Synthesis and biological evaluation of resveratrol-coumarin hybrid compounds as potential antitumor agents

Article abstract of DOI:10.1007/s00044-012-0159-y

Eighteen resveratrol-coumarin hybrid compounds (6 or 7-styryl-3- phenylcoumarin) were designed, synthesized and thirteen compounds were evaluated for their antitumor activities against MCF-7, HCT-28, and K562 tumor cell lines. Among them, compounds 2Z, 2E, 5E, and 7E showed varying degrees of growth inhibition of the above cell lines (IC₅₀: 3.78-19.16 μmol/L). On the basis of the biological results, structure-activity relationships were obtained and discussed.

Full text of DOI:10.1007/s00044-012-0159-y

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:1630–1640
DOI 10.1007/s00044-012-0159-y
ORIGINAL RESEARCH
Synthesis and biological evaluation of resveratrol–coumarin
hybrid compounds as potential antitumor agents
•
Wei Shen Jianfeng Mao Juan Sun
•
•
•
Minjie Sun Can Zhang
Received: 10 November 2011 / Accepted: 14 June 2012 / Published online: 1 July 2012
Ó Springer Science+Business Media, LLC 2012
Abstract Eighteen resveratrol–coumarin hybrid com-
pounds (6 or 7-styryl-3-phenylcoumarin) were designed,
synthesized and thirteen compounds were evaluated for
their antitumor activities against MCF-7, HCT-28, and
K562 tumor cell lines. Among them, compounds 2Z, 2E,
5E, and 7E showed varying degrees of growth inhibition of
the above cell lines (IC50: 3.78–19.16 lmol/L). On the
basis of the biological results, structure–activity relation-
ships were obtained and discussed.
anti-obesity, and anti-diabetic activity (Szkudelska and
Szkudelski, 2010). One of the most striking biological
activities of RV, which has been extensively investigated,
is its antitumor property, and it was discovered as a
promising cancer chemopreventive agent on account of its
outstanding inhibition on cellular events associated with
cancer initiation, promotion, and progression (Jang et al.,
1997). It has been documented that RV can modulate
various signal transduction pathways resulting in the pre-
vention of the carcinogenesis from diverse aspects. Several
transcription factors such as NF-JB, AP-1, cyclooxygen-
ase, and kinases can be targeted by RV (Athar et al., 2009).
However, its low bioavailability and rapid clearance from
the circulation restrict it to behaving as an antitumor drug
(Jiang, 2008).
Keywords Resveratrol ꢀ Coumarin ꢀ Wittig reaction ꢀ
Perkin reaction ꢀ Antitumor activity
Introduction
On the other hand, coumarins which present another large
family of natural and synthetic origin showing numerous
biological effects such as anti-HIV, antitumor, antibacterial,
antioxidation, and so on have a skeleton of benzopyrone
Resveratrol (trans-3,40,5-trihydroxystilbene, RV) (Fig. 1)
is a phytoalexin which is present in a number of plant
species. Many researches on the biological activities of
resveratrol have been reported including antioxidation
(Fauconneau et al., 1997), antiplatelet aggregation (Pace-
Asciak et al., 1995), cardioprotective activity (Mokni
et al., 2007), antitumor activity (Bishayee et al., 2010),
´
(Pengsuparp et al., 1996; Elinos-Baeza et al., 2005; Cottig-
lial et al., 2001; Torresa et al., 2006). For example, osthole
showed significant antiproliferative activity against some
tumor cell lines in vitro (Fujioka et al., 1999) (Fig. 2).
Bearing in mind the antitumor activity of RV and cou-
marin derivates and the similarity of the skeletons between
these two series of compounds, we designed a series of
compounds which combined two RV molecules by a
skeleton of benzopyrone in which one double bond is fixed
to the trans isomeric form by the ring of pyrone and the
other remained as cis–trans isomerism (Fig. 3). It was
reported that methylation of the hydroxyl groups in the RV
(trans-3,40,5-trimethoxyresveratrol, TMRV) (Fig. 4) can
enhance its antitumor activity (Cardile et al., 2005), so we
used the methoxyl groups instead of hydroxyl groups in the
same position as those in the RV fragment. In this way, 18
Wei Shen and Jianfeng Mao contributed equally to this work.
W. Shen ꢀ J. Mao ꢀ J. Sun ꢀ C. Zhang (&)
Center for Drug Discovery, School of Pharmacy,
China Pharmaceutical University, Nanjing 210009,
People’s Republic of China
e-mail: zhangcancpu@yahoo.com.cn
M. Sun
Department of Pharmaceutics, School of Pharmacy,
China Pharmaceutical University, Nanjing 210009,
People’s Republic of China
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Med Chem Res (2013) 22:1630–1640
Fig. 1 Structure of trans-resveratrol
Fig. 2 Osthole
1631
Fig. 4 Trans-3,40,5-trimethoxyresveratrol
conditions were investigated: The compound 2 reacted
with phenylacetyl chloride in acetone when potassium
carbonate existed or reacted with arylacetic acid when
acetic anhydride and triethylamine existed. The latter
condition resulted in a better yield. The compound 5 was
synthesized by bromination of the compound 3 with
N-bromosuccinimide (NBS) in benzene followed by
formylation with hexamine. Subsequently, the final prod-
ucts (Tables 1, 2) were synthesized by treatment of the
compound 5 with phosphorus ylides (the compound 8)
formed by the reaction of triphenyl phosphine with corre-
sponding benzylchloride, and the E and Z isomers were
isolated by column chromatography.
new resveratrol–coumarin hybrids based on replacing the
methoxyl groups in different positions of two benzene rings
were prepared by convenient synthesis methods and first
reported. 13 of these compounds’ in vitro antitumor
activity was evaluated against MCF-7, HCT-28, and K562
tumor cell lines and the structure–activity relationships
were discussed.
Biological activity and discussion
The cytotoxic activities of the 13 new compounds against
MCF-7, HCT-28, and K562 tumor cell lines are summa-
rized in Table 3. The results indicated that compounds
3Z–7Z showed no inhibition activity to these three tumor
cell lines. Compound 3E only exhibited cytotoxic activity
against MCF-7 tumor cell line. Compounds 6E, 8Z, and 8E
have no inhibition activity against K562 tumor cell line.
Compounds 2Z, 2E, 5E, and 7E showed varying degrees of
growth inhibition of all test tumor cell lines (IC50:
3.78–19.16 lmol/L).
Compound 7E shows the most activity against MCF-7
cell lines (IC50: 4.23 lmol/L; TMRV IC50: 8.41 lmol/L).
Compound 2E is the most active compound against
HCT-28 cell lines (IC50: 3.78 lmol/L; TMRV IC50:
4.83 lmol/L). Compound 2Z exhibits the most activity
Results and discussion
Chemistry
The synthesis of the resveratrol–coumarin hybrid com-
pounds (Scheme 1) was started with methyl-substituted
phenol (the compound 1). The compound 2 was synthe-
sized by the Duff reaction involving direct treatment of the
compound 1 and hexamine in glycerol and boric acid under
150–160 °C. It was found that the Remier–Tiemann reac-
tion was not valid here due to the orienting effect of the
substitute group on the benzene ring. The Perkin reaction
was accomplished to form the compound 6 and two
Fig. 3 Target compounds
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Med Chem Res (2013) 22:1630–1640
Scheme 1 Synthesis of resveratrol–coumarin hybrid compounds.
Reagents and conditions
anhydride reflux; c NBS, benzene, reflux for 6 h; d hexamine, 50 %
AcOH, reflux; e SOCl2, 0–10 °C; f triphenyl phosphine, chloroform,
reflux for 2 h; g 50 % NaOH, CH2Cl2, 0 °C
a hexamine, glycerol, boric acid,
150–160 °C; b substituted phenylacetic acid, triethylamine, acetic
Table 2 Structures of the 7-styryl-3-phenylcoumarin derivates
Table 1 Structures of the 6-styryl-3-phenylcoumarin derivates
Compound
Configuration
R
R1
Compound
Configuration
R
R1
2Z
2E
3Z
3E
4Z
5Z
5E
6Z
6E
7Z
7E
8Z
8E
Z isomer
E isomer
Z isomer
E isomer
Z isomer
Z isomer
E isomer
Z isomer
E isomer
Z isomer
E isomer
Z isomer
E isomer
H
4-OCH3
4-OCH3
3,5-OCH3
3,5-OCH3
H
H
9E
E isomer
E isomer
E isomer
E isomer
E isomer
H
4-OCH3
3,5-OCH3
H
H
10E
11E
12E
13E
H
H
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
3,4-OCH3
3,4-OCH3
3,4-OCH3
3,4-OCH3
3,4-OCH3
3,4-OCH3
4-OCH3
3,5-OCH3
3,5-OCH3
3,5-OCH3
H
(3Z–7Z) cannot bind to the receptor, while the trans form
hybrid compounds could be fixed in the receptor. These
results suggested to us that the steric conformation of the
double bond at the 6 position should be a very important
factor for the inhibition activity of these compounds.
Meanwhile, 4-methoxyl group on the benzene ring was
found to play a very important role in the cytotoxic potency,
while 3,5-methoxyl group is unnecessary. These results
provided us a better understanding of the structure activity
relationships of resveratrol–coumarin hybrid compounds as
a potential antitumor agent. Further studies are being
undertaken in our group to explore more resveratrol–cou-
marin hybrid compounds.
H
4-OCH3
4-OCH3
3,5-OCH3
3,5-OCH3
against k562 cell lines (IC50: 3.79 lmol/L; TMRV IC50:
6.39 lmol/L). In onecertain cellline, each compound reveals
more potent cytotoxic activity than TMRV, respectively.
Among all thirteen resveratrol–coumarin hybrid com-
pounds, the cytotoxic activities of the trans-6-substituted
styryl hybrid compounds were more active than cis-6-
substituted styryl hybrid compounds. All the trans form
hybrid compounds showed inhibition activities to the
MCF-7 tumor cell line and exhibited a certain extent of
specificity. Among the cis form hybrid compounds, only
2Z and 8Z showed inhibition activities. It may be
explained by the fact that most cis form hybrid compounds
Conclusions
The synthesis of the resveratrol–coumarin hybrid com-
pounds (Scheme 1) was started with methyl-substituted
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Med Chem Res (2013) 22:1630–1640
1633
Table 3 IC50 (lmol/L) of resveratrol–coumarin hybrid compounds on three tumor cell lines
Compound
MCF-7
HCT-28
K562
TMRV
2Z
8.41
10.89
7.32
N/A
13.50
N/A
N/A
11.23
N/A
14.50
N/A
4.23
9.00
7.41
4.83
10.65
3.78
N/A
6.39
3.79
13.02
N/A
N/A
N/A
N/A
11.53
N/A
N/A
N/A
8.76
N/A
N/A
2E
3Z
3E
N/A
4Z
N/A
5Z
N/A
5E
19.16
N/A
6Z
6E
10.75
N/A
7Z
7E
7.14
13.46
10.09
8Z
8E
IC50 represents the half maximal (50 %) inhibitory concentration
N/A represents that the compound shows no growth inhibition effect on the cell line
H3CO
O
O
2E
O
O
2Z
OCH3
OCH3
H3CO
O
O
3E
O
O
3Z
H3CO
OCH3
OCH3
O
O
4Z
OCH3
OCH3
OCH3
H3CO
O
O
5Z
O
O
5E
H3CO
OCH3
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Med Chem Res (2013) 22:1630–1640
Table 3 continued
OCH3
OCH3
OCH3
OCH3
6E
O
O
O
O
6Z
OCH3
OCH3
OCH3
H3CO
OCH3
O
O
O
O
7E
7Z
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
H3CO
O
O
O
O
8E
8Z
H3CO
OCH3
H3CO
O
O
O
O
9E
H3CO
10E
OCH3
OCH3
OCH3
O
O
O
O
12E
11E
H3CO
OCH3
OCH3
H3CO
H3CO
O
O
TMRV
OCH3
13E
OCH3
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Med Chem Res (2013) 22:1630–1640
1635
phenol (the compound 1). The compound 2 was further
synthesized by the Duff reaction involving direct treatment
of the compound 1 and hexamine in glycerol and boric acid
under 150–160 °C. The Remier–Tiemann reaction was
found invalid here due to the orienting effect of the sub-
stitute group on the benzene ring. The Perkin reaction was
accomplished to form the compound 6 and two scenarios
were investigated: the compound 2 reacted either with
phenylacetyl chloride in acetone when potassium carbonate
existed or arylacetic acid when acetic anhydride and tri-
ethylamine existed. The latter condition resulted in a better
yield. The compound 5 was synthesized by bromination of
the compound 3 with N-bromosuccinimide (NBS) in ben-
zene followed by formylation with hexamine. Subse-
quently, the final products (Tables 1, 2) were synthesized
by treatment of the compound 5 with phosphorus ylides
(the compound 8) formed by the reaction of triphenyl
phosphine with corresponding benzylchloride, and the
E and Z isomers were isolated by column chromatography.
In summary, eighteen hybrid compounds with resvera-
trol–coumarin skeleton were synthesized and first reported.
Their cytotoxic activities against MCF-7, HCT-28, and
K562 tumor cell lines were evaluated. Compounds 2Z, 2E,
5E, and 7E showed varying degrees of growth inhibition of
these three tumor cell lines. Due to the poor solubility
of the compounds containing 7-styryl-3-phenylcoumarin
skeleton, the in vitro antitumor activities of these com-
pounds were not evaluated. At present, we are exploring
demethylation or glycosylation after demethylation (via a
linker-like succinate (Biasutto et al., 2009) of these com-
pounds to increase their solubility, and comparing antitumor
activities to the demethylation products of the 6-styryl-3-
phenylcoumarin derivates. These modifications were
expected to produce some compounds with potentially
higher antitumor activities and complete the structure–
activity relationships.
using silica gel GHLF uniplates from Yantai Huiyou Silica
Gel Development Co. Ltd. (China) visualized under long-
and short-wave UV irradiation along with staining with
phosphomolybdic acid/heat, iodine, or KMnO4. Solvent
extracts were dried over anhydrous sodium sulfate unless
otherwise stated. Where appropriate, the crude products
were separated by column chromatography on silica gel
(230–400 mesh) from Qingdao Haiyang Chemical Co. Ltd.
(China).
Melting points are uncorrected and were determined
employing an RY-1 apparatus from Tianjin Analytical
Instrument Factory (China). The 1H-NMR spectra were
recorded employing Bruker AV-300 or AV-500 instru-
ments using a deuterated solvent and were referenced to
either TMS or the solvent. The reported figures are given as
ppm. Infrared spectra were recorded on a FT-IR spectro-
photometer employing Nicolet Impact 410 instrument
using thin KBr disks prepared under high pressure or liquid
films prepared with CH2Cl2. Mass spectra were recorded
employing Agilent 1100 LC–MS instrument. Elemental
analyses were determined employing Vario EL III instru-
ment (German).
General experimental procedure for the synthesis
of 2a–b
To a three-neck round-bottomed flask, glycerol (148 mL)
and boric acid (43.2 g, 0.70 mol) were added; the mixture
was heated to 170 °C and maintained for 0.5 h. Then, it
was cooled to 150 °C, and hexamine (30.8 g, 0.22 mol)
and compound 1 (21.6 g, 0.20 mol) were added without
delay. The reaction mixture was maintained at 150–160 °C
for 10 min, then cooled to 110 °C rapidly. A solution of
concentrated sulfuric acid (36.8 ml) in water (124 mL) was
added, and the mixture was stirred for 1 h. The product was
obtained by steam distillation.
2-Hydroxy-5-methylbenzaldehyde (2a) (yield 27 %);
yellow solid; mp 56 °C; 1H-NMR (300 MHz, CDCl3,
dppm): 10.83 (s, 1H, –OH), 9.85 (s, 1H, –CHO), 7.33–7.35
(m, 2H, 4-H, 6-H), 6.89 (d, 1H, J = 9.0 Hz, 3-H), 2.33
(s, –CH3).
Experimental
Chemistry
2-Hydroxy-4-methylbenzaldehyde (2b) (Yield 16.1 %);
1
3,4-Dimethoxyphenylacetic acid hydrazide (99.6 %) was
purchased from Zhejiang Liaoyuan Pharmaceutical Co. Ltd.
(China). 2-Chloro-1-methylpyridiniumiodide (99.4 %) was
obtained from Suzhou Highfine Biotech Co. Ltd. (China).
3,5-Dimethoxybenzaldehyde (99.93 %) was provided by
Jiangsu Yadong Chemicals Co. Ltd. (China). 4-Methoxy-
phenylacetic acid (99.2 %) was supplied by Liyang Organo
Synthesis Chemical Co. Ltd. (China). 4-Methoxybenzyl
alcohol (99 %) was purchased from Shanghai Jiachen Chemi-
cals Co. Ltd. (China). Other reagents were used as purchased
unless otherwise stated. Reactions were monitored by TLC
colorless needle crystal; mp 60 °C; H-NMR (300 MHz,
CDCl3, dppm): 10.98 (s, 1H, –OH), 9.76 (s, 1H, –CHO),
7.36 (d, 1H, J = 7.8 Hz, 6-H), 6.76 (d, 1H, J = 8.1 Hz,
5-H), 6.73 (s, 1H,3-H), 2.31 (s, –CH3).
General experimental procedure for the synthesis
of 3a–e
Method A To a three-neck round-bottomed flask, compound
2 (4 g, 30 mmol), sodium carbonate (15 g, 141.5 mol), and
acetone (300 mL) were added; then, a solution of
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Med Chem Res (2013) 22:1630–1640
phenylacetyl chloride (8.1 mL) in acetone (50 mL) was
added dropwise. The reaction mixture was refluxing for 6 h,
and then cooled to room temperature. After evaporated under
vacuum, 200 ml water was added to the residue to give a
white solid. The resulting precipitate was filtered, washed,
and dried. Recrystallization from alcohol afforded crystal
products.
further purification and was used directly for the next
step.
General experimental procedure for the synthesis
of 5a–e
Compound 4 (2.5 mmol) and hexamine (5 mmol) were
refluxing in 50 % acetic acid (40 mL) for 4 h. Then, con-
centrated hydrochloric acid (20 mL) was added, and the
mixture continued refluxing for 15 min, was cooled, and
poured into ice water (200 mL) to give the solid. The solid
was filtered, dried, purified by flash chromatography.
6-Formyl-3-phenylcoumarin (5a) (Yield 70 %); white
solid; mp 206–208 °C; 1H-NMR (300 MHz, CDCl3, dppm):
10.06 (s, 1H, –CHO), 8.05–8.10 (m, 2H, C-5 and C-7-H),
7.90 (s, 1H, C-4-H), 7.49–7.73 (m, 6H, C-8 and Ar–H).
6-Formyl-3-(4-methoxyphenyl)coumarin (5b) (Yield
Method B To a three-neck round-bottomed flask, com-
pound 2 (7.8 g, 58 mmol), 4-methoxyphenylacetic acid
(9.6 g, 58 mmol), acetic anhydride (23.7 g, 232 mmol), and
triethylamine (11.7 g, 116 mmol) were added. The reaction
mixture was refluxing for 6 h. Then, the reflux device was
changed into a distillation device. The reaction mixture was
distilled until no distillate came out, then cooled, and anhy-
drous diethyl ether (50 mL) was added to give a yellow
solid. The resulting precipitate was filtered, washed, and
dried. Recrystallization from alcohol afforded crystal
products.
1
69 %); white solid; mp 193–194 °C; H-NMR (300 MHz,
3-(4-Methoxyphenyl)-6-methylcoumarin (3a) (Yield
95 %); Method A; colorless needle crystal; mp 146–
CDCl3, dppm): 10.05 (s, 1H, –CHO), 7.84–8.08 (m, 2H,
C-5 and C-7-H), 7.84 (s, 1H, C-4-H), 7.67–7.72 (m, 2H, C0-
2 and C0-6-H), 7.49 (d, 1H, J = 8.4 Hz, C-8-H), 6.98–7.02
(m, 2H, C0-3 and C0-5-H), 3.87 (s, 3H, –OCH3).
1
147 °C; H-NMR (300 MHz, CDCl3, dppm): 7.75 (s, 1H,
4-H), 7.24–7.71 (m, 8H, Ar–H), 2.42 (s, 3H, –CH3).
7-Methyl-3-phenylcoumarin (3b) (Yield 97 %); Method
A; colorless needle crystal; mp 174–176 °C; 1H-NMR
(500 MHz, CDCl3, dppm): 7.72 (s, 1H, 4-H), 7.04–7.64
(m, 8H, Ar–H), 2.41 (s, 3H, –CH3).
6-Formyl-3-(3,4-dimethoxy-phenyl)coumarin (5c) (Yield
65 %); yellow solid; mp 196–197 °C; 1H-NMR (300 MHz,
CDCl3, dppm): 10.06 (s, 1H, –CHO), 8.02–8.10 (m, 2H, C-5
and C-7-H), 7.86 (s, 1H, C-4-H), 7.51 (d, 1H, J = 8.4 Hz,
C-8-H), 7.26–7.32 (m, 2H, C0-2 and C0-6-H), 6.97 (s, 1H,
J = 9.0 Hz), 3.96 (s, 3H, –OCH3), 3.95 (s, 3H, –OCH3).
7-Formyl-3-phenylcoumarin (5d) (Yield 61 %); white
solid; mp 187–188 °C; 1H-NMR (500 MHz, CDCl3,
dppm): 10.10 (s, 1H, –CHO), 7.81–7.85 (m, 3H), 7.70–7.74
(m, 3H), 7.44–7.50 (m, 3H).
3-(4-Methoxyphenyl)-6-methylcoumarin (3c) (Yield
81 %); Method B; yellow needle crystal; mp 151–152 °C;
1H-NMR (300 MHz, CDCl3, dppm): 7.72(s, 1H, 4-H), 7.68
(d, 2H, J = 9 Hz, C-20 and C-60-H), 7.24–7.33 (m, 3H, C-5, 7
and 8-H), 6,99 (d, 2H, J = 9 Hz, C-30 and C-50-H), 3.87 (s,
3H, –OCH3), 2.43 (s, 3H, –CH3).
3-(3, 4-Dimethoxyphenyl)-6-methylcoumarin (3d) (Yield
73.6 %); Method B; Yellow needle crystal; mp: 156–
7-Formyl-3-(4-methoxyphenyl)coumarin (5e) (Yield
71.4 %); yellow solid; mp 214–215 °C; 1H-NMR
(500 MHz, CDCl3, dppm): 10.09 (s, 1H, –CHO), 7.67–7.82
(m, 6H), 7.00 (m, 2H), 3.87 (s, 3H).
1
158 °C, H-NMR (300 MHz, CDCl3, dppm): 7.69 (s, 1H),
7.22–7.31 (m, 5H), 6.92 (d, J = 8.3 Hz, 1H), 3.92 (s, 3H),
3.91 (s, 3H), 2.40 (s, 3H).
3-(4-Methoxyphenyl)-7-methylcoumarin (3e) (Yield
50 %); Method B; light yellow needle crystal; mp 169–
172.5 °C; 1H-NMR (300 MHz, CDCl3, dppm): 7.71 (s, 1H,
4-H), 7.65 (d, J = 8.6 Hz, 2H), 7.38 (d, J = 7.8 Hz 1H),
7.14 (s, 1H), 7.08 (d, J = 7.8 Hz, 1H), 6.96 (d, J = 8.6 Hz,
2H), 3.84 (s, 3H, –OCH3), 2.45 (s, 3H, –CH3).
General experimental procedure for the synthesis
of 7a–b
Compound 6 (7.6 g, 45.2 mmol) was dissolved in diethyl
ether (34 mL), and then thionyl dichloride (10.8 g,
90.4 mmol) in diethyl ether (34 mL) was added dropwise
under 0 °C, and was continuously stirred for 2 h. Then,
50 mL water was added, and the organic layer was sepa-
rated. The water layer was extracted with diethyl ether
(50 mL 9 3), and the organic layers were combined, dried,
filtered, and evaporated to afford the products. The
resulting crude products, 4-methoxybenzyl chloride (7a)
and 3,5-dimethoxylbenzyl chloride (7b), were used as a
starting compound in the subsequent step without
purification.
General experimental procedure for the synthesis of 4
Compound 3 (4 mmol), N-bromosuccinimide (4.4 mmol),
and benzoyl peroxide (1 % mmol) were refluxing in ben-
zene (20 mL) for 6 h. The mixture was evaporated under
vacuum, and the residue was washed by hot water (50 mL)
and ethanol (5 mL) in turn and dried. The crude solid 6 or
7-bromomethyl-3-substituted phenylcoumarin needed no
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Med Chem Res (2013) 22:1630–1640
1637
lamellar crystal; mp 183–185 °C; IR (KBr) v(cm-1): 3055,
2830, 1717, 1604, 1510, 1447, 1356, 1253, 1176, 1108,
General experimental procedure for the synthesis
of 8a–c
1
963, 786, 696; H-NMR (300 MHz, CDCl3, dppm): 7.63
Method A Triphenyl phosphine (44 mmol) and the com-
pound 7 (40 mmol) were refluxing in trichloromethane for
3–4 h, then cooled to room temperature, and poured into
anhydrous diethyl ether (160 ml). The mixture was stirred
fiercely under 0 °C to give a white solid. The solid was
filtered and dried.
(s, 1H, H-4), 7.60–7.62 (m, 2H, H-5 and H-7), 7.25–7.38
(m, 5H, H-phenyl), 7.09–7.20 (m, 3H), 6.67–6.72 (m, 2H),
6.55 (d, J = 12 Hz, 1H), 6.44 (d, J = 12 Hz, 1H), 3.73 (s,
3H, OCH3); MS (ESI) m/z: 355.2 (M? ? 1). Anal. Calcd
for C24H18O3: C, 81.34; H, 5.12. Found: C, 81.58; H, 5.16.
Trans-6-(4-methoxystyryl)-3-phenylcoumarin
(2E)
Method B Triphenyl phosphine (44 mmol) and benzyl
chloride (40 mmol) were refluxing in trichloromethane for
3–4 h, then cooled to the room temperature, and poured
into anhydrous diethyl ether (160 ml). The mixtures were
stirred fiercely under 0 °C to give a white solid. The solid
was filtered and dried.
(Yield 16.9 %); Method A was used in combination with
5a and 8a; yellow lamellar crystal; mp 231–232 °C (Rf:
0.22, chloroform: petroleum ether = 3:2); IR (KBr)
v(cm-1): 3048, 2989, 2935, 1712, 1604, 1510, 1447, 1388,
1249, 1177, 1117, 1031, 963, 831, 789, 718, 706; 1H-NMR
(500 MHz, CDCl3, dppm): 7.82 (s, 1H, H-4), 7.71–7.73
(m, 2H, H-5 and H-7), 7.60–7.68 (m, 2H), 7.42–7.48 (m,
5H), 7.08 (d, J = 16.3 Hz, 1H), 6.99 (d, J = 16.3 Hz, 1H),
6.91–6.93 (m, 2H), 3.84 (s, 3H, OCH3); MS (ESI) m/z:
355.2 (M? ? 1). Anal. Calcd for C24H18O3: C, 81.34; H,
5.12. Found C, 81.62; H, 5.14.
4-Methoxybenzyl triphenylphosphonium chloride (8a)
(Yield 95.6 %); white solid; mp 246–248 °C; 1H-NMR
(300 MHz, CDCl3, dppm): 3.69 (s, 3H), 5.30 (d, 2H,
J = 13.8 Hz), 6.76 (d, 2H, J = 8.1 Hz), 6.96 (d, 2H,
J = 8.4 Hz), 7.19–7.92 (m, 15H).
3,5-Dimethoxybenzyltriphenylphosphoniumchloride (8b)
1
Cis-6-(3,5-dimethoxystyryl)-3-phenylcoumarin
(3Z)
(Yield 94.8 %); white solid; mp: 263–265 °C; H-NMR
(Yield 13.0 %); Method A was used in combination with
5a and 8b (Rf: 0.37, acetic ether: petroleum ether = 1:5);
white solid; mp 151–152 °C; IR (KBr) v(cm-1): 3003,
2948, 2826, 1723, 1589, 1485, 1462, 1392, 1330, 1232,
1194, 1154, 1110, 960, 850, 788, 705; 1H-NMR (300 MHz,
CDCl3, dppm): 7.71 (s, 1H, H-4), 7.68–7.69 (m, 2H),
7.43–7.50 (m, 5H), 7.25 (d, J = 8.7 Hz, 1H), 6.66 (d,
J = 12.3 Hz, 1H), 6.61 (d, J = 12.3 Hz, 1H), 6.41–6.42
(d, J = 2.2 Hz, 2H), 6.36–6.38 (m, 1H), 3.69 (s, 6H,
2 9 OCH3); MS (ESI) m/z: 385.2 (M? ? 1). Anal. Calcd
for C25H20O4: C, 78.11; H, 5.24. Found: C, 78.37; H, 5.17.
Trans-6-(3,5-dimethoxystyryl)-3-phenylcoumarin (3E)
(Yield 26.0 %); Method A was used in combination with
5a and 8b (Rf: 0.31, acetic ether: petroleum ether = 1:5);
yellow lamellar crystal; mp 170–172 °C; IR (KBr)
v(cm-1): 3048, 2989, 2934, 2830, 1721, 1592, 1454, 1358,
1317, 1296,1275, 1204, 1156, 1148, 1106, 1069, 951, 785,
697; 1H-NMR (300 MHz, CDCl3, dppm): 7.83 (s, 1H,
H-4), 7.63–7.73 (m, 4H), 7.43–7.50 (m, 3H), 7.37
(d, J = 8.4 Hz, 1H), 7.14 (d, J = 16.2 Hz, 1H), 6.07
(d, J = 16.3 Hz, 1H), 6.68–6.69 (d, J = 2.1 Hz, 2H),
6.43(m, 1H), 3.85 (s, 6H, 2 9 OCH3); MS (ESI) m/z: 385.2
(M? ? 1). Anal. calcd for C25H20O4: C, 78.11; H, 5.24.
Found: C, 77.86; H, 5.26.
(300 MHz, CDCl3, dppm): 3.51 (s, 6H), 5.33 (d, 2H,
J = 14.4 Hz), 6.28–6.29 (d, J = 2.4 Hz, 3H), 7.60–7.78 (m,
15H).
Benzyl triphenylphosphonium chloride (8c) (Yield
96.8 %); white solid; mp 330–332 °C; 1H-NMR (300 MHz,
CDCl3, dppm): 5.40 (d, 2H, J = 14.4 Hz), 7.04–7.21 (m,
5H), 7.56–7.76 (m, 15H).
General experimental procedure for the synthesis
of the resveratrol–coumarin hybrid compounds
(2Z–13E)
Method
A
Compound
5
(1 mmol), compound
8
(1.1 mmol), potassium carbonate (1.54 mmol), and water
(28 lL) were refluxing in 1,4-dioxane (6.6 mL) for 6 h.
The reaction mixture was cooled to educe the solid and
filtered to isolate the E isomer. Then, the filtrate was
evaporated under reduced pressure and isolated by column
chromatography to obtain the Z isomer.
Method B Compound 5 and compound 8 were solved in
dichloromethane and 50 % sodium hydroxide solution
(5 mL) was added under 0 °C. The reaction mixture was
maintained for 40 min. Then, 50 ml water was added, and
the organic layer was separated. The water layer was
extracted with trichloromethane (20 mL 9 3), and the
organic layers were combined, dried, filtered, and evapo-
rated to afford the crude products. The Z isomer and
E isomer were isolated by column chromatography.
Cis-6-(4-methoxystyryl)-3-phenylcoumarin (2Z) (Yield
19.8 %); Method A was used in combination with 5a and
8a (Rf: 0.28, chloroform: petroleum ether = 3:2); yellow
Cis-3-(4-methoxyphenyl)-6-styrylcoumarin (4Z) (Yield
14.1 %); Method B was used in combination with 5b and
8c; colorless lamellar crystal; mp 140–142 °C; IR (KBr)
v(cm-1): 3049, 2956, 2939, 2830, 1715, 1607, 1513, 1250,
1181, 1110, 931, 824, 782, 693; 1H-NMR (300 MHz,
CDCl3, dppm): 7.67 (s, 1H, H-4), 7.62–7.68 (m, 2H),
7.20–7.40 (m, 8H), 6.97–7.00(d, J = 8.7 Hz, 2H), 6.71 (d,
J = 12 Hz, 1H), 6.62 (d, J = 12 Hz, 1H), 3.87 (s, 3H,
123

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Med Chem Res (2013) 22:1630–1640
OCH3); MS (ESI) m/z: 355.2 (M? ? 1). Anal. Calcd for
C24H18O3: C, 81.34; H, 5.12. Found: C, 81.05; H, 5.10.
Cis-6-(3,5-dimethoxystyryl)-3-(4-methoxyphenyl)cou-
marin (5Z) (Yield 19.3 %); Method B was used in com-
bination with 5b and 8b (Rf: 0.21, acetic ether: petroleum
ether = 1:5); yellow solid; mp 125–127 °C; IR (KBr)
v(cm-1): 3049, 2935, 2834, 1712, 1597, 1456, 1388, 1250,
3007, 2962, 2835, 1709, 1606, 1514, 1456, 1391, 1360, 1255,
1101, 1025, 819, 772; 1H-NMR (500 MHz, CDCl3, dppm):
7.69 (s, 1H), 7.43–7.47 (m, 2H), 7.20–7.34 (m, 5H), 6.97 (d,
J = 8.4 Hz, 1H), 6.81–6.83 (m, 2H), 6.65 (d, J = 12.1 Hz,
1H), 6.56 (d, J = 12.1 Hz, 1H), 3.98 (s, 3H, OCH3), 3.97 (s,
3H, OCH3), 3.83 (s, 3H, OCH3); MS (ESI) m/z: 415.2
(M? ? 1). Anal. Calcd for C26H22O5: C, 75.35; H, 5.55.
Found: C, 75.11; H, 5.37.
1
1158, 1110, 832, 794, 683; H-NMR (300 MHz, CDCl3,
dppm): 7.69 (s, 1H), 7.63–7.68 (m, 2H), 7.22–7.44 (m, 3H),
6.99–7.01 (d, J = 8.8 Hz, 2H), 6.65 (d, J = 12 Hz, 1H),
6.61 (d, J = 12 Hz, 1H), 6.36–6.42 (m, 3H), 3.88 (s, 3H,
OCH3), 3.69 (s, 6H, 2 9 OCH3); MS (ESI) m/z: 415.2
(M? ? 1). Anal. Calcd for C26H22O5: C, 75.35; H, 5.35.
Found: C, 75.62; H, 5.37.
Trans-3-(3,4-dimethoxyphenyl)-6-(4-methoxystyryl)cou-
marin (7E) (Yield 15.9 %); Method B was used in com-
bination with 5c and 8a; yellow solid (Rf: 0.19, acetic
ether: petroleum ether = 1:5); mp 172–173 °C; IR (KBr)
v(cm-1): 3006, 2959, 2942, 2844, 1735, 1605, 1513, 1466,
1384, 1258, 1092, 1019, 831, 818, 774; 1H-NMR
(500 MHz, CDCl3, dppm): 7.79 (s, 1H), 7.59–7.66 (m, 2H),
7.46–7.47 (m, 2H), 7.29–7.35 (m, 3H), 7.08 (d, J = 16.3 Hz,
1H), 6.98 (d, J = 16.3 Hz, 1H), 6.91–6.96 (m, 3H), 3.96 (s,
3H, OCH3), 3.94 (s, 3H, OCH3), 3.84 (s, 3H, OCH3); MS
(ESI) m/z: 415.2 (M? ? 1). Anal. Calcd for C26H22O5: C,
75.35; H, 5.55. Found: C, 75.61; H, 5.32.
Trans-6-(3,5-dimethoxystyryl)-3-(4-methoxyphenyl)cou-
marin (5E) (Yield 16.9 %); Method B was used in com-
bination with 5b and 8b (Rf: 0.15, acetic ether: petroleum
ether = 1:5); yellow solid; mp 194–195 °C; IR (KBr)
v(cm-1): 3068, 3033, 2961, 2921, 2840, 1720, 1592, 1459,
1425, 1385, 1250, 1152, 1108, 1065, 949, 832, 804,
686; 1H-NMR (300 MHz, CDCl3, dppm): 7.77 (s, 1H),
7.60–7.71 (m, 4H), 7.34 (d, J = 8.6 Hz, 1H), 7.11 (d,
J = 16.3 Hz, 1H), 7.03 (d, J = 16.3 Hz, 1H), 6.98–7.01
(m, 2H), 6.68 (d, J = 2.2 Hz, 2H), 6.42–6.43 (m, 1H), 3.86
(s, 3H, OCH3), 3.84 (s, 6H, 2 9 OCH3); MS (ESI) m/z:
415.2 (M? ? 1). Anal. Calcd for C26H22O5: C, 75.35; H,
5.35. Found: C, 75.08; H, 5.38.
Cis-3-(3,4-dimethoxyphenyl)-6-(3,5-dimethoxysty-
ryl)coumarin (8Z) (Yield 23.6 %); Method B was used in
combination with 5c and 8b (Rf: 0.22, acetic ether: petro-
leum ether = 1:5); yellow solid; mp 114–115 °C; IR (KBr)
v(cm-1): 3049, 3003, 2933, 2833, 1708, 1590, 1515, 1454,
1388, 1255, 1154, 1108, 1058, 1025, 852, 820, 790, 744,
685; 1H-NMR (500 MHz, CDCl3, dppm): 7.65 (s, 1H),
7.40–7.42 (t, 2H), 7.21–7.29 (m, 3H), 6.93 (d, J = 8.4 Hz,
1H), 6.62 (d, J = 12.2 Hz, 1H), 6.59 (d, J = 12.2 Hz, 1H),
6.39–6.40 (d, J = 1.7 Hz, 2H), 6.34–6.35 (t, 1H), 3.94
(s, 3H, OCH3), 3.93 (s, 3H, OCH3), 3.67 (s, 6H, 2 9
OCH3); GC–MS m/z: 444.1 (M? ? 1). Anal. Calcd for
C27H24O6: C, 72.96; H, 5.44. Found: C, 72.71; H, 5.42.
Trans-3-(3,4-dimethoxyphenyl)-6-(3,5-dimethoxysty-
ryl)coumarin (8E) (Yield 43.9 %); Method B was used in
combination with 5c and 8b (Rf: 0.14, acetic ether: petro-
leum ether = 1:5); yellow solid; mp 178–179 °C; IR (KBr)
v(cm-1): 3033, 2996, 2961, 2843, 1713, 1591, 1450, 1390,
1255, 1148, 1100, 1026, 980, 808, 681, 630; 1H-NMR
(500 MHz, CDCl3, dppm): 7.79 (s, 1H), 7.62–7.68 (m,
2H), 7.29–7.36 (m, 3H), 7.10 (d, J = 16.2 Hz, 1H), 7.04
(d, J = 16.2 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 6.67–6.68
(d, J = 2.1 Hz, 2H), 6.42–6.43 (t, 1H), 3.96 (s, 3H, OCH3),
3.94 (s, 3H, OCH3), 3.84 (s, 6H, 2 9 OCH3); MS (ESI)
m/z: 445.2 (M? ? 1). Anal. Calcd for C27H24O6: C, 72.96;
H, 5.44. Found: C, 72.52; H, 5.46.
Cis-3-(3,4-dimethoxyphenyl)-6-styrylcoumarin
(6Z)
(Yield 36.7 %); Method B was used in combination with
5c and 8c (Rf: 0.31, acetic ether: petroleum ether = 1:5);
yellow solid; mp 91–92 °C; IR (KBr) v(cm-1): 3010, 2904,
2834, 1707, 1600, 1518, 1468, 1445, 1384, 1263, 1170,
1151, 1101, 1018, 815, 776, 696; 1H-NMR (500 MHz,
CDCl3, dppm): 7.62 (s, 1H), 7.36–7.39 (m, 2H), 7.20–7.29
(m, 8H), 6.92 (d, J = 8.4 Hz, 1H), 6.69 (d, J = 12.1 Hz,
1H), 6.60 (d, J = 12.1 Hz, 1H), 3.93 (s, 3H, OCH3), 3.92
(s, 3H, OCH3); MS (ESI) m/z: 385.2 (M? ? 1). Anal.
Calcd for C25H20O4: C, 78.11; H, 5.24. Found: C, 78.42; H,
5.20.
Trans-3-(3,4-dimethoxyphenyl)-6-styrylcoumarin (6E)
(Yield 24.0 %);Method B was used in combination with 5c
and 8c (Rf: 0.24, acetic ether: petroleum ether = 1:5);
yellow solid; mp 197–198 °C; IR (KBr) v(cm-1): 3003,
2967, 2925, 2825, 1716, 1518, 1259, 1102, 1026, 807, 759,
699; 1H-NMR (500 MHz, CDCl3, dppm): 7.79 (s, 1H,
H-4), 7.52–7.69 (m, 4H), 7.25–7.40 (m, 6H), 7.12 (s, 2H),
6.95 (d, J = 8.3 Hz, 1H), 3.95 (s, 3H, OCH3), 3.94 (s, 3H,
OCH3); MS (ESI) m/z: 385.2 (M? ? 1). Anal. Calcd for
C25H20O4: C, 78.11; H, 5.24. Found: C, 77.90; H, 5.22.
Cis-3-(3,4-dimethoxyphenyl)-6-(4-methoxystyryl)couma-
rin (7Z) (Yield 16.7 %); Method B was used in combination
with 5c and 8a (Rf: 0.25, acetic ether: petroleum
ether = 1:5); yellow solid; mp 90–92 °C; IR (KBr) v(cm-1):
Trans-7-(4-methoxystyryl)-3-phenylcoumarin
(9E)
(Yield 42.4 %);Method A was used in combination with 5d
and 8a; yellow solid; mp 192–192.5 °C; IR (KBr) v(cm-1):
3067, 3017, 2953, 2829, 1721, 1598, 1511, 1446, 1383,
1251, 1175, 1134, 977, 827, 784, 694, 621; 1H-NMR
(300 MHz, CDCl3, dppm): 7.79 (s, 1H), 7.71–7.74 (q, 2H),
7.41–7.52 (m, 8H), 7.20 (d, J = 16.2 Hz, 1H), 7.01
123

Med Chem Res (2013) 22:1630–1640
1639
(d, J = 16.2 Hz, 1H), 6.92–6.98 (d, J = 18.9 Hz, 2H), 3.85
(s, 3H, OCH3); MS (ESI) m/z: 355.2 (M? ? 1). Anal. Calcd
for C24H18O3: C, 81.34; H, 5.12. Found: C, 81.70; H, 5.12.
Trans-7-(3,5-dimethoxystyryl)-3-phenylcoumarin (10E)
(Yield 36.5 %); Method A was used in combination with 5d
and 8b; yellow solid; mp 188 °C; IR (KBr) v(cm-1): 3046,
2832, 1724, 1606, 1479, 1383, 1322, 1299, 1203, 1110, 1065,
950, 818, 783, 676, 629;1H-NMR (300 MHz, CDCl3, dppm):
7.81(s, 1H), 7.71–7.74 (q, 2H), 7.36–7.54 (m, 6H), 7.18 (d,
J = 16.2 Hz, 1H), 7.11 (d, J = 16.2 Hz, 1H), 6.70–6.71 (d,
J = 2.1 Hz, 2H), 6.45–6.46 (t, 1H), 3.86 (s, 6H, 2 9 OCH3);
MS(ESI)m/z:385.2(M? ? 1).Anal. CalcdforC25H20O4:C,
78.11; H, 5.24. Found: C, 78.39; H, 5.24.
and 50 % sodium hydroxide solution (5 mL) was added at
0 °C. The reaction mixtures were maintained for 40 min.
Then, 50 mL water was added, and the organic layer was
separated. The water layer was extracted with trichlorome-
thane (20 mL 9 3), and the organic layers were combined,
dried, filtered, and evaporated to afford the crude products.
The E isomer was isolated by column chromatography (PE:
EA = 20:1).
Trans-3,40,5-trimethoxystilbene (TMRV) (Yield 30.8 %);
white solid; mp 61–62 °C; IR (KBr) v(cm-1): 2931, 2831,
1591, 1511, 1458, 1425, 1250, 1154, 961, 822; H-NMR
1
(300 MHz, CDCl3, dppm): 7.45 (d, J = 8.8 Hz, 2H,
H-20,60), 7.04 (d, J = 16.4 Hz, 1H), 6.91 (d, J = 16.4 Hz,
1H), 6.90 (d, J = 8.7 Hz, 2H, H-30,50), 6.65 (s, 2H, H-2,6),
6.38 (s, 1H, H-4), 3.83 (s, 9H, OCH3); MS (ESI) m/z: 271.1
(M? ? 1). Anal. Calcd for C17H18O3: C, 75.53; H, 6.71.
Found: C, 75.76; H, 6.69.
Trans-(-3-(4-methoxyphenyl)-7-styrylcoumarin (11E)
(Yield 14.1 %); Method B was used in combination with
5e and 8c; amber solid, mp 218–222 °C; IR (KBr)
v(cm-1): 3039, 2956, 2836, 1712, 1607, 1383, 1250, 1183,
1140, 1032, 827, 779, 692, 625; 1H-NMR (300 MHz,
CDCl3, dppm): 7.79 (s, 1H), 7.70–7.71 (q, 2H), 7.58–7.61
(d, J = 7.2 Hz, 2H), 7.35–7.52 (m, 6H), 7.28 (d,
J = 16.2 Hz, 1H), 7.17 (d, J = 16.2 Hz, 1H), 7.00–7.03
(d, J = 8.4 Hz, 2H), 3.86 (s, 3H, OCH3); MS (ESI) m/z:
355.2 (M? ? 1). Anal. Calcd for C24H18O3: C, 81.34; H,
5.12. Found: C, 81.60; H, 5.10.
MTT assay
The cytotoxicity was evaluated by MTT assay using KB
cells, HCT-28 cells, and MCF-7 cells (Mo et al., 2011). First,
target tumor cells which were grown well were diluted to
5 9 104 cells ml-1. Then, 200 ll of the obtained cell sus-
pension was added to each well of 96-well culture plates.
The suspension was incubated at 37 °C, 5 % CO2 atmo-
sphere in DMEM ? 10 % calf serum for 24 h before the
tested compounds at pre-set concentration in DMSO were
added. After 48 h incubation, MTT (5 mg/mL) was added to
each well and reacted for 4 h. The medium was replaced by
150 ll DMSO to solubilize the purple formazan crystals
produced. The absorbance at 570 nm of each well was
measured on an ELISA plate reader. And the IC50 was cal-
culated by a dose of Logarithmic linear regression analysis.
Trans-3-(4-methoxyphenyl)-7-(4-methoxystyryl)couma-
rin (12E) (Yield 18.2 %);Method B was used in combina-
tion with 5e and 8a; yellow solid, mp 217–218 °C; IR (KBr)
v(cm-1): 3024, 3010, 2833,1706, 1605, 1513, 1456, 1383,
1
1253, 1175, 1031, 825, 778, 624; H-NMR (300 MHz,
CDCl3, dppm): 7.67(s, 1H), 7.60–7.63 (d, 2H), 7.28–7.44
(m, 5H), 7.04–7.15 (d, J = 31.8 Hz, 2H), 6.93 (d,
J = 16.2 Hz, 1H), 6.87 (d, J = 16.2 Hz, 1H), 6.87–6.92 (d,
J = 16.2 Hz, 2H), 3.78 (s, 6H, 2 9 OCH3); MS (ESI) m/z:
385.2 (M? ? 1). Anal. Calcd for C25H20O4: C, 78.11; H,
5.24. Found: C, 77.83; H, 5.25.
Acknowledgments This study is financially supported by the Ph.D.
Programs Foundation of Ministry of Education of China (2009
0096110005), the 111 Project from the Ministry of Education of China,
and the State Administration of Foreign Expert Affairs of China (No.
111-2-07).
Trans-7-(3,5-dimethoxystyryl)-3-(4-methoxyphenyl)cou-
marin (13E) (Yield 48.3 %); Method B was used in com-
bination with 5e and 8b; yellow solid, mp 198–199 °C; IR
(KBr) v(cm-1): 3075, 3035, 2989, 2835, 1708, 1599, 1429,
1384, 1250, 1204, 1150, 1106, 1060, 842, 832, 775, 686,
633. 1H-NMR (300 MHz, CDCl3, dppm): 7.68 (s, 1H),
7.58–7.64 (d, 2H), 7.37–7.44 (m, 3H), 7.10 (d,
J = 16.2 Hz, 1H), 7.02 (d, J = 16.2 Hz, 1H), 6.90–6.93
(d, J = 8.7 Hz, 2H), 6.63–6.64 (d, J = 2.1 Hz, 2H),
6.30–6.37 (m, 1H), 3.78 (s, 9H, 3 9 OCH3); MS (ESI) m/z:
415.2 (M? ? 1). Anal. Calcd for C26H22O5: C, 75.35; H,
5.35. Found: C, 75.60; H, 5.33.
References
Athar M, Back JH, Kopelovich L, Bickers DR, Kim AL (2009)
Multiple molecular targets of resveratrol: anti-carcinogenic
mechanisms. Arch Biochem Biophys 486:95
Biasutto L, Marotta E, Bradaschia A, Fallica M, Mattarei A, Garbisa
S, Zoratti M, Paradisi C (2009) Soluble polyphenols: synthesis
and bioavailability of 3,40,5-tri(a-D-glucose-3-O-succinyl) res-
veratrol. Bioorg Med Chem Lett 19:6721
Bishayee A, Politis T, Darvesh AS (2010) Resveratrol in the
chemoprevention and treatment of hepatocellular carcinoma.
Cancer Treat Rev 36:43
General experimental procedure for the synthesis
of TMRV
Cardile V, Lombardo L, Spatafora C, Tringali C (2005) Chemo-
enzymatic synthesis and cell-growth inhibition activity of
resveratrol analogues. Bioorg Chem 33:22
Compound 8a (2.62 g, 6.3 mmol) and 3,5-dimethoxybenz-
aldehyde (0.8 g, 4.8 mmol) were solved in dichloromethane
123

1640
Med Chem Res (2013) 22:1630–1640
Cottiglial F, Loy G, Garau D, Floris C, Casu M, Pompei R,
Bonsignorel L (2001) Antimicrobial evaluation of coumarins and
flavonoids from the stems of Daphne gnidium L. Phytomedicine
8:302
Mo R, Jin X, Li N, Cy Ju, Sun Mj, Zhang C, Ping Qn (2011) The
mechanism of enhancement on oral absorption of paclitaxel by
N-octyl-O-sulfate chitosan micelles. Biomaterials 32:4609
Mokni M, Limam F, Elkahoui S, Amri M, Aouani E (2007) Strong
cardioprotective effect of resveratrol, a red wine polyphenol, on
isolated rat hearts after ischemia/reperfusion injury. Arch
Biochem Biophys 457:1
´
´
Elinos-Baeza CM, Leonb F, Santosb E (2005) Effects of coumarin
and 7OH-coumarin on bcl-2 and Bax expression in two human
lung cancer cell lines in vitro. Cell Biol Int 29:703
Fauconneau B, Waffo-Teguo P, Huguet F, Barrier L, Decendit A,
Merillon JM (1997) Comparative study of radical scavenger and
antioxidant properties of phenolic compounds from Vitis vinifera
cell cultures using in vitro tests. Life Sci 61:2103
Fujioka T, Furumi K, Fujii H, Okabe H, Mihashi K, Nakano Y,
Matsunaga H, Katano M, Mori M (1999) Antiproliferative
constituents from umbelliferae plants. V. A new furanocoumarin
and falcarindiol furanocoumarin ethers from the root of Angelica
japonica. Chem Pharm Bull 47:96
Jang M, Cai L, Udeani GO, Slowing KV, Thomas CF, Beecher CW,
Fong HH, Farnsworth NR, Kinghorn AD, Mehta RG, Moon RC,
Pezzuto JM (1997) Cancer chemopreventive activity of resve-
ratrol, a natural product derived form grapes. Science 275:218
Jiang YL (2008) Design, synthesis and spectroscopic studies of
resveratrol aliphatic acid ligands of human serum albumin.
Bioorg Med Chem 16:6406
Pace-Asciak CR, Hanh S, Diamandis EP, Soleas G, Goldberg DM
(1995) The red wine phenolics trans-resveratrol and quercetin
block human platelet aggregation and eicosanoid synthesis:
implications for protection against coronary heart disease. Clin
Chim Acta 235:207
Pengsuparp T, Serit M, Hughes SH, Soejarto DD, Pezzuto JM (1996)
Specific inhibition of human immunodeficiency virus type 1
reverse transcriptase mediated by soulattrolide, a coumarin
isolated from the latex of Calophyllum teysmannii. J Nat Prod
59:839
Szkudelska K, Szkudelski T (2010) Resveratrol, obesity and diabetes.
Eur J Pharmacol 635:1
´
Torresa R, Faini F, Modak B, Urbina F, Labbe C, Guerrero J (2006)
Antioxidant activity of coumarins and flavonols from the
resinous exudate of Haplopappus multifolius. Phytochemistry
27:984
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