Kinetic regularities of NO donation by binuclear dinitrosyl iron complexes with thiolate ligands based on thiophenol derivatives in the presence of red blood cells

Article abstract of DOI:10.1007/s11172-020-2989-y

The kinetics of nitrogen oxide release by binuclear dinitrosyl iron complexes (B-DNICs) with thiolate ligands based on thiophenol and its several oxy, amino, and nitro derivatives was studied using a suspension of red blood cells simulating the internal medium of a blood vessel. The NO donating ability of the complexes was estimated by the kinetic parameters of first-order equation, which described the formation of intra-erythrocytic methemoglobin. Three typical kinetic profiles of NO donation were distinguished: pseudosaturation donation and donation with prolonged and explosive profiles. In the case of first-type NO donation typical of complexes with thiophenol and its nitro derivatives, the curves display a fast coming to saturation long before the complete release of all NO groups contained in the structure of the starting complex into a solution. Such a type of donation is likely due to the formation of long-lived nitrosyl intermediates in the system. The prolonged type of NO donation shown by the complex with hydroxyphenyl ligand is characterized by virtually constant rate of NO release into a solution without pronounced transition to saturation during experiment (10–12 min). In the case of explosive-type donation characteristic of the complex with aminophenyl ligands, a considerable portion of NO was fast released into a solution within 1–3 min. All complexes under study caused hemolysis of a 0.2% suspension of red blood cells. The complex with aminophenyl ligands exhibited the highest hemolytic activity.

Full text of DOI:10.1007/s11172-020-2989-y

Russian Chemical Bulletin, International Edition, Vol. 69, No. 10, pp. 1987—1993, October, 2020
1987
Kinetic regularities of NO donation by binuclear dinitrosyl iron complexes
with thiolate ligands based on thiophenol derivatives
in the presence of red blood cells
N. I. Neshev, E. M. Sokolova, G. I. Kozub, T. A. Kondrat´eva, and N. A. Sanina
Institute of Problems of Chemical Physics, Russian Academy of Sciences,
prosp. Akad. Semenova, 142432 Chernogolovka, Moscow Region, Russian Federation.
Fax: +7 (496) 522 3507. E-mail: neshev@icp.ac.ru
1
The kinetics of nitrogen oxide release by binuclear dinitrosyl iron complexes (B-DNICs)
with thiolate ligands based on thiophenol and its several oxy, amino, and nitro derivatives was
studied using a suspension of red blood cells simulating the internal medium of a blood vessel.
The NO donating ability of the complexes was estimated by the kinetic parameters of first-
order equation, which described the formation of intra-erythrocytic methemoglobin. Three
typical kinetic profiles of NO donation were distinguished: pseudosaturation donation and
donation with prolonged and explosive profiles. In the case of first-type NO donation typical
of complexes with thiophenol and its nitro derivatives, the curves display a fast coming to satu-
ration long before the complete release of all NO groups contained in the structure of the
starting complex into a solution. Such a type of donation is likely due to the formation of long-
lived nitrosyl intermediates in the system. The prolonged type of NO donation shown by the
complex with hydroxyphenyl ligand is characterized by virtually constant rate of NO release
into a solution without pronounced transition to saturation during experiment (10—12 min).
In the case of explosive-type donation characteristic of the complex with aminophenyl ligands,
a considerable portion of NO was fast released into a solution within 1—3 min. All complexes
under study caused hemolysis of a 0.2% suspension of red blood cells. The complex with amino-
phenyl ligands exhibited the highest hemolytic activity.
Key words: red blood cells, methemoglobin, hemolysis, nitrogen oxide, binuclear dinitrosyl
iron complexes.
Nitrogen oxide as a signaling molecule fulfills impor-
regulatory effect of DNIC on different physiological pro-
cesses was found to completely coincide with the physi-
tant biological function in a body associated, first of all,
with blood pressure modulation, inhibition of thrombosis,
nerve impulse transmission, and nonspecific immune
6
ological effect exerted by free nitrogen oxide. It means
that the bioactivity of DNICs with thiol-containing ligands
is governed by their capability of acting as nitrogen oxide
donors. This conclusion scientifically proves that DNICs
are promising from the pharmacological point of view as
exogenous sources of nitrogen oxide. Dinitrosyl iron
complexes in question are not only complexes with endo-
genous ligands, such as cysteine and glutathione, but also
those with any other organic thio derivatives. Such low-
molecular-weight DNICs are currently considered as
promising depot of nitrogen oxide to design new-genera-
tion pharmacological products for the treatment of socially
significant diseases, first of all, cardiovascular and onco-
1
defence. The insufficiency of enzymatic synthesis of
nitrogen oxide underlies the pathogenesis of many cardio-
vascular diseases, the pharmacological management of
which can be carried out using exogenous donors of nitro-
gen oxide.2
Clinically widely used nitrogen oxide donors based on
organic nitrates and nitrites have grave disadvantages as-
sociated with the development of tolerance and a number
3
of endothelial dysfunctions. For this reason, the search
and study of bioactivity of new NO-donating compounds
in order to design highly efficient medicines is one of
4
,5
7,8
important trends in modern medicinal chemistry.
logical diseases. The development of synthesis methods
The long-term studies of A. F. Vanin summarized in
the recently published monograph provide a comprehen-
that enabled preparation of various mono- and binuclear
dinitrosyl complexes with thiol-containing ligands based
on aromatic and heterocyclic thiols, as well as aliphatic
sulfhydryl derivatives of amino acids and thiourea became
6
sive insight into various manifestations of physiological
activity of dinitrosyl iron complexes (DNICs) with thiol-
containing ligands of endogenous nature. The observed
9
—11
a good basis for the progress of this research trend.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 1987—1993, October, 2020.
066-5285/20/6910-1987 © 2020 Springer Science+Business Media LLC
1

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Russ. Chem. Bull., Int. Ed., Vol. 69, No. 10, October, 2020
Neshev et al.
At the same time, the chemically stipulated NO-do-
Experimental
nating activity is realized under body conditions with
certain specificity due to the features of interactions be-
tween exogenous NO donors and biosubstrates, which
required special studies on the nature and mechanism of
above-mentioned interactions. Nitrogen oxide is known
to be physiologically active first of all in blood vessels filled
with blood where erythrocytes are 90% of total blood cells.
For this reason, a suspension of red blood cells was pro-
posed as a model of the internal content of blood vessel,
using which one can study the pharmacological potential
of nitrogen oxide donors with regard to cardiovascular
system.1
Nitrosyl complexes. The binuclear dinitrosyl iron complexes
(B-DNICs) used in the present work had the composition
1
7
[Fe2(SR)2(NO)4], where R is phenyl (1), 3-hydroxylphenyl
1
8
19
20
(
2), 3-nitrophenyl (3), 4-nitrophenyl (4), and 4-amino-
21
phenyl (5). Compounds 1—5 were identified by elemental analysis
and IR spectroscopy using equipment of the Center for Shared Use
at the Institute of Problems of Chemical Physics of the Russian
Academy of Sciences (IPCP RAS) and their physicochemical
17—21
properties coincided with those obtained earlier.
The com-
plexes were added to a suspension of red blood cells as the DMSO
solutions which were freshly prepared prior to experiments. The
concentration of DMSO in the samples did not exceed 3%.
Red blood cells. Blood was sampled from C 57 Bl/6f mice
2,13
During these studies it was found that the rate constants
of oxidation of intra-erythrocytic oxyhemoglobin to met-
hemoglobin can serve as a measure of the NO donating
ability of exogenous NO donor. At the same time, the most
of DNICs showed a regular decrease in the NO donating
(
3-month-old, the weight was 18—20 g) obtained from the nurs-
ery at the IPCP RAS. Red blood cells were isolated according to
1
2
the described procedure using pH 7.4 normal saline (145 mM
NaCl, 3.88 mM Na HPO , and 1.12 mM NaH PO ).
2
4
2
4
Total hemoglobin (the total content of all hemoglobin forms)
was determined by the absorbance of hemolysate (taking into
account corrections for light scattering) at a wavelength of
525 nm, which is an isosbestic point for the absorption spectra
of deoxy-, oxy- and methemoglobin using an extinction coeffi-
1
4
ability with an increase in the cell level in a suspension.
This effect was found to be due to partial adsorption of
DNICs on the cell surface to result in the formation of
additional equilibrium pool of the membrane-bound
complex, the rate of hydrolytic dissociation of which
decreased due to a limited contact with the aqueous me-
dium. The NO donating ability of DNICs in the presence of
red blood cells depends on the ratio of equilibrium con-
–
1
–1
22
cient of 7.5 L mmol cm (per one heme).
Intra-erythrocytic methemoglobin (HbFe3+]) was deter-
mined in preliminary hemolyzed aliquots of the red blood cell
suspension by the absorbance at 630 nm. The concentration of
methemoglobin was determined by the following equation
12
1
3,15
centrations of free and membrane-bound complexes.
The biochemical transformation of nitrogen oxide to form
peroxynitrite, which under certain conditions can induce the
,
(1)
hemolysis of erythrocytes, is yet another important feature
in the interaction of DNICs with red blood cells.12,13,16
where А630 is the absorbance increment of the sample at 630 nm
compared to the control sample, met and oxy are the extinction
coefficients of methemoglobin and oxyhemoglobin, respectively,
and d is the dilution factor in a cuvette.
Thus, the data obtained using the erythrocytic model
and generalization made using these data provide a good
basis for the study of new low-molecular-weight analogs
of DNICs. In particular, fine relationships between the
structural features of ligands belonging to one chemical
family and the functional properties of corresponding
DNICs should be studied.
12
Hemolysis of red blood cells. Hemolytic experiments were
carried out using a 0.2% (v/v) suspension of red blood cells in
normal saline at 37 C with continuous slow stirring. The course
of the red cell lysis was monitored by a change in the absorbance
of the suspension at 700 nm. The degree of hemolysis was deter-
mined by Eq. (2)
The aim of the present work was to study the NO do-
nating and hemolytic ability of binuclear dinitrosyl com-
,
(2)
plexes 1—5 containing a {Fe(NO) } moiety and thio-
2
phenol-derived thiolate ligands.
where D and D are the absorbances of control and test samples,
0
respectively, and D
is the absorbance of the sample under
H O
2
conditions when all red blood cells underwent complete lysis by
distilled water. The hemolytic activity of complexes was quanti-
tatively characterized by the induction period of hemolysis (I20
)
determined graphically as a time when the degree of hemolysis
reached 20%.
Results and Discussion
The presently studied compounds 1—5 relate to -S-
type complexes. In their structures, two iron atoms each
bearing two NO groups are linked through the bridging
sulfur atoms of the corresponding thiol.
Compound
R1
H
OH
NO2
R2
H
H
Compound
4
5
R1
H
H
R2
NO2
NH2
1
2
3
H

NO donation by binuclear DNICs
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 10, October, 2020
1989
[HbFe3+]•10 /mol L
5
–1
Processes occurring during decomposition of B-DNIC
in a suspension of red blood cells can be represented as
two successive reactions. First, B-DNIC undergoes hydr-
olytic dissociation outside of a red blood cell (reaction (3)):
2
1
1
0
5
2
6
2
8
4
[
Fe (SR) (NO) ]
2 2 4
4
NO + Decomposition products of complex. (3)
4
Then, nitrogen oxide entering into a red blood cell
through diffusion is rapidly oxidized as a result of the bi-
molecular reaction with oxyhemoglobin (reaction (4)):
1
3
[
HbFe2+]O + NO
HbFe3+ + NO –
.
3
(4)
2
2
4
6
8
10
12
t/min
A high rate of the reaction between oxyhemoglobin
Fig. 1. Kinetic curve for the formation of methemoglobin
7
–1 –1
and nitrogen oxide (3—5•10 L mol
s
) (see Ref. 23)
3+
(
HbFe ) in the presence of complexes 1—5 at concentrations
combined with a high concentration of oxyhemoglobin in
–4
–1
of 1.2•10 mol L . The concentration of hemoglobin was
–
2
–1
2•10 mol L–1. The highest concentration of methemoglobin
(corresponds to the starting concentration of hemoglobin) is
shown as a dashed line.
–4
a red blood cell (higher than 10 mol L per heme) of-
fer a higher priority to this channel of oxidative nitrogen
oxide transformation, allowing one to consider a red blood
2
4
cell suspension as an efficient trap of free nitrogen oxide.
According to the stoichiometry of reaction (4), the molar
concentration of methemoglobin forming in the system
should correspond to the number of moles of NO released
from the complex into a free solution. In accordance with
this, the course of formation of intra-erythrocytic methe-
moglobin gives us a kinetic profile of NO donation into
a solution.
tion of methemoglobin at t  ∞, and A is the preexpo-
nential factor.
The kinetic parameters of methemoglobin formation
in the presence of compounds 1—5 are given in Table 1.
The analysis of kinetic curves (see Fig. 1) and corre-
sponding quantitative parameters (see Table 1) allows us
to distinguish three characteristic types of the kinetic
profiles of NO donation. The kinetic curves for complexes
Figure 1 shows the kinetics of formation of intra-
erythrocytic methemoglobin in the presence of complexes
1
, 3, and 4 almost coincide. These complexes are charac-
1
—5. As it has been shown earlier,12 the above-mentioned
terized by moderate rates of NO donation (k ) and low
eff
process is well described by the exponential dependence (5)
yields of NO. After a small portion of NO groups was
released into a solution, the release of NO into a free
solution is dramatically retarded followed by coming to
saturation. It is important that saturation occurs long
before the complete release of all NO groups contained in
the complex into a solution. We will refer to such a profile
HbFe3+] = Ae–
k
eff
t
+ [HbFe3+]∞
[
,
(5)
where [HbFe3+] is the actual concentration of methemo-
globin, t is time, keff is the effective rate constant of met-
hemoglobin formation, [HbFe3 ]∞ is the limit concentra-
+
Table 1. Kinetic parameters for the formation of methemoglobin and erythrocyte hemolysis
3
[HbFe3+]∞•105
Complex
keff•10
(NO)
(%)
I20/min
•10–6/mol L–1
–
1
–1
/
s
/mol L
2•10–5/mol L–1
5
1
2
3
4
5
6.7±0.9
1.1±0.3
6.4±0.2
25.4±5.1
6.2±0.3
8.2±0.4
13
52
13
17
–
33.0±1.5
7.2±0.4
25.1±0.8
23.5±1.0
<1
63.8±1.2
130.5±2.1
–
5.9±1.3
3.9±0.6 a
a
a
38.6±11.5
19.4±0.5b
40
3.5±0.3
2.7±6.0b
17.1±0.4
35
b
3
Note: keff is the effective rate constant of methemoglobin formation (characterizes the NO donating ability of the
3
+
complex), [HbFe ]∞ is the limit concentration of methemoglobin (characterizes the depth of decomposition of
3
+
the complex), (NO) is the yield of NO determined as the ratio of [HbFe ]∞ to the total content of NO groups in
the complex (4[B-DNIC] ); and I is the induction period (the time for which the degree of hemolysis reaches
0
20
–
6
–5
–1
2
0%) at concentrations of the complex equal to 5•10 and 2•10 mol L
According to the data of Fig. 1.
According to the data of Fig. 3.
.
a
b

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990
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 10, October, 2020
Neshev et al.
of NO donation as "donation with pseudosaturation". Note
that the most of earlier studied B-DNICs with thiol-
containing ligands of other chemical nature shows this
type of NO donation.12 It is likely that, in this case, NO
groups are stabilized by some means being preserved in
the system as long-lived nitrosyl-containing structures.
The second type of kinetics of NO donation is typical
of complex 2. In this case, the course of NO donation
throughout experiment appears as a straight line, where
a slight bend caused by a critical decrease in the content
of oxyhemoglobin begins to take shape. Upon an increase
in the concentration of oxyhemoglobin in the system, this
effect is not observed and donation during the experiment
proceeds at almost constant rate (Fig. 2, a). Qualitatively
this type of kinetic profile can be described as "prolonged
donation without pronounced coming out to saturation".
Among its quantitative characteristics are a low rate of
in vitro model system can be quite useful for the primary
estimation of pharmacological properties of exogenous
nitrogen oxide donors. For example, the studies of com-
plexes 1—5 on the models of cell and bacterial cultures
showed that complex 2 assigned to the prolonged profile
of NO donation exhibited the highest cytotoxicity (ac-
cording to the data of MTT test on Vero cells) and the
highest antibacterial activity (inhibition of the growth of
2
5
E. coli). The earlier studied B-DNIC with cysteamine
ligands, relating to the prolonged type of NO donation,
demonstrated high indices of the anticancer activity in the
comprehensive in vitro and in vivo studies of tumor growth
7
inhibition and was recommended for preclinical trials.
Let us consider in more detail the properties of com-
plexes 2 and 5 relating to the prolonged and explosive types
of NO donation, respectively.
Figure 2, a shows the kinetic curves for the formation
of methemoglobin in the presence of complex 2. It is seen
that the rate of methemoglobin formation characterizing
the NO-donating ability of the complex considerably
decreases with an increase in the concentration of hemo-
globin in the suspension. Figure 2, b shows the effective
rate constant of methemoglobin formation keff as a func-
tion of the concentration of red blood cells in the suspen-
sion. A drift in the effective rate constant observed in this
3
+
donation (k ) combined with a high [HbFe ]∞ value
eff
and a high yield of NO. For example, among all studied
complexes complex 2 showed the lowest k value and the
eff
highest values of [HbFe3 ]∞ and yield of NO (see Table 1).
Earlier, we have observed such a type of NO donation in
the case of B-DNIC with cysteamine ligands.12
+
Finally, the third type of NO donation kinetics ob-
served in the case of complex 5 can be defined qualitatively
1
3,15
as an explosive one. It features a fast release of NO into
case has been studied in detail in our earlier works.
3
a solution, high values of keff and [HbFe +] , and a high
This phenomenon was explained by the fact that a portion
of the complex molecules adsorb on the cell surface to
form an additional equilibrium pool of the bound complex,
which possesses a lower rate of hydrolytic dissociation due
to a decreased content of water in the cell surface contact
area. As a result, the effective rate constant observed in
certain experiment is found to be a weighted mean value
depending on the volume ratio of the aqueous and mem-
brane-bound pools of the complex.
∞
yield of NO. The keff value characterizing the rate of NO
release into a solution for complex 5 is by about one order of
magnitude higher than that for remaining complexes (see
Table 1). As a result, the system shows a fast depletion in oxy-
hemoglobin with the level of methemoglobin reaching the
limit value. Importantly, this type of donation has been ob-
1
4,15
served earlier for B-DNIC with penicillamine ligands.
In general, the proposed typology of the kinetic profiles
of NO donation derived from the kinetic regularities of
formation of intra-erythrocytic methemoglobin in a simple
The analysis of this issue in terms of the Langmuir
monomolecular adsorption theory resulted in a hyperbolic
HbFe3+]•10 /mol L
5
–1
keff•10 /s
.2
3
–1
[
a
b
1
1
0
0
1
1
1
4
1
2
2
0
8
6
4
2
.0
.8
.6
3
0.4
4
–1
2
4
6
8
10
12 t/min
2
3
4
C•10 /mol L
3
+
Fig. 2. (a) Kinetic curves for the formation of methemoglobin (HbFe ) in the presence of complex 2 at a concentration of
.2•10 mol L . The concentration of hemoglobin was 2•10–4 (1), 3•10 (2), and 4•10 mol L (3). (b) Effective rate constant
–
4
–1
–4
–4
–1
1
of methemoglobin formation (keff) as a function of the red cell concentration in the suspension (C).

NO donation by binuclear DNICs
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 10, October, 2020
1991
equation of type (6) describing the relationship between
the effective rate constant and the concentration of free
binding sites [P] in the system13
values for three different concentrations of cells were
detected. This means that, in this case, there is no drift in
the keff constant typical of 2. Table 1 gives parameters for
complex 5 determined using the data from Figs 1 and 3 at
identical concentrations of red blood cells in the suspen-
sion. It is seen that a three-fold decrease in the concentra-
tion of complex 5 did not result in a statistically significant
change in the limit level of methemoglobin formation and
the yield of NO. This means that, in this case, there is no
stoichiometrically complete release of nitrogen oxide into
a solution, which we have observed earlier for the complex
,
(6)
where k and k are the limit k values for the aqueous
w
m
eff
and membrane-bond pools of complex, respectively, and
K is the equilibrium constant.
a
As Fig. 2, b shows, the behavior of complex 2 com-
pletely agrees with these perceptions. Namely, with an
increase in the concentration of red blood cells in the
suspension the concentration of free binding sites [P]
increases, which leads to a decrease in keff in accordance
with Eq. (6).
1
5
with penicillamine ligands.
All studied complexes possessed hemolytic activity
being evident on diluted suspensions of red blood cells.
Figure 4, a shows the kinetics of erythrocyte lysis in the
presence of complex 2 at different concentrations. As the
quantitative characteristic of the hemolytic activity of the
The dependence of the NO-donating ability of complex 2
on the concentration of red blood cells in the medium
should be taken into account upon its possible pharma-
cological application as an NO donor. A low rate of NO
donation interferes with achievement of a fast vasorelax-
ation under conditions of hypertensive crisis. However,
the lifetime of a NO-donating substance in a body will
increase upon a low rate of donation, which will provide
a long-term pharmacological effect upon different forms
of cardiac failures.
complexes we used the induction period of hemolysis I20
(
the time for which the degree of hemolysis reaches 20%),
which was determined graphically. As Fig. 4, b shows, the

(arb. units)
a
1.0
1
2
3
4
The concentration of complex 5 in the experiment
0
0
0
0
.8
.6
.4
.2
–
4
–1
shown in Fig. 1 was 1.2•10 mol L . It is seen that
oxyhemoglobin was consumed rapidly at this concentra-
tion. This means that the limit of methemoglobin forma-
tion and the yield of NO can depend on the initial con-
centration of oxyhemoglobin. To clarify this issue, we
repeated the experiment with the three-fold deceased
concentration of complex 5 at three different concentra-
tions of red blood cells. The obtained data are shown in
Fig. 3. No statistically significant differences in the keff
I20
2
0
40
60
80
100 t/min
I20/min
b
HbFe3+]•10 /mol L
5
–1
[
7
60
50
6
5
4
3
2
1
4
3
2
1
0
0
0
0
1
2
3
6
–1
8
12
С•10 /mol L
2
4
6
8
10
12 t/min
Fig. 4. (а) Kinetics of hemolysis of the 0.2% red cell suspension
–
6
Fig. 3. Kinetic curves for the formation of methemoglobin
in the presence of complex 2 at concentrations of 15•10 (1),
3
+
–6
–6
–6
–1
(
4
HbFe ) in the presence of complex 5 at a concentration of
10•10 (2), 7.5•10 (3), and 5•10 mol L (4) at 37 C;
 is the degree of hemolysis. (b) Induction period (I20) of eryth-
rolysis as a function of the concentration of complex 2 (C).
–
5
–1
•10 mol L – . The concentration of hemoglobin in the suspen-
4 –4 –4 –1
sion was 2•10 (1), 3•10 (2), and 4•10 mol L (3).

1
992
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 10, October, 2020
Neshev et al.
hemolytic effect of complex 2 depends on its concen-
tration. Complexes 1 and 3—5 were studied in a similar
manner. Due to a wide range of hemolytic characteris-
tics, the hemolytic activities of the complexes were com-
pared by the I value at concentrations of 5•10– and
5. P. G. Wang, T. B. Cai, N. Taniguchi, Nitric Oxide Donors for
Pharmaceutical and Biological Application, Wiley-VCH Verlag,
Weinheim, 2005, 390 pp.
6
. A. F. Vanin, Dinitrosil´nye kompleksy zheleza s thiolsoder-
zhashchimi ligandami: fizikokhimiya, biologiya, meditsina
6
2
0
[
Dinitrosyl Iron Complexes with Thiol-Containing Ligands:
–
5
–1
2
•10 mol L (see Table 1). It follows from the obtained
Physical Chemistry, Biology, and Medicine], Institut Kom-
p´yuternykh Issledovanii, Moscow—Izhevsk, 2015, 220 pp.
(in Russian).
data that complex 5 is the most efficient hemolytic agent,
its hemolytic activity is by one or more orders of magnitude
higher than that of the other complexes. The hemo-
lytic activity of complex 5 directly correlates with its
NO-donating ability estimated by the kinetic parameters
of methemoglobin formation.
7. S. M. Aldoshin, N. A. Sanina, in Fundamental´nye nauki—
meditsine: Biofizicheskie i meditsinskie tekhnologii [Fundamental
Sciences for Medicine: Biophysical and Medicinal Technologies],
Eds A. I. Grigor´eva, Yu. V. Vladimirova, MAKS Press,
Moscow, 2015, vol. 1, 72 (in Russian).
In general, the obtained data show that the NO-do-
nating activity of B-DNICs can significantly differ for
complexes not only with S-ligands of different chemical
nature, but also with ligands belonging to the same
chemical family. The typology of kinetic profiles of NO
donation proposed in the present work can be used to
analyze the pharmacological potential of representatives
of the entire class of NO donors based on DNICs with
thiol-containing ligands. A considerable portion of DNICs
studied by us (both bi- and mononuclear ones) are char-
acterized by the profile of NO donation with pseudosatu-
ration. This is likely explained by the fact that NO groups
are stabilized by some means being preserved in the system
as long-lived nitrosyl-containing structures. Adsorp-
tion of complexes on the surface of biosubstrates,
which can decrease the rate of hydrolytic dissociation,
8
. S. M. Aldoshin, N. A. Sanina, M. I. Davydov, E. I. Chazov,
Herald Russ. Acad. Sci., 2016, 86, 158.
9
. N. A. Sanina, S. M. Aldoshin, Russ. Chem. Bull., 2004,
5
3, 2428.
10. N. A. Sanina, S. M. Aldoshin, Russ. Chem. Bull., 2011, 60, 1223.
11. N. A. Sanina, S. M. Aldoshin, N. Yu. Shmatko, D. V. Kor-
chagin, G. V. Shilov, E. A. Knyaz´kina, N. S. Ovanesyan,
A. V. Kulikov, New J. Chem., 2015, 39, 1030.
1
2. N. I. Neshev, B. L. Psikha, E. M. Sokolova, N. A. Sanina,
T. N. Rudneva, S. V. Blokhina, Russ. Chem. Bull., 2010,
9, 2215.
3. E. M. Sokolova, Ph. D. Thes. (Biol.), Institute of Problems
5
1
of Chemical Physics, Russ. Acad. Sci., Chernogolovka, 2016,
121 pp. (in Russian).
14. N. I. Neshev, E. M. Sokolova, B. L. Psikha, N. A. Sanina,
T. N. Rudneva, Russ. Chem. Bull., 2014, 63, 2020.
5. N. I. Neshev, E. M. Sokolova, B. L. Psikha, T. N. Rudneva,
N. A. Sanina, Russ. Chem. Bull., 2016, 65, 779.
6. E. M. Sokolova, T. N. Rudneva, N. I. Neshev, B. L. Psikha,
N. A. Sanina, S. V. Blokhina, in Progress in Organic and
Physical Chemistry: Structures and Mechanisms, Eds G. E.
Zaikov, A. N. Goloshchapov, A. V. Lobanov, Apple Acad.
Press, Oakville, 2013, p. 131.
1
can be one among the mechanisms of such stabiliza-
1
tion.1
3—15
At the same time, our recent studies showed
that long-lived nitrosyl intermediates can form in a solu-
1
8,26,27
tion during transformation of the starting bi-
and
mononuclear2
8,29
DNICs even in the absence of biosub-
strates. Regardless of certain mechanism, the capability
of forming long-lived nitrosyl-containing structures is an
important feature of DNICs with thiol-containing ligands
exerting a significant effect on their pharmacological
potential.
17. N. A. Sanina, N. S. Emel´yanova, A. N. Chekhlov, A. F.
Shestakov, I. V. Sulimenkov, S. M. Aldoshin, Russ. Chem.
Bull., 2010, 59, 1126.
18. G. I. Kozub, N. A. Sanina, N. S. Emel´yanova, A. N.
Utenishev, T. A. Kondrat´eva, V. N. Khrustalev, N. S.
Ovanesyan, N. E. Kupchinskaya, S. M. Aldoshin, Inorg. Chim.
Acta, 2018, 480, 132.
9. N. A. Sanina, A. G. Krivenko, R. A. Manzhos, N. S.
Emel´yanova, G. I. Kozub, D. V. Korchagin, G. V. Shilov,
T. A. Kondrat´eva, N. S. Ovanesyan, S. M. Aldoshin, New
J. Chem., 2014, 38, 292.
0. N. A. Sanina, G. I. Kozub, T. A. Kondrat´eva, A. A.
Terent´ev, V. A. Mumyatova, P. Yu. Barzilovich, N. S.
Ovanesyan, S. M. Aldoshin, Russ. Chem. Bull., 2017, 66, 1706.
21. L. V. Tat´yanenko, O. V. Dobrokhotova, A. I. Kotel´nikov,
N. A. Sanina, G. I. Kozub, T. A. Kondrat´eva, S. M.
Aldoshin, Pharm. Chem. J., 2013, 47, 455.
This work was financially supported by the Ministry of
Science and Higher Education of the Russian Federation
1
(
State Task No. 0089-2019-0014).
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Received July 17, 2019;
in revised form January 13, 2020;
accepted March 10, 2020
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