32 -H); 6.14 (H, dd, J = 12 Hz, 1.5 Hz,
Z-32 -H); 5.24 (2H, m, 15-CH2 ); 5.02 (2H, broad. dd, 133 -CH2 ); 4.58
(2H, broad. t, 137 -CH2 ); 4.47 (H, q, 18-H); 4,35 (H, d, J = 10 Hz,
17-H); 4,01 (4H, s, CHcarb ); 4.88 (2H, broad t, 138 -CH2 ); 3.75 (3H, s,
152 -COOCH3 ); 3.76 (2H, m, 81 -CH2 ); 3.65 (2H, broad, t, 1310 -CH2 );
3.60 (3H, s, 12-CH3 ); 3.49 (3H, s, 173 -COOCH3 ); 3.43 (3H, s, 2-CH3 ),
3.35 (2H, t, 1311 -CH2 ); 3.26 (3H, s, 7-CH3 ), 2.91 [9H, d (CH3 )3 NH+ ];
2.78 (H, m, 171 -CH2 ); 2.58–2.91 (3H, m, 171 -CH2 , 172 -CH2 ); 1.70
(3H, d, 18-CH3 ); 1.02 (3H, t, J = 8 Hz, 82 -CH3 ); 1.9–0.1 (11H, broad
m, BH); −1.52 (1H, broad s, NH); −1.70 (1H, broad s, NH). 11 B NMR
(CDCl3 , δ, ppm): 22.7 (1B, s); 3.5 (1B, d); 0.4 (1B, d); −2.2 (1B, d);
−4.6 (2B, d); −8.2 (6B, d); −17.3 (2B, d); −20.3 (2B, d); −21.3 (1B,
d); −28.3 (1B, d). Chemical analysis and 13 C NMR data were not
collected due to insufficient amount of the compound.
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