Synthesis and biological evaluation of some stilbene derivatives

Article abstract of DOI:10.1007/s00044-010-9484-1

Several trans and cis stilbenes with substitution n the olefinic bridge were synthesized and characterized by IR, NMR and mass spectroscopy in an effort to obtain ubstances that could be more readily formulated. All the synthesized compounds were screened against Molt4/C8, CEM and L1210 cell lines. None of these compounds were ndowed with pronounced cytostatic activity. However,Schiff derivatives emerged as cytostatic agents (IC50: 0.77-10 μg/ml) that deserve further investigation. Springer Science+Business Media, LLC 2010.

Full text of DOI:10.1007/s00044-010-9484-1

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:1349–1356
DOI 10.1007/s00044-010-9484-1
ORIGINAL RESEARCH
Synthesis and biological evaluation of some stilbene derivatives
•
Subhas Somalingappa Karki Santosh Ramarao Bhutle
•
•
Subhas Sahoo Ratnakar Reddy Jan Balzarini
•
•
•
Erik De Clercq Satyanarayana Y. Darji
Received: 5 August 2010 / Accepted: 19 October 2010 / Published online: 5 November 2010
Ó Springer Science+Business Media, LLC 2010
Abstract Several trans and cis stilbenes with substitution
on the olefinic bridge were synthesized and characterized
by IR, NMR and mass spectroscopy in an effort to obtain
substances that could be more readily formulated. All the
synthesized compounds were screened against Molt4/C8,
CEM and L1210 cell lines. None of these compounds were
endowed with pronounced cytostatic activity. However,
Schiff derivatives emerged as cytostatic agents (IC50:
0.77–10 lg/ml) that deserve further investigation.
properties via the inhibition of tumor initiation, promotion
and progression (Jang et al., 1997). It has also been dem-
onstrated that RSV inhibits ribonucleotide reductase cata-
lyzing the rate limiting step of de novo DNA synthesis
(Fontecave, 1998). It exerts a nonselective cyclooxygenase-
1 (COX-1) and cyclooxygenase-2 (COX-2) inhibition (Jang
and Pezzuto, 1999). The antioxidant properties of resvera-
trol have been related to its polyphenolic nature, especially
to the presence of hydroxyl groups (Wright et al., 2001;
Stivala et al., 2001). Phenolic groups are also known as an
important structural determinant for estrogen receptor (ER)
binding (Sadler et al., 1998; Ekena et al., 1998; Gao et al.,
1999). Various trans stilbene compounds were reported
to be inhibitors of Cytochrome P450 (CYP). Resveratrol
showed an inhibitory effect on human CYP1A1 and
CYP1B1 (Chun et al., 1999; Chang et al., 2000). Recently,
Keywords Stilbenes ꢀ Cytostatic ꢀ Schiff ꢀ Olefine
Introduction
Cancer is one of the main reasons of death in both men and
women. One promising natural product is resveratrol
(3,40,5-trihydroxy-trans-stilbene) (RSV), a phytoalexin
found in grapes and in red wine. The interest in this mole-
cule has considerably increased in the last 10–12 years. The
anticancer activity of resveratrol was first revealed by its
ability to reduce the incidence of carcinogen-induced
development of cancers in experimental animals (Jang
et al., 1997; Dong, 2003). Since then, it has been demon-
strated that it possesses chemopreventive and cytostatic
rhapontigenin,
a natural hydroxystilbene, showed a
strong selectivity of CYP1A1 inhibition (Chun et al., 2001),
and it was found that the selectivities and inhibitory
potency of stilbene compounds tested against CYP1s were
sensitive to the substitution patterns on the trans stilbene
template. Cushman et al. (1992) have synthesized and
evaluated analogues of (Z)-l-(4-methoxyphenyl)-2-(3,4,5-
trimethoxyphenyl)ethene as potential cytotoxic and anti-
mitotic agents. Lion et al. (2005) synthesized a novel family
of monohydroxylated (E)-stilbenes and studied their ability
to inhibit the growth and induce apoptosis in human tumor
cell lines. Heynekamp et al. (2006) synthesized various
substituted trans stilbene including analogue of resveratrol
and proved that they inhibit the human tumor necrosis
factor a-induced activation of transcription factor nuclear
factor kappaB. Sangjun et al. (2009) synthesized cis stil-
bene derivative related to VIOXX and studied for their
inhibitory effects on cell cycle progression and anti-estr-
ogenicity in human adenoma breast cancer MCF-7 cells.
S. S. Karki (&) ꢀ S. R. Bhutle ꢀ S. Sahoo ꢀ R. Reddy ꢀ
S. Y. Darji
Department of Pharmaceutical Chemistry, KLE University’s
College of Pharmacy, Bangalore 560010, Karnataka, India
e-mail: subhasskarki@gmail.com
J. Balzarini ꢀ E. De Clercq
Rega Institute for Medical Research, Katholieke Universiteit
Leuven, B-3000 Leuven, Belgium
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Med Chem Res (2011) 20:1349–1356
Moran et al. (2009) synthesized fluorinated analogues of
resveratrol and assayed on a variety of cell lines, primarily
the non-small lung carcinoma cell line DLKP-A.
In this article we performed isosteric modifications of
resveratrol by keeping the stilbene backbone of RSV to
design substances that could be more readily formulated by
(i) replacing the hydroxyl by various functional groups and
(ii) introducing substituents on olefinic carbons and (iii)
Schiff bases derivatives.
and residue were purified by preparative TLC using 5%
ethanol in hexane as the eluent (3a–f) (Scheme 1,
Table 1).
Several derivatives containing acidic and basic func-
tional groups were prepared in an attempt to make com-
pounds that were more soluble in water and therefore be
formulated more easily (Cushman et al., 1992). Base-cat-
alyzed condition of phenyl acetic acid (4) with aryl alde-
hyde (5) in the presence of triethylamine gave the
carboxylic acid (6a–c) (Scheme 2, Table 2). Reaction of
SOCl2 with the carboxylic acid (6) in refluxing benzene
gave the corresponding acid chlorides (7), which, upon
subsequent reaction with appropriate amines, gave com-
pounds (8a–g) (Scheme 2, Table 2). 9a and b derivatives
were prepared by compound 6 with methanol using cata-
lytic H2SO4.
Results and discussion
Chemistry
Wittig reaction was carried out by using phosphonium
chloride (2) with aryl aldehyde in benzene in the pres-
ence of sodium hydride. Excess of sodium hydride was
quenched by addition of methanol and then chloroform
and water were added. After evaporating, organic layer
Several Schiff derivatives (12a–d) were prepared as
bioisosteric compounds of stilbene by refluxing aldehyde
(10) and aromatic amines (11) in toluene in a Dean stark
apparatus (Scheme 3, Table 3).
R'''
Scheme 1 General procedure
for the preparation of
3a–f reagents and conditions:
e CH3CN, triphenyl phosphine,
f NaH, aryl aldehyde, benzene,
0–5°C
e
Cl
f
P(Ph3)Cl
R''
R''
R''
2
1
3a-f
Table 1 Trans stilbenes 3a–f, and standard melphalan
R'"
R"
S. no
R00
R000
MP (°C)
IC50 (lg/ml)
L1210
Molt4/C8
CEM
3a
4-F
4-OCH3
4-N(CH3)2
4-OCH3
2-F
136–138
139–140
143–145
115–121
135–138
121–123
–
26 10
143 4.0
[200
[200
156 75
[200
3b
4-CH3
4-CH3
4-F
[200
3c
[200
[200
3d
62 15
72 1.0
[200
61 9.0
30 7.0
[200
83 11
78 18
[200
3e
4-CH3
4-F
2-F
3f
H
Melphalan
–
–
2.1 0.02
3.2 0.6
2.5 0.2
IC50: 50% inhibitory concentration
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Med Chem Res (2011) 20:1349–1356
1351
O
Scheme 2 General procedure
for the preparation of 6a–c,
8a–g, 9a and b reagents and
conditions: a triethyl amine,
acetic anhydride, dil HCl
b H2SO4, MeOH c SOCl2,
benzene, d Amines, 2 h, rt
COOCH3
COOH
COOH
a
b
+
R'
R'
R'
4
9a,9b
5
6a-c
c
COCl
R'
7
d
Y
R'
8a-g
Biological evaluation
(8c), the cytostatic activity somewhat increased, as par-
ticularly noted for 8c and 9a. However, the N-methyl-
amide derivatives (8a, b, f and g) were clearly less
cytostatic.
The effects of 18 stilbene analogues and 4 analogues of
Schiff derivatives as bioisosteres of stilbene on cell growth
are summarized in Tables 1, 2 and 3. This group of com-
pounds include 6 trans stilbenes (3a–f) (Table 1), 12 cis
stilbene derivatives with substitution on the bridge con-
necting two phenyl rings (6a–c, 8a–g, 9a and b) (Table 2),
and bioisosteres of stilbenes as Schiff derivatives
(12a–f) (Table 3).
In the third set of modifications, we designed Schiff
derivatives as a bioisosteric replacement of trans stilbenes.
All these compounds (12a–d) turned out to be much more
potent than trans stilbenes and cis restricted stilbenes in
inhibiting tumor cell proliferation (IC50: 0.77–10 lg/ml).
Several cytostatic activities were as potent as those found
for melphalan. These data justify more in-depth studies on
this type of compounds by introducing a variety of modi-
fications on the aryl moieties of these molecules.
All the trans stilbenes (3a–f) were poorly cytostatic
(Table 1). The IC50 values ranged between 26 and
[200 lM.
Regarding the cis stilbenes with substitutions on the
olefinic bridge (Table 2), there was not much improve-
ment in cytostatic activity. In separate experiments, a
COOH group was introduced on the olefinic carbon
linkage, and this resulted in the formation of compounds
6a, b and c (IC50 37 to [200 lg/ml). However, when the
–COOH group of the compound was converted to a
methyl ester (compound 9a and b) or the N-diethylamide
Conclusion
Several trans and cis stilbenes with substitution on the
olefinic bridge were synthesized in an effort to obtain
substances that could be more readily formulated. None of
these compounds emerged as cytostatic compounds. But
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Med Chem Res (2011) 20:1349–1356
Table 2 Compounds 6a–c, 8a–g and 9a and b
Y
R'
S. no
Y
R0
MP (°C)
IC50 (lg/ml)
L1210
Molt4/C8
CEM
93 10
6a
6b
6c
8a
8b
8c
8d
8e
8f
COOH
2-Cl
105–108
170–172
139–140
100–103
182–185
60–63
76 12
[200
37 24
89 2.0
[200
COOH
2-F
[200
[200
60
COOH
2-OH
2-Cl
[200
CONHCH3
CONHCH3
CON(C2H5)2
CONHC2H5
CONHC2H5
CONHCH3
CONHCH3
COOCH3
COOCH3
65 25
68 47
24 11
132 40
148 45
77 0.0
1
4-OCH3
2-Cl
166 16
128 58
18 12
14
2
H
99–102
135–138
77–80
112 44
150 71
26
8
4-OCH3
2-F
116 87
89 15
[200
85
9
72
[200
16
3
8g
9a
9b
2-OH
2-Cl
69–70
[200
113–115
127–130
25 10
66 46
1
9
19
7
4-OCH3
71
71 46
IC50: 50% inhibitory concentration
Scheme 3 General procedure
for the preparation of
12a–d reagents and conditions:
g toluene, Dean Stark apparatus
g
H2N
Ar'
N
+
Ar
Ar'
Ar
O
10
11
12a-d
Table 3 Compounds 12a–d
Ar'
Ar
N
S. no
Ar
Ar0
MP (°C)
IC50 (lg/ml)
L1210
Molt4/C8
CEM
10
12a
12b
12c
12d
2-Cl-phenyl
2-Cl-phenyl
2-Cl-phenyl
2-thiophene
3-Cl-4-F-phenyl
4-F-phenyl
57–55
35–37
38–40
40–42
6.4 2.9
6.0 0.7
2.1 1.4
3.2 1.8
3.9 3.0
0.77 0.22
1.5 0.9
4
2.1 1.7
4.5 2.6
25 18
4-Br-phenyl
3-Cl-4-F-phenyl
16
8
IC50: 50% inhibitory concentration
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Med Chem Res (2011) 20:1349–1356
1353
Schiff derivatives emerged as interesting antiproliferative
compounds against the three tumor cell lines evaluated.
J = 8 Hz), 6.99 (1H, d), 6.92 (1H, d), 6.71 (2H, d,
J = 8.8 Hz), 2.98 (6H, s, –N(CH3)2), 2.35 (3H, s, CH3).
(E)-1-(4-Methylphenyl)-2-(4-methoxyphenyl)-ethene (3c)
Experimental
Yield 25%; Anal. Calcd for C16H16O: C, 85.68; H, 7.19.
Found: C, 85.34; H, 6.99. FT-IR vmax cm-1 (KBr):
1
3049–3021, 2954–2916, 1603, 1515, 1439 and 1377. H-
Chemistry
NMR (CDCl3) d; 7.44 (2H, d, J = 8.8 Hz), 7.38 (2H, d,
J = 8 Hz), 7.15 (2H, d, J = 8 Hz), 7.01 (1H, d,
J = 16.4 Hz), 6.93 (1H, d, J = 16. 4 Hz), 6.89 (2H, d, J =
8.8 Hz), 3.83 (3H, s, OCH3), 2.36 (3H, s, –CH3).
The solvents (AR grades) were obtained from Sd Fine
Chem., Mumbai, and E. Merck, Mumbai. The reagents
(puriss grade) were obtained from Fluka and E. Merck.
FT-IR spectra were recorded in KBr powder on a Jasco
V410 FT-IR spectrometer by diffuse reflectance technique.
1H/13C NMR spectra were measured in CDCl3 and DMSO-
d6 on a Bruker Ultraspec AMX 400 MHz spectrometer.
The reported chemical shifts were against that of TMS.
Elemental Analysis was carried out at CDRI, Lucknow on
Elementar Vario EL III, Carlo Erba 1108.
(E)-1-(4-Fluorophenyl)-2-(2-fluorophenyl)-ethene (3d)
Yield 26%; Anal. Calcd for C14H10F2: C, 77.77; H, 4.66.
Found: C, 77.34; H, 4.29. FT-IR vmax cm-1 (KBr):
3077–3055, 2918, 1590, 1484 and 1438.
(E)-1-(4-Methylphenyl)-2-(2-fluorophenyl)-ethene (3e)
General procedure for the preparation of stilbenes 3a–f
Yield 24%; Anal. Calcd for C15H13F: C, 84.88; H, 6.17.
Found: C, 84.64; H, 5.99. FT-IR vmax cm-1 (KBr):
3081–3056, 2953–2919, 1590, 1483 and 1437.
A stirred solution of benzyl chloride 1 (2.88 g, 31.7 mmol)
in acetonitrile (20 ml) was treated with triphenylphosphine
(8.57 g, 32.7 mmol), and the mixture was refluxed with
stirring for 12 h and then evaporated. The crude product
was purified by crystallization from chloroform and ether,
affording 95% yield as a white solid 2. Sodium hydride (72
mg, 3 mmol) was added in portions to a well-stirred sus-
pension of phosphonium chloride 2 (2 mmol) and aryl
aldehyde (2 mmol) in benzene (20 ml) at 0–5°C, and the
mixture was allowed to warm up to room temperature.
After an additional stirring for 16 h, excess sodium hydride
was quenched by the addition of methanol (1 ml), after
which 30 ml of chloroform and water was added. The
organic and aqueous layers were then separated. Distilled
of the organic layer, the residue was purified by preparative
TLC using 5% ethanol in hexane as the eluent.
(E)-1-(4-Fluorophenyl)-2-phenyl-ethene (3f)
Yield 22%; Anal. Calcd for C14H14F: C, 84.82; H, 5.59.
Found: C, 84.67; H, 5.25. FT-IR vmax cm-1 (KBr):
3080–3023, 2953–2849, 1593, 1508 and 1448.
General procedure for the preparation
of compounds (6a–c)
A mixture of phenyl acetic acid 4 (2 mmol) substituted
benzaldehyde 5 (2 mmol) and triethylamine (0.5 ml) in
acetic anhydride (5 ml) was heated under reflux for 12 h
and poured into hot saturated sodium carbonate solution
(50 ml) and left overnight. The mixture was extracted with
ether (2 9 50 ml), the ether extracts were discarded, and
the aqueous solution was acidified with dilute HCl, after
which the precipitated product was filtered and dried.
Recrystallization from ethyl acetate–hexane gave the pure
products.
(E)-1-(4-Fluorophenyl)-2-(4-methoxyphenyl)-ethene (3a)
Yield 25%; FT-IR vmax cm-1 (KBr): 3042–3017,
2924–2844, 1604, 1573, 1511 and 1463. Anal. Calcd for
C15H13OF: C, 78.93; H, 5.74. Found: C, 78.25; H, 5.55.
(E)-1-(4-Methylphenyl)-2-(4-dimethylaminophenyl)-
ethene (3b)
(E)-3-(2-Chlorophenyl)-2-phenyl-prop-2-enoic acid (6a)
Yield 33%; Anal. Calcd for C15H11O2Cl: C, 69.64; H, 4.29.
Found: C, 69.25; H, 4.15. FT-IR vmax cm-1 (KBr):
Yield 23%; Anal. Calcd for C17H19N: C, 86.03; H, 8.07; N,
5.90 Found: C, 86.25; H, 7.89; N, 6.05. FT-IR vmax cm-1
(KBr): 3197–3021, 2916–2808, 1600, 1528, 1437 and
1363. 1H-NMR (CDCl3) d; 7.42 (4H, m), 7.13 (2H, d,
1
3250–2500, 1685, 1425 and 1266. H-NMR (CDCl3) d;
8.20 (1H, s), 7.37 (1H, d, J = 8 Hz), 7.31–7.26 (3H, m),
7.21–7.19 (2H, m), 7.15 (t, J = 15.2 Hz), 6.90 (1H, t,
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(E)-N-Diethyl-3-(2-chlorophenyl)-2-(phenyl)-
prop-2-enamide (8c)
J = 15.2 Hz), 6.76 (1H, d, J = 8 Hz). MS: m/z (%) 259
(M ? 1).
Yield 23%; Anal. Calcd for C19H20NOCl: C, 72.72; H,
6.42; N, 4.46. Found: C, 72.02; H, 6.99; N, 4.51. FT-IR
vmax cm-1 (KBr): 3442, 3077–3020, 2986–2873, 1621,
(E)-3-(2-Fluorophenyl)-2-phenyl-prop-2-enoic acid (6b)
Yield 44%; Anal. Calcd for C15H11O2F: C, 74.37; H, 4.58.
Found: C, 74.09; H, 4.41. FT-IR vmax cm-1 (KBr):
3200–2600, 1682 and 1620. 1H-NMR (CDCl3) d; 8.15 (1H,
s), 7.38–7.30 (3H, m), 7.25–7.21 (3H, m), 7.06–7.01 (1H,
m), 6.81–6.74 (2H, m). MS: m/z (%) 243 (M ? 2).
1
1573, 1470 and 1433. H-NMR (CDCl3) d; 7.39 (1H, d,
J = 8 Hz), 7.25–7.21 (5H, m), 7.16–7.11 (1H, m),
6.98–6.95 (1H, m), 6.79 (1H, s), 3.48 (2H, d, J = 8 Hz),
3.36 (2H, d, J = 8 Hz), 1.18 (3H, t, J = 12 Hz), 1.02 (3H,
t, J = 12 Hz).
(E)-3-(2-Hydroxyphenyl)-2-phenyl-prop-2-enoic acid (6c)
(E)-N-Ethyl-3-(phenyl)-2-(phenyl)-prop-2-enamide (8d)
Yield 46%; Anal. Calcd for C15H12O3: C, 74.99; H, 5.03.
Found: C, 75.12; H, 4.79. FT-IR vmax cm-1 (KBr): 3405,
3109–3051, 2970, 1713, 1613, 1454 and 1262.
Yield 44%; Anal. Calcd for C17H16NOCl: C, 71.45; H,
5.64; N, 4.90. Found: C, 69.98; H, 5.25; N, 5.01. FT-IR
vmax cm-1 (KBr): 3329, 3077–3018, 2974–2871, 1654,
1528, 1493 and 1261.
General procedure for the preparation
of compounds (8a–g)
(E)-N-Ethyl-3-(4-methoxyphenyl)-2-(phenyl)-
prop-2-enamide (8e)
A mixture of carboxylic acid 6 (0.5 mmol) and thionyl
chloride (1 ml) and benzene (10 ml) was refluxed for 6 h.
The excess thionyl chloride and benzene were removed at
reduced pressure, and the residue 7 was subsequently
mixed with amines (5 ml) and kept at room temperature for
2 h. The precipitated product was filtered, washed subse-
quently with 2% NaOH solution and water and dried. The
product was purified with suitable solvent.
Yield 44%; Anal. Calcd for C18H19NO2: C, 76.84; H, 6.81;
N, 4.98. Found: C, 76.02; H, 6.53; N, 5.01. FT-IR vmax
cm-1 (KBr): 3303, 3053–3004, 2966–2842, 1650, 1606,
1
1525, 1459 and 1349. H-NMR (CDCl3) d; 7.81 (1H, s),
7.49–7.43 (3H, m), 7.27–7.25 (2H, m), 6.90 (2H, d,
J = 8.8 Hz), 6.65 (2H, d, J = 8.8 Hz), 5.41 (1H, s, br, NH,
D2O exchangeable), 3.74 (3H, s, OCH3), 3.37–3.30 (2H, q,
CH2), 1.07 (3H, t, J = 14.5 Hz, CH3).
(E)-N-Methyl-3-(2-chlorophenyl)-2-(phenyl)-
prop-2-enamide (8a)
(E)-N-Methyl-3-(2-fluorophenyl)-2-(phenyl)-
prop-2-enamide (8f)
Yield 46%; Anal. Calcd for C16H14ONCl: C, 70.72; H,
5.19; N, 5.15. Found: C, 70.15; H, 5.07; N, 5.21. FT-IR
vmax cm-1 (KBr): 3320, 3078–3023, 2940–2931, 1654,
Yield 45%; Anal. Calcd for C16H14NOF: C, 75.28; H, 5.53;
N, 5.49. Found: C, 69.89; H, 5.36; N, 5.35. FT-IR vmax
cm-1 (KBr): 3316, 3079–3022, 2933, 1656, 1619, 1454
1
1617, 1403 and 1269. H-NMR (CDCl3) d; 8.01 (1H, s),
1
7.35–7.33 (3H, m), 7.26 (2H, s), 7.20–7.18 (2H, m),
7.10–7.06 (1H, m), 6.85 (1H, t, J = 18.8 Hz), 6.65 (1H, d,
J = 7.6 Hz), 5.55 (1H, s, br, NH, D2O exchangeable), 2.88
(3H, s, –CH3). MS: m/z (%) 272 (M ? 1).
and 1271. H-NMR (CDCl3): d; 8.01 (1H, s), 7.43–7.39
(3H, m), 7.24–7.22 (2H, m), 7.17–7.15 (1H, m), 7.01–6.97
(1H, m), 6.74 (1H, t, J = 15.2 Hz), 6.61 (1H, t,
J = 15.2 Hz), 5.53 (1H, s, br, NH, D2O exchangeable),
2.86 (3H, s, –CH3).
(E)-N-Methyl-3-(4-methoxyphenyl)-2-(phenyl)-
prop-2-enamide (8b)
(E)-N-Methyl-3-(2-hydroxyphenyl)-2-(phenyl)-
prop-2-enamide (8g)
Yield 48%; Anal. Calcd for C17H17NO2: C, 76.38; H, 6.41;
N, 5.24. Found: C, 76.19; H, 6.25; N, 5.29. FT-IR vmax
cm-1 (KBr): 3442, 3099–3006, 2958–2836, 1661, 1599,
Yield 38%; Anal. Calcd for C16H15NO2: C, 75.87; H, 5.97;
N, 5.53. Found: C, 75.19; H, 5.55; N, 5.61. FT-IR vmax
cm-1 (KBr): 3406, 3106–3057, 2966–2929, 1714, 1667,
1
1514, 1460 and 1405. H-NMR (CDCl3) d; 7.82 (1H, s),
1
7.48–7.42 (3H, m), 7.26–7.24 (2H, m), 6.90 (2H, d,
J = 8.8 Hz), 6.64 (2H, d, J = 8.8 Hz), 5.44 (1H, s, br, NH,
D2O exchangeable), 3.74 (3H, s, OCH3), 2.84 (3H, s, CH3).
1612, 1488 and 1454. H-NMR (CDCl3) d; 8.01 (1H, s),
7.35–7.33 (3H, m), 7.26 (2H, s), 7.20–7.18 (2H, m),
7.10–7.06 (1H, m), 6.85 (1H, t, J = 18.8 Hz), 6.65 (1H, d,
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Med Chem Res (2011) 20:1349–1356
1355
1
J = 7.6 Hz), 5.55 (1H, s, br, NH, D2O exchangeable), 2.88
(3H, s, –CH3).
cm-1 (KBr): 3075–2997, 2918–2848, 1617 and 1498. H-
NMR (CDCl3): d = 8.9 (1H, s), 8.22 (1H, d, J = 7.6 Hz),
7.47–7.35 (3H, m), 7.27–7.23 (2H, m), 7.13–7.08 (2H, m),
6.85 (1H, t, J = 18.8 Hz), 6.65 (1H, d, J = 7.6 Hz), 5.55
(1H, s, br, NH), 2.88 (3H, s, –CH3).
General procedure for the preparation of compounds
9a and b
Concentrated H2SO4 (0.5 ml) was added to a stirred solu-
tion of carboxylic acid (0.5 mmol) in absolute methanol
(20 ml) and the mixture was heated under reflux for 6 h.
Excess of methanol was removed by evaporation, and the
residue was poured into ice water. The product was
extracted with ether (2 9 20 ml), and the combined
extracts were washed with 2% aqueous NaOH solution
(2 9 50 ml) followed by water (200 ml). Evaporation of
ether layer gave the desired product.
(E)-N-(2-Chlorobenzyledene)-4-bromobenzenamine (12c)
Yield 52%; Anal. Calcd for C13H9ClNBr: C, 53.01; H,
3.08; N, 4.75. Found: C, 52.75; H, 2.94; N, 4.94. FT-IR
v
max cm-1 (KBr): 3061–3018, 2918–2848, 1618 and 1484.
1H-NMR (CDCl3): d = 8.92–8.90 (1H, m), 7.26–7.22 (1H,
m), 7.56–7, 52 (2H, m), 7.47–7.38 (2H, m), 7.26 (1H, d,
J = 9.6 Hz), 7.16–7.12 (2H, m).
(E)-3-Chloro-4-fluoro-N-(thiophen-2-ylmethylene)-
benzenamine (12d)
(E)-Methyl-3-(2-chlorophenyl)-2-(phenyl)-prop-
2-enoate (9a)
Yield 56%; Anal. Calcd for C11H7ClFNS: C, 55.12; H,
2.94; N, 5.84. Found: C, 55.01; H, 3.01; N, 5.55. FT-IR
Yield 48%; Anal. Calcd for C16H13O2Cl: C, 70.46; H, 4.80.
Found: C, 69.99; H, 4.98. FT-IR vmax cm-1 (KBr): 3057,
2991–2848, 1704, 1570, 1496 and 1387.
1
vmax cm-1 (KBr): 3060, 2954, 2886, 1615 and 1492. H-
NMR (CDCl3): d = 8.53 (1H, s), 7.54 (1H, d,
J = 5.2 Hz), 7.50 (1H, d, J = 3.6 Hz), 7.29–7.26 (1H, m),
7.17–7.08 (3H, m).
(E)-Methyl-3-(4-methoxyphenyl)-2-(phenyl)-prop-
2-enoate (9b)
Cytostatic activity
Yield 45%; Anal. Calcd for C17H16O3: C, 76.10; H, 6.10.
Found: C, 75.98; H, 5.79. FT-IR vmax cm-1 (KBr): 3055,
2954–2837, 1704, 1597, 1513 and 1385.
The methodology for measuring the cytostatic activity in
Molt 4/C8, CEM and L1210 assays has been published pre-
viously (Baraldi et al., 2004). In brief, varying concentrations
of compounds were incubated at 37°C with the cells for 72
(human Molt 4/C8 or CEM T-lymphocytes) or 48 h (murine
L1210 cells). After the incubation period, the cell number
was counted by a coulter counter (Harpenden Herz, UK).
General procedure for the preparation of Schiff
derivatives (12a–d)
A solution of aldehyde 10 (1 mmol) and aniline 11
(1 mmol) in toluene (5 ml) were heated to reflux in a Dean
Stark apparatus for 16 h. After the solvent was removed in
vacuo, the crude product was recrystallised from ethanol to
give 45–50% yield.
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