Thermodynamics and Kinetics of the Reaction between Pyridoxal-5-Phosphate and Hydrazides of 2-Methylfuran-3-Carboxylic and Thiophene-3-Carboxylic Acids in an Aqueous Solution

Article abstract of DOI:10.1134/S0036024419020110

Abstract: The stability constants of pyridoxal-5-phosphate hydrazones formed with 2-methylfuran-3-carbohydrazide and thiophene-3-carbohydrazide in an aqueous solution at pH 1.9, 6.6, 7.0, and 7.4 are determined via spectrophotometry. The kinetics of the processes of formation and hydrolysis of the Schiff bases are studied, and the constant of the direct and reverse reactions are calculated from the electronic absorption spectra. The stability constants of the Schiff bases are calculated from their ratio. The thermodynamic parameters of the reaction of formation (log K, ΔH, and TΔS) of both hydrazones at pH 6.6 are determined via calorimetry. The reasons for the differences between the equilibrium constants calculated from the data of spectrophotometric and kinetic experiments are discussed, and the reliability of the obtained results is analyzed.

Full text of DOI:10.1134/S0036024419020110

ISSN 0036-0244, Russian Journal of Physical Chemistry A, 2019, Vol. 93, No. 2, pp. 192–197. © Pleiades Publishing, Ltd., 2019.
Russian Text © G.A. Gamov, M.N. Zavalishin, D.N. Kabirov, T.R. Usacheva, V.A. Sharnin, 2019, published in Zhurnal Fizicheskoi Khimii, 2019, Vol. 93, No. 2, pp. 176–181.
CHEMICAL THERMODYNAMICS
AND THERMOCHEMISTRY
Thermodynamics and Kinetics of the Reaction
between Pyridoxal-5-Phosphate and Hydrazides
of 2-Methylfuran-3-Carboxylic and Thiophene-3-Carboxylic Acids
in an Aqueous Solution
G. A. Gamova,*, M. N. Zavalishina, D. N. Kabirova, T. R. Usachevaa, and V. A. Sharnina
aIvanovo State University of Chemistry and Technology, Ivanovo, 153000 Russia
*e-mail: oxt705@isuct.ru
Received March 29, 2018
Abstract—The stability constants of pyridoxal-5-phosphate hydrazones formed with 2-methylfuran-3-carbo-
hydrazide and thiophene-3-carbohydrazide in an aqueous solution at pH 1.9, 6.6, 7.0, and 7.4 are determined
via spectrophotometry. The kinetics of the processes of formation and hydrolysis of the Schiff bases are stud-
ied, and the constant of the direct and reverse reactions are calculated from the electronic absorption spectra.
The stability constants of the Schiff bases are calculated from their ratio. The thermodynamic parameters of
the reaction of formation (logK, ΔH, and TΔS) of both hydrazones at pH 6.6 are determined via calorimetry.
The reasons for the differences between the equilibrium constants calculated from the data of spectrophoto-
metric and kinetic experiments are discussed, and the reliability of the obtained results is analyzed.
Keywords: pyridoxal-5-phosphate, 2-methylfuran-3-carbohydrazide, thiophene-3-carbohydrazide, stability,
enthalpy, rate constant
DOI: 10.1134/S0036024419020110
INTRODUCTION
The hydrolysis of hydrazones is capable of greatly
altering their action on the body [12], so we must study
the stability of Schiff bases along with the kinetics of
their formation and decomposition.
The aim of this work was to determine the thermo-
dynamic and kinetic characteristics of the reaction
between PLP and 2MF3H and T3CH in an aqueous
solution under conditions that mimic physiological
conditions (pH 6.6–7.4 and an ionic strength of
0.25 [13]).
Hydrazones with different compositions and struc-
tures are of interest to researchers because of the wide
possibilities for their use as sensors for anions and
metal ions in analytical chemistry [1, 2], as antibacte-
rial and antimicotic agents [2, 3], in switches of
molecular machines [1] sensitive to the changes in pH
and UV irradiation, and as catalysts [3]. Hydrazones,
which are derivatives of vitamin B6, pyridoxal, or its
vitamer, pyridoxal-5-phosphate (PLP), have biologi-
cal activity and can inhibit in particular the oxidation
of ascorbic acid induced by copper(II) ions [4, 5].
EXPERIMENTAL
The assumed useful properties of the hydrazones of
pyridoxal-5-phosphate can be intensified by changing
the hydrazide residue. The forecasting of biological
activity performed using the PASS software [6–8]
showed that the hydrazones formed by PLP and
hydrazides of 2-methylfuran-3-carboxylic and thio-
phene-3-carboxylic acids (referred to below as
2MF3H and T3CH, respectively) are potential inhib-
itors of the beta-adrenergic-receptor kinase. Cardiac
insufficiency is associated with the hyperactivity of
beta-adrenergic receptors [9–11], and some authors
Chemicals
Pyridoxal-5-phosphate (abcr GmbH, Germany)
and 2-methylfuran-3-carbohydrazide, and thio-
phene-3-carbohydrazide (Sigma-Aldrich, United
States) with the claimed purity of >99 wt % were used
without preliminary preparation. The absence of
1
impurities was monitored via H NMR spectroscopy.
Buffer solutions with pH values of 6.6, 7.0, and
7.4 were prepared using Na2HPO4 · 12H2O and
NaH2PO4 · 2H2O (Spektr-Khim, Russia). A pH 1.9
consider the development of new inhibitors for them was adjusted using preliminarily standardized solu-
as a promising way of managing diseases of blood cir- tions. The acidity of buffer solutions was controlled
culation [9].
potentiometrically. All solutions were prepared using
192

THERMODYNAMICS AND KINETICS OF THE REACTION
193
H
O
NH2
NH
O
N N
OPO3H2
H2O3PO
O
4
−H2O
k1
OH
3
OH
5
6
3
+
4
5
R
k−1
+H2O
R
X
2
N
2
N
X
X=O, R=CH3
X=S, R=H
Scheme 1. Formation of hydrazone as a result of the reaction between pyridoxal-5-phosphate and 2-methylfuran-3-carbohydra-
zide and thiophene-3-carbohydrazide.
bidistilled water (κ = 1.7 μS/cm and pH 6.6). Ionic [5]). The initial concentrations of PLP were constant
((1.5 0.03) × 10−4 mol/L), while the total concentra-
tions of 2MF3H and T3CH varied from (1.5 0.03) ×
10−5 to (1.5 0.03) × 10−4 mol/L.
strength I = 0.25, close to the value of I in erythro-
cytes, was set using the components of a buffer mixture
(at pH 6.6, 7.0, and 7.4) or KNO3 (pH 1.9).
Calculations were performed using the experimen-
tal dependences of absorbance at three wavelengths on
the total concentrations of the reagents (Figs. 1a, 1b).
Instruments
The molar extinction coefficients of PLP, 2MF3H,
and T3CH needed for calculations in FTMT at each
pH and wavelength were preliminarily determined
from the calibration plots. The values of ε were calcu-
lated by FTMT software during stability constant
refining.
Electronic absorption spectra of the solutions of
PLP, 2M3FH, and T3CH with concentrations of
1.5 × 10−5–1.5 × 10−4 mol/L, and of solutions of
PLP + 2MF3H and mixtures of PLP + T3CH, were
recorded on a Shimadzu UV1800 double-beam spec-
trophotometer (United States) in the 190–500 nm
range of wavelengths and absorbance. The corre-
sponding buffers (distilled water for the pH 1.9) were
used as blank solutions. The error in determining the
wavelength did not exceed 0.5 nm, and the maximum
The stability constants and ΔH of the formation of
PLP–2MF3H and PLP–T3CH hydrazones at a
pH 6.6 were determined calorimetrically as described
in [15]. An aliquot (15.00 mL) of a PLP solution with
error in measuring absorbance was 0.006 units. A a concentration of (7.29–8.66) × 10−4 mol/L was
temperature of 298.2 0.1 K was maintained using an placed into a calorimetric cell; a solution of 2MF3H
external thermostat. Quartz cells 1 cm in size were or T3CH with a concentration of 0.04358–
used in this work.
0.05949 mol/L in the corresponding buffer served as
a titrant. The titrant was introduced into the cell via
15–20 injections (25 μL each). The heat effect of the
dilution of the hydrazides per the volume of the cell
was allowed for using a blank experiment, during
which 15.00 mL of the buffer mixture was titrated
with a solution of 2MF3H or T3CH. The results from
each experiment were processed using the TAM
Assistant program [16]. An example of data process-
ing is presented in Fig. 2.
The equilibrium constants and changes in the
enthalpy of the reaction of formation of hydrazones at
pH 6.6 were determined using a TAM III titration
microcalorimeter (TA Instruments, United States)
equipped with a 20-mL cell. The calorimeter was cal-
ibrated as described in [14].
Procedures for Determining Stability Constants
The formation of a hydrazone is described by
Scheme 1.
Procedure for Determining the Rate Constants
of the Reaction
Our kinetic spectrophotometric experiments were
performed in a manner similar to the one described in
[15], except for the total concentrations. In this work,
The stability constants of the PLP–2MF3H and
PLP–T3CH Schiff bases were determined according
to the procedure described in [5], using the electronic
spectra of nine to ten solutions, in which the ratio of they were set at a level of ((1.5 0.03) × 10−4 mol/L)
the total concentrations PLP : 2MF3H and for both reagents (PLP on one hand and 2MF3H or
PLP : T3CH varied from 10 : 1 to 1 : 1. After prepara- T3CH on the other). The concentrations of the hydra-
tion, all of the solutions were exposed for 24 h so that zone and both reagents at each point in time were cal-
the system reached the equilibrium state. The spectral culated from the values of absorbance at a fixed wave-
data were processed using the FTMT software (the length using the molar extinction coefficients of the
principle of calculating the constants was described in initial compounds and reaction products, determined
RUSSIAN JOURNAL OF PHYSICAL CHEMISTRY A Vol. 93 No. 2 2019

194
GAMOV et al.
q, mJ
A
3
316
344
1
2
3
4
5
6
7
8
9
10
(а)
70
50
2
1
0
30
10
−10
0.2
0.6
1.0
1.4
1.8
250
300
350
400
Ctot(titrant)/Сtot(titrated substance)
λ, nm
A
3
Fig. 2. Experimental (points) and calculations (solid line)
curves of calorimetric titration of a 0.000866 mol/L solu-
tion of PLP with a 0.05949 mol/L solution of T3CH at
pH 6.6.
297
(b)
1
2
3
4
5
6
7
8
9
2
1
0
where Hydrazide denotes 2MF3H or T3CH and SB
denotes a Schiff base.
Examples of the calculated and experimental
dependences of absorbance on time are presented in
Figs. 3a, 3b, along with the kinetic curves.
At a pH 1.9, it was impossible to reliably determine
the kinetic characteristics of the formation and hydro-
lysis of the hydrazone, due to the rapid rate of the pro-
cess.
340
10
388
250
300
350
400
450
500
λ, nm
RESULTS AND DISCUSSION
The results from determining equilibrium con-
stants from spectrophotometric data (Ksph), along with
the rate constants of the formation (k1) and hydrolysis
(k−1) of Schiff bases at different values of pH are sum-
marized in Table 1. The table also presents the values
of the equilibrium constants determined by dividing
the rate constant of the direct reaction by k of the
reverse reaction (Kkin), along with the values of the
Fischer criterion (F) that characterize the adequacy of
the mathematical model of the experiment. The
results from our calorimetric investigation of the for-
mation of the hydrazones at pH 6.6 are summarized in
Table 2.
Fig. 1. Electronic spectra of (a) PLP + 2MF3H and (b)
PLP + T3H mixtures at pH (a) 1.9 and (b) 6.6. The total
–4
concentrations (PLP + hydrazide) are (1) 1.5 × 10
+
+
+
+
+
–5
–4
–5
–4
–4
–4
–4
1.4 × 10 , (2) 1.5 × 10 + 2.9 × 10 , (3) 1.5 × 10
4.4 × 10 , (4) 1.5 × 10 + 5.9 × 10 , (5) 1.5 × 10
7.3 × 10 , (6) 1.5 × 10 + 8.7 × 10 , (7) 1.5 × 10
1.0 × 10 , (8) 1.5 × 10 + 1.2 × 10 , (9) 1.5 × 10
–5
–4
–5
–5
–4
–5
–5
–4
–5
–5
–4
–5
1.3 × 10 , and (10) 1.5 × 10 + 1.5 × 10
.
independently from the calibration curve and using
the FTMT program, respectively. In order to deter-
mine the rate constants of the formation and hydroly-
sis of hydrazone, we processed the dependences of the
The values of the errors (Tables 1 and 2) are the
concentration of PLP and a Schiff base on time using half-width of the confidence interval at a confidence
the Kinet program developed by Prof. A.V. Abramen- probability of 0.95 and a sample size of three experi-
kov [17, 18]. It was assumed that the following pro- ments.
cesses occurred:
The stability of PLP–2MF3H and PLP–T3CH
hydrazones was high at all considered values of pH of
the medium. For the Schiff bases of pyridoxal-5-
phosphate studied so far, including the products of the
interaction with the derivatives of pyridine and pyra-
k1
(1)
(2)
PLP + Hydrazide ⎯→ SB,
k−1
SB ⎯⎯→ PLP + Hydrazide,
RUSSIAN JOURNAL OF PHYSICAL CHEMISTRY A
Vol. 93
No. 2
2019

THERMODYNAMICS AND KINETICS OF THE REACTION
195
hydrazones. However, the values of the equilibrium
constants determined in the kinetic experiment (using
a known correlation) differed:
A
1.0
(a)
(3)
K = k1/k–1.
0.8
0.6
0.4
0.2
The difference between the stability constants of
the hydrazones determined in the spectrophotometric
and kinetic experiments was due to aspects of calculat-
ing the value of quantity k−1, which is low. Process (2)
can in all cases be excluded from the mathematical
model used to describe the experimental data. This
alters the value of the rate constant of the direct reac-
tion, but the change is smaller than the statistical error
in determining k1 (compare Figs. 4 to 3).
It should be noted that excluding process (2)
(which indeed proceeds in the considered system)
appreciably alters neither the sum of the squares of the
deviations of the experimental dependence of absor-
bance from the calculated dependence nor the value of
the dispersion of adequacy nor the value of the Fischer
criterion. Both models (1, which assumes the revers-
ibility of the formation of hydrazone, and 2, which
assumes the irreversible formation of a Schiff base) are
therefore satisfactory. Based solely on the results of the
F-test, we could make a false negative conclusion on
the hydrolysis of hydrazone proceeding in the solu-
tion.
0
10
20
30
40
50
τ, min
60
Ceq × 104, mol/L
k1 = 43.5 L/(mol min)
k−1 = 44 × 10−4, 1/min
1.4
1.2
(b)
1.0
0.8
0.6
0.4
0.2
0
1
2
3
4
5
6
The values of k−1 determined directly from the
results of the kinetic experiment can be unreliable.
They should most likely be calculated using Eq. (3)
with the values of logKsph and k1 (Table 1); i.e., k−1
k1/Ksph.
=
There is also a risk of drawing false positive conclu-
sions. For example, when the results of the investiga-
tion of the interaction of PLP with 2MF3H at pH 7.4
are processed, the following process can be identified
instead of the hydrolysis of hydrazone:
0
10
20
30
40
50
τ, min
60
Fig. 3. Experimental (points) and calculations (solid line)
dependences of (a) absorbance at λ = 297 nm and (b) the
equilibrium concentrations of PLP, 2MF3H, and hydra-
k2
(4)
2PLP ⎯→ 2MF3H.
zone on time at a pH 7.0: (1) [PLP] , (2) [2MF3H]
,
exp
exp
A model including reaction (1) and admittedly absurd
(3) [SB]
(6) [SB]
,
(4) [PLP]
,
(5) [2MF3H]
, and
exp
calc
calc
process (4) allows us to calculate k2 and is also satisfactory
.
calc
(k1 = 26.0 L mol−1 min−1, k2 = 8 × 10−4 L mol−1 min−1,
and F = 0.01).
zole [5, 19], logK values of around 4.2–5.2 are charac-
teristic as well. The equilibrium constant of the forma-
tion of the Schiff bases of pyridoxal-5-phosphate thus
depended relatively weakly on the nature of the aro-
matic ring in the hydrazide residue.
False positive conclusions can also be drawn in cal-
culating stability constants from spectrophotometric
data. For example, when calculating the stability con-
stant of PLP–2MF3H hydrazone at a pH 7.0, we can
include the following process in the mathematical
model, in addition to the formation of the Schiff base
(Scheme 1):
Both Schiff bases (PLP–2MF3H and PLP–
T3CH) became less stable upon moving from a pH 6.6
to one of 7.4. The rate of formation of hydrazones fell
considerably upon moving from a weakly acidic
medium to a weakly alkaline medium.
(5)
3(2MF3H) ⇔ PLP,
which even increases the accuracy of the model some-
what (F = 0.03).
In a weakly acidic medium, the values of logK
The above examples demonstrate that the accuracy
determined via spectrophotometry and calorimetry of a model does not provide grounds for considering it
were in good agreement among themselves for both a true model [20]. Note that when investigating a sim-
RUSSIAN JOURNAL OF PHYSICAL CHEMISTRY A Vol. 93 No. 2 2019

196
GAMOV et al.
Table 1. Stability and rate constants of the reaction of formation and hydrolysis of Schiff bases, derivatives of pyridoxal-5-
phosphate and 2MF3H and T3CH, at different values of pH
Hydrazone
pH
1.94
6.6
7.0
7.4
PLP–2MF3H logKsph (F)
k1, L mol–1 min–1 (F)
5.30 0.10 (0.04) 5.41 0.08 (0.03) 5.21 0.08 (0.04) 4.93 0.16 (0.08)
—
—
—
81 3 (0.02)
(8 2) × 10–4
5.01 0.15
43.8 1.0 (0.01)
(4.3 0.5) × 10–4 (3.8 0.7) × 10–4
5.01 0.10 4.84 0.11
26.5 1.1 (0.03)
k−1, min–1
logKkin
PLP–T3CH
logKsph (F)
k1, L mol–1 min–1 (F)
k−1, min–1
logKkin
5.27 0.09 (0.10) 5.39 0.11 (0.06) 4.78 0.10 (0.04) 4.77 0.12 (0.21)
—
—
—
67.3 1.5 (0.03)
(3.1 0.8) × 10–4 (1.4 0.6) × 0–3
5.34 0.14 4.45 0.22
39.1 1.0 (0.01)
24.1 0.9 (0.01)
(2.1 0.7) × 10–4
5.06 0.19
ple system in which only the formation and hydrolysis
of hydrazones proceed, there is little possibility of
making a mistake. In more complex cases, however,
where a set of reactions with unknown equilibrium
constants is possible, the probability of drawing false
conclusions increases.
The data in Table 2 show that the main contribu-
tion to the stability of the Schiff bases at pH 6.6 comes
from the enthalpic component. Negative values of the
change in the entropy are expected, since a hydrazone
molecule has fewer degrees of freedom than the
reagents.
The higher stability of both hydrazones at a pH 6.6,
relative to solutions with pH 7.0 and 7.4, means that
2MF3H and T3CH can bond to PLP more in tissues
whose intercellular fluid has a lower pH (e.g., certain
tumors [21, 22] or ischemic tissues [23], which is of
additional interest when we consider the potential
activity of Schiff bases as inhibitors of beta-adrener-
gic-receptor kinase).
CONCLUSIONS
The values of ΔH of the formation of the hydrazones
of pyridoxal-5-phosphate and five-membered hetero-
cycles (Table 2) are close to the change in the enthalpy
of the reaction between PLP and isoniazid [15].
Ceq × 104, mol/L
A
k1 = 43.9 L/(mol min)
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0
1.0
(b)
(а)
0.8
0.6
0.4
0.2
1
2
3
4
5
6
0
10
20
30
40
50
τ, min
60
0
10
20
30
40
50
τ, min
60
Fig. 4. Experimental (points) and calculations (solid line) dependences of (a) absorbance at λ = 297 nm and (b) the equilibrium con-
centrations of PLP, 2MF3H, and hydrazone on time at a pH 7.0: (1) [PLP] , (2) [2MF3H] , (3) [SB] , (4) [PLP]
,
calc
exp
exp
exp
(5) [2MF3H] , and (6) [SB] . The existence of a direct reaction is only assumed.
calc
calc
RUSSIAN JOURNAL OF PHYSICAL CHEMISTRY A
Vol. 93
No. 2
2019

THERMODYNAMICS AND KINETICS OF THE REACTION
197
Table 2. Stability constants and changes in the enthalpy
and entropy of the reaction of formation of the Schiff bases
of pyridoxal-5-phosphate and 2MF3H and T3CH at pH 6.6
and T = 298.2 K according to the data of isothermal titra-
tion calorimetry
7. O. A. Fliz and V. V. Poroikov, Russ. Chem. Rev. 81, 158
(2012). doi 10.1070/RC2012v081n02ABEH004222
8. V. V. Poroikov, D. A. Filimonov, Yu. V. Borodina,
et al., J. Chem. Inf. Comput. Sci. 40, 1349 (2000).
doi 10.1021/ci000383k
9. A. Cannavo, K. Komici, L. Bencivenga, et al., Expert
Opin. Ther. Targets 22, 75 (2018). doi 10.1080/
14728222.2018.1406925
−ΔS,
−ΔH,
kJ/mol
Hydrazone
log K
J mol−1 K−1
10. D. M. Thal, R. Y. Yeow, C. Schoenau, et al., Mol.
PLP–2MF3H 5.41 0.10
49.9 1.0
63.7 1.1
67.3 1.1
Pharmacol. 80, 294 (2011). doi 10.1124/mol.111.071522
PLP–T3CH
5.42 0.09 50.8 1.0
11. H. V. Waldschmidt, K. T. Homan, O. Cruz-Rodríguez,
et al., J. Med. Chem. 59, 3793 (2016). doi 10.1021/
acs.jmedchem.5b02000
ACKNOWLEDGMENTS
12. J. L. Buss and P. Ponka, Biochim. Biophys. Acta–
Gen. Sub. 1619, 177 (2003). doi 10.1016/S0304-
4165(02)00478-6
This work was performed at the Institute of Ther-
modynamics and Kinetics of Chemical Processes,
Ivanovo State University of Chemistry and Technol-
ogy. It was supported by the Russian Foundation for
Basic Research, project 16-33-60017; by the RF Pres-
idential Council on Grants, project 14.Z56.18.877-
MK, and by RF Ministry of Science and Higher Edu-
cation, project 4.7305.2017/8.9. Our calorimetric
experiments were performed on equipment at the
shared resource center of the Ivanovo State University
of Chemistry and Technology.
13. M. F. Mouat and K. L. Manchester, Compar. Haema-
tol. Int. 8, 58 (1998). doi 10.1007/BF02628107
14. I. Wadso and R. N. Goldberg, Pure Appl. Chem. 73,
1625 (2001). doi 10.1351/pac200173101625
15. G. A. Gamov, M. N. Zavalishin, T. R. Usacheva, and
V. A. Sharnin, Russ. J. Phys. Chem. A 91, 843 (2017).
doi 10.1134/S0036024417050107
16. www.tainstruments.com/support/software-down-
loads-support/downloads/. Accessed March 20, 2018.
17. Practical Guide on Physical Chemistry. Kinetics and
Catalysis. Electrochemistry, Ed. by V. V. Lunin and
E. P. Ageev (Akademiya, Moscow, 2012), p. 70 [in
Russian].
REFERENCES
1. X. Su and I. Aprahamian, Chem. Soc. Rev. 43, 1963
18. www.chem.msu.su/rus/teaching/KINET2012/. Accessed
(2014). doi 10.1039/C3CS60385G
March 20, 2018.
2. L. N. Suvarapu, Y. K. Seo, S.-O. Baek, and
V. R. Ammireddy, E-J. Chem. 9, 1288 (2012).
doi 10.1155/2012/534617
19. G. A. Gamov, V. V. Aleksandriiskii, M. N. Zavalishin,
A. Yu. Khokhlova, and V. A. Sharnin, Russ. J. Gen.
Chem. 87, 1161 (2017). doi 10.1134/S1070363217060093
3. M. M. E. Shakdofa, M. H. Shtaiwi, N. Morsy, and 20. V. I. Asaturyan, Theory of Planning of Experiment
T. M. A. Abdel-rassel, Main Group Chem. 13, 187
(Radio Svyaz’, Moscow, 1983), p. 91 [in Russian].
(2014). doi 10.3233/MGC-140133
21. Y. Kato, S. Ozawa, C. Miyamoto, Y. Maehata, et al.,
Cancer Cell Int. 13, 89 (2013). doi 10.1186/1475-2867-
13-89
4. M. Hermes-Lima, M. S. Goncalves, and R. G. Andrade,
Jr., Mol. Cell. Biochem. 228, 73 (2001).
doi 10.1023/A:1013348005312
22. V. Estrella, T. Chen, M. Lloyd, et al., Cancer Res. 73,
1524 (2013). doi 10.1158/0008-5472.CAN-12-2796
5. G. A. Gamov, A. N. Kiselev, V. V. Aleksandriiskii, and
V. A. Sharnin, J. Mol. Liq. 242, 1148 (2017). 23. C. Lazzeri, S. Valente, M. Chiostri, et al., Int. Emerg.
doi 10.1016/j.molliq.2017.07.106
Med. 5, 61 (2010). doi 10.1007/s11739-009-0338-0
6. http://way2drug.com/PassOnline/predict.php. Accessed
Translated by E. Boltukhina
March 20, 2018.
RUSSIAN JOURNAL OF PHYSICAL CHEMISTRY A Vol. 93 No. 2 2019