New promising porphyrazine-based agents for optical theranostics of cancer

Article abstract of DOI:10.1134/S1070363217030173

New porphyrazine bases containing peripheral benzyloxyphenyl groups have been synthesized by the template method. The procedure includes condensation of aromatic aldehydes with malononitrile, transformation of arylmethylidenemalononitriles to arylethenetricarbonitriles, template assembly of porphyrazine macrocycle on bis(indenyl)ytterbium(II) complex, and removal of the central metal ion. Luminescence properties of the synthesized porphyrazines and their dependence on the viscosity of the medium were studied, and the light and dark toxicities of the porphyrazines have been estimated. The obtained results suggest the possibility of using these porphyrazines as optical theranostic agents of new generation.

Full text of DOI:10.1134/S1070363217030173

ISSN 1070-3632, Russian Journal of General Chemistry, 2017, Vol. 87, No. 3, pp. 479–484. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © S.A. Lermontova, I.S. Grigor’ev, N.N. Peskova, E.Yu. Ladilina, I.V. Balalaeva, L.G. Klapshina, V.P. Boyarskii, 2017, published in
Zhurnal Obshchei Khimii, 2017, Vol. 87, No. 3, pp. 474–480.
New Promising Porphyrazine-Based Agents
for Optical Theranostics of Cancer
S. A. Lermontovaa,b, I. S. Grigor’eva,c, N. N. Peskovab, E. Yu. Ladilinaa,
I. V. Balalaevab, L. G. Klapshinaa,b, and V. P. Boyarskiic*
a Razuvaev Institute of Organometallic Chemistry, Russian Academy of Sciences,
ul. Tropinina 49, Nizhny Novgorod, 603137 Russia
b Lobachevsky State University of Nizhny Novgorod, pr. Gagarina 23, Nizhny Novgorod, 603950 Russia
c St. Petersburg State University, Universitetskaya nab. 7–9, St. Petersburg, 199034 Russia
*e-mail: v.boiarskii@spbu.ru
Received October 6, 2016
Abstract—New porphyrazine bases containing peripheral benzyloxyphenyl groups have been synthesized by
the template method. The procedure includes condensation of aromatic aldehydes with malononitrile, trans-
formation of arylmethylidenemalononitriles to arylethenetricarbonitriles, template assembly of porphyrazine
macrocycle on bis(indenyl)ytterbium(II) complex, and removal of the central metal ion. Luminescence
properties of the synthesized porphyrazines and their dependence on the viscosity of the medium were studied,
and the light and dark toxicities of the porphyrazines have been estimated. The obtained results suggest the
possibility of using these porphyrazines as optical theranostic agents of new generation.
Keywords: porphyrazines, template synthesis, ytterbium complexes, optical theranostic agents, photo-
sensitizers, optical intracellular viscosity probes
DOI: 10.1134/S1070363217030173
Porphyrazines belong to a huge family of aromatic
tetrapyrrole macrocycles. Interest in these compounds
is determined by the fact that they can be regarded as
porphyrin analogs in which the meso-CH groups are
replaced by nitrogen atoms. Tetrapyrrole macrocycles
occupy a central position in modern bioorganic chemistry
due to their ability to selectively accumulate in tumor
tissues and then, under irradiation at an appropriate
wavelength, produce singlet oxygen which induces cell
death. This concept underlies photodynamic therapy of
cancer.
It has recently been found that photodynamic effect
is accompanied by a strong increase of intracellular
viscosity [2, 3]. This means that intracellular viscosity
may be an important parameter allowing real-time
monitoring of dynamic processes occurring in cancer
cells during their photoinduced destruction. Thus,
photosensitizers acting as intracellular viscosity
sensors, i.e., showing fluorescence sensitivity to
viscosity of the environment, acquire additional poten-
tialities as theranostic agents [2–4].
We previously reported the synthesis and photo-
physical properties of new fluorescent porphyrazine
dyes which revealed a unique combination of pro-
perties as efficient photodynamic therapy sensitizers
and optical sensors for intracellular viscosity [3, 4]. It
is known that the relation between photphysical
properties and viscosity depends on the rate of rotation
of particular molecular fragments of some dyes upon
photoexcitation [2, 5]. Highly viscous medium
hampers internal rotation of molecules and hence
dissipation of the excitation energy. As a result, the
fluorescence intensity sharply increases. By contrast,
Over a long time, design of new drugs has been
based on the concept of separate diagnostic and thera-
peutic approaches in medicine. However, in recent
time there is a strong tendency to create medications
that efficiently combine diagnostic and therapeutic
functions. Such medications are called theranostic
agents. In particular, as applied to oncology, they make
it possible to not only precisely localize tumors in an
organism and exert therapeutic effect thereon but also
ensure direct monitoring of individual therapeutic
response to the treatment procedure [1].
479

480
LERMONTOVA et al.
low-viscosity media facilitate internal motion of
molecular fragments, so that fluorescence in such
media is strongly weakened. Dyes characterized by
strong dependence of the fluorescence parameters
(such as fluorescence quantum yield and lifetime, as
well as rate constants of radiative transition from the
excited state to ground state) on solvent viscosity are
called fluorescent molecular rotors [5].
before and after photodynamic therapy on cell cultures
by measuring the fluorescence lifetime of a new
photosensitizer and fluorescent molecular rotor,
tetrakis(4-fluorophenyl)tetracyanoporphyrazine 1 [3].
Ar
NC
N
CN
Ar
NH
N
N
By measuring fluorescence parameters of a mole-
cular rotor in a living cell, we can monitor some
intracellular processes by the change of local viscosity.
Modern bioimaging technologies, especially fluore-
scence lifetime imaging microscopy (FLIM), ensure
mapping of molecular rotor distribution over a cell or
tissue by the fluorescence lifetime [6]. This method
features a high sensitivity, non-invasiveness, and
almost instantaneous response, which allows real-time
monitoring of processes occurring in cells or tissues
[2]. Thus, a combination of fluorescent molecular rotor
and photodynamic therapy sensitizer properties in a
dye molecule gives rise to a very convenient optical
theranostic agent.
N
N
HN
Ar
NC
N
CN
Ar
1
Ar = 4-FC6H4.
The goal of the present work was to obtain porphy-
razines with enhanced photodynamic activity com-
pared to compound 1 by varying peripheral sub-
stituents on the macrocycle. For this purpose, we
synthesized new porphyrazine bases 12 and 13 con-
taining additional donor substituents and studied the
possibility of using them as optical theranostic agents
(Scheme 1).
We have recently demonstrated the above approach
by performing monitoring of photodynamic therapy
and quantitative assessment of intracellular viscosity
Scheme 1.
CN
CN
R
Ar
CN
CN
Ar
CN
CN
CH2(CN)2
KCN, HCl
NCS
ArCHO
Ar
NC
NC
4, 5
6, 7
8, 9
2, 3
CN
NC
C
N
NC
Ar
Ar
NC
N
O
O
Ar
N
Yb
CN
Ar
CN
Ar
N
HN
N
N
N
N
TFA
N
N
N
Yb
N
NH
N
Ar
NC
NC
N
N
CN
Ar
Ar
CN
10, 11
12, 13
F
Ar =
(2, 4, 6, 8, 10, 12),
(3, 5, 7, 8, 11, 13).
O
O
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 3 2017

NEW PROMISING PORPHYRAZINE-BASED AGENTS
Compounds 12 and 13 were synthesized starting
481
QY, %
from aromatic aldehydes 2 and 3 which were
converted to arylethylenetricarbonitriles 8 and 9,
followed by template assembly of macrocycles 10 and
11 on Yb3+ complex and removal of the central metal
ion. Analogous scheme was used by us previously for
the synthesis of porphyrazine 1 [3]. As we showed in
this work, replacement of the fluorine atom in the
initial benzaldehyde by benzyloxy group does not
impair synthetic potential of the procedure. As a result,
new porphyrazines 12 and 13 were isolated in overall
yields of 32 and 33%, respectively (calculated on the
initial benzaldehydes 2 and 3).
1 (α = 0.64)
12 (α = 0.57)
13 (α = 0.61)
To estimate the potential of 12 and 13 as multi-
modal cancer theranostic agents and compare their
properties with those of previously described por-
phyrazine 1, we examined their spectral properties,
quantitatively estimated their dark and photoinduced
cytotoxicities, and determined viscosity dependence of
the fluorescence quantum yield.
η, sP
Viscosity dependence of the fluorescence quantum yield of
porohyrazines 1, 12, and 13: QY = αη.
centration of a drug inducing 50% cell growth
inhibition (or death). This parameter was measured
both in the dark and under irradiation. The IC50 values
are given in Table 2. It is seen that compounds 1, 12,
and 13 insignificantly differ from each other in
photoinduced cytotoxicity [IC50(light)] which charac-
terizes cell survival rate under irradiation. However,
the dark inhibitory concentrations of benzyloxy-
substituted porphyrazines 12 and 13 [IC50(dark)] were
considerably higher than that of 1, the most impressive
difference being observed for compound 13. The
intrinsic cytotoxicity of 13 (i.e., cytotoxicity not
related to photodynamic process) is lower by more
than an order of magnitude than that of compound 1
having no oxygen atoms in the peripheral substituents.
Therefore, porphyrazines 12 and 13 are potentially
more efficient photodynamic sensitizers than 1 since
their photoinduced cytotoxicity is determined mainly
Table 1 contains the long-wave absorption and fluore-
scence maxima and fluorescence quantum yields of
porphyrazines 1, 12, and 13 in water. On the whole,
introduction of benzyloxy groups resulted in red shift
of the absorption and fluorescence maxima, which is
favorable for photodynamic therapy due to enhance-
ment of the permeability of living tissues for radiation
both on excitation and emission measurement.
The data in Table 1 also show some increase of the
red fluorescence quantum yield (QY) in aqueous
medium in the series 1 < 12 < 13 upon excitation at
λ 590 nm. Interestingly, the presence of a fluorine
atom in the para position of the benzyloxy groups
increases the fluorescence quantum yield of in 13
compared to 12 (see figure). Analogous pattern was
observed by us previously for 4-fluorophenyl-
substituted tetracyanoporphyrazine [7]. Obviously, the
favorable effect of para-fluorine substitution on the
red fluorescence intensity of teraaryltetracyanoporphy-
razines as potential photodynamic therapy sensitizers
should be taken into account in further design of
peripheral environment of tetrapyrrole macrocycle.
Table 1. Long-wave absorption and fluorescence maxima
and fluorescence quantum yields of porphyrazines 1, 12, and
13 in water (c = 4.0 μM)
Parameter
1
12
13
The improved potential of new tetra(aryl)tetra-
cyanporphyrazines as photosensitizers was demon-
strated by quantitative assessment of their dark and
photoinduced cytotoxicities against human epidermoid
carcinoma A431 cell line. A widely used experimental
procedure for such assessment is based on measure-
ment of the inhibitory concentration IC50, i. e., con-
Absorption maximum (Q band), nm 580
590
591
Excitation wavelength, nm
Fluorescence maximum, nm
Fluorescence quantum yield,a %
590
650
590
670
590
670
0.096 0.11 0.13
a
Relative to Rhodamine 6G.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 3 2017

482
LERMONTOVA et al.
Table 2. Dark and photoinduced cytotoxicities (IC50) of
porphyrazines 1, 12, and 13
EXPERIMENTAL
The IR spectra were recorded in mineral oil on an
FSM 1201 spectrometer with Fourier transform. The
electronic absorption spectra in the UV and visible
regions were measured on a Perkin Elmer Lambda 25
Porphyrazine
no.
IC50(dark)/
IC50(light)
IC50(light), M IC50(dark), M
1
12
13
8.2×10–7
1.0×10–6
8.9×10–7
6.3×10–6
4.0×10–5
7.4×10–5
7.7
40.0
83.1
1
spectrophotometer. The H, 13C, and 19F NMR spectra
were recorded on a Bruker Avance II+ instrument at
400, 100, and 375 MHz, respectively, at 25°C. Fluore-
scence measurements were performed in a stationary
mode on a Perkin Elmer LS 55 instrument in the range
λ 300–800 nm. The mass spectra (MALDI TOF) were
obtained on a Bruker Microflex LT mass spectrometer.
The dynamic viscosities of binary ethanol (methanol)–
glycerol mixtures were measured with an accuracy of
±0.35% on an Anton Paar SVM 3000 Stabinger
viscometer. Porphyrazines were dissolved by mechanical
stirring and ultrasonic treatment for at least 15 min.
by just photoinduced cell death rather than by
undesirable intrinsic cytotoxicity. A quantitative param-
eter characterizing the efficiency of a photosensitizer is
the ratio IC50(dark)/IC50(light) or so-called therapeutic
index. This parameter reflects the range of safe
administration of a drug and is the ratio of the toxic
dose to the effective therapeutic dose. Compound 1
showed a very low therapeutic index in cell cultures
(7.7), whereas the corresponding value of 13 is 83.
These findings lead us to expect high therapeutic index
of 13 in vivo.
The survival rate of cell culture was estimated by
MTT assay [8]. Cells were distributed over a 96-well
plate (4000 cells per well) and were incubated
overnight. The nutrient medium in the wells was replaced
by 100 μL of a medium containing porphyrazine PZ1,
PZ2, or PZ3 at different concentrations, and the plate
was incubated for 4 h. The medium in the wells was
then replaced by fresh portions of nutrient medium.
It should be noted that high dark cytotoxicity of
drugs for photodynamic therapy is an important
problem related to serious undesirable side effects in
patients. Therefore, we believe that our results are
useful for further design of fluorescent tetrapyrrole
structures with reduced dark cytotoxicity.
The cells in 96-well plates were irradiated with a
radiation source with a replaceable LED module
ensuring uniform light flux [9]; the radiation dose was
20 J/cm2 (λ 615–635 nm) at a power density of of
20 mW/cm2. After irradiation for 24 h, 3-(4,5-dimethyl-
1,3-thiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide
(MTT reagent, Alfa Aesar, UK) was added to a con-
centration of 0.5 mg/mL, and the cells were incubated
for 4 h. The incubation medium was withdrawn, and
colored MTT formazan crystals were dissolved in
100 μL of dimethyl sulfoxide. The optical density for
each well was measured at λ 570 nm with a BioTek
Synergy MX microplate spectrophotometer (USA).
The cell survival rate was estimated by the ratio of the
optical densities of the formazan solution for each well
and that of control (not irradiated). The dark
cytotoxicity was determined without irradiation.
A unique feature of porphyrazine 1 (for details, see
[3]) is a combination of its photodynamic activity with
high sensitivity of its fluorescence parameters to
viscosity of the medium, so that compound 1 can be
used as intracellular viscosity sensor. We examined the
dependence of the fluorescence quantum yield of
porphyrazines 12 and 13 on the solvent viscosity and
revealed strong increase of the fluorescence intensity
and quantum yield with increase of the viscosity of
ethanol–glycerol mixtures (see figure). It is seen that
introduction of benzyloxy and 4-fluorobenzyloxy
groups into the para position of peripheral phenyl
substituents does not reduce the sensitivity of their
fluorescence parameters to viscosity as compared to
compound 1.
All operations in the synthesis and analysis of
porphyrazines were carried out in purified anhydrous
solvents. N-Chlorosuccinimide, malononitrile, 4-hyd-
roxybenzaldehyde, benzyl chloride, and 4-fluorobenzyl
chloride were commercial products (from Acros
Organics). Bis(indenyl)ytterbium was synthesized
according to the procedure described in [10].
In summary, we have synthesized new fluorescent
porphyrazine macrocycles exhibiting enhanced photo-
dynamic activity. A combination of photodynamic
sensitizer and intracellular viscosity sensor properties
of these compounds makes them promising as optical
theranostic agents of new generation.
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NEW PROMISING PORPHYRAZINE-BASED AGENTS
483
Tetracyanotetrakis(4-fluorophenyl)porphyrazine 1 was
synthesized by us previously [3].
was added, and the mixture was stirred for 1 h on
cooling with an ice bath. Water, 150 mL, was added,
the organic phase was separated and washed with
water (3×150 mL), the solvent was removed under
reduced pressure, and the product was purified by
vacuum sublimation.
Aldehydes 2 and 3 (general procedure). Aldehydes
2 and 3 were synthesized by alkylation of 4-hyd-
roxybenzaldehyde according to modified procedure
[11]. A mixture of 30 mL of DMF, 6.1 g (50 mmol) of
4-hydroxybenzaldehyde, 48 mmol of benzyl or 4-
fluorobenzyl chloride, 6.9 g (50 mmol) of potassium
carbonate , and 83 mg (0.5 mmol) of potassium iodide
was heated for 3 h at 100°C on an oil bath. The
mixture was cooled to room temperature and diluted
with 200 mL of water, and the precipitate was filtered
off, washed several times with water, and dried.
2-(4-Benzyloxyphenyl)ethene-1,1,2-tricarbonitrile
(8). Yield 72%, yellow solid, mp 153°C. IR spectrum,
ν, cm–1: 2222, 2236 (C≡N). 1H NMR spectrum (CDCl3),
δ, ppm: 5.21 s (2H), 7.14 d (2H, J = 9.1 Hz), 7.42 m
(5H), 8.09 d (2H, J = 9.1 Hz). 13C NMR spectrum
(CDCl3), δC, ppm: 70.94, 87.69, 111.91, 111.96,
113.84, 116.49, 121.59, 127.55, 128.75, 128.93,
132.53, 135.02, 140.27, 165.10. Found, %: C 76.95; H
3.81; N 14.19. C18H11N3O. Calculated, %: C 75.78; H
3.89; N 14.73.
4-(Benzyloxy)benzaldehyde (2). Yield 8.9 g (88%),
1
white solid, mp 70°C. H NMR spectrum (CDCl3), δ,
ppm: 5.18 s (2H, CH2), 7.11 d (2H, J = 8.7 Hz), 7.38–
7.47 m (5H), 7.87 d (2H, J = 8.7 Hz), 9.91 s (1H,
CHO). 13C NMR spectrum (CDCl3), δC, ppm: 70.29,
115.18, 127.50, 128.35, 128.75, 130.16, 132.01,
135.98, 163.77, 190.80. Mass spectrum: m/z 212 (Irel
100%) [M]+.
2-(4-Fluorobenzyloxyphenyl)ethene-1,1,2-tricarbo-
nitrile (9). Yield 66%, yellow solid, mp 127°C. IR
1
spectrum, ν, cm–1: 2222, 2239 (C≡N). H NMR spec-
trum (CDCl3), δ, ppm: 5.17 s (2H), 7.11 m (4H), 7.41
m (2H), 8.10 d (2H, J = 9.1 Hz). 13C NMR spectrum
(CDCl3), δC, ppm: 70.19, 87.87, 111.82, 111.87,
113.77, 115.87 d (JCF = 21.8 Hz), 116.38, 121.65,
129.51 d (JCF = 8.3 Hz), 130.80, 132.48, 140.22,
162.86 d (JCF = 246.0 Hz), 164.81. 19F NMR spectrum
(CDCl3): δF –113.50 ppm. Found, %: C 72.38; H 3.24;
N 13.34; F 6.12. C18H10FN3O. Calculated, %: C 71.28;
H 3.32; N 13.85; F 6.26.
4-(4-Fluorobenzyloxy)benzaldehyde (3). Yield 9.4
1
g (85%), white solid, mp 99°C. H NMR spectrum
(CDCl3), δ, ppm: 5.13 s (2H, CH2), 7.08–7.13 m (4H),
7.45–7.42 m (2H), 7.87 d (2H, J = 8.7 Hz), 9.91 s (1H,
CHO). 13C NMR spectrum (CDCl3), δC, ppm: 69.60,
115.12, 115.69 d (JCF 21.6 Hz), 129.41 d (JCF
=
8.2 Hz), 130.27, 131.88, 132.02, 162.69 d (JCF = 246.0 Hz),
163.55, 190.75. 19F NMR spectrum (CDCl3): δF
–113.50 ppm. Mass spectrum: m/z 230 (Irel 100%) [M]+.
Ytterbium complexes 10 and 11 (general
procedure). A solution of 2.3 mmol of tricyanoethylene
8 and 9 in 5 mL of preliminarily degassed THF was
added in small portions in an inert atmosphere to a
solution of 0.25 g (0.46 mmol) of bis-indenyl
ytterbium(II) complex in 5 mL of THF. After 24 h, the
precipitate was filtered off under reduced pressure,
washed with preliminarily degassed toluene until
colorless washings, and dried under reduced pressure.
Arylethenetricarbonitriles 8 and 9 (general
procedure) [12, 13]. Aldehyde 2 or 3, 10 mmol, was
dissolved in 100 mL of ethanol, 0.56 g (10 mmol) of
malononitrile and two drops of piperidine were added,
and the mixture was stirred for 24 h at room
temperature. The precipitate was filtered off, washed
with water (4×80 mL), and dried at room temperature
under reduced pressure. The crude product (2-aryl-
methylidenemalononitrile) was dissolved in 150 mL of
ethanol, a solution of 1.62 g (25 mmol) of potassium
cyanide in 80 mL of water was added, 240 mL of water
was then added, and the mixture was stirred for 45 min
at room temperature. The mixture was treated with
6 mL of 37% aqueous HCl and cooled in an ice bath,
and the precipitate was filtered off, thoroughly washed
with water, and dried at room temperature under
reduced pressure. Crude 2-arylethane-1,1,2-tricarbo-
nitrile thus obtained was dissolved in 100 mL of
diethyl ether, 1.20 g (9 mmol) of N-chlorosuccinimide
[Tetrakis(4-benzyloxyphenyl)tetracyanoporphyra-
zinato]ytterbium(II) (10). Yield 53%, black solid, mp >
300°C. IR spectrum, ν, cm–1: 2204, 2118 (C≡N); 1687,
1678 (C=N), 1601 (C=C); 1219, 1024 (Carom–O–C).
Found, %: C 62.46; H 4.03; N 12.63; Yb 12.99.
C72H49N12O7Yb. Calculated, %: C 63.25; H 3.61; N
12.29; Yb 12.66.
{Tetracyanotetrakis[4-(4-fluorobenzyloxy)phenyl]-
porphyrazinato}ytterbium(II) (11). Yield 73%, black
solid, mp > 300°C. IR spectrum, ν, cm–1: 2204, 2119
(C≡N); 1687 (C=N), 1603 (C=C); 1224, 1029
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 3 2017

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LERMONTOVA et al.
(Carom–O–C); 1158, 1101 (C–F). Found, %: C 60.89; H
3.37; F 5.08; N 11.35; Yb 12.46. C72H45F4N12O7Yb.
Calculated, %: C 60.09; H 3.15; F 5.28; N 11.68; Yb
12.02.
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(12). Yield 83%, black solid, mp > 300°C. IR
spectrum, ν, cm–1: 3400 (N–H), 2205 (C≡N); 1687,
1678 (C=N), 1600 (C=C); 1218, 1025 (Carom–O–C).
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617 (Q band). Found, %: C 76.70; H 4.16; O 5.4; N
14.02. C72H46N12O4. Calculated, %: C 75.64; H 4.06;
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porphyrazine (13). Yield 69%, black solid, mp > 300°C.
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(C=N), 1603 (C=C); 1218, 1038 (Carom–O–C); 1164,
1102 (C–F). UV spectrum (THF), λmax, nm: 356, 397
(Soret band), 610 (Q band). Found, %: C 72.16; H
3.56; F 6.11; N 13.19. C72H42F4N12O4. Calculated, %:
C 71.16; H 3.48; F 6.25; N 13.83.
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ACKNOWLEDGMENTS
12. Harvey, M.D., Pace, J.T., and Yee, G.T., Polyhedron,
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13. Yakimansky, A.V., Meleshko, T.K., Ilgach, D.M.,
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This study was performed under financial support
by the Russian Foundation for Basic Research (project
nos. 16-33-50217-mol_nr, 16-34-60117- mol_a_dk,
15-02-05468-a) and by the Ministry of Education and
Science of the Russian Federation (project
no. 14.Z50.31.022).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 3 2017