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10Chemical Journal of Kazakhstan
ISSN 1813-1107, elSSN 2710-1185 https://doi.org/10.51580/2021-1/2710-1185.50
Volume 4, Number 76 (2021), 72 - 87
UDC 577.1; 577.1: 547.94
CYCLODEXTRIN INCLUSION COMPLEXES OF PHARMACEUTICALLY ACTIVE DERIVATIVES OF THE CYTISINE ALKALOID AND THEIR HEMORHEOLOGICAL ACTIVITY
G.K. Mukusheva* 1, Zh.B. Satpayeva 1, Ye.V. Minayeva 1, Zh.S. Nurmaganbetov 2, Z.T. Shulgau 3, A.R. Zhasymbekova 1, O.A.Nurkenov 2, T.M. Seilkhanov4
1Karaganda Buketov University, Karaganda, Kazakhstan 2Institute of Organic Synthesis and Coal Chemistry of the Republic of Kazakhstan, Karaganda, Kazakhstan 3RSE "National Center for Biotechnology ", Nur-Sultan, Kazakhstan 4Sh. Ualikhanov Kokshetau University, Kokshetau, Kazakhstan E-mail: [email protected]
Abstract: The alkaloid cytisine is of great importance for modern pharmacological studies. This alkaloid can be used as a component of the supramolecular system with cyclic oligosaccharides, namely p-cyclodextrins, which have a truncated cone-shaped molecule with internal protons H3 and H5 and external ones H2 and H4. The aim of the work is to obtain inclusion complexes of pharmaceutically active derivatives of the alkaloid cytisine. The inclusion complexes of cytisine alkaloid derivatives with p-CD and 2-HP-p-CD were obtained by the coprecipitation method. Thermogravimetric, differential thermal, and differential scanning calorimetric analyzes were performed. It was shown that inclusion complexes of substrate with cyclodextrin cavity of receptors were formed. The greatest change in the chemical shifts of protons during the formation of supra-molecular complexes occurs with the internal protons H-3 and H-5 of the cyclodextrin cavity. All calculated values are in good agreement with experimental data. The preparation of supramolecular complexes has been proven using a variety of physicochemical methods of analysis. According to DSC data, the process of complexes destruction in the temperature range of 30-610°C was studied in comparison with the data of the initial cyclodextrin. The hemorheological effects of the investigated samples were studied in vitro. Among four samples studied, two samples showed the ability to reduce blood viscosity in vitro in the blood hyperviscosity model.
Citation: Mukusheva G.K., Satpayeva Zh.B., Minayeva Ye.V., Nurmaganbetov Zh.S.,
Shulgau Z.T., Zhasymbekova A.R., Nurkenov O.A., Seilkhanov T.M. Cyclodextrin
inclusion complexes of pharmaceutically active derivatives of the cytisine alkaloid and their hemorheological activity. Chem. J. Kaz., 2021, 4(76), 72-84. DOI:
https://doi.org/10.51580/2021-1/2710-1185.50
Key words: alkaloids, derivatives, cytisine, cyclodextrins, supramolecular complexes, DSC data, blood viscosity, blood hyperviscosity model.
1. Introduction
The alkaloid cytisine is of a great interest for modern pharmacology [1, 2]. It is promising to use this alkaloid as a component of the supramolecular system (substrate) with cyclic oligosaccharides, namely P-cyclodextrins [3, 4] (receptors), which have a truncated cone-shaped molecule with internal protons H3 and H5 and external ones H2 and H4. The possibility of including the active substance in the P-cyclodextrin capsule is due to hydrophobic interactions between the biologically active substance and the complexing agent. The application of the complexation method for obtaining clathrates of biologically active substances (BAS) with cyclodextrins will increase the water solubility of hydrophobic and poorly soluble substances, their bioavailability, and chemical stability. It contributes to protection against biodegradation and reduction of toxicity [5-9]. This will extend the half-life of the active ingredient and, therefore, reduce the dose of the medicine used. The synthesis of the starting compounds of substrates 1-4 was described earlier in the works [10-11].
JH
N
^rrO
■-C-C=C-Q
H H y
N-C-NH-C— C=CH
The shape, size, and geometric complementarity of the interacting components play a significant role in supramolecular chemistry; therefore, P-CD and its 2-hydroxy derivative, 2-hydroxypropyl-P-CD were used to obtain inclusion complexes with substrates (1-4). In order to obtain inclusion complexes (1-4) of cytisine alkaloid derivatives with P-cyclodextrins, we chose the copre-cipitation method, since that method was simple and easy to carry out.
1; 5
-
-
2
1
S
-
-
4
3
2; 6
Thus, a saturated solution of p-cyclodextrin in water was added dropwise to a concentrated solution of BAS (1, 2) in DMF in a 1: 1 ratio. Then it was stirred with a magnetic stirrer at a temperature of 50-60°C. The individuality of the proposed complexes was determined by thin-layer chromatography on Silufol UV-254 plates in the isopropyl alcohol-25% ammonia-water = 7: 2: 1 system. The final product was dried at a temperature of 35oC in a vacuum drying at an atmospheric pressure of 0.4 kgf/cm2. Inclusion complexes (5, 6) of cytisine derivatives with cyclodextrins were obtained in the powder form. The yield of products (5, 6) was 72 and 81%, respectively. The inclusion complexes (7, 8) of compounds (3, 4) with 2-hydroxypropyl-P-cyclodextrin were obtained in a similar way. The products yields were 79 and 65%, respectively.
н,с
н3с
H3C
но О
OH 7-J HO I HO 4
о0H \ '
r^S^O 4o C^H VO
-CH,
OH ?OH H2J HO H c>-OH ^H H°J HO
о ОН о OH
' ; m
CH3 CH3
3;7 4;8
2. Results and discussion
The investigation of supracomplexes with P-CD (5, 6) and 2-HP-P-CD (7, 8) showed that in both cases, there were formed substrate inclusion complexes (1-4) into cyclodextrin cavity of the receptors. The greatest change in the chemical shifts of protons during the formation of supramolecular complexes occurs with the internal protons H-3 and H-5 of the cyclodextrin cavity [4, 10-12].
IR spectra of inclusion complexes (5-7) are shown in figure 1.
gsm «So " ' ' 15M 20» " " ' ' 35» 0
c
Figure 1 - IR spectra of inclusion complexes (a - 5, b - 6, c - 7).
In the IR spectra of P-cyclodextrin OH-groups appear as a wide characteristic band in the region of 3310-3320 cm-1, the vibrations of the CH bond are recorded in the region of 887-892 cm-1. In the IR spectra of cyclodextrin complexes (5-7), the main absorption bands of the substrate (1-3) do not appear, since this can be explained by the screening of the cyclodextrin bands. However, shifts of absorption bands are observed.
Then, using DSC, it is possible to establish the dependence of the change in the mass of the synthesized supramolecular inclusion complexes on temperature (thermogravimetric curve) and accurately determine the maximum burning rate of the complex from its peak [13-14]. Figure 2 shows the TG / DSC curves of inclusion complexes (5, 6).
20 40 60 B0 1 DO 13C МП 160 100 200 220 240 260 200 000 320 34Û 360 3fifl 400 420 440 460 400 500 620 640 560 500 600 620 040
Sample Temperature |*C)
a
b
20 40 60 BO 100 120 140 160 100 200 220 240 260 200 300 320 340 3S0 380 400 420 440 460 400 500 520 540 560 5B0 600 620 640
Sample Temperature (*C)
c
Figure 2 - TG / DSC curves of inclusion complexes a - 5, b - 6, c - 8.
The NMR spectrum of compound 8 is characterized by the presence of the multiplet with the 2H intensity of two H8 protons of the heterocyclic nucleus in the upfield region at 1.86-1.97 ppm. The H9 proton resonates as a broadened singlet at 2.44 as an integral of 1H. Further, a multiplet, corresponding to the H7 proton and the axial protons H11ax and H13ax, appears in the region of 2.903.40 ppm with an integrated intensity of 3H. Equatorial protons H11eq and H13eq appear as a multiplet signal at 4.24-4.65 ppm with an integrated intensity of 2H. Two protons H10ax' 10eq appear as a multiplet in the region of 3.63-3.97 ppm with integral 2H as a result of spin-spin interaction with each other, as well as spinspin splitting through three bonds with the proton H9. Doublet at 6.14 ppm with an integral of 2H and 3J, 6.1 Hz corresponds to the protons H3 and H5. An unsaturated proton H15 (1H) appears in the resonance region of olefinic protons as a multiplet at 6.49-6.75 ppm, while the adjacent unsaturated proton H16 is detected together with aromatic protons H18-22 and a proton H4 multiplet in the lowest-field part of the spectrum at 7.16-7.64 ppm with an integrated intensity of 7H.
Signals of carbon atoms of heterocyclic rings are observed at 25.95 (C8), 27.86 (C9), 35.13 (C7), 49.05 (C10), 51.31 (C11), 53.04 (C13), 105.29 (C5), 116.40 (C3), 135.55 (C4), 150.47 (C6) and 162.66 (C2) ppm in the 13C NMR spectrum of compound 8. Signals with chemical shifts at 128.85 and 139.09 ppm correspond to carbon atoms C15 and C16, respectively. The aromatic ring carbons appear at 129.99 (C20), 129.24 (C18,19,21,22) and 141.32-142.17 (C17). Carbonyl carbon atom C14 resonates in the lowest-field part of the spectrum at 165.65 ppm.
The structure of compound 8 was also confirmed by two-dimensional HMQC (1H-13C) NMR spectroscopy (figure 3), which makes it possible to establish spin-spin interactions of a heteronuclear nature. Heteronuclear
interactions of protons with carbon atoms through one bond were established for the pairs, namely H8-C8 (1.96, 26.60), H9-C9 (2.44, 28.48), H7-C7 (3.13, 35.65), H10ax-C10ax(3.59, 49.56), H10ax-C10ax(3.98, 49.58), H5-C5(6.14, 105.76), H3-C3(6.12, 116.82) and h18,19,21,22-C18,19,21,22(7.37, 129.52).
Figure 3 - Scheme of correlations in the HMQC (a) and COSY (b spectra) of the compound 8
The observed correlations in the molecule are shown in figure 3. The chemical shifts of the :H and 13C nuclei of substrate 4 and complex 8 are presented in table 1.
Table 1 - Chemical shifts of the 1H and 13C nuclei of the substrate (4) and P-cyclodextrin in the free state (S0) and in the complex 8 (5)
Atom # Group So, ppm S, ppm AS = S - S0
'Н 13С •Н 13С *Н 13С
Substrate (4)
2 СО - 162.66
3 СН 6.14 d, 3J 6.1 Hz 116.40 6.14 с 116.19 0 -0.21
4 СН 7.31 m 135.55 7.31
5 СН 6.14 d, 3J 6.1 Hz 105.29 6.14 с 105.64 0 0.35
6 C - 150.47 - 150.70 - 0.23
7 СН 3.11 m 35.13 3.12 34.68 0.01 -0.45
8ax СН2 1.89 m 25.95 1.88 25.56 -0.01 -0.39
8eq 1.94 m 1.94 0
9 СН 2.44 m 27.86 2.42 28.06 -0.02 0.20
10ax СН2 3.63 m 49.05 3.63 49.69 0 0.64
10eq 3.97 m 3.97 0
11ax СН2 3.11 m 51.31 3.12 51.21 0.01 -0.10
11eq 4.47 m 4.46 -0.01
13ax СН2 3.11 m 53.04 3.12 54.70 0.01 1.66
13eq 4.47 m 4.46 -0.01
14 СО - 165.65 - -
15 СН 6.75 m 128.85 6.72 128.61 -0.02 -0.24
16 СН 7.12 m 139.09 7.14 139.16 0.02 0.17
17 С - 141.32 - -
18,22 СН 7.32 m 129.24 7.31 129.51 0.01 0.37
19,21 CH 7.32 m 129.24 7.31 129.51 0.01 0.37
20 CH 7.32 m 129.99 7.31 129.99 0.01 0
3-Cyclodextrin
1 CH 4.77 s 102.87 4.77 c 102.37 0 -0.50
2 CH 3.24 m 72.87 3.26 72.87 0.02 0
3 CH 3.60 m 73.64 3.58 73.54 -0.02 -0.10
4 CH 3.28 m 81.98 3.30 82.99 0.02 0.01
5 CH 3.49 m 72.50 3.49 72.52 0 0.02
6 CH2 3.60 m 60.42 3.58 60.39 -0.02 -0.03
Small changes in chemical shifts (AS = -0.02 - (+0.02) ppm in the proton spectra of P-CD occurred both in protons H-3 (0.04 ppm) directed towards the interior of the cyclodextrin cavity, and protons H-2, H-4 and H-6 located on the outer surface of the cyclodextrin cone. The ethylene fragment protons and H-15 and H-16, as well as bispidin proton H-9 (AS = +0.02) ppm have undergone small changes due to the supramolecular self-assembly of molecules (4) with cyclodextrin receptors in the substrate molecule.
3. Conclusion
Thus, the analysis of the obtained IR and TG data on the formation of inclusion complexes confirmed the possibility of obtaining supramolecular complexes. According to DSC data, the process of complexes destruction in the temperature range of 30-610°C was studied in comparison with the data of the initial cyclodextrin itself.
The investigation of the hemorheological effects of the studied substances samples was carried out in vitro. Syndrome of increased blood viscosity (SIBV) in vitro was reproduced by incubating blood at 43.0°C for 60 minutes. Blood viscosity was measured on a Brookfield DV2T rotational viscometer at various spindle velocities (from 2 to 60 rpm).
After taking blood from laboratory animals (female Wistar rats), the initial blood viscosity was determined, and then the blood samples were incubated with the test substances at a temperature of 43.0°C for 60 minutes and then the studied parameters were measured. The blood was incubated with the test objects dissolved in physiological saline; the final concentration of the substances was 10-5 g/ml of blood. Blood samples, into which physiological solution in an equivalent volume was added, served as a control. Incubation of blood for 1 hour under these conditions was accompanied by the SIBV formation [15].
In experiments on the investigation of the samples hemorheological activity, it was found that incubation of blood for 60 minutes at a temperature of 43.0°C leads to a significant increase in blood viscosity at different spindle velocities from 2 to 60 rpm, which indicates the formation of blood hyperviscosity. Two samples, namely 8 and 6 showed the ability to reduce blood viscosity among four samples studied in an in vitro blood hyperviscosity model. The results of samples 5, 7, 8 and 6 screening for the presence of hemorheological activity in the in vitro blood hyperviscosity model are shown in tables 2-5 and in figures 4-7.
Table 2 - Influence of sample 5 on blood viscosity (mPa*s) at different spindle rotation velocities on the in vitro blood hyperviscosity model
The investigated indicator Blood viscosity (mPa*s) at different spindle velocity, rpm
2 4 6 8 12 20 40 60
Initial viscosity, n = 2 3.4±0.04 3.27±0.08 3.17±0.04 3.03±0.03 2.88±0.08 2.37±0.03 2.22±0.04 2.12±0.02
Blood viscosity after 1 hour of incubation at 43°C in control, n = 4 5.62±0.19 p1=0.0015 5.17±0.06 p1=0.0001 4.71±0.11 p1=0.0009 4.31±0.04 p1=0.00003 3.95±0.08 p1=0.0010 3 § о о я Д ro ft 3.33±0.03 p1=0.00001 3.16±0.02 p1=0.000003
Blood viscosity after 1 hour of incubation at 43°C, samples with 5, n = 4 5.43±0.18 p1=0.0017 p2=0.5045 5.06±0.05 p1=0.00005 p2=0.2689 4.56±0.10 p1=0.0007 p2=0.3636 4.12±0.03 p1=0.00002 p2=0.0063 3.78±0.06 p1=0.0007 p2=0.1261 3.38±0.02 p1=0.00001 p2=0.0157 3.23±0.04 p1=0.0001 p2=0.0479 3.06±0.02 p1=0.00001 p2=0.0056
Note: n is the number of samples in the group; p is the level of significance; pi < 0.05 - statistically significant differences compared to baseline values; p2 < 0.05 - statistically significant differences compared to the corresponding values in control samples.
Table 3 - Influence of sample 7 on blood viscosity (mPa*s) at different spindle rotation velocities on the in vitro blood hyperviscosity model
The investigated indicator Blood viscosity (mPa*s) at different spindle velocity, rpm
2 4 6 8 12 20 40 60
Initial viscosity, n = 2 3.28±0.02 3.13±0.02 2.98±0.03 2.74±0.13 2.50±0.06 2.33±0.04 2.20±0.03 2.13±0.02
Blood viscosity after 1 hour of incubation at 43°C in control, n = 4 5.20±0.08 p1=0.0001 4.35±0.02 p1=0.000002 4.29±0.01 p1=0.000001 4.08±0.05 p1=0.0003 3.85±0.11 p1=0.0013 3.59±0.08 p1=0.0005 3.35±0.02 p1=0.000004 3.26±0.02 p1=0.000002
Blood viscosity after 1 hour of incubation at 43°C, samples with 7, n = 4 5.06±0.10 p1=0.0003 p2=0.3180 4.30±0.02 p1=0.000003 p2=0.0621 4.19±0.03 p1=0.00003 p2=0.0437 3.98±0.06 p1=0.0005 p2=0.2406 3.75±0.14 p1=0.0039 p2=0.5976 3.52±0.09 p1=0.0010 p2=0.5956 3.28±0.01 p1=0.000001 p2=0.0117 3.19±0.01 p1=0.0000001 p2=0.0104
Note:n is the number of samples in the group; p is the level of significance; p1 < 0.05 - statistically significant differences compared to baseline values; p2 < 0.05 - statistically significant differences compared to the corresponding values in control samples.
Table 4 - Influence of sample 8 on blood viscosity (mPa*s) at different spindle rotation velocities on the in vitro blood hyperviscosity model
The investigated indicator Blood viscosity (mPa*s) at different spindle velocity, revolutions per minute
2 4 6 8 12 20 40 60
Initial viscosity, n = 2 3.33±0.03 3.19±0.01 3.00±0.04 2.68±0.05 2.47±0.01 2.30±0.03 2.24±0.08 2.12±0.01
Blood viscosity after 1 hour of incubation at 43°C in control, n = 4 6.20±0.03 p1=0.000001 <N £ <4 S о о гй ° Д чп ft 5.16±0.27 p1=0.0057 4.75±0.21 p1=0.0030 S § о о ° д ^ ft 3.48±0.01 p1=0.000002 3.36±0.01 p1=0.00002 3.25±0.02 p1=0.000001
Blood viscosity after 1 hour of incubation at 43°C, samples with 8, n = 4 5.36±0.32 p1=0.0128 p2=0.0387 4.65±0.25 p1=0.0168 p2=0.0209 4.15±0.07 p1=0.0005 p2=0.0107 3.91±0.08 p1=0.0005 p2=0.0097 3.48±0.08 p1=0.0010 p2=0.0108 3.32±0.02 p1=0.000004 p2=0.0002 3.25±0.01 p1=0.00005 p2=0.0006 3.17±0.005 p1=0.0000001 p2=0.0036
Note: n is the number of samples in the group; p is the level of significance; pi < 0.05 - statistically significant differences compared to baseline values; p2 < 0.05 - statistically significant differences compared to the corresponding values in control samples.
Table 5 - Influence of sample 6 on blood viscosity (mPa*s) at different spindle velocity on the in vitro blood hyperviscosity model
The investigated indicator Blood viscosity (mPa * s) at different spindle velocity, rpm
2 4 6 8 12 20 40 60
Initial viscosity, n = 2 3.58±0.04 3.38±0.02 3.15±0.01 2.84±0.18 2.51±0.03 2.37±0.02 2.24±0.01 2.18±0.01
Blood viscosity after 1 hour of incubation at 43°C in control, n = 4 6.12±0.03 p1=0.000001 5.58±0.03 p1=0.000001 4.54±0.15 p1=0.0037 4.08±0.03 p1=0.0004 3.86±0.02 p1=0.000004 3.42±0.04 p1=0.00007 3.29±0.01 p1=0.000001 3.19±0.03 p1=0.00002
Blood viscosity after 1 hour of incubation at 43°C, samples with ZhB-11, n = 4 5.45±0.17 p1=0.0017 p2=0.0080 4.95±0.19 p1=0.0053 p2=0.0174 4.33±0.10 p1=0.0014 p2=0.2972 3.94±0.03 p1=0.0007 p2=0.0117 3.51±0.09 p1=0.0022 p2=0.0108 3.23±0.03 p1=0.0001 p2=0.0080 3.14±0.02 p1=0.00001 p2=0.0010 3.07±0.02 p1=0.00001 p2=0.0210
Note: n is the number of samples in the group; p is the level of significance; p1 < 0.05 - statistically significant differences compared to baseline values; p2 < 0.05 - statistically significant differences compared to the corresponding values in control samples.
4. Experimental part
As a result of the studies carried out, inclusion complexes of cytisine alkaloid derivatives with P-CD and 2-HP-p-CD were obtained. It has been shown that in both cases, inclusion complexes of the substrate into the cyclodextrin cavity of the receptors are formed. The preparation of supramolecular complexes has been proven using a variety of physicochemical methods of analysis. According to DSC data, the process of complexes destruction in the temperature range of 30-610°C was studied in comparison with the data of the initial cyclodextrin. The hemorheological effects of the investigated samples were studied in vitro. Among four samples studied, two samples, namely 8 and 6, showed the ability to reduce blood viscosity in vitro in the blood hyperviscosity model.
The :H and 13C NMR spectra of the compounds were recorded on a Bruker DRX500 spectrometer (500 MHz) in DMSO-d6 solution in accordance with the internal standard, TMS. Chemical shifts are measured relative to residual protons or carbons of deuterated dimethyl sulfoxide.
The progress of the reaction and the purity of the obtained compounds were monitored by thin layer chromatography on Silufol UV-254 plates in the iso-propyl alcohol - ammonia - water 7: 2: 1 system. The plates were developed with iodine vapors. The reaction products were isolated by column chromatography on alumina.
Melting points were determined on a Boetius apparatus.
IR spectra were recorded on a spectrometer with a Fourier transform FSM 1201 according to the wavenumber in the range from 4000 to 500 cm- 1 in KBr pellets.
Thermogravimetric (TG), differential thermal (DTG), and differential scanning calorimetric (DSC) analyzes were performed on DTA / DSC equipment (Labsys EVO, Setaram, France) in a dynamic mode in the temperature range of 30-5000°C at a heating rate of 100°C / min in an atmosphere of nitrogen and air.
Funding: The work was carried out within the framework of the project No. AP08855433 on grant financing of the Science Committee of the Ministry of Education and Science of the Republic of Kazakhstan.
Conflict of Interest: The authors declare that they have no competing interests.
Information about authors:
Mukusheva Gulim Kenesbekovna (corresponding author) - Candidate of chemical sciences, Associated Professor; e-mail: [email protected]; ORCID ID: https://orcid.org/0000-0001-6706-4816
Satpaeva Zhanarkul Bolsynbekovna - Senior Lecturer; e-mail: [email protected]; ORCID ID: https://orcid.org/0000-0003-0962-1148
Minayeva Yelena Viktorovna - Candidate of chemical sciences; e-mail: [email protected]; ORCID ID: https://orcid.org/0000-0001-9382-5965
Nurmaganbetov Zhangeldy Seitovich - Candidate of chemical sciences, Associated Professor; e-mail: [email protected]; ORCID ID: https://orcid.org/0000-0002-0978-5663
Shulgau Zarina Toktamysovna - Candidate of Medical Sciences; e-mail: [email protected]; ORCID ID: https://orcid.org/0000-0001-8148-0816
Nurkenov Oralgazy Aktayevich - Doctor of chemical sciences, Professor; e-mail: [email protected]; ORCID ID: https://orcid.org/0000-0003-1878-2787
Zhasymbekova Aigerym Rysbekovna - PhD student; e-mail: [email protected]; ORCID ID: https://orcid.org/0000-0003-1272-9096
Seilkhanov Tulegen Muratovich - Doctor of chemical sciences, Professor; e-mail: [email protected]; ORCID: 0000-0003-0079-4755
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Тушндеме
ЦИТИЗИН АЛКАЛОИДЫ ТУЫНДЫЛАРЫНЬЩ ФАРМАЦЕВТИКАЛЬЩ БЕЛСЕНД1 ЦИКЛОДЕКСТРИНД1 КЕШЕНДЕР1 ЖЭНЕ ОЛАРДЫЦ ГЕМОРЕОЛОГИЯЛЫЩ БЕЛСЕНД1Л1КТЕР1
Г.К. Мукушева 1, Ж.Б. Сатпаева1, Е.В. Минаева1, Ж.С. Нурмаганбетов2, З. Т. Шульгау3, А.Р. Жасымбекова1, О.А.Нуркенов2, Т. М. Сеилханов4
1 «Е.А. Бекетов атындагы Караганды мемлекеттжynueepcumemi» КЕАК, Караганды, Казахстан
2"Органикалыц синтез жэне KeMip химиясы институты"ЖШС, Караганды, Казахстан
3"¥лттъщ биотехнология орталыгы" РМК, Нур-Султан, Казацстан 4Ш. Уэлиханов атындагы Кекшетау университетi, Кекшетау, Казацстан E-mail: [email protected]
Фармакологияльщ зерттеулер ушш цитизин алкалоиды ете мацызды болып саналады. Б^л алкалоид циклды олигосахаридтермен супрамолекулярлы жуйелерде, атап айтканда ß-циклодекстриндермен, шш протондары Н3 жэне Н5 жэне сырткы Н2 жэне Н4 бар кесшген конус пiшiнi бар компонент репнде кенiнен колданылады.
Ж^мыстын максаты - цитизин алкалоиды туындыларынын фармацевтикалык белсендi циклодекстриндi кешендерiн алу. Цитизин алкалоидынын ß-CD жэне
2 - HP - ß - CD кешендi туындылары бiрге тандыру эдга аркылы алынды. Сол сиякты термогравиметриялык, дифференциалды термиялык жэне дифференциалды сканерлеушi калориметриялык мэлiметтер алынды. Рецепторлардын циклодекстрин куысымен бiрiгiп субстраттын кешендерi тYзiлетiнi керсеплдг Супрамолекулалык кешендердiн тYзiлуi кезiнде протондардын химиялык ыгысуынын ен Yлкен езгерга циклодекстрин куысынын Н-3 жэне Н-5 iшкi протондарында болады. Барлык есеп-телген мэндер эксперименттiк деректермен жаксы сэйкес келедi. Супрамолекулалык кешендердi дайындау эртYрлi физика-химиялык талдау эдютерш колдану аркылы дэлелдендi. Дифференциалды сканерлеушi калориметриялык мэлiметтерi бойынша, 30-610 °С температура аралыгында кешендердiн ыдырау процес бастап-кы циклодекстрин молекуласымен салыстырлып аныкталды. Зерттелген заттардын гемореологиялык эффекпа in vitro аныкталды. Зерттелген терт заттардын iшiнде екi косылыс in vitro гипертущырлык кан моделiнде каннын тущырлыгын темендете алатыны аныкталды.
ТYЙiндi сездер: алкалоидтар, туындылар, цитизин, циклодекстрин, супрамо-лекулярлы кешендер.
Резюме
ЦИКЛОДЕКСТРИНОВЫЕ КОМПЛЕКСЫ ВКЛЮЧЕНИЯ ФАРМАЦЕВТИЧЕСКИ АКТИВНЫХ ПРОИЗВОДНЫХ АЛКАЛОИДА ЦИТИЗИНА И ИХ ГЕМОРЕОЛОГИЧЕСКАЯ АКТИВНОСТЬ
Г.К. Мукушева 1, Ж.Б. Сатпаева1, Е.В. Минаева1, Ж.С. Нурмаганбетов2, З. Т. Шульгау3, А.Р. Жасымбекова1, О.А. Нуркенов2, Т. М. Сеилханов4
1НАО «Карагандинский университет имени Е.А. Букетова», Караганда, Казахстан 2ТОО «Институт органического синтеза и углехимии», Караганда, Казахстан 3РГП "Национальный центр биотехнологии ", Нур-Султан, Казахстан 4Кокшетауский университет им. Ш. Уалиханова, Кокшетау, Казахстан E-mail: [email protected]
Алкалоид цитизин имеет большое значение для современных фармакологических исследований. Данный алкалоид может быть использован как компонент супрамолекулярной системы с циклическими олигосахаридами, а именно ß-цикло-декстринами, которые имеют форму усеченного конуса с внутренними протонами Н3 и Н5 и внешними протонами Н2 и Н4. Целью работы является получение комплексов включения фармацевтически активных производных алкалоида цитизина. Комплексы включения производных алкалоида цитизина с ß-CD и 2-HP-ß-CD получали методом соосаждения. Были выполнены термогравиметрический, дифференциальный термический и дифференциальный сканирующий калориметрический анализы. Было показано, что образуются комплексы включения субстрата с цикло-декстриновой полостью рецепторов. Наибольшее изменение химических сдвигов протонов при образовании супрамолекулярных комплексов происходит с внутренними протонами H-3 и H-5 полости циклодекстрина. Все расчетные значения хорошо согласуются с экспериментальными данными. Получение супрамолекуляр-ных комплексов доказано с помощью различных физико-химических методов анализа. По данным дифференциального сканирующего калориметрического анализа, процесс разрушения комплексов в интервале температур 30-610 °С исследовали в сравнении с данными исходного циклодекстрина. Гемореологические эффекты исследуемых образцов изучали in vitro. Среди четырех исследованных образцов, два образца показали способность снижать вязкость крови in vitro в модели гипервязкости крови.
Ключевые слова: алкалоиды, производные, цитизин, циклодекстрины, супра-молекулярные комплексы.
