The synthesis of arginine derivatives of chromone and azauracil

Article abstract of DOI:10.1134/S1068162006030095

The coupling of N-succinimide esters of 3-[7-hydroxy-3-(4-methyl-1,3- thiazol-2-yl)-6-ethyl-4-oxo-4H-chromen-2-yl]propanoic acid and 5-carboxymethyl-6-azauracil with free arginine yielded the corresponding arginine derivatives, which were purified by crys

Full text of DOI:10.1134/S1068162006030095

ISSN 1068-1620, Russian Journal of Bioorganic Chemistry, 2006, Vol. 32, No. 3, pp. 277–279. © Pleiades Publishing, Inc., 2006.
Original Russian Text © A.A. Poyarkov, M.S. Frasinyuk, V.K. Kibirev, S.A. Poyarkova, 2006, published in Bioorganicheskaya Khimiya, 2006, Vol. 32, No. 3, pp. 308–310.
The Synthesis of Arginine Derivatives
of Chromone and Azauracil
1
A. A. Poyarkov, M. S. Frasinyuk, V. K. Kibirev, and S. A. Poyarkova
Institute of Bioorganic Chemistry and Oil Chemistry, National Academy of Sciences of Ukraine, ul. Murmanskaya 1,
Kiev, 02094 Ukraine
Received March 3, 2005; in final form, November 20, 2005
Abstract—The coupling of N-succinimide esters of 3-[7-hydroxy-3-(4-methyl-1,3-thiazol-2-yl)-6-ethyl-4-
oxo-4H-chromen-2-yl]propanoic acid and 5-carboxymethyl-6-azauracil with free arginine yielded the corre-
sponding arginine derivatives, which were purified by crystallization. The structures of the compounds were
confirmed by 1H NMR spectroscopy
Key words: arginine, azauracil, 7-hydroxychromone
DOI: 10.1134/S1068162006030095
INTRODUCTION
Flavones can enter the guanidine-induced recycliza-
tion reactions [8]; therefore, we were not sure that the
chromone core would not be damaged in the presence
of L-arginine containing a guanidine group. However,
we did not observe in our experiments the processes
described in [8]. The L-arginine derivative (III) of
2,3,6,7-substituted chromone (I) we synthesized [9]
contained a small admixture of the starting compound.
The purification of the reaction product by adsorption
chromatography on alumina with methanol as eluent
did not result in homogeneous compounds. It turned
out that the usual crystallization from 50% ethanol
gives a good result. A D-arginine derivative of 5-car-
boxymethyl-6-azauracil (V) was prepared in a high
yield via the corresponding N-succinimide ester (IV) in
a similar way. The structures and the purity of the
resulting compounds were confirmed by 1H NMR spec-
troscopy.
Natural and synthetic derivatives of chromones [1]
and azauracil [2] exhibit a wide spectrum of biological
activities. They display cerebroprotective, antispas-
modic, antitumor, and cardiostimulating properties [3].
Chromone derivatives are agonists of γ-aminobutyric
acid receptors and, therefore, strong tranquilizers
devoid of side effects, such as amnesia, myorelaxation,
and sedative effect. L-Arginine is a very interesting
amino acid with a clearly pronounced biological activ-
ity. Arginine stimulates in organism the insulin and
somatostatin release, displays vasodilating properties
at hypercholesteremia, and regulates metabolism of
nitrogen monoxide [4]. The introduction of an arginine
residue into the chromone molecule may essentially
alter its hydrophilic–lipophilic properties and affect in
this way its transport in biological systems. It was
shown that the modification of a hydrophobic com-
pound with arginine allows the preparation of reverse
inhibitors of thrombin, a therapeutic target for potential
anticoagulants, which may be used for therapy of car-
diovascular disorders [5].
EXPERIMENTAL
We used D- and L-arginines from Reanal (Hungary),
5-carboxymethyl-6-azauracil kindly presented by
S.S. Tarnavsky (Institute of Molecular Biology and
Genetics, National Academy of Sciences of Ukraine),
and domestic solvents and chemicals of the special
purity grade. Melting points were determined on a Boe-
tius hot plate (Germany). Monitoring of the reaction
and the analysis of product purity were carried out by
TLC on precoated silica gel 60 F254 plates (Merck, Ger-
many) in (A) 4 : 1 : 1 n-butanol–acetic acid–water and
(B) 5 : 4 benzene–ethyl acetate. The syntheses were
carried out according to the given scheme.
RESULTS AND DISCUSSION
We used a classical method of peptide chemistry for
coupling arginine with chromone derivatives and aza-
uracil, namely, the method of active esters [6]
(Scheme 1). An advantage of these active agents is their
high reactivity along with hydrolytic stability, which
enables their coupling in aqueous dioxane or DMF and
the use of N-succinimide esters for the synthesis of pep-
tides with C-terminal free arginine [7].
3-[7-Hydroxy-3-(4-methyl-1,3-thiazol-2-yl)-6-
ethyl-4-oxo-4H-chromen-2-yl]propanoic acid (I). A
suspension of 1-(2,4-dihydroxy-5-ethylphenyl)-2-(4-
methyl-1,3-thiazol-2-yl)ethanone (1.55 g, 5 mmol) [9],
1
Corresponding author; phone: (38044) 573-2728;
e-mail: alexp@bpci.kiev.ua.
277

278
POYARKOV
OH
N
CH3
HO
+
S
O
O
O
O
O
OH
HN
O
N
O
HO
H3C
O
O
O
N
H
DCC
OH
N
HONSu
S
O
(I)
DCC
N
O
O
O
HONSu
HN
O
N
O
HO
H3C
O
O
N
H
(IV)
O
O
N
N
D-Arg
O
O
O
S
S
(II)
HO
NH
O
L-Arg
O
NH
NH
OH
NH2
HN
HO
H3C
O
O
NH
N
O
O
O
N
(V)
H
N
(III)
HN
H2N
NH
Scheme 1.
succinic anhydride (3.03 g, 30 mmol), and dry pyridine
(10 ml) was heated at 40°ë under stirring and kept for
72 h. The reaction mixture was poured onto ice, acidi-
fied with concentrated HCl to pH 2–3, and allowed to
be heated to room temperature. The solution was
adjusted to pH 6–7 with 5% sodium hydroxide, and the
resulting crystals were filtered, washed with cold water,
and reprecipitated from an alkaline solution with dilute
HCl. The precipitate was filtered and crystallized from
a water–DMF mixture to give (I), yield 85%,
mp >300°C (dec.)
N1-{3-[7-Hydroxy-3-(4-methyl-1,3-thiazol-2-yl)-
6-ethyl-4-oxo-4H-chromen-2-yl]propionyl}-L-argi-
nine (III). A solution of L-arginine (0.46 g, 2.6 mmol)
in water (10 ml) was added to a solution of (II) (0.6 g,
1.3 mmol) in dry DMF (20 ml), the mixture was stirred
for 48 h at room temperature, and evaporated in a vac-
uum at 40°C. The oil-like residue was recrystallized
from 50% ethanol to give (III); yield 0.38 g (60%); mp
238°C (dec.); Rf 0.45 (A); 1H NMR spectra were regis-
tered on a Varian VXC-400 (Germany) with a working
frequency of 400 MHz in DMSO-d6 (99.9%) relative to
residual solvent protons (δ, ppm, J, Hz)2: 8.80 (1 H, br.
s, II, Arg), 7.78 (1 H, s, H5, Chr), 7.69 (1 H, s, 7-OH,
Chr), 7.42 (5 ç, 4 NH + NH2); 7.40 (1 H, s, H5, Thia),
6.93 (1 H, s, H8, Chr), 4.01 (1 H, q, J 6.0, CI, Arg), 3.60
(2 H, m, ëç2-NH)), 3.45 (2 H, m, ëç2, propionyl),
2.85 (2 H, m, ëç2, Et); 2.60 (2 H, m, ëç2, propionyl),
2.40 (3 H, s, ëç3, Et), 1.35–1.75 (4 H, m, 2 ëç2, Arg),
and 1.25 (3 H, t, J 8.9, ëç3, Thia).
N-Succinimide ester of 3-[7-hydroxy-3-(4-
methyl-1,3-thiazol-2-yl)-6-ethyl-4-oxo-4H-chromen-2-
yl]propanoic acid (II). N-Succinimide (0.12 g,
1.01 mmol) and dicyclohexylcarbodiimide (0.21 g,
1.01 mmol) were added to a solution of (I) (0.4 g,
1 mmol) in dry DMF (20 ml) at 4°C. The reaction mix-
ture was stirred at 4°C for 4 h and at room temperature
for 18 h. After the reaction was over, dicyclohexylurea
was filtered off, DMF was evaporated in a vacuum at
40°C, and the residue was crystallized from isopro-
panol to give 0.6 g (80%) of (II), mp 110°C, Rf 0.6 (B).
2
Chr, Thia, and AzU are chromone, thiazoline, and 6-azauracil res-
idues, respectively.
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 32 No. 3 2006

THE SYNTHESIS OF ARGININE DERIVATIVES
279
N-Succinimide ester of 5-carboxymethyl-6-aza-
REFERENCES
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