Synthesis of glycoconjugates of physiologically active compounds

Article abstract of DOI:10.1134/S1070427207030329

Synthesis of N-glycosylamines derived from D-glucose and D-galactose (glycoconjugates of aniline derivatives and of d-pseudoephedrine and cytisine alkaloids) was studied with the aim to develop new pharmaceuticals.

Full text of DOI:10.1134/S1070427207030329

ISSN 1070-4272, Russian Journal of Applied Chemistry, 2007, Vol. 80, No. 3, pp. 506 508. Pleiades Publishing, Ltd., 2007.
Original Russian Text
No. 3, pp. 510 512.
D.V. Bessonov, I.V. Kulakov, A.M. Gazaliev, O.A. Nurkenov, 2007, published in Zhurnal Prikladnoi Khimii, 2007, Vol. 80,
BRIEF
COMMUNICATIONS
Synthesis of Glycoconjugates of Physiologically
Active Compounds
D. V. Bessonov, I. V. Kulakov, A. M. Gazaliev, and O. A. Nurkenov
Institute of Organic Synthesis and Coal Fuel Chemistry of Kazakhstan Republic, Limited Liability Company,
Karaganda, Kazakhstan
Received August 3, 2006
Abstract Synthesis of N-glycosylamines derived from D-glucose and D-galactose (glycoconjugates of
aniline derivatives and of d-pseudoephedrine and cytisine alkaloids) was studied with the aim to develop new
pharmaceuticals.
DOI: 10.1134/S1070427207030329
N-Glycosylamines find growing use for preparing
natural glycopeptides, their analogs, and glycocon-
jugates used for various biological studies. N-Glyco-
sylamines, the reaction products of carbohydrates with
alkyl- and arylamines, attract attention of chemists,
biochemists, and biologists. N-Glycosylamines can
also be used for preparing new pharmaceuticals [2].
creases the lipophilicity of pharmaceuticals and facili-
tates their penetration through biomembranes [2]. For
example, p-thiocyanatoaniline is a strong insecticide
[3], and p-bromoaniline is a precursor for preparing
Fenazepam, which is a tranquilizer with hypnotic and
anticonvulsant effect [4].
N-Glycosylamines were prepared by condensation
of p-substituted anilines and D-glucose (1, 3, 5) or
D-galactose (2, 4, 6). Their biological activity was
studied. The condensation was performed in an al-
coholic solution on heating by the procedure described
in [5]:
It is known than aniline is an antipyretic. However,
it is too toxic to be used as a pharmaceutical. Intro-
duction of various substituents into the benzene ring
or the amino groups yields compounds with a wide
range of pharmacological properties. Halogenation in-
1 6
1, 3, 5
1, 2
2, 4, 6
5, 6
3, 4
1
N-Glycosylamines 1 6 are white crystalline com-
pounds readily soluble in water, ethanol, and DMF.
The presence of the band at 891 7 cm in the
IR spectra of compounds 1 6 suggests the -confor-
506

SYNTHESIS OF GLYCOCONJUGATES
507
mation at the anomeric center. The bands in the range
1010 1090 cm are assigned to the pyranose form of
duction of carbohydrate residues into the structure of
biologically active molecules increases their solubility
in water, decreases their toxicity, and increases their
target transport and penetrability into a cell.
1
the glycoside residue. The bands in the range 2130
1
2160 cm in the IR spectrum of compound 5 are due
to the S C N group. The C Hal and C N stretching
To prepare biologically active compounds and to
increase the solubility and decrease the toxicity of
alkaloid derivatives, we used commercial D-galactose
as a substituent at the nitrogen atom. Condensation of
D-galactose with an alkaloid, d-pseudoephedrine or
cytisine, in a small volume of ethanol containing
catalytic amounts of acetic acid yields N-galactosyl-
amines 7 and 8:
bands of compounds 1 4 are observed in the ranges
1
500 700 and 1280 1330 cm , respectively.
New biologically active compounds can be pre-
pared by functionalization of monosaccharide with
phramacophore groups and physiologically active
alkaloid fragments. In addition, it is known that intro-
7, 8
7
8
Galactosylamines 7 and 8 are white crystalline
observed at 1.14 ppm (J = 5.75 Hz), and the intense
singlet of the N-methyl group, at 2.53 ppm. The sig-
nal of the methine proton of the CH N group appears
in the form of complex multiplet at 2.64 2.85 ppm.
The doublet at 4.55 ppm is assigned to the methine
proton of the CHO group (J = 3.5 Hz). The doublet of
the anomeric proton H(1) of the carbohydrate residue
is observed at 4.48 ppm (J = 9.2 Hz), which confirms
the -conformation of the reaction product.
compounds; their composition and structure were con-
1
firmed by elemental analysis and by H NMR and
IR spectroscopy. The absence of the band at 844
1
8 cm in the IR spectra of these compounds suggests
their -conformation. According to data of [6], ab-
1
sorption in the range 1120 1170 cm is typical for
cyclic sugars, and open-chain sugars do not absorb
in this range. The strong band of the amide group
1
(N C=O) of the alkaloid at 1640 1650 cm
is
present, along with bands of the carbohydrate frag-
ment, in the IR spectrum of compound 8.
EXPERIMENTAL
The properties of compounds 1 8 are presented
1
The H NMR spectra of solutions in DMF d were
7
in the table.
recorded on a Varian XL-100 spectrometer operating
at 100 MHz. The IR spectra of the samples in KBr
pellets were recorded on an Avatar-320 spectrometer.
Melting points were determined on a Boetius ap-
paratus. The reaction course was monitored and the
purity of the condensation products was determined
by thin-layer chromatography on Sorbfil plates using
isopropanol : benzene : ammonia = 10 : 5 : 2 system
The IR spectra of all the compounds presented in
the table are characterized by strong stretching
bands of the OH and NH groups in the range 3250
1
3400 cm .
1
The H NMR spectrum of compound 7 contains
the signals of the protons of the alkaloid and carbohy-
drates moieties. The doublet of the CH C group is
3
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 80 No. 3 2007

508
BESSONOV et al.
Physicochemical constants and elemental analyses of the compounds
Found, %
Calculated, %
H
Compound Yield, %
mp,
C
Empirical formula
C
H
N
C
N
1
2
3
4
5
6
7
8
75.5
65.2
72.5
64.9
87.6
70.1
55.4
71.6
118 119
181 182
117 118
119 120
171 172
179 180
146 147
188 189
38.25
38.19
43.46
43.50
50.43
50.41
59.12
58.41
4.04
4.01
4.61
4.56
4.89
4.91
7.46
6.59
3.93
3.99
4.47
4.42
9.23
9.25
4.55
8.29
C12H16INO5
C12H16INO5
C12H16BrNO5
C12H16BrNO5
C13H16N2O5S
C13H16N2O5S
C16H25NO6
37.81
37.81
43.13
43.13
49.99
49.99
58.70
57.94
4.21
4.21
4.83
4.83
5.16
5.16
7.70
6.86
3.67
3.67
4.19
4.19
8.97
8.97
4.28
7.95
C17H24N2O6
as the eluent. The chromatograms were developed
with iodine vapor.
Galactosylcytisine (8). To a solution of galactose
(0.01 mol) in ethanol (15 ml), cytisine (0.01 mol) was
added. The mixture was stirred at 55 60 C for 24 h in
the presence of 1 2 drops of glacial acetic acid. White
crystals that precipitated on cooling were washed with
absolute ether. The product was recrystallized from an
isopropanol : benzene : ethanol (3 : 2 : 1) mixture.
Glucosyl-p-iodoaniline (1). To a solution of glu-
cose (0.02 mol) in ethanol (20 ml), p-iodoaniline
(0.02 mol) was added. The mixture was stirred at 50
55 C for 4 h. Excess solvent was removed on a water
bath. White crystals that precipitated on slight cooling
were filtered off and washed with cold isopropanol.
The product was recrystallized from an ethanol: iso-
propanol (5 : 1) mixture. Galactosyl-p-iodoaniline (2)
was prepared similarly.
CONCLUSIONS
(1) The carbohydrates were condensed with bio-
logically active amines (p-iodoaniline, p-bromoani-
line, and p-thiocyanatoaniline) and with alkaloids
(d-pseudoephedrine and cytisine).
Glucosyl-p-bromoaniline (3). To a solution of
glucose (0.02 mol) in ethanol (20 ml), p-bromoaniline
(0.02 mol) was added with stirring. The mixture was
stirred at 55 60 C for 5 h. Excess solvent was re-
moved on a water bath. White crystals that precipi-
tated on slight cooling were filtered off and washed
with cold isopropanol. The product was recrystallized
from ethanol. Galactosyl-p-bromoaniline was pre-
pared similarly.
(2) The physicochemical constants, compositions,
and structures of the condensation products were
determined.
REFERENCES
Glucosyl-p-thiocyanatoaniline (5). To a solution
of glucose (0.01 mol) in ethanol (15 ml), p-thiocyana-
toaniline (0.01 mol) was added. The mixture was
stirred at 60 65 C for 6 h. Crystals that precipitated
on cooling were filtered off and washed with cold iso-
propanol. The product was recrystallized from an
ethanol : isopropanol (2 : 1) mixture. Galactosyl-
p-thiocyanatoaniline (6) was prepared similarly.
1. Grogan, M.J., Pratt, M.R., and Marcaurelle, L.A.,
Ann. Rev. Biochem., 2002, vol. 71, p. 593.
2. Soldatenkov, A.T., Kolyadina, N.M., and Shend-
rik, I.V., Osnovy organicheskoi khimii lekarstvennykh
veshchestv (Foundations of the Organic Chemistry of
Pharmaceuticals), Moscow: Khimiya, 2001.
3. Mel’nikov, N.N., Pestitsidy: Khimiya, tekhnologiya i
primenenie (Pesticides: Chemistry, Technology, and
Application), Moscow: Khimiya, 1987.
Galactosyl-d-pseudoephedrine (7). To a solution
of galactose (0.01 mol) in ethanol (15 ml), d-pseudo-
ephedrine (0.01 mol) was added. The mixture was
stirred at 55 60 C for 24 h in the presence of 1
2 drops of glacial acetic acid. White crystals that pre-
cipitated on cooling were washed with cold iso-
propanol and then with absolute ether. The product
was recrystallized from isopropanol.
4. Granik, V.G., Osnovy meditsinskoi khimii (Foundations
of Medical Chemistry), Moscow: Vuzovskaya Kniga,
2001.
5. Sorokin, W., Ber, 1887, vol. 20, p. 783.
6. Prima, A.M., Zhbanov, R.G., and Marunov, R., Zh.
Strukt. Khim., 1964, vol. 5, no. 6, pp. 845 850.
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 80 No. 3 2007