Syntheses, structural, and biological studies of two new peptide compounds, 2(s)-(5-fluorouracil-1-aceto)amino-2-isopropyl acetate hemihydrate and 2(s)-(5-fluorouracil-1-aceto)amino-2-isopropyl acetic acid

Article abstract of DOI:10.1007/s10870-008-9396-9

Two new peptide compounds, 2(s)-(5-fluorouracil-1-aceto)amino-2-isopropyl acetate hemihydrate (1:1/2H₂O) and 2(s)-(5-fluorouracil-1-aceto) amino-2-isopropyl acetic acid (2), have been synthesized and characterized by elemental analysis, IR,

Full text of DOI:10.1007/s10870-008-9396-9

J Chem Crystallogr (2008) 38:807–813
DOI 10.1007/s10870-008-9396-9
ORIGINAL PAPER
Syntheses, Structural, and Biological Studies of Two New Peptide
Compounds, 2(s)-(5-fluorouracil-1-aceto)amino-2-isopropyl
Acetate Hemihydrate and 2(s)-(5-fluorouracil-1-aceto)amino-
2
-isopropyl Acetic Acid
Mao-Lin Hu Æ Ping Yin Æ Zhi-Cheng Ma Æ
Ali Morsali
Received: 4 November 2007 / Accepted: 2 April 2008 / Published online: 15 April 2008
Ó Springer Science+Business Media, LLC 2008
Abstract Two new peptide compounds, 2(s)-(5-fluoro-
uracil-1-aceto)amino-2-isopropyl acetate hemihydrate (1:1/
therapy with various cytotoxic drugs [1–4]. However, its
administration is accompanied by significant toxic side
effects and delivery problem [5–9]. Many derivatives of
5-FU have been synthesized to improve the topical delivery
of 5-FU and reduce the side effects. In previous investiga-
tions, we have successfully obtained 2-(2-(5-fluoro-2,4-
dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamido)acetic acid
[10]. To extend our interest in searching for new deriva-
tives of 5-FU with higher bioactivity and take advantage of
the concept of bioisosterism, the title compounds contain-
ing 5-FU ring, 2(s)-(5-fluorouracil-1-aceto)amino-2-isopropyl
2
acetic acid (2), have been synthesized and characterized by
H O) and 2(s)-(5-fluorouracil-1-aceto)amino-2-isopropyl
2
1
13
elemental analysis, IR, H- and C NMR spectroscopy.
Two new compounds were structurally characterized by
single-crystal X-ray diffraction. The thermal stabilities of
compounds 1:1/2H O and 2 were studied by DSC-TGA
2
techniques. The result of the biological test showed that the
compounds 1:1/2H O and 2 have certain antitumor
2
activities.
acetate hemihydrate (1:1/2H O) and 2(s)-(5-fluorouracil-1-
2
Keywords 2(s)-(5-Fluorouracil-1-aceto)amino-
aceto)amino-2-isopropyl acetic acid (2), was firstly designed
and synthesized.
2
2
-isopropylacetate Á 2(s)-(5-Fluorouracil-1-aceto)amino-
-isopropyl acetic acid Á Crystal structure Á Thermal
analysis Á Antitumor activity
Experimental
Introduction
Materials and Instruments
5
-Fluorouracil (5-FU) is an antimetabolite with good anti-
All chemicals were obtained from a commercial source and
used without further purification. The elemental analyses
were performed on a Carlo-Erba 1112 Elemental Analyzer.
IR spectrum was recorded on a Perkin Elmer 2000 system in
microbial and antitumor activity and most frequently used
for treating solid tumors, such as breast, colorectal, and
gastric cancers, in either monotherapy or combination
-
1
the range of 4,000–400 cm with KBr disk technique. NMR
spectra were obtained with Bruck AM-300 spectrometer
with DMSO as solvent. To access the thermal stability of the
title compound, DSC-TGA (Differential Scanning Calo-
rimetry and Thermogravimetric Analysis) analyses were
carried out on a Universal V4.1D TA Instruments (SDT
Q600) under a nitrogen atmosphere. Antimicrobial activities
M.-L. Hu (&) Á P. Yin Á Z.-C. Ma
College of Chemistry and Materials Engineering,
Wenzhou University, Wenzhou 325027,
People’s Republic of China
e-mail: maolin_hu@yahoo.com
A. Morsali
of the compounds 1:1/2H O and 2 were evaluated at the
2
Department of Chemistry, Faculty of Sciences,
Tarbiat Modares University, Tehran, 14115-175,
Islamic Republic of Iran
National Center for Drug Screening, Shanghai, China. All
measurements were made on a Bruker Smart-Apex CCD
diffractometer by using a graphite-monochromated MoKa
e-mail: morsali_a@yahoo.com
123

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J Chem Crystallogr (2008) 38:807–813
(
k = 0.071073 nm) radiation with an x-scan technique.
was prepared from 5-fluorouracil and bromoacetic acid
following the method of the reported [11].
Determination of the crystal class, orientation matrix, and
cell dimensions was performed according to the established
procedures. Lorentz polarization and absorption corrections
were applied. Empirical absorption corrections were per-
formed with SADABS program. Most of the non-hydrogen
atoms were located by direct methods, and those remaining
were derived by subsequent Fourier syntheses. All non-
hydrogen atoms were refined anisotropically, and all
hydrogen atoms were held stationary and included in the
final stage of full-matrix least-squares refinement based on
Preparation of Compound 1:1/2H O
2
The compound 1:1/2H O was synthesized from 5-fluoro-
2
uracil-1-acetic acid, dicyclohexyl carbodiimide (DCC), and
1-hydroxybenzotriazole (HOBT). A solution (25 mL) of
N,N-dimethyl formamide (DMF) with DCC (0.030 mol)
was added dropwise to a DMF solution (75 mL) with
5-fluorouracil-1-acetic acid (0.020 mol) and HOBT
(0.022 mol) at 273 K. After 5 h reaction at room temper-
ature, 2(s)-amino-2-isopropyl acetate (0.020 mol) and
triethylamine (0.020 mol) was added to the above mixture.
After 4 h stirring, a white solid 2(s)-(5-fluorouracil-
1-aceto)amino-2-isopropyl acetate hemihydrate (1) was
obtained after filtration, reduced pressure distillation of
DMF, and column chromatography separation, m.p.
115 °C. IR (KBr): m = 3555 (bs), 3283 (s), 2969 (s), 1723
2
F using SHELXL-97 program packages [12]. The final
cycle of refinement gave R = 0.0934, wR = 0.2588 for
compound 1:1/2H O and R = 0.0319, wR = 0.0790 2588
2
2
2
o
2
for compound 2 (w = 1/[r (F ) + (0.1183P) + 0.8793P],
where P = (F + 2F )/3). The all H atoms were positioned
2
o
2
c
geometrically and allowed to ride on their parent atoms. The
anisotropic displacement parameters, the calculated struc-
ture factors, and full lists of bond distances, bond angles and
torsion angles are given in the supplementary material. X-ray
crystal structure and perspective views of the packing are
shown in Figs. 1–4. The reason for the relatively high values
-
1
(s), 1665 (s), 1380 (m), 1219 (m) cm . Anal. Calcd for
compound 1:1/2H O: C 46.45, H 5.48, N 13.55; found C
2
46.50, H 5.37, N 13.62.
of the R factors for compound 1:1/2H O is the poor quality
2
of the crystal.
Preparation of Compound 2
Synthesis of Compounds (1:1/2H O) and 2
2
The 2(s)-(5-fluorouracil-1-aceto)amino-2-isopropyl acetic
acid (2), was obtained by hydrolysis with sodium hydrox-
ide solution (1 mol/L) of compound 1:1/2H O, d.p.
The starting material of 5-fluorouracil-1-acetic acid (5-
fluoro-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-acetic acid)
2
1
255 °C. H-NMR(DMSO-d ): IR (KBr): m = 3296 (s),
6
Fig. 1 Ortep plot at the 50%
probability level of compound
2
(s)-(5-fluorouracil-1-
aceto)amino-2-isopropyl acetate
hemihydrate (1:1/2H O)
2
1
23

J Chem Crystallogr (2008) 38:807–813
809
Fig. 2 Ortep plot at the 50%
probability level of compound
2(s)-(5-fluorouracil-1-
aceto)amino-2-isopropyl acetic
acid (2)
Fig. 3 Depiction of packing
and showing the N–H_O and
O–H_O hydrogen bonds in
compound 2(s)-(5-fluorouracil-
1-aceto)amino-2-isopropyl
acetate hemihydrate (1:1/2H
2
O)
1
13
3
9
4
082 (bs), 2977 (s), 1724 (s), 1661 (s), 1386 (m), 1216 (m),
absorption of mC–O–C. The assignment of H- and CNMR
of compounds 1:1/2H O and 2 is shown in Tables 1 and 2.
-
77 (m) cm . Anal. Calcd for compound 2: C 45.99, H
1
2
.88, N 14.34; found C 46.02, H 4.76, N 14.43.
Single X-ray crystal analysis reveals that compounds 1:1/
2H O and 2 crystallize in monoclinic system with space
The purified products 1:1/2H O and 2 were dissolved in
2
2
9
1
5% ethanol and single crystals were separated after
0 days.
groups of C2 and P2 , respectively (Table 3). A displace-
1
ment ellipsoid plot with the numbering scheme of
compounds 1:1/2H O and 2 is shown in Figs. 1 and 2,
2
respectively. Figures 3 and 4 display a perspective view of
Results and Discussion
the crystal packing of compounds 1:1/2H O and 2, respec-
2
tively. The compound 1:1/2H O has been formed from three
2
In the infrared spectrum of the title compounds, the broad
components, two 2(s)-(5-fluorouracil-1-aceto)amino-2-iso-
propyl acetate molecules with very slight difference in the
bond lengths and angles and one lattice water molecule. In
-
1
absorption bands at 3,283 and 2,969 cm were assigned to
the N–H and the C–H stretching vibration, and the strong
-
1
ones at 1,723 and 1,665 cm
were to the stretching
the crystal structure of compounds 1:1/2H O and 2, bond
2
vibration of mC=O of carbonyl group. The characteristic
strong bands at 1,219 cm were attributed to the vibration
lengths and angles in 5-FU ring are generally normal [13–
16]. The C–F bonds length is similar to the earlier reported
-
1
123

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J Chem Crystallogr (2008) 38:807–813
Fig. 4 Depiction of packing
and showing the N–H_O and
O–H_O hydrogen bonds in
compound 2(s)-(5-fluorouracil-
1-aceto)amino-2-isopropyl
acetic acid (2)
1
Table 1 Assignment of the H NMR signals of the compounds 1:1/2H
2
O and 2
Compound 1 Assignment
Compound 2
Assignment
COOH
3
1
8
8
4
4
2
0
.65 (3H, s)
COOCH
FCCNH
CONH
FCCH
3
12.71(1H, s)
4
4
1.80 (1H, d, JFH = -5.0 Hz)
11.80(1H, d, JFH = 5.0Hz)
FCCNH
CONH
FCCH
3
3
.54 (1H,d, JHH = 7.5 Hz)
8.40(1H,d, JHH = 7.5 Hz)
3
3
.01 (1H, d, JFH = 6.8 Hz)
8.02(1H, d, JFH = 6.8 Hz)
.39 (2H, s)
CH
2
4.39(2H, s)
CH
2
3
.22 (1H, m, 3JHH = 7.2Hz)
3
.04 (1H, m, JHH = 6.6 Hz)
NCH
CCH
C(CH
4.19(1H, m, JHH = 5.7 Hz)
NCH
CCH
C(CH
3
2.05(1H, m, JHH = 6.9 Hz),
3
3
.89 (6H, d, JHH = 6.0 Hz)
3
)
2
0.89(6H, d, JHH = 6.6 Hz)
3 2
)
results [17]. The bond lengths of C3–C4 = 1.437(13) and
˚
C14–C15 = 1.341(12) A in the compound 1:1/2H O and
2(s)-(5-fluorouracil-1-aceto)amino-2-isopropyl acetate mol-
ecules and the lattice water molecules themselves are forming
hydrogen bonds with the C=O groups of two different 2(s)-(5-
fluorouracil-1-aceto)amino-2-isopropyl acetate molecules
(Table 4). Also the N–H group of amide groups is acting as
hydrogen bond donor toward the C=O group of amide groups
of adjacent molecules (Table 4). Consequently, the molecules
2
C3–C4 = 1.334(4) in the compound 2 are indicative of the
considerable double-bond character. The bond lengths of
C1–O1 = 1.202(11), C2–O2 = 1.201(10), C13–O6 =
˚
.205(11), and C14–O7 = 1.220(11) A in the compound
1
1
1
:1/2H O as well as C1–O1 = 1.198(3) and C2–O2 =
2
˚
.231(3) A in the compound 2 are similar to the earlier
in the compound 1:1/2H O are grown by the hydrogen bonds
2
˚
reported bond lengths, 1.17 to 1.25 A [18]. The bond lengths
˚
of N3–C6 = 1.332(10) and N6–C18 = 1.338(10) A in the
into a two-dimensional network (Fig. 3). In the compound 2,
there are three different hydrogen bonds (Fig. 4). The –OH
group of acetic acid fraction is acting as hydrogen bond donor
toward the C=O group of 5-fluorouracil rings and the C=O
groups of acetic acid fraction themselves are forming hydro-
gen bonds with the NH groups of 5-fluorouracil rings
(Table 5). Also the N–H of amino group is acting as hydrogen
bond donor toward the O atoms of the C=O group of –COOH
fraction of adjacent molecules (Table 5). Consequently, the
molecules in the compound 2 are also grown by the hydrogen
bonds into a two-dimensional network (Fig. 4).
˚
compound 1:1/2H O and N3–C6 = 1.332(3) A in the
2
compound 2 are shorter than a typical C–N bond length [ca.
1
˚
.443 A], but longer than a typical double C=N bond (ca.
˚
.269 A) [19], indicating the electron delocalization at the
1
O–C–N fraction.
Solvate water molecule is found in the lattice of compound
1
:1/2H O and involved in a hydrogen bonding network
2
(
Fig. 3). The water molecule is acting as hydrogen bond
donors toward the N atoms of the amide groups of
1
23

J Chem Crystallogr (2008) 38:807–813
811
1
3
C
Table 2 Assignment of the
NMR signals of the compounds
:1/2H O and 2
Compound 1
Assignment
Compound 2
Assignment
1
2
1
1
1
1
1
4
1
5
5
4
3
1
1
71.89
COOCH
CONH
FCCO
NCON
FC
3
172.83
166.98
COOH
CONH
FCCO
NCON
FC
67.13
2
2
57.69 (d, JFC = 25.8 Hz)
157.72(d, JFC = 25.8 Hz)
49.80
149.82
1
1
37.82 (d, JFC = -228.2 Hz)
139.32(d, JFC = -228.2 Hz)
.22 (1H, m, 3JHH = 7.2 Hz)
2
31.34 (d, JFC = 33.9 Hz)
NCH
–
–
2
FCC
131.42(d, JFC = 33.9 Hz)
FCC
7.66
1.89
9.52
0.38
9.03
8.28
CHCOOCH
OCH
CH
CCH
3
–
–
3
57.53
49.60
30.34
19.24
18.09
CHCOOH
2
CH
2
CCH
CH
CH
3
3
CH
CH
3
3
Table 3 Crystal data and
structure refinement for
Identification code
Empirical formula
Formula weight
Temperature
1:1/2H
2
O
2
C
24 34
H F
2
N
O
6 11
11 3 5
C H14 FN O
2
compounds 1:1/2H O and 2
620.57
287.25
298(2) K
0.71073
298(2) K
0.71073
˚
Wavelength (A)
Crystal system
Space group
Monoclinic
C2
Monoclinic
P2
a = 4.8255(8) A
1
˚
a = 33.668(10) A
˚
Unit cell dimensions
˚
b = 4.856(1) A
˚
b = 11.2512(19) A
˚
c = 17.755(5) A
˚
c = 12.036(2) A
b = 93.572(6)°
˚
2,897.2(15) A
b = 99.051(3)°
645.33(19) A
3
3
˚
Volume
Z
4
2
-
3
Density (calculated) (g cm
Absorption coefficient (mm
F(000)
)
1
1.423
1.478
0.126
300
-
)
0.121
1,304
3
3
Crystal size
0.29 9 0.09 9 0.06 mm
1.15–25.02°
-39 B h B 40
0.34 9 0.22 9 0.14 mm
1.71–25.04°
-5 B h B 5
-13 B k B 13
-14 B l B 14
4,630
Theta range for data collection
Index ranges
-
-
5 B k B 5
19 B l B 21
Reflections collected
7,653
2,881
Independent reflections
Absorption correction
Max. and min. transmission
Refinement method
1,211
Empirical from equivalents
0.990 and 0.966
Empirical from equivalents
0.980 and 0.958
2
2
Full-matrix least-squares on F
2,881/4/400
Full-matrix least-squares on F
1,211/1/183
Data/restraints/parameters
2
Goodness-of-fit on F
1.122
1.115
Final R indices [I [ 2r (I)]
R Indices (all data)
R
1
= 0.0934
= 0.2588
= 0.1143
= 0.2791
0.30 and -0.34 e A
R
1
= 0.0319
= 0.0790
= 0.0332
= 0.0799
0.16 and -0.15 e A
wR
2
wR
2
R
1
R
1
wR
2
wR
2
-
3
-3
˚
˚
Largest diff. peak, hole
123

8
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J Chem Crystallogr (2008) 38:807–813
˚
Table 4 Hydrogen bonds for compound 1:1/2H
2
O (A and °)
first lost their crystal water with an endothermic peak at
1
10 °C to maintain the equilibrium pressure. A crystal–
D-H_A
d(D–H) d(H_A) d(D_A) \(DHA)
crystal transition might be taken into account for the small
exothermic peak at 200 °C. The two endothermic peaks at
328 and 364 °C represented the pyrolysis of the compound
N(2)-H(2)_O(7)#1
N(3)-H(3)_O(11)#2
N(5)-H(5)_O(5)#3
N(6)-H(6)_O(8)#4
0.86
0.86
0.86
0.86
2.30
1.98
2.12
2.08
3.164(10) 176.3
2.835(11) 174.3
2.983(9) 178.0
2.931(9) 170.7
2.977(10) 141.0(11)
1:1/2H O. The TGA of the compound 2 shows an overall
2
weight loss of about 100% (Fig. 6). It is evident that there
is no weight loss up to 240 °C. At higher temperatures
there are two main losses. The first one takes place in the
240–425 °C range (75%), the second loss is completed up
to 760 °C (25%). Both the two stages are due to the deg-
radation of the compound 2 and in good agreement with the
range of the endothermic and exothermic peaks that appear
in DSC. The DSC curve exhibits four endothermic peaks
O(11)-H(11D)_O(7)#1 0.82(2) 2.30(9)
O(11)-H(11D)_O(5)#5 0.82(2) 2.60(11) 3.094(11) 120.0(11)
O(11)-H(11E)_O(1) 0.82(2) 1.93(3) 2.746(10) 171.0(15)
Symmetry transformations used to generate equivalent atoms: #1 x,
y - 1, z + 1; #2 -x + 1, y + 1, -z + 1; #3 - x + 1, y, -z; #4 x,
y - 1, z; #5 - x + 1, y-1, -z + 1
(
the sharpest one is at 260 °C and the other three are small
˚
Table 5 Hydrogen bonds for compound 2 (A and °)
and well resolved centered at 360, 470 and 575 °C,
respectively) and two exothermic peaks (310 and 736 °C).
In summary, the thermogravimetric analysis shows that
two compounds have a remarkably thermal stability that
they only decompose above temperatures of ca 240 °C.
The anticarcinogenic activities of both the compound
D-H_A
d(D-H)
d(H_A)
d(D_A) \(DHA)
O(4)–H(4)_O(2)#1
N(2)–H(2)_O(5)#2
N(3)–H(3)_O(3)#3
0.82
0.86
0.86
1.97
1.97
2.10
2.779(3)
2.797(3)
2.943(3)
169.6
160.3
166.5
Symmetry transformations used to generate equivalent atoms: #1
x + 1, y - 1,z; #2 x, y + 1, z; #3 x + 1, y, z
1
:1/2H O and 2 were tested by using microculture tetra-
2
zolium assay [23] on HL-60 cells and sulforhodamine B
protechromosomic method [24] on BEL-7402 cells.
In order to examine the thermal stabilities of compounds
As shown in Table 6, the compound 1:1/2H O has more
2
1
3
1
:1/2H O and 2, TGA and DSC were carried out between
2
antitumor activities than compound 2 which is due to the
0 and 700 °C. The DSC-TGA curves for the compound
:1/2H O are illustrated in Fig. 5 and the hydrated form of
2
compound 1:1/2H O was used for TGA and DSC experi-
2
ments. TGA shows a weight loss in three stages. The first
ranges between 75 and 175 °C and showed about 3.4% loss
in weight. This might correspond to the loss of crystal
water [20–22]. The second of weight loss started at 250 °C
and continues up to 320 °C during which there was 89%
weight loss, the third completed up to 750 °C with 6% loss
in weight. Both the last two stages are due to the degra-
dation of the compound 1:1/2H O. In DSC, the compound
2
Fig. 6 The DSC-TGA curves for the compound 2(s)-(5-fluorouracil-
-aceto)amino-2-isopropyl acetic acid (2)
1
2
Table 6 Antitumor activity of compounds 1:1/2H O and 2 against
Hl-60 and BEL-7402 tumor cells line
Compound
Tumor cell
Concentration (mol/L)
-
0
4
-5
-6
10
-7
10
-8
10
1
10
1
:1/2H
2
O
HL-60
85.2
50.9
60.1
30.4
29.3
18.7
15.1
9.8
4.1
5.6
2.2
3.1
0
0
0
0
0
BEL-7402
HL-60
1.2
0
2
Fig. 5 The DSC-TGA curves for the compound 2(s)-(5-fluorouracil-
1
BEL-7402
1.1
2
-aceto)amino-2-isopropyl acetate hemihydrate (1:1/2H O)
1
23

J Chem Crystallogr (2008) 38:807–813
813
lower fat-solubility of compound 2. Obviously, both the
compound 1:1/2H O and 2 displayed prominent inhibition
3. Huang ZH, Lin ZL, Huang JL (2001) Eur J Med Chem 36:863
4
. Shi DQ, Chen Q, Li ZH (2005) Chin J Org Chem 5:549
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2
(
activity to HL-60 cell at high concentration and relatively
lower inhibition against BEL-7402 cell, while the effects of
inhibition against the two cells were opposite at low con-
centrations. Despite the sensitivity difference between
these cell lines, it might be indicated that the compound
5
. Li CZ, Wang LF, Li YZ, Xia CG, Dai RB (2000) Acta Cryst
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7
8
1
:1/2H O and 2 possibly had different inhibition mecha-
2
nisms against various tumor cells. Extensive antitumor
screening and intensive mechanism investigation are
demanded in this area to elucidate the mechanism and
develop more desirable bioactive agents.
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