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16SYNTHESIS OF NEW TYPES N-GLYCOSIDES
'Sidamonidze N. N., Doctor of Chemical Sciences, Associate Professor
2Vardiashvil R. O., Doctor of Chemical Sciences, Head laboratories of bioorganic Chemistry
3Tabatadze L. V., Doctor of Chemical Sciences, Associate Professor
4Onashvili K. Z., Doctoral student of Bioorganic Chemistry
',2,4Georgia, Tbilisi, Iv. Javakhishvili Tbilisi State University 3Georgia, Tbilisi, Sokhumi State University
DOI: https://doi.org/10.31435/rsglobal_ws/12072018/6023
ARTICLE INFO
Received: 21 May 2018 Accepted: 29 June 2018 Published: 12 July 2018
KEYWORDS
N-glycosides;
Nitrosogroup;
Hydrophilous;
Nitrosometylurea;
p-aminobenzoic acids- N-p
carboxyphenyl-p-D-
glucosyl(galactosyl)amine.
Citation: SidamonidzeN. N., Vardiashvil R. O., Tabatadze L. V., Onashvili K. Z. (2018) Synthesis of New Types N-Glycosides. World Science. 7(35), Vol.4. doi: 10.31435/rsglobal_ws/12072018/6023
Copyright: © 2018 Sidamonidze N. N., Vardiashvil R. O., Tabatadze L. V., Onashvili K. Z. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
ABSTRACT
The reactions of N-p-carboxyphenyl-p-D-glucopyranosylamine and N-p-carboxy-phenyl-p-D-galactopyranosylamine with dicyclohexylcarbodiimide in the presence of tetrahydrofuran and triethylamine were studied for the first time. The interaction of synthesized N-acyl ureas with sodium nitrite produced N-glycosides containing a nitroso (N = O) group.
Introduction. Among the drugs offered in recently years for therapy of tumor-bearing patients, appeared as one of the most perspective derivatives of nitrosourea [1,2]. In this respect it seems important the synthesis of its new structural analogues with attraction of various amino acids, biogenic amines, some alkaloids and other biologically and pharmacologically active compounds.
Well known nitrosoalkylurea (NAU) possess polarity and can be used as an acceptor at formation of hydrogen bonds, nevertheless it is not enough hydrophilous to provide good solubility in water. In this respect typical NAU with low-polarity substituent are characterized with small solubility in water and good solubility in most of organic solvents. As most legible instance in this regard can be considered antibiotic streptozotocin (possessing high solubility in water and in low-polarity organic solvents), the derivative of nitrosometylurea (NMU) and 2-deoxy-D-glucose. Expressed antineoplastic efficiency of this preparation in respect of some experimental tumoral and cellular culture and Its specific diabetogenic action have formed the basis for application of streptozotocin in treatment of patients with metastasizing insulom [3-5].
Recently the growing attention is attracted to the synthesis of the derivatives of nitrosourea. However the opportunities of all structural modifications of this class of compounds are still not exhausted.
In recent years there has been considerable interest of medical researchers in lactams, especially a-pyrrolidone and s-caprolactam derivatives, which are characterized by sedative, tranquilizing and psychotropic action [6-7].
Results and Discussion. The goal of present investigation consists in synthesis of N-glycosides containing in a molecule nitrosogroup (N=O). As an initial substance in the given work has
been used the products of condensation of glucose (1), galactose (2) and ^-aminobenzoic acids -N-p-carboxyphenyl-p-D-glucosyl(galactosyl)amine (3,4) [6]. By interaction of the last agent in usual peptide synthesis conditions with N, N'-Dicyclohexylcarbodiimide had been received N-urea (5,6). By interaction of compounds (5, 6) with sodium nitrite corresponding nitrosoderivatives (7,8) has been received. Reaction proceeds according to the following scheme:
5,6 7,8
R=H, R/=OH (1,3,5,7) R=OH, R/=H (2,4,6,8)
Table - 1 Some parameters of synthesized compounds
N-gly-cosides Initial the United m.p. 0C Rf [a]D (c, C2H5OH) Elemental analysis found, % Calculated, % Yield
G Mole C H N g %
5 0.6 0.002 146-1470 0.72* _34.60(0.41, t=170) 62.02 61.9 7.35 7.82 8.34 8.04 0.59 59.4
6 0.6 0.002 162-163.50 0.49** _44.80(0.39, t=170) 62.02 62.89 7.35 7.97 8.34 7.93 0.52 52.8
7 0.2 0.0003 132-1340 0.62*** _27.30(0.59, t=180) 58.64 58.02 67 7.08 10.83 10.53 0.13 62.4
8 0.2 0.0003 154-1550 0 59**** _41.90(0.44, t=170) 57.53 58.02 7.91 7.08 9.98 10.53 0.11 52.3
chloroform-methanol 19: 1 benzene-chloroform 2: 1 benzene-ethylacetate 2: 1 benzene-chloroform 5: 2
*
Experimental. The optical rotation was measured on an SU-3 universal saccharimeter at 20±20C. The purity of products and Rf values were determined on Silufol UV-254 using solvent systems CHCl3:CH3OH (19:1, system a); C6H6:CHCI3 (2:1, system b); C6H CH3COOC2H5 (2:1 system c); C6H6:CHCI3 (5:2, system d). IR spectra were obtained in KBr disk on a UR-20 spectrometer. 13C NMR spectra were recorded on a Bruker AM-300 (75,5 and 300 MHz) in CDCI3. PMR spectra were recorded in CDCI3 on a Bruker WM-250 spectrometer (250 MHz) with TMS internal standart The preparation N-p-carboxyphenyl-p-D-glucosyl (galactosyl)amine (3,4) has been reported [8].
N-p-carboxyphenyl-p-D-glucosylamine (3). Yield (90%), mp. 125.5-1270 C, Rf 0.53 (system d), [a]D20 - 77.80 (c 0.64, ethanole) [8].
N-p-carboxyphenyl-p-D-galactosylamine (4). Yield (85.8%), mp. 151-1530C, Rf 0.41 (system d), [a]D20 - 52.50 (c 0.4, pyridin) [8].
P- N-(p-carboxyphenylglucopyranosyl)-acylurea (5). To a solution of 0.6 g (0.002 mole) N-P-carboxyphenyl-D-glucopyranosylamine in 20 ml of tetrahydrofuran under cooling up to 0 C° and stirring was added 0.52g (0.002 mole) dicyclohexylcarbodiimide and 0.4 ml triethylamine. Mixture was stirred for 2 h and kept in the refrigerator for 20 hours. Sediment was filtered out and after treatment with activated carbon solvent was removed by vacuum stripping. The residue was dissolved in chloroform, washed by 5% solution of citric acid, water and dried over Na2SO4. After filtration, chloroform was evaporated and residue was treated with petroleum ether at simultaneous rubbing with stirring rod. Recrystallized from ethanol. Yield 0.59 (59.4%), m.p. 146-1470 C, Rf 0.72 (system a), [a]D17 - 34.60 (c 0.41, C2H5OH). Found, %: C 61.9; H 7.82; N 8.04. C26H37N3O7. Calculated, %: C 62.02; H 7.35; N 8.35.
IR spectrum (v, cm-1): 2840, 2935 (CH2_cyclohexanole), 3230 (NH), 3300-3400 (OH), 760, 820, 900 (Benzol), 1380, 1430 (CO - NH), 1510 (CO_N<), 1720 (C=O), 3080 (C-Harom).
PMR spectrum (5, ppm, J/Hz), TMS: 5.50 (1H, d, Ju = 8.0, H-1), 4.94 (1H, dd, Jz,1 = 8.0, J2,3= 9.5, H-2), 5.20 (1H, dd, J3,2 = 9.5, J3,4 = 3.0, H-3), 4.30 (1H, dd, J43 = 3.0, J4,5 =9.5, H-4), 3.80 (1H, ddd, J5,4 = 9.5, J5,6' = 5.0, J5,6" = 2.5, H-5), 4.06 (1H, H-6 ', dd, Jff,6- = 12, Jff5 = 2.5,), 4.20 (1H, H-6", dd, Jff6" = 12, J6"5 = 5.0, ), 1.8-0.8 (20 H, m, 10CH cyclohexyl), 7.0 (1H, m, NH), 7.5-7.8 (4H, m, aromatic group), 3.1 and 4.1 (2H, s, CH=NH).
13C NMR spectrum (5, ppm), CDCI3: 85.76 (C-1), 74.02 (C-2), 78.51 (C-3), 72.1 (C-4), 76.44 (C-5), 59.72 (C-6), 167.5-170.0 (C=O), 12.5-23.0 (CH2-cyclohexyl). Aromatic group: 150.58 (C-1), 113.40 (C-2), 130.22 (C-3), 117.70 (C-4), 131.20 (C-5), 111.35 (C-6).
P- N-(p-carboxyphenylgalactopyranosyl)-acylurea (6) was prepred analogously. Yield 0.52 (52.8%), m.p. 162-163.50C, Rf 0.49 (system c), [a]D17 - 27.30 (c 0.39, C2H5OH). Found, %: N 7.93. C26H37N3O7. Calculated, %: N 8.35.
IR spectrum (v, cm"1): 2935 (CH2_cyclohexanole), 3319 (NH), 3340 (OH), 764, 920 (Benzol), 1700-1600 (CO - NH), 1529 (CO_N<), 1715 (C=O), 3060 (C-Harom).
PMR spectrum (5, ppm, J/Hz), TMS: 5.70 (1H, d, Ju = 8.0, H-1), 4.94 (1H, dd, J2,1 = 8.0, J2,3= 9.5, H-2), 5.22 (1H, dd, J3,2 = 9.5, J3,4 = 3.0, H-3), 4.40 (1H, dd, J43 = 3.0, J4,5 =9.5, H-4), 3.84 (1H, ddd, J5,4 = 9.5, J5,ff = 5.0, J5,6" = 2.5, H-5), 4.22 (1H, H-6 ', dd, Jff,6- = 12, Jff5 = 2.5, ), 4.03 (1H, H-6", dd, Jff6" = 12, J6"5 = 5.0, ), 1.8-1.2 (20 H, m, 10CH cyclohexyl), 7.1 (1H, m, NH), 7.3-7.5 (4H, m, aromatic group), 2.6 and 4.32 (2H, s, CH=NH).
13C NMR spectrum (5, ppm), CDCI3: 92.7 (C-1), 79.3 (C-2), 77.54 (C-3), 77.0 (C-4), 76.6 (C-5), 62.5 (C-6), 166-168.5 (C=O), 12.0-22.8 (CH2-cyclohexyl). Aromatic group: 150.40 (C-1), 112.5 (C-2), 130.0 (C-3), 116.80(C-4), 132.10 (C-5), 112.5 (C-6).
P- N-(p-carboxyphenylglucopyranosyl)-nitrosourea (7). To a solution of 0.2 g (0.0003 mole) of compound 5 in 1 ml of glacial acetic acid and 2 ml of acetic anhydride under cooling up to 0 C° and stirred for 2 hours was added portionwise 0.5, the NaNO2. The mixture was kept for 20 hours in the refrigerator and then was processed in cold water with ice cubes. Solid matter repeatedly was extracted with ether. Ether extract was washed with water, dried over Na2SO4 and the solvent was evaporated under vacuo. The residue, which is a yellowish powder mass was treated with petroleum ether and recrystallized from ethanol. Yield 0.13 (62.4%), m.p. 132-1340C, Rf 0.62 (system b), [a]D18 - 27.30 (c 0.59, C2H5OH). Found, %: C 58.02; H 7.08; N 10.81. C26H36N4O8. Calculated, %: C 58.64; H 6.76; N 10.53.
IR spectrum (v, cm-1): 2938 (CH2-cyclohexanole), 3339 (NH), 2990-3300 (OH), 761, 910 (Benzol), 1525 (-CO-N-N=O), 1020 (-N-N-)
PMR spectrum (5, ppm, J/Hz), TMS: 5.42 (1H, d, Ju = 8.0, H-1), 5.30 (1H, dd, J2,1 = 8.0, J2,3= 9.5, H-2), 5.05 (1H, dd, J3,2 = 9.5, J3,4 = 3.0, H-3), 5.20 (1H, dd, J43 = 3.0, J4,5 =9.5, H-4), 3.80 (1H, ddd, J5,4 = 9.5, J5,6' = 5.0, J5,6" = 2.5, H-5), 4.0 (1H, H-6 ', dd, Jff,6- = 12, Jff5 = 2.5, ), 4.16 (1H, H-6", dd, Jff6" = 12, J6"5 = 5.0, ), 1.8-1.0 (20 H, m, 10CH2 cyclohexyl), 7.1-7.5 (4H, m, aromatic group), 3.25 and 4.1 (2H, s, CH=NH).
13C NMR spectrum (5, ppm), CDCI3: 87.82 (C-1), 71.12 (C-2), 76.60 (C-3), 69.52 (C-4), 74.83 (C-5), 61.8 (C-6), 168.5-172.0 (C=O), 12.0-25.5 (CH2-cyclohexyl). Aromatic group: 150.32 (C-1), 112.20 (C-2), 129.85(C-3), 116.40 (C-4), 130.8 (C-5), 111.22 (C-6).
P-N-(p-carboxyphenylgalactopyranosyl)-nitrosourea (8) was prepred analogously. Yield
0.11.(52.3%), m.p. 154-1550C, Rf 0.59 (system d), [a]D17 - 41.90 (c 0.44, C2H5OH). Found, %: N 9.98; C26H36N5O8. Calculated, %: C N 10.53.
IR spectrum (v, cm"1): 2850, 1440 (CH2_cyclohexanole), 3310 (NH), 3330 (OH), 760(Benzol), 1690 (C=O), 3060 (C-Harom), 1520 (-CO-N-N=O), 1080 (-N-N-).
PMR spectrum (5, ppm, J/Hz), TMS: 5.64 (1H, d, Ju = 8.0, H-1), 5.08 (1H, dd, J2,1 = 8.0, J2,3= 9.5, H-2), 5.21 (1H, dd, J3,2 = 9.5, J3,4 = 3.0, H-3), 5.32 (1H, dd, J43 = 3.0, J4,5 =9.5, H-4), 4.14 (1H, ddd, J5,4 = 9.5, J5,6' = 5.0, J5,6" = 2.5, H-5), 3.86 (1H, H-6 ', dd, Jff,6- = 12, Jff5 = 2.5, ), 3.72 (1H, H-6", dd, J66" = 12, J6"5 = 5.0, ), 1.8-1.0 (20 H, m, 10CH cyclohexyl), 7.4-7.7 (4H, m, aromatic group), 2.8 and 4.2 (2H, s, CH=NH).
13C NMR spectrum (5, ppm), CDCI3: 98.6 (C-1), 76.4 (C-2), 74.8 (C-3), 74.3 (C-4), 72.4 (C-5), 61.8 (C-6), 169.5-172.4 (C=O), 13.0-24.4 (CH2-cyclohexyl). Aromatic group: 149.20 (C-1), 112.33 (C-2), 131.84(C-3), 119.70 (C-4), 130.72 (C-5), 111.00(C-6). Conclusions.
1. N-glycosides containing a nitroso (N = O) group was synthesized: p-N-(p-carboxyphenylglucopyranosyl)-acylurea, P-N-(p-carboxyphenylgalactopyranosyl)-acylurea, P-N-(p-carboxyphenylglucopyra-nosyl)-nitrosourea and P- N-(p-carboxyphenylgalactopyranosyl)-nitrosoursa.
2. The structures of obtained compounds were established by physical-chemical methods of analysis.
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