The complex of zinc with N-(5,6-dihydro-4H-1,3-thiazine-2-yl)benzamide

Article abstract of DOI:10.1007/s11172-018-2135-2

A complex of zinc with N-(5,6-dihydro-4H-1,3-thiazin-2-yl)benzamide (L) ligand, LZnCl₂, was synthesized for subsequent medical trials. The molar extinction coefficients were determined for LHBr solutions in water and physiological saline, and for LZnCl₂ ethanol solution. The ligand stability in various solvents was evaluated and the value of its protonation constant was found for the physiological saline solution, logK = 5.3±0.2. The impossibility of determination of the complex stability constant by the potentiometric titration method was demonstrated. The complex exhibited an insufficient stability in aqueous and physiological saline solutions, but was stable as the solution in alcohol. There was no sorption observed upon the treatment of ligand with hydroxyapatite nanoparticles, which could be a potential carrier for the therapeutic form of LZnCl₂, providing additional degrees of freedom for the interaction of ligand with cell membranes and a prolonged action of zinc ions.

Full text of DOI:10.1007/s11172-018-2135-2

Russian Chemical Bulletin, International Edition, Vol. 67, No. 4, pp. 768—773, April, 2018
768
The complex of zinc with N-(5,6-dihydro-4H-1,3-thiazine-2-yl)benzamide
T. P. Trofimova,a,b M. A. Orlova,a,b A. V. Severin,a E. S. Shalamova,a A. N. Proshin,c and A. P. Orlova
aDepartment of Chemistry, M. V. Lomonosov Moscow State University,
Bld. 3, 1 Leninskie Gory, 119991 Moscow, Russian Federation.
E-mail: orlova.radiochem@mail.ru
bD. Rogachev National Research Clinical Center of
Pediatric Hematology, Oncology, and Immunology,
1 ul. Samory Mashela, 117997 Moscow, Russian Federation
cInstitute of Physiological Active Compounds of Russian Academy of Sciences,
1 Severnyi proezd, 142432 Chernogolovka, Moscow Region, Russian Federation
A complex of zinc with N-(5,6-dihydro-4H-1,3-thiazin-2-yl)benzamide (L) ligand, LZnCl2,
was synthesized for subsequent medical trials. The molar extinction coefficients were determined
for LHBr solutions in water and physiological saline, and for LZnCl2 ethanol solution. The
ligand stability in various solvents was evaluated and the value of its protonation constant was
found for the physiological saline solution, logK = 5.3 0.2. The impossibility of determination
of the complex stability constant by the potentiometric titration method was demonstrated. The
complex exhibited an insufficient stability in aqueous and physiological saline solutions, but
was stable as the solution in alcohol. There was no sorption observed upon the treatment of
ligand with hydroxyapatite nanoparticles, which could be a potential carrier for the therapeutic
form of LZnCl2, providing additional degrees of freedom for the interaction of ligand with cell
membranes and a prolonged action of zinc ions.
Key words: dihydrotiazine derivatives, zinc complex, stability, protonation constant, sorption
on hydroxyapatite.
Simple and complex zinc salts have been practically
medicine; and also complex cyclic salicylate-containing
compounds such as [Zn4(C7H4O3)4(C10H8N2)4]•10H2O,13
which contain zinc in a distorted trigonal-bipyramidal
coordination and bridges between zinc and four carb-
oxylate groups of salicylate ligands, were obtained. Zinc
is capable of various coordinations in complexes, which
is clearly demonstrated by tetranuclear complexes14 of zinc
citrates with N-donor chelates, [Zn4(HCit)2(phen)4-
(H2O)4]2+•2NO3–•10H2O (1) and [Zn4(HCit)2(bipy)4-
(H2O)6]2+•2NO3–•12H2O (2) (HCit is citric acid). Both
chelates contain the two crystallographically independent
zinc ions with a different coordination geometry. In com-
plex 1, the Zn(1) atom is five-coordinated due to three
O atoms (from two Cit) and two N atoms (from phen),
and Zn(2) is six-coordinated due to two O (Cit) atoms,
two N atoms (phen) and two water molecules, while Zn(1)
and Zn(2) are connected via a citrate bridge. In complex 2,
the two citrate bridges and the two pairs of symmetrically
bound zinc ions are in a tetranuclear coordination. The
difference between these complexes is caused by the dif-
ferent steric hindrance of chelating agents, which having
a critical importance in the selection of ligands for zinc
chelation. Among the zinc compounds important for biol-
ogy and medicine, a complex of tris(2-hydroxyethyl)-
amine with zinc bis(2-methylphenoxyacetate) (cin-
used in medicine for a long time and with different pur-
poses. The zinc administration is known1 for the immune
activity activation by regulating T-lymphocytes, NK-cells,
and Interleukin-2 (IL-2), and increases antiviral activity.
The protective properties of zinc in tumor processes have
also been extensively studied, including children with
leukemia in order to improve the quality of life during
a chemotherapy. Even a trivial ZnCl2 salt at high concen-
trations2 can inhibit the cell migration and proliferation,
for example, of HLE B-3 (human lens epithelial cell line)
cells. Recently, salts and complexes of zinc and other metal
ions with salicylic acid (HSal) and aspirin became espe-
cially popular due to their possession of various, including
antitumor, properties.3—8
Zinc complexes with various organic ligands have been
already synthesized and their biological activity has been
evaluated. For example, the [Zn(3,5-PriSal)2(H2O)2]
complex demonstrated9 anticonvulsant properties,
while [Zn(Sal)2(phen)], [Zn(3,5-ButSal)2(H2O)2],10 and
[ZnSalNic]Sal•3H2O (Nic is nicotinamide)11 also exhib-
ited the biological activity. The prepared12 mixed hetero-
ligand Zn(HSal)2(2-MeHim)2 and Zn(Han)2(2-MeHim)2
complexes (wherein 2-MeHim is 2-methylimidazole and
Han is NH2C6H4COO–) are of potential interest for
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 0768—0773, April, 2018.
1066-5285/18/6704-0768 © 2018 Springer Science+Business Media, Inc.

Zn N-(dihydro-4H-1,3-thiazinyl)benzamide
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 4, April, 2018
769
katran)15 should be mentioned since it is an inhibitor of
the synthesis of acidic cholesterol esterase of platelets and
mononuclear cells. Moreover, the cinkatran is considered
as a possible stimulator for the production of endogenous
heparin. 4-Nitrocinnamic acid (L´) (which having differ-
ent pharmacological properties16 like all cinnamic acids)
with zinc, ethylenediamine, and DMSO forms com-
plexes [ZnL´2(H2O)2] (3), [ZnL´2(DMSO)2] (4), and
[Zn(en)2(H2O)2]L´2(H2O)2 (5), wherein complexes 3
and 5 have a distorted octahedral geometries while 4 is
tetrahedral.17 These complexes (especially 3) have an
inhibitory activity towards the alkaline phosphatase and
a significant affinity for DNA. Zinc-containing complexes
dichloro[2-(3,4-dichlorophenyl)imino-κN-(2-thiazoline-
κN-2-yl)thiazolidine]zinc (6) and dichloro[2-(3,4-di-
chlorophenyl)imino-κN-(4H-5,6-dihydro-1,3-thiazine-
κN-2-yl)tetrahydrothiazine]zinc (7) have a distorted
tetrahedral geometry where the zinc atom is coordinated
with two Cl atoms, one imine N atom, and one N atom
from thiazoline (complex 6) or thiazine (complex 7).
However, the percentage of phagocytosis efficiency was
increased for human neutrophils18 only in the case of
thiazine complex 7. The phagocytic function of human
neutrophils is affected by the following ligands that are
thiazine derivatives: 2-(1-pyrazolyl)-1,3-thiazine (PzTz),
2-(3,5-dimethyl-1-pyrazolyl)-1,3-thiazine (DMPzTz),
and 2-(3,5-diphenyl-1-pyrazolyl)-1,3-thiazine (DPhPzTz);
and also their zinc complexes: [ZnCl2(H2O)(PzTz)] (8),
[ZnCl2(DMPzTz)] (9), and [ZnCl2(DPhPzTz)] (10).
However, the activity of cells under the administration of
zinc complexes 8—10 was much higher than in the case
of using only ligands.19 Complexes of thiosemicarbazones
with metals and, in particular, with zinc have the increased
lipophilicity and ability to diffuse through the cell mem-
Therefore, the synthesis and study of biologically sig-
nificant zinc complexes are remaining the actual problem
due to their great potential for the chemotherapy.
In the present work, the previously obtained27,28
N-(5,6-dihydro-4H-1,3-thiazine-2-yl)benzamide ligand
was used for the synthesis of its complex with zinc and
further investigations of the stability of both compounds
in various solvents, and the ability to sorb on hydroxy-
apatite, which is necessary for its possible transportation
inside the body and subsequent applications as an anti-
tumor medication, and also for the development of radio-
pharmaceuticals containing radioactive isotopes of zinc.28
Experimental
1H NMR spectra were recorded on a Bruker CXP-200
spectrometer (200 MHz).
N-(5,6-Dihydro-4H-1,3-thiazine-2-yl)benzamide (L) was
prepared in the form of its hydrobromide (LHBr) according to
the known procedure.27 To obtain its complex with zinc, an
aqueous solution of the LHBr ligand was treated with NaOH
for its conversion into the form of base with m.p. 107—108 °C
(the reported29 m.p. value is 104—105 °C). Then a solution of
zinc chloride (0.10 g, 0.7 mmol) in diethyl ether (50 mL) was
slowly added to a solution of N-(5,6-dihydro-4H-1,3-thiazine-
2-yl)benzamide (0.16 g, 0.7 mmol) in diethyl ether (35 mL).
A formation of white precipitate was started immediately. The
reaction mixture was stirred for 0.5 h. The precipitate was filtered
off and washed with ether. LZnCl2 was obtained as white crystals
in the yield of 0.21 g (64%), m.p. 218—220 °C. Found (%):
C, 37.23; H, 3.50; N, 7.88. [C11H12N2OS]ZnCl2. Calculated (%):
C, 37.05; H, 3.39; N, 7.86. 1H NMR (DMSO-d6), δ: 2.13
(m, CH2, CCH2C); 3.10 (t, 2 H, SCH2, J = 6.8 Hz); 3.54 (t, 2 H,
NCH2, J = 6.8 Hz); 7.36 (m, 3 H, Harom); 8.04 (m, 2 H, Harom);
11.30 (br.s, 1 H, NH).
20
21—23
branes. Some Zn-selenosemicarbazones
have
also demonstrated the biological activity. The complex
of 2-quinolinecarboxaldehyde selenosemicarbazone
(Hqasesc) ligand with zinc [Zn(Hqasesc)2](ClO4)2•EtOH
(11) exhibited an antitumor activity against acute mono-
cytic leukemia (THP-1) cells and some other cancers.24
A described25 complex of flavonoid rutin with zinc
contains the zinc ion coordinated with rutin via the benzo-
furan and aromatic rings with addition of water mole-
cules. This complex increases the antitumor activity
(towards the KG1, K-562, and Jurkat lines) and also
prevents side effects of chemotherapy, i.e. is having a multi-
ple action.
It should be noted that any zinc chelator with a high
binding constant can have a cytotoxic effect on cells due
to a successful competition for zinc with important
cell constituents, which leading to the apoptosis and/
or necrosis. In certain cases of this situation, a specificity
was observed towards cancer cells,26 which should be
especially evident in the case of disorders of their zinc
homeostasis.
Spectrophotometry. Spectrophotometric measurements of
the stability of the LHBr ligand and complex were carried out on
a UV-1280 spectrophotometer (Shimadzu, Japan) in the wave
range of 190—400 nm with 0.2 nm spectral resolution, using
a 1 cm quartz cell at the temperature of 22 2 °C. The calibration
for the ligand hydrobromide and the complex was performed in
aqueous, physiological saline (0.15 M NaCl), and alcohol (95%
EtOH) solutions. The molar extinction coefficients of the com-
plex in alcohol solution and the ligand in aqueous, physiological
saline, and alcohol solutions were also determined. The molar
extinction coefficients were measured for two major absorption
bands in the spectra for both the ligand and complex.
Sorption of the ligand on hydroxyapatite (HAP). The proce-
dure of HAP preparation was reported30 by us earlier; HAPT is

770
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 4, April, 2018
a
Trofimova et al.
A
A
b
0.8
0.6
0.4
0.2
280
252
1.0
0.8
0.6
0.4
0.2
280
6
5
4
4
5
247
3
2
1
3
2
1
210 230 250 270 290 310 330 350 λ/nm
210 230 250 270 290 310 330
λ/nm
A
A
c
d
281
282
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.7
0.6
0.5
0.4
0.3
0.2
0.1
6
5
6
5
4
245
245
4
3
3
2
1
2
1
220 240 260 280 300 320 340 λ/nm
220
240 260 280
300 320
λ/nm
Fig. 1. Determination of the molar extinction coefficient of L ligand in aqueous (a), physiological saline (b), and alcohol (c) solutions,
and LZnCl2 complex in alcohol solution (d); the numbers at the curves indicate the wavelengths of the maxima (nm); a: C = 1.80 (1),
2.70 (2), 5.40 (3), 9.00 (4), and 13.50 μg L–1 (5); b: C = 1.07 (1), 2.14 (2), 3.57 (3), 5.35 (4), 7.13 (5), and 10.7 μg L–1 (6); c: C = 1.51 (1),
2.26 (2), 3.01 (3), 6.02 (4), 7.53 (5), and 9.04 μg L–1 (6); d: C = 1.29 (1), 2.58 (2), 5.17 (3), 25.8 (4), 38.8 (5), and 51.7 μg L–1 (6).
an aqueous suspension of HAP that was subjected to a thermal
treatment at 95 °C for 4—5 h. To estimate the sorption kinetics
of the ligand on the HAP and HAPT nanoparticles, a solution of
ligand (0.7 mL, 0.2 mg mL–1) was mixed in plastic vials (volume
of 30 mL) with physiological saline solution (13.3 mL, 0.9%
NaCl) to make the final concentration of 10–2 mg mL–1. A sus-
pension (1 mL) of HAP (5 wt.%) or HAPT (6 wt.%) was added
to the vials, the vials were placed on a S3-0.8L orbital shaker
(Elmy, Latvia) and mixed for 5, 10, 15, 30, and 60 min. The
phases were separated by centrifugation at 4000 rpm for 2 min on
a T-51.1 centrifuge (MLW, GDR). An aliquot of the liquid phase
was transferred into the quartz cuvette for spectrophotometric
analysis. The measurements were repeated in the same way for
the control solution (0.7 mL of ligand solution with C = 0.2 mg mL–1
dissolved in 13.3 mL of physiological saline solution).
The protonation and stability constants were determined
potentiometrically using a Metrohm 848 Titrino Plus autotitrator
(Switzerland). During evaluation of the protonation constant of
the ligand, solutions of potassium nitrate (1 mol L–1 in the case
of an aqueous solution) and physiological saline were used as the
background electrolyte. The stability constant of the complex
was determined while the titration was carried out on the auto-
titrator with a glass indicator electrode. Hyperquad 2013 software
was used for the calculations.
A
a
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
1
4
5
2
3
13
6
7
8
9
10
11
12
210 230 250 270 290 310 330
λ/nm
A
b
.14
1
0
2
3
0.12
0.10
0.08
0.06
0.04
0.02
6
5
4
230 250 270 290
310
330
λ/nm
Fig. 2. The ligand stability in aqueous solution at large
(>6 μg mL–1, a) and low (2—6 μg mL–1, b) concentrations; (a):
initial solution (1), the solution was stored for 1 (2), 2 (3), 3 (4),
4 (5), 5 (6), 7 (7), 8 (8), 9 (9), 10 (10), and 11 days (11), benzoic
acid (12), and thiazine (13); (b): initial solution (1), the solution
was stored for 1 (2), 2 (3), 3 (4), 5 (5), and 6 days (6).*
Results and Discussion
The molar extinction coefficients of the ligand and
complex (Fig. 1) were determined in various solvents
(Table 1). The ligand stability in the aqueous solution was
dependent on its concentration, which may be related to
* Figures 2, 8, and 9 are available in full color on the web page
of the journal (http://www.link.springer.com/journal/11172).

Zn N-(dihydro-4H-1,3-thiazinyl)benzamide
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 4, April, 2018
771
A
Table 1. The molar extinction coefficients of the ligand and
complex in different solvents
0.9
0.7
0.5
0.3
0.1
2
3
1
Compound
(solvent)
λ/nm
ε•10–4
/L mol–1 cm–1
4
6
5
LHBr
(aqueous)
LHBr
(physiological saline)
LHBr
(alcohol)
LZnCl2
(alcohol)
252
280
247
280
245
282
245
281
2.15 0.03
2.13 0.07
1.26 0.04
2.53 0.06
1.09 0.01
2.26 0.02
1.12 0.04
2.37 0.07
7
8
210 230 250 270 290 310 330
λ/nm
Fig. 3. The ligand stability in physiological saline solution: initial
solution (1), the solution was stored for 1 (2), 2 (3), 3 (4), 4 (5),
5 (6), and 7 days (7), and thiazine (8).
tautomeric transitions and/or a possibility of the hydrogen
bonding. LHBr was stable for at least 7 days (Fig. 2, b) at
the concentration of 8•10–6 mol L–1, while it remained
stable for at least 11 days (Fig. 2, a) at the concentration
of 5.6•10–5 mol L–1. In the physiological saline solution,
there was no observed concentration dependence, the
ligand was stable for 6 days and then decomposed with the
formation of thiazine (Figs 3 and 4), which is in agreement
with the reported data.29
equal for the aqueous (logK = 5.1 0.1) and physiolog-
ical (logK = 5.3 0.2) saline solutions. An attempt was
made to determine the stability constant of the complex,
thus the potentiometric titration was performed (Fig. 7)
for this purpose. During Hyperquad 2013 calculations,
formation constants of the following substances were
taken into account: Zn(OH)2, Zn(OH)3–, Zn(OH)4
,
2–
Zn2(OH)62–, Zn2OH3+, Zn4(OH)44+, and ZnOH+.
However, the calculations of the complex stability con-
stant were unsuccessful. This might be explained by the
The protonation constants o f the ligand obtained by
the potentiometric titration method (Figs 5 and 6) were
С/mg mL–1
a
E/mV
a
300
200
0.015
0.012
0.009
0.006
0.003
100
0
–100
–200
2
4
6
t/day
0.5
1.0
1.5
2.0
2.5
V/mL
С/mg mL–1
0.010
b
E/mV
b
300
200
0.008
0.006
0.004
0.002
100
0
–100
–200
2
4
6
t/day
0.5
1.0
1.5
2.0
V/mL
Fig. 4. Dependences of the ligand concentration change on time,
calculated from changes in the maxima of the ligand absorption
bands at 247 (a) and 280 nm (b).
Fig. 5. Titration curves of LHBr ligand for aqueous (a) and
physiological saline (b) solutions; V is the titrant volume.

772
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 4, April, 2018
Trofimova et al.
α (%)
100
A
a
0.20
0.15
0.10
0.05
HL+
L
1
5
2
80
60
40
20
4
3
210 230 250 270 290 310 330 350 λ/nm
A
b
0.35
0.30
0.25
0.20
0.15
0.10
0.05
4
6
8
10
12 pH
3
Fig. 6. Distribution of ligand forms as a function of pH calcu-
4
lated using the Hyperquad 2013 software; C(L) = 1•10–3 mol L–1
,
2
5
I = 0.15 mol L–1 of NaCl (0.1 mol L–1 of KNO3); α is the per-
centage of the form.
1
E/mV
300
230 250 270 290 310 330 350 λ/nm
Fig. 8. The complex stability in aqueous (a) and alcohol (b)
solutions: the initial solution (1), the solution was stored for 5 (2),
6 (3), 7 (4), and 13 days (5).
200
100
0
A
a
3
4
0.7
0.6
0.5
0.4
0.3
0.2
0.1
5
2
–100
–200
6
1
2
3
6
0.5
1.0
1.5
2.0
2.5
V/mL
4 5
Fig. 7. Titration curve of the LZnCl2 complex.
formation of zinc hydroxide, which hindered the titra-
tion experiments.
200
250
300
350
400 λ/nm
The spectrophotometric study (Fig. 8) revealed insuf-
ficient stability of the complex in aqueous solutions, while
it remained stable in the alcohol solution for 3—4 days.
At the first moment during the ligand sorption on HAP
and HAPT (Fig. 9), the major absorption bands of the
ligand were shifted with changing of the peak heights. After
that, no changes were observed. One might assume that
the ligand initially interacts with calcium, which presented
in the solution due to the increased solubility of HAPnano
(HAP with particle size <100 nm). The absence of further
changes might indicate that the ligand was almost not
sorbed on either HAP or HAPT. This could be a positive
factor since the binding of HAP nanoparticles specifically
to zinc could be expected upon LZnCl2 complex deposi-
tion on HAP, while the ligand would retain a certain degree
of freedom for interactions. Zinc poorly passes through
A
b
2
6
3
4
3
4
0.7
0.6
0.5
0.4
0.3
0.2
0.1
5
2
6
5
1
200
250
300
350
400 λ/nm
Fig. 9. Spectra of the LHBr solution (10–2 mg mL–1), which was
in contact with HAPT (a) and HAP (b) for 0 (1), 5 (2), 10 (3),
15 (4), 30 (5), and 60 min (6).

Zn N-(dihydro-4H-1,3-thiazinyl)benzamide
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 4, April, 2018
773
15. M. M. Rasulov, K. A. Abzaeva, M. I. Yakhkind, I. V.
Zhigacheva, I. S. Nikolaeva, R. M. Rasulov, M. G. Voronkov,
Russ. Chem. Bull., 2015, 64, 1686.
16. S. Adisakwattana, W. Sompong, A. Meeprom, S. Ngamukote,
S. Yibchokanun, Int. J. Mol. Sci., 2012, 13, 1778.
17. S. T. Hafeez, S. Ali, M. N. Tahir, M. Iqbal, K. S. Munawar,
J. Coordin. Chem., 2014, 67, 2479.
18. F. J. Barros-Garcıa, A. Bernalte-Garcıґa, A. M. Lozano-Vila,
F. Luna-Giles, J. A. Pariente, R. Pedrero-Marin, A. B.
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the plasma membrane since its concentration in the cell
is under the strongest control (buffering and extinguish-
ing31). The ligand design of the zinc complex may facilitate
the zinc absorption by cells in some cases. It is especially
important to choose the ligand, which is mainly recognized
by the cancer cells. Therefore, it is crucially important for
the choice of ligand design to take into account not only the
biochemical effect on the cell constituents, but also the
increased absorption of the compounds carrying zinc ions by
the cancer cell due to the ligand properties. Such approach
may provide the increased selectivity of zinc delivery.
21. H. Shen, H. Zhu, M. Song, Y. Tian, Y. Huang, H. Zheng,
R. Cao, J. Lin, Z. Bi, W. Zhong, BMC Cancer, 2014, 14, 629.
22. A. Molter, G. N. Kaluđerović, H. Kommera, R. Paschke,
T. Langer, R. Pottgen, F. Mohr, J. Organomet. Chem., 2012,
70, 80.
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 16-08-00139).
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Received August 3, 2017;
in revised form September 18, 2017;
accepted November 7, 2017