Synthesis and biological evaluation of novel (E) stilbene-based antitumor agents

Article abstract of DOI:10.1016/j.ejmech.2012.06.015

Several new (E) stilbenes were synthesized by a combination of a Wittig olefination followed by Mizoroki-Heck coupling reactions. These compounds were screened for antitumor activity in a panel of 8 human cancer cell lines by a colorimetric SRB assay. Several of these compounds exhibit strong cytotoxicity. The most active compound of this series showed an average IC₅₀ value of 0.03 μmol; it acts by apoptosis as shown by a dye-exclusion test, an extra acridine orange/ethidium bromide staining and DNA-laddering experiments.

Full text of DOI:10.1016/j.ejmech.2012.06.015

European Journal of Medicinal Chemistry 54 (2012) 669e678
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European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and biological evaluation of novel (E) stilbene-based antitumor agents
*
René Csuk , Sabrina Albert, Bianka Siewert, Stefan Schwarz
Bereich Organische Chemie, Martin-Luther-Universität Halle-Wittenberg, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Several new (E) stilbenes were synthesized by a combination of a Wittig olefination followed by Mizoroki
eHeck coupling reactions. These compounds were screened for antitumor activity in a panel of 8 human
cancer cell lines by a colorimetric SRB assay. Several of these compounds exhibit strong cytotoxicity. The
most active compound of this series showed an average IC50 value of 0.03 mmol; it acts by apoptosis as
shown by a dye-exclusion test, an extra acridine orange/ethidium bromide staining and DNA-laddering
Received 26 March 2012
Received in revised form
5 June 2012
Accepted 9 June 2012
Available online 18 June 2012
experiments.
Ó 2012 Elsevier Masson SAS. All rights reserved.
Keywords:
Stilbenes
Antitumor activity
MizorokieHeck reactions
Apoptosis
1. Introduction
2. Results
Stilbene-based compounds have become of particular interest to
chemists because of their range of different biological activities
[1,2]. Hydroxylated stilbenes, among them trans-resveratrol
(1, Fig. 1) are largely present in nature and play a significant role in
the prevention of coronary artery disease [3] due to its antioxidant
[4,5] and anti-inflammatory properties. Resveratrol has been sug-
gested as an anticancer agent [6] acting by the inhibition of cell
proliferation [7]. The stilbene derivative tamoxifen (2) is currently
used for the treatment of several types of breast cancer in women,
and as a hormone treatment for male breast cancer. In addition, the
naturally occurring cis-stilbene combretastatin A-4 (3) [8,9] from
the bark of the South African tree Combretum caffrum showed
significant antitumor activity. The same is true for several analogs
of 2 [9e21]. Its derivative ombrabulin (4) [22] is currently in phase
III clinical trials for the treatment of advanced-stage soft-tissue
carcinoma. The mechanism of action for (Z) stilbene derivatives
finally led to endothelial cell damage and subsequent necrosis [17].
For several monohydroxylated (E) stilbenes apoptosis in a breast
cell line was induced [23].
2.1. Chemistry
In continuity of our previous investigations devoted to the
synthesis of bioactive compounds, we became interested in the
synthesis of stilbenes since several of them have been shown to
behave as a sensitizer for anticancer drugs [26,27], cytokines [28]
and radiation [29].
Although stilbenes can be obtained by a near endless list of
reactions and transformations, most prominent among them are
Wittig (eHorner, (Horner)eWadswortheEmmons) reactions
[30,31], aldol-type condensations [32], as well as NegishieStille
reactions [33] or by McMurry couplings [34]. The use of
MizorokieHeck reactions [35e38], however, to make (E) con-
figurated stilbenes seems most promising.
Several stilbenes showing antibacterial and/or antifungal
activity have previously been prepared by a sequence of a Wittig
olefination followed by a MizorokieHeck coupling [39]. We
applied the same synthetic scheme (Scheme 1) for the synthesis
of the cytotoxic stilbenes. Thus, Wittig reaction of suitable
substituted aldehydes with methyl triphenylphoshonium iodide
and tBuOK in THF gave styrenes. These styrenes were subjected to
MizorokieHeck couplings to yield (E) configurated stilbenes 5e38.
The use of triethanolamine acting simultaneously as a base and as
a solvent allows the economic synthesis of substituted (E) con-
figurated stilbenes [35]. For example, 38 is characterized in its 19F
Contrary to the findings for (E) resveratrol, most of (E) or (Z)
configurated synthetic methylated stilbenes stop mitosis at the M
phase (hence leading to polyploidic cells) whereas (E) resveratrol
blocks cells at the S phase [24,25].
NMR spectrum by a signal at
(to H-2 in meta position to the fluorine substituent) and 9.4 Hz
d
¼ ꢀ127.1 ppm showing JF,H ¼ 7.2 Hz
* Corresponding author. Tel.: þ49 (0) 345 55 25660; fax: þ49 (0) 345 55 27030.
E-mail address: rene.csuk@chemie.uni-halle.de (R. Csuk).
0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2012.06.015

670
R. Csuk et al. / European Journal of Medicinal Chemistry 54 (2012) 669e678
Scheme 1. Synthesis of the stilbenes 5e38: reagents and conditions: triethanolamine,
Pd(II) acetate, 24 h, 100 ꢁC.
combretastatin analogs, these compounds did not show any
significant antibacterial/antifungal effects.
To prove that cell death was triggered by apoptosis rather
than by necrosis, an extra dye-exclusion test (trypan blue) and an
acridine orange/ethidium bromide assay [43,44] as well as a DNA-
laddering experiment were performed [45e47]. Thus, to determine
the extent of apoptosis, trypan blue staining and counting experi-
ments were performed (Fig. 2). The apoptotic cells have an intact
cell membrane and can exclude the dye whereas necrotic cell are
colored blue. The results from these experiments are summarized
in Table 2.
Fig. 1. Structure of resveratrol (1), tamoxifen (2), combretastatin A-4 (3) and ombra-
bulin. (4).
(to the adjacent proton). Carbon C-6 bearing the fluorine substit-
uent shows a 1JC,F ¼ 241.3 Hz. The coupling constant 3J ¼ 16.6 Hz for
the alkenic protons is typical for a (E) configurated double bond.
Additional AO/EB tests support these results. In this test, green
fluorescent cells were found, hence indicating an apoptotic
behavior of the compounds. On principle, an AO/EB assay doesn’t
allow quantification of the extent of apoptosis but confirms the
results from the trypan blue staining experiments. Another
evidence for apoptosis is DNA laddering [45,47] as observed by gel
electrophoresis. The programmed cell death is characterized by
fragmentation of DNA into smaller parts of 180 bp; these can be
observed as DNA laddering in gel electrophoresis.
2.2. Biology
Compounds 5e38 (and tamoxifen (2) as a standard) were tested
for antitumor activity in a panel of 8 human cancer cell lines using
a sulforhodamine B assay (SRB) [40]. The results from these tests
are summarized in Table 1.
Compounds 25, 26, 28, 30, 31, 33, 34 and 37 showed only weak
activity in the colorimetric SRB test. Also, the selectivity towards
tumor cells compared to non-malignant mouse fibroblasts is low.
Compound 22 was found to be inactive at all with IC50 values for all
3. Conclusions
cell lines >30 mmol. A minimum of three methoxy groups in the
molecule seems to be a prerequisite for activity.
In this study we have synthesized highly substituted (E) con-
figurated stilbenes. In conclusion, these compounds are initiators of
programmed cell death and several of them show high antitumor
activity against a panel of 8 human cell lines. Cell death is triggered
by apoptosis as shown by a dye-exclusion test, extra AO/EB assays
and DNA-laddering experiments. Compound 38 shows a biological
activity comparable to compretastatin A-4. Whereas compretasta-
tins and analogs (possessing a cis configurated alkenic bond)
possess in vitro a high tendency to undergo cis/trans isomerization
(with accompanying decreasing loss of cytotoxicity) compound 38
was shown to be configurationally stable. Thus, as exemplified with
38 a (Z) configuration seems not to be a prerequisite for a high
cytotoxicity. Cell death was triggered by apoptosis. It remains
From the comparison of activity of 9 and 10 we assumed that an
extra fluorine substituent [41] led to a decreased activity. This
trend, however, did not hold for compounds 6 and 7 both showing
a comparable cytotoxicity. Cytotoxicity drops for the 2,4-dimethoxy
analog 8 (as compared to a 2,5-dimethoxy compound 7). In this
series, a 3,5-dimethoxy substitution pattern seems to work best.
Whereas dihydroxy substituted 37 showed only weak cytotoxicity,
an improvement was observed for its 2,5-dimethoxy analog 36. An
even better result was observed for fluorinated 35, but the highest
cytotoxicity was found for 38 with IC50 values between 10 nmol and
60 nmol. Compared to tamoxifen (3) this reflects an improvement
in cytotoxicity by factor 3. Contrary to halogenated [42]
Fig. 2. Trypan blue assay (for ovarian cancer cell line A2780, left), acridine orange/ethidium bromide staining (for ovarian cancer cell line A2780, middle) and DNA laddering (for
ovarian cancer cell line A2780, right) of compound 38 after treatment of the cells with IC50 concentrations for 24 h.

R. Csuk et al. / European Journal of Medicinal Chemistry 54 (2012) 669e678
671
Table 1
Cytotoxicity (IC50 [in mmol]) for 5e38 (in order of decreasing cytotoxicity) and tamoxifen (2) in a panel of various cancer cell lines [518A2 (melanoma), A253 (head), A549
(lung), A2780 (ovarian), DLD1 (colon), 850C (anaplastic thyroid), MCF7 (mamma), LIPO (liposarcoma) and non-malignant mouse fibroblasts (NiH3T3)]. Values were obtained
from SRB assays after 96 h of treatment; the values are averaged from at least 5 independent experiments; variation ꢃ7%. Average corresponds to an averaged IC50 value (in
m
mol) including all cell lines, selectivity was calculated from the ratio of the averaged IC50 values for the tumor cells to the IC50 value for the mouse fibroblasts.
No
518A2
850C
0.03
0.13
0.21
0.70
0.86
1.33
2.26
2.62
2.46
A253
0.03
0.48
0.83
0.52
0.80
1.53
1.34
1.34
2.35
A549
0.03
0.18
0.25
0.67
0.96
1.80
2.21
2.35
3.04
2.28
3.65
5.14
8.90
7.17
8.11
11.41
18.96
14.74
22.16
14.31
5.28
15.86
12.24
12.75
10.00
12.66
15.77
22.46
21.61
>30
19.01
17.27
>30
>30
9.66
A2780
DLD1
0.04
0.20
0.21
0.85
0.91
2.00
2.26
2.73
2.86
Lipo
0.03
MCF7
0.06
0.22
0.51
0.39
0.54
1.64
2.09
0.89
1.89
0.89
1.80
2.34
13.00
9.87
7.50
13.00
7.71
13.16
11.20
5.80
11.58
14.11
12.17
16.41
8.03
14.17
10.63
7.25
9.75
5.69
Average
NiH3T3
Selectivity
38
35
5
6
7
0.03
0.20
0.22
0.52
0.72
1.33
1.74
2.11
2.81
0.01
0.11
0.15
0.64
0.87
1.27
2.01
1.40
2.06
0.03
0.22
0.35
0.61
0.79
1.54
1.99
1.95
2.54
0.05
0.19
0.21
0.92
1.54
2.08
2.66
1.87
3.68
2.55
3.01
4.90
10.78
10.57
7.16
1.34
0.88
0.60
1.50
1.95
1.35
1.34
0.96
1.45
1.43
1.21
1.26
0.91
0.81
0.52
0.61
0.89
0.86
0.39
0.89
0.30
0.77
0.41
0.91
0.61
0.53
1.46
0.37
0.94
0.55
0.55
0.67
0.55
0.77
0.89
0.21
0.40
0.61
0.65
1.41
1.98
2.12
2.86
1.56
8
36
16
9
17
18
20
14
15
27
12
13
11
10
23
19
21
24
32
29
26
37
25
30
28
34
31
33
22
Tamoxifen
1.49
2.47
3.67
2.02
1.93
3.30
1.79
2.19
3.64
8.93
2.06
1.93
3.21
2.22
2.65
4.74
1.79
2.49
3.88
3.28
4.98
13.05
14.89
15.13
15.40
17.49
17.73
18.04
16.49
15.99
17.39
22.45
15.53
28.47
28.36
19.43
22.03
25.32
22.92
22.00
27.35
>30
13.67
19.75
14.53
13.68
17.42
18.16
17.72
13.35
22.94
15.18
21.79
11.95
23.01
18.70
16.77
24.76
22.49
30.17
24.45
10.23
10.84
15.87
12.99
25.96
29.94
23.92
11.84
11.66
15.56
4.15
16.15
16.68
16.62
10.47
18.89
28.05
28.20
12.42
15.90
>30
12.09
14.05
25.70
29.46
17.65
19.42
14.95
12.43
16.42
16.45
19.28
9.30
21.64
22.91
18.00
26.83
16.52
17.58
18.11
24.06
25.34
15.29
14.15
12.45
15.55
15.61
13.16
16.51
19.87
21.98
14.05
23.63
17.01
18.26
17.37
11.90
13.05
13.82
15.53
16.90
17.40
17.54
12.92
15.02
15.74
16.93
13.53
17.11
18.24
14.42
20.09
20.88
21.56
18.47
20.22
19.16
>30
13.65
11.28
12.78
14.43
12.87
15.83
9.30
14.33
17.33
19.75
9.10
10.76
15.16
9.88
17.25
16.76
20.74
14.53
21.89
9.46
15.00
14.96
6.76
11.53
4.51
12.19
6.86
12.35
10.52
9.59
> 30
21.06
7.45
21.28
26.57
25.61
24.07
>30
>30
>30
19.56
11.80
12.38
11.13
14.80
24.22
7.26
13.18
14.85
12.97
>30
7.10
>30
>30
>30
>30
>30
8.92
>30
7.62
>30
7.77
>30
4.78
11.09
8.64
8.20
subject to additional experiments whether these compounds show
significant tubulin binding properties and may act as anti-
angiogenic agents.
product was subjected to chromatography (silica gel, hexane/ethyl
acetate mixtures).
4.3. (E) 3-hydroxy-30,4,50-trimethoxystilbene (5)
4. Experimental
Following the general procedure,
5 was obtained from
4.1. General
3-hydroxy-4-methoxystyrene and 3,5-dimethoxyiodobenzene;
yield: 58.7%; colorless solid; mp 94e96 ꢁC (lit.: 90e91 ꢁC [49],
89e90 ꢁC [50]); RF ¼ 0.48 (silica gel, hexanes/ethyl acetate, 3:1); IR
Instrumentation, cell lines and culture conditions, SRB cyto-
toxicity assay and DNA fragmentation assay as described previously
[48].
(KBr):
n
¼ 3506br, 2999m, 2940m, 2838m, 1592s, 1511s, 1472m,
1456m, 1443m, 1427m, 1357w, 1329w, 1316m, 1293m, 1279m, 1268s,
1225m, 1198m, 1151s, 1130m, 1060m, 1027m cmꢀ1; UVevis (meth-
anol): lmax (log ε) ¼ 220 (4.54), 326 (4.51) nm; 1H NMR (400 MHz,
4.2. General procedure for the MizorokieHeck reactions
CDCl3):
d
¼ 7.12 (d, 1 H, 4J ¼ 1.7 Hz, CH (2)), 6.96 (d, 1H, 3J
A mixture of the styrene (3 mmol), the halogenated benzene
(3 mmol), triethanolamine (3 mmol) and Pd (II) acetate (0.03 g) was
stirred under argon at 100 ꢁC for 24 h. The reaction was cooled to
25 ꢁC, quenched by the addition of dil. aq. hydrochloric acid (2 N,
10 ml), and extracted with ether (3 ꢂ 100 ml). The organic phases
were dried (Na2SO4), the solvents evaporated, and the crude
(trans) ¼ 16.2 Hz, CH] (1)), 6.96 (dd, 1H, 3J ¼ 8.3 Hz, 4J ¼ 1.7 Hz, CH
(6)), 6.86 (d, 1H, 3J (trans) ¼ 16.2 Hz, CH] (2)), 6.81 (d, 1H,
3J ¼ 8.3 Hz, CH (5)), 6.62 (d, 2H, 4J ¼ 2.0 Hz, CH (20) þ CH (60)), 6.35
4
(t, 1H, J ¼ 2.0 Hz, CH (40)) 3.89 (s, 3H, OCH3), 3.80 (s, 6H,
OCH3) ppm; 13C NMR (100 MHz, CDCl3):
d
¼ 160.9 (C30 þ C50,
Cquart.), 146.5 (C3, Cquart.), 145.7 (C4, Cquart.), 139.6 (C10, Cquart.), 130.9
Table 2
Apoptotic effect [in %] of derivatives on A549 cells: (ꢃstandard error, 6 experiments each); cells were treated with 5 (0.5
m
M), 6 (2.5
m
M), 8 (3
m
M), 9 (2.5
m
M), 17 (20 mM), 20
(10
m
M), 35 (0.4
m
M), 36 (20
m
M) and 38 (0.3
mM), respectively.
Compound
5
6
8
9
17
20
35
36
38
Apoptosis [%]
78.0 ꢃ 5.2
73.9 ꢃ 4.7
74.1 ꢃ 4.2
77.1 ꢃ 3.2
77.7 ꢃ 3.7
78.6 ꢃ 4.0
64.1 ꢃ 5.2
72.2 ꢃ 3.3
77.3 ꢃ 3.4

672
R. Csuk et al. / European Journal of Medicinal Chemistry 54 (2012) 669e678
(C1, Cquart.), 128.8 (CH]), 127.1 (CH]), 119.4 (C6, CH), 111.9 (C2, CH),
110.6 (C5, CH), 104.4 (C20 þ C60, CH), 99.7 (C40, CH), 56.0 (OCH3),
55.3 (OCH3) ppm; MS (ESI, MeOH): m/z (%) ¼ 285.3 (100%
[M ꢀ H]ꢀ), 570.8 (13% [2M ꢀ H]ꢀ); analysis for C17H18O4 (286.32): C,
71.31; H, 6.34; found: C, 71.14; H, 6.61.
6.49 (dd, 1H, 3J ¼ 8.5 Hz, 4J ¼ 2.5 Hz, CH (50)), 6.45 (d, 1H, 4J ¼ 2.5 Hz,
CH (30)), 3.88 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 3.81 (s, 3H,
OCH3) ppm; 13C NMR (100 MHz, CDCl3):
d
¼ 160.2 (C40, Cquart.),157.9
(C20, Cquart.), 145.9 (C3, Cquart.), 145.7 (C4, Cquart.), 132.2 (C1, Cquart.),
126.9 (C60, CH), 126.6 (CH]), 121.8 (CH]), 119.7 (C10, Cquart.), 118.9
(C6, CH), 111.7 (C2, CH),110.6 (C5, CH), 104.9 (C50, CH), 98.5 (C30, CH),
55.9 (OCH3), 55.5 (OCH3), 55.74 (OCH3) ppm; MS (ESI, MeOH): m/z
(%) ¼ 285.2 (100% [M ꢀ H]ꢀ); 570.7 (4% [2M ꢀ H]ꢀ); analysis for
C17H18O4 (286.32): C, 71.31; H, 6.34; found: C, 71.11; H, 6.52.
4.4. (E) 40-fluoro-3-hydroxy-30,4,50-trimethoxystilbene (6)
Following the general procedure, 6 was obtained from 3-hydroxy-
4-methoxystyrene and 3,5-dimethoxy-4-fluorobromobenzene;
yield: 61.6%; colorless solid; mp 179e181 ꢁC; RF ¼ 0.12 (silica gel,
4.7. (E) 3,30,4,50-tetramethoxystilbene (9)
hexanes/ethyl acetate, 8:2); IR (KBr):
n
¼ 3504br, 2943m, 2844m,
2363w, 1733w, 1605s, 1519s, 1458m, 1425m, 1363m, 1334m, 1264s,
Following the general procedure, 9 was obtained from 3,4-
dimethoxystyrene and 3,5-dimethoxyiodobenzene; yield: 58.8%;
off-white solid; mp 72e74 ꢁC (lit.: 66e67 ꢁC [51], 67e68 ꢁC [52]);
1222m, 1206m, 1163m, 1128s, 1025m cmꢀ1; UVevis (methanol): lmax
(log ε) ¼ 326 (4.30) nm; 1H NMR (400 MHz, CDCl3):
¼ 7.06 (d, 1H,
d
4J ¼ 2.1 Hz, CH (2)), 7.05 (d,1H, 3J (trans) ¼ 16.2 Hz, CH] (1)), 6.96 (dd,
1H, 3J ¼ 8.3 Hz, 4J ¼ 2.1 Hz, CH (6)), 6.93 (d, 1H, 3J (trans) ¼ 16.2 Hz,
CH] (2)), 6.90 (d,1H, 3J ¼ 8.3 Hz, CH (5)), 6.85 (d, 2H, 4JH,F ¼ 7.3 Hz, CH
(20) þ CH (60)), 3.87 (s, 6H, OCH3), 3.85 (s, 3H, OCH3) ppm; 13C NMR
RF ¼ 0.77 (silica gel, hexanes/ethyl acetate, 3:1); IR (KBr): ¼ 3057s,
n
2999s, 2942s, 2833s, 1838m, 1625w, 1593s, 1575m, 1496s, 1464s,
1439s, 1419s, 1334s, 1301m, 1292m, 1272s, 1243s, 1218s, 1184s, 1161s,
1107s, 1047s, 1022s cmꢀ1; UVevis (methanol): lmax (log ε) ¼ 211
(4.34), 285 (4.05), 3240 (4.09) nm; 1H NMR (400 MHz, CDCl3):
(100 MHz, CDCl3):
d
¼ 148.4 (d, 2JC,F ¼ 8.9 Hz, C30 þ C50, Cquart.), 147.3
(C4, Cquart.), 146.2 (C3, Cquart.), 141.5 (d, 1JC,F ¼ 246.2 Hz, C40, Cquart.),
d
¼ 7.04 (d, 1H, 4J ¼ 2.1 Hz, CH (2)), 7.02 (dd, 1H, 3J ¼ 8.1 Hz,
4
133.6 (d, JC,F ¼ 1.8 Hz, C10, Cquart.), 130.7 (C1, Cquart.), 128.5 (CH]),
4J ¼ 2.1 Hz, CH (6)), 6.99 (d, 1H, 3J (trans) ¼ 16.4 Hz, CH] (1)), 6.98
(d, 1H, 3J (trans) ¼ 16.4 Hz, CH] (2)), 6.83 (d, 1H, 3J ¼ 8.1 Hz, CH (5)),
6.64 (d, 2H, 4J ¼ 2.0 Hz, CH (20) þ CH (60)), 6.36 (t, 1H, 4J ¼ 2.0 Hz, CH
(40)), 3.92 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 3.81 (s, 6H, OCH3) ppm;
126.0 (CH]), 119.1 (C6, CH), 111.9 (C2, CH), 111.7 (C5, CH), 103.8
(C20 þ C60, CH), 56.0 (OCH3), 55.7 (OCH3) ppm; 19F NMR (188 MHz,
4
CDCl3):
d
¼ ꢀ161.2 (t, JF,H ¼ 7.3 Hz, eF) ppm; MS (ESI, MeOH): m/
z ¼ 303.3 (100% [M ꢀ H]ꢀ), 349.0 (8% [M þ HCO2]ꢀ), 606.8 (18%
[2M ꢀ H]ꢀ); analysis for C17H17FO4 (304.31): C, 67.10; H, 5.63; found:
C, 67.01; H, 5.82.
13C NMR (100 MHz, CDCl3):
d
¼ 160.9 (C30 þ C50, Cquart.), 149.1 (C4,
Cquart.), 149.0 (C3, Cquart.), 139.5 (C10, Cquart.) 130.2 (C1, Cquart.), 128.9
(CH]), 126.7 (CH]), 120.0 (C6, CH), 111.2 (C5, CH), 108.8 (C2, CH),
104.3 (C20 þ C60, CH), 99.7 (C40, CH), 55.9 (OCH3), 55.8 (OCH3), 55.3
(OCH3) ppm; MS (i.e. 70 eV): m/z (%) ¼ 270 (100), 255 (19), 240 (16),
121 (20); analysis for C18H20O4 (300.35): C, 71.98; H, 6.71; found: C,
71.77; H, 6.98.
4.5. (E) 3-hydroxy-20,4,50-trimethoxystilbene (7)
Following the general procedure, 7 was obtained from 3-
hydroxy-4-methoxystyrene
and
2,5-dimethoxyiodobenzene;
yield: 49.2%; off-white solid; mp 97e98 ꢁC; RF ¼ 0.27 (silica gel,
4.8. (E) 40-fluoro-3,30,4,50-tetramethoxystilbene (10)
hexanes/ethyl acetate, 8:2); IR (KBr):
n
¼ 3538br, 2992w, 2935w,
2834w, 2360w,1586w,1508m,1492w,1439w,1426w,1312w,1286m,
1270m, 1243w, 1219w, 1195w, 1158w, 1131w, 1119w, 1047w, 1022w
cmꢀ1; UVevis (methanol): lmax (log ε) ¼ 233 (4.41), 314 (4.21), 362
Following the general procedure, 10 was obtained from 3,4-
dimethoxystyrene and 3,5-dimethoxy-4-fluorobromobenzene;
yield: 56.1%; colorless solid; mp 110e111 ꢁC; RF ¼ 0.14 (silica gel,
(4.34) nm; 1H NMR (400 MHz, CDCl3):
d
¼ 7.29 (d, 1H, 3J
hexanes/ethyl acetate, 8:2); IR (KBr):
n
¼ 3001m, 2961m, 2935s,
4
(trans) ¼ 16.6 Hz, CH] (1)), 7.20 (d, 1H, J ¼ 2.9 Hz, CH (60)), 7.12
(d, 1H, 3J (trans) ¼ 16.6 Hz, CH] (2)), 7.10 (d, 1H, 4J ¼ 2.1 Hz, CH (2)),
6.98 (dd, 1H, 3J ¼ 8.3 Hz, 4J ¼ 2.1 Hz, CH (6)), 6.93 (d, 1H, 3J ¼ 8.3 Hz,
2836m, 1605s, 1521s, 1463s, 1425s, 1361s, 1336m, 1289m, 1263s,
1222s, 1198m, 1159s, 1161s, 1135s, 1024s cmꢀ1; UVevis (methanol):
lmax (log ε) ¼ 219 (4.35), 326 (4.48) nm; 1H NMR (400 MHz,
3
CH (5)), 6.90 (d, 1H, J ¼ 8.9 Hz, CH (30)), 6.74 (dd, 1H, 3J ¼ 8.9 Hz,
acetone-d6):
d
¼ 7.19 (d, 1H, 4J ¼ 2.1 Hz, CH (2)), 7.14 (d, 1H, 3J
4J ¼ 2.9 Hz, CH (40)), 3.85 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 3.77
(trans) ¼ 16.4 Hz, CH] (1)), 7.04 (dd, 1H, 3J ¼ 8.1 Hz, 4J ¼ 2.1 Hz, CH
(6)), 7.03 (d, 1H, 3J (trans) ¼ 16.4 Hz, CH] (2)), 6.93 (d, 2H,
4JH,F ¼ 7.0 Hz, CH (20) þ CH (60)), 6.91 (d, 1H, 3J ¼ 8.1 Hz, CH (5)), 3.89
(s, 6H, 2ꢂ OCH3), 3.84 (s, 3H, OCH3), 3.80 (s, 3H, OCH3) ppm; 13C
(s, 3H, OCH3) ppm; 13C NMR (100 MHz, CDCl3):
d
¼ 154.7 (C50,
Cquart.), 152.0 (C20, Cquart.), 148.2 (C3, Cquart.), 147.5 (C4, Cquart.), 132.1
(C1, Cquart.), 129.7 (CH]), 127.9 (C10, Cquart.), 121.7 (CH]), 119.5 (C6,
CH), 114.0 (C40, CH), 113.1 (C2, CH), 113.0 (C30 þ C5, CH), 111.8 (C60,
CH), 56.4 (OCH3), 56.1 (OCH3), 55.7 (OCH3) ppm; MS (ESI, MeOH):
m/z ¼ 285.2 (100% [M ꢀ H]ꢀ); 570.7 (4% [2M ꢀ H]ꢀ); analysis for
C17H18O4 (286.32): C, 71.31; H, 6.34; found: C, 71.22; H, 6.52.
NMR (100 MHz, acetone-d6):
Cquart.), 149.3 (d, JC,F
d
¼ 150.4 (C4, Cquart.), 150.3 (C3,
2
¼
7.6 Hz, C30 C50, Cquart.), 142.4
þ
4
(d, 1JC,F ¼ 250.8 Hz, C40, Cquart.), 134.3 (d, JC,F ¼ 0.8 Hz, C10, Cquart.),
131.1 (C1, Cquart.), 129.3 (CH]), 126.7 (CH]), 120.7 (C6, CH), 112.6
(C5, CH), 110.2 (C2, CH), 104.5 (C20 þ C60, CH), 56.5 (OCH3), 56.4
4.6. (E) 3-hydroxy-20,4,40-trimethoxystilbene (8)
(OCH3); 19F NMR (188 MHz, acetone-d6):
d
¼
ꢀ160.5
(t, 4JF,H ¼ 7.0 Hz, eF) ppm; MS (i.e., 70 eV): m/z (%) ¼ 318 (100), 303
(20), 244 (7); analysis for C18H19FO4 (318.34): C, 67.91; H, 6.02;
found: C, 67.78; H, 6.27.
Following the general procedure,
8 was obtained from
3-hydroxy-4-methoxystyrene and 2,4-dimethoxyiodobenzene;
yield: 54.7%; off-white solid; mp 139e140 ꢁC; RF ¼ 0.46 (silica gel,
hexanes/ethyl acetate 3:1); IR (KBr):
n
¼ 3382br, 2990m, 2962m,
4.9. (E) 4-hydroxy-40-fluoro-3,30,50-trimethoxystilbene (11)
2932m, 2837m, 1604s, 1577s, 1517s, 1500s, 1460s, 1440m, 1416m,
1348w, 1323m, 1291s, 1250s, 1202s, 1157s, 1120s, 1038s, 1023s cmꢀ1
;
Followingthegeneral procedure,11 wasobtained from 4-hydroxy-
3-methoxystyrene and 3,5-dimethoxy-4-fluorobromobenzene;
yield: 52.0%; off-white solid; mp 115e117 ꢁC; RF ¼ 0.12 (silica gel,
UVevis (methanol): lmax (log ε) ¼ 210 (4.60), 294 (4.48), 330
(4.65) nm; 1H NMR (400 MHz, CDCl3):
d
¼ 7.45 (d, 1H, 3J ¼ 8.5 Hz,
CH (60)), 7.23 (d, 1H, 3J (trans) ¼ 16.4 Hz, CH] (1)), 7.13 (d, 1H,
4J ¼ 1.9 Hz, CH (2)), 6.94 (dd, 1H, 3J ¼ 8.6 Hz, 4J ¼ 1.9 Hz, CH (6)), 6.88
(d,1H, 3J (trans) ¼ 16.4 Hz, CH] (2)), 6.79 (d, 1H, 3J ¼ 8.6 Hz, CH (5)),
hexanes/ethyl acetate, 8:2); IR (KBr):
n
¼ 3431br, 3000w, 2937w,
2841w, 1606m, 1517s, 1456m, 1428m, 1383w, 1346m, 1279m, 1259m,
1244m, 1226m, 1185w, 1160w, 1133s, 1030w cmꢀ1
;
UVevis

R. Csuk et al. / European Journal of Medicinal Chemistry 54 (2012) 669e678
673
(methanol): lmax (log ε) ¼ 327 (4.44) nm; 1H NMR (400 MHz, CD3CN):
1H NMR (400 MHz, CD3CN):
d
¼ 6.98 (d, 1H, 3J (trans) ¼ 16.2 Hz,
d
¼ 7.16 (d,1H, 4J ¼ 2.1 Hz, CH (2)), 7.09 (d,1H, 3J (trans) ¼ 16.4 Hz, CH]
CH] (1)), 6.91 (d, 1H, 3J (trans) ¼ 16.2 Hz, CH] (2)), 6.90 (br s, 2H,
OH), 6.83 (s, 2H, CH (2) þ CH (6)), 6.48 (d, 2H, 4J ¼ 2.1 Hz, CH
(1)), 6.98 (dd, 1H, 3J ¼ 8.1 Hz, 4J ¼ 2.1 Hz, CH (6)), 6.96 (d, 1H, 3J
(trans)¼ 16.4 Hz, CH](2)), 6.86 (d, 2H, 4JH,F ¼7.2 Hz, CH(20)þCH(60)),
6.81 (d, 1H, 3J ¼ 8.1 Hz, CH (5)), 3.90 (s, 3H, OCH3), 3.88 (s, 6H,
4
(20) þ CH (60)), 6.33 (br s, 1H, OH), 6.17 (t, 1H, J ¼ 2.1 Hz, CH (40)),
3.85 (s, 6H, OCH3) ppm; 13C NMR (100 MHz, CD3CN):
d
¼ 159.2
OCH3) ppm; 13C NMR (100 MHz, CD3CN):
d
¼ 149.4.0 (d, 2JC,F ¼ 8.2 Hz,
(C30 þ C50, Cquart.), 148.7 (C3 þ C5, Cquart.) 141.0 (C10, Cquart.), 136.4
(C4, Cquart.), 129.9 (CH]), 129.6 (C1, Cquart.), 127.4 (CH]), 105.9
(C20 þ C60, CH), 105.0 (C2 þ C6, CH), 102.6 (C40, CH), 57.0
(OCH3) ppm; MS (ESI, MeOH): m/z (%) ¼ 287.5 (100% [M ꢀ H]ꢀ),
333.3 (21% [M þ HCO2]ꢀ), 575.0 (32% [2M ꢀ H]ꢀ); analysis for
C16H16O5 (288.30): C, 66.66; H, 5.59; found: C, 66.42; H, 5.81.
C50 þ C30, Cquart.), 148.5 (C3, Cquart.), 147.2 (C4, Cquart.), 142.5
(d, 1JC,F ¼ 251.4 Hz, C40, Cquart.),134.7 (d, 4JC,F ¼ 0.8 Hz, C10, Cquart.) 130.7
(C1, Cquart.), 129.8 (CH]), 126.5 (CH]), 121.3 (C6, CH), 115.9 (C5, CH),
110.1 (C2, CH),104.7 (C20 þ C60, CH), 56.5 (OCH3), 56.4 (OCH3) ppm; 19F
NMR (188MHz, CD3CN):
d
¼ ꢀ161.1 (t, 4JF,H ¼ 7.2 Hz, eF) ppm; MS (ESI,
MeOH): m/z (%) ¼ 303.2 (100% [M ꢀ H]ꢀ); analysis for C17H17FO4
(304.31): C, 67.10; H, 5.63; found: C, 66.86; H, 5.76.
4.13. (E) 40-fluoro-4-hydroxy-3,30,5,50-tetramethoxystilbene (15)
4.10. (E) 3-methoxy-20,4,50-trihydroxystilbene (12)
Following the general procedure, 15 was obtained from
3,5-dimethoxy-4-hydroxystyrene
and
3,5-dimethoxy-4-
Following the general procedure, 12 was obtained from
4-hydroxy-3-methoxystyrene and 2,5-dihydroxyiodobenzene:
yield: 48.5%; grey solid; mp 178e179 ꢁC; RF ¼ 0.62 (silica gel,
fluorobromobenzene; yield: 55.4%; colorless solid; mp 65e166 ꢁC;
RF ¼ 0.10 [silica gel, hexanes/ethyl acetate, 8:2 þ AcOH (0.1%)]; IR
(KBr):
n
¼ 3505m, 3005w, 2961w, 2938w, 2841w, 1608m, 1516s,
hexanes/ethyl acetate, 1:1); IR (KBr):
1513w, 1459w, 1363w, 1297w, 1264w, 1220w, 1197w, 1121w, 1035w
cmꢀ1; UVevis (methanol): lmax (log ε) ¼ 295 (4.24), 347 (4.30) nm;
n
¼ 3395br, 2925w, 1607w,
1462m, 1429w, 1373w, 1348m, 1252w, 1219m, 1161w, 1127s, 1108s,
cmꢀ1; UVevis (methanol): lmax (log ε) ¼ 240 (4.30), 327 (4.44) nm;
1H NMR (400 MHz, acetone-d6):
d
¼ 7.32 (br s, 1H, OH), 7.13 (d, 1H, 3J
1H NMR (400 MHz, acetone-d6):
d
¼ 7.89 (br s, 1H, OH), 7.67 (br s,
(trans) ¼ 16.4 Hz, CH] (1)), 7.03 (d,1H, 3J (trans) ¼ 16.4 Hz, CH] (2)),
6.92 (d, 2H, 4JH,F ¼ 7.3 Hz, CH (20) þ CH (60)), 6.87 (s, 2H, CH (2) þ CH
1H, OH), 7.62 (br s, 1H, OH), 7.28 (d, 1H, 3J (trans) ¼ 16.4 Hz, CH]
(1)), 7.17 (d, 1H, 4J ¼ 1.9 Hz, CH (2)), 7.04 (d, 1H, 3J (trans) ¼ 16.4 Hz,
CH] (2)), 7.02 (d, 1H, 4J ¼ 2.9 Hz, CH (60)), 6.99 (dd, 1H, 3J ¼ 8.3 Hz,
4J ¼ 1.9 Hz, CH (6)), 6.79 (d, 1H, 3J ¼ 8.3 Hz, CH (5)), 6.70 (d, 1H,
4J ¼ 8.8 Hz, CH (30)), 6.58 (dd, 3J ¼ 8.8 Hz, 4J ¼ 2.9 Hz, CH (40)), 3.88
(6)), 3.89 (s, 6H, OCH3), 3.85 (s, 6H, OCH3) ppm; 13C NMR (100 MHz,
2
acetone-d6):
d
¼ 149.2 (d, JC,F ¼ 8.8 Hz, C30 þ C50, Cquart.), 148.7
1
(C3 þ C5, Cquart.) 142.3 (d, JC,F ¼ 244.4 Hz, C40, Cquart.), 136.9 (C4,
4
Cquart.), 134.3 (d, JC,F ¼ 5.0 Hz, C10, Cquart.) 129.8 (CH]), 128.9 (C1,
(s, 3H, OCH3) ppm; 13C NMR (100 MHz, acetone-d6):
d
¼ 151.2 (C50,
Cquart.), 126.3 (CH]), 104.8 (C20 þ C60, CH), 104.4 (C2 þ C6, CH), 56.5
Cquart.), 148.5 (C3, Cquart.), 148.3 (C20, Cquart.), 147.1 (C4, Cquart.), 130.9
(C1, Cquart.), 129.0 (CH]), 126.0 (C10, Cquart.) 121.7 (CH]), 120.7 (C6,
CH), 117.1 (C30, CH), 115.6 (C40 þ C5, CH), 112.5 (C60, CH), 109.8 (C2,
(OCH3), 56.4 (OCH3) ppm; 19F NMR (188 MHz, CD3CN):
d
¼ ꢀ160.6
4
(t, JF,H ¼ 7.3 Hz, eF) ppm; MS (ESI, MeOH): m/z (%) ¼ 333.2 (100%
[M ꢀ H]ꢀ); analysis for C18H19FO5 (334.34): C, 64.66; H, 5.73; found:
C, 64.42; H, 5.84.
CH), 56.0 (OCH3) ppm; MS (ESI, MeOH): m/z (%)
¼
257.5
(100% [M ꢀ H]ꢀ); 303.3 (30% [M þ HCO2]ꢀ); 515.0 (81% [2M ꢀ H]ꢀ);
analysis for C15H14O4 (258.27): C, 69.76; H, 5.46; found: C,
69.68; H, 5.66.
4.14. (E) 4-hydroxy-20,3,5,50-tetramethoxystilbene (16)
Following the general procedure, 16 was obtained from 3,5-
dimethoxy-4-hydroxystyrene and 2,5-dimethoxyiodobenzene;
yield: 49.0%; off-white solid; mp 119e121 ꢁC; RF ¼ 0.09 (silica gel,
4.11. (E) 4-hydroxy-3,30,5,50-tetramethoxystilbene (13)
Following the general procedure, 13 was obtained from 3,5-
dimethoxy-4-hydroxystyrene and 3,5-dimethoxyiodobenzene;
yield: 57.9%; colorless solid; mp 96e98 ꢁC; RF ¼ 0.29 (silica gel,
hexanes/ethyl acetate, 8:2); IR (KBr):
n
¼ 3509br, 2997w, 2937m,
2833m, 2362w, 1780w, 1608m, 1517s, 1497s, 1463s, 1427m, 1371m,
1342m, 1312m, 1292m, 1222s, 1179m, 1163m, 1111s, 1042s cmꢀ1
;
hexanes/ethyl acetate, 3:1); IR (KBr):
n
¼ 3425br, 2930w, 1593w,
UVevis (methanol): lmax (log ε) ¼ 214 (4.38), 342 (4.26) nm; 1H
1520w, 1456w, 1427w, 1361w, 1334w, 1285w, 1252w, 1208w, 1157w,
1114w, 1067w cmꢀ1; UVevis (methanol): lmax (log ε) ¼ 224 (4.40),
NMR (400 MHz, acetone-d6):
d
¼ 7.29 (d, 1H, 3J (trans) ¼ 16.4 Hz,
CH] (1)), 7.18 (d, 1H, J ¼ 2.9 Hz, CH (60)), 7.13 (d, 1H, 3J
(trans) ¼ 16.4 Hz, CH] (2)), 6.91 (d, 1H, 3J ¼ 9.9 Hz, CH (30)), 6.87 (s,
2H, CH (2) þ CH (6)), 6.78 (dd, 3J ¼ 9.9 Hz, 4J ¼ 2.9 Hz, CH (40)), 3.87
(s, 6H, OCH3), 3.82 (s, 3H, OCH3), 3.77 (s, 3H, OCH3) ppm; 13C NMR
4
325 nm (4.44); 1H NMR (400 MHz, CDCl3):
d
¼ 6.98 (d, 1H, 3J
(trans) ¼ 16.2 Hz, CH] (2)), 6.86 (d, 1H, 3J (trans) ¼ 16.2 Hz, CH]
(1)), 6.73 (s, 2H, CH (2) þ CH (6)), 6.63 (d, 2H, 4J ¼ 2.1 Hz, CH
4
(20) þ CH (60)), 6.42 (t, 1H, J ¼ 2.1 Hz, CH (40)), 5.55 (br s, 1H, OH),
(100 MHz, acetone-d6):
d
¼ 154.6 (C50, Cquart.), 151.9 (C20, Cquart.),
3.93 (s, 6H, OCH3), 3.81 (s, 6H, OCH3) ppm; 13C NMR (100 MHz,
148.7 (C3 þ C5, Cquart.), 136.8 (C4, Cquart.), 130.4 (CH]), 129.5 (C1,
Cquart.), 128.0 (C10, Cquart.), 121.3 (CH]), 113.9 (C40, CH), 113.0 (C3,
CH), 111.9 (C60, CH), 104.8 (C2 þ C6, CH), 56.4 (OCH3), 56.3 (OCH3),
55.7 (OCH3) ppm; MS (ESI, MeOH): m/z (%) ¼ 315.2 (100%
[M ꢀ H]ꢀ); analysis for C18H20O5 (316.35): C, 68.34; H, 6.37; found:
C, 68.09; H, 6.54.
CDCl3):
d
¼ 161.0 (C30 þ C50, Cquart.), 147.2 (C3 þ C5, Cquart.) 139.4
(C10, Cquart.), 134.9 (C4, Cquart.), 129.3 (CH]), 128.7 (C1, Cquart.), 126.8
(CH]), 104.3 (C20 þ C60, CH), 103.4 (C2 þ C6, CH), 99.76 (C40, CH),
56.3 (OCH3), 55.3 (OCH3) ppm; MS (ESI, MeOH): m/z (%) ¼ 315.6
(100% [M ꢀ H]ꢀ); analysis for C18H20O5 (316.35): C, 68.34; H, 6.37;
found: C, 68.17; H, 6.57.
4.15. (E) 40-fluoro-30,4,50-trimethoxystilbene (17)
4.12. (E) 3,5-dimethoxy-30,4,50-trihydroxystilbene (14)
Following the general procedure, 17 was obtained from 4-
Following the general procedure, 14 was obtained from 3,5-
dimethoxy-4-hydroxystyrene and 3,5-dihydroxyiodobenzene;
yield: 53.4%; colorless solid; mp 94e97 ꢁC; RF ¼ 0.08 (silica gel,
methoxystyrene
and
3,5-dimethoxy-4-fluorobromobenzene;
yield: 58.0%; colorless solid; mp 125e127 ꢁC; RF ¼ 0.36 (silica gel,
hexanes/ethyl acetate, 8:2); IR (KBr):
n
¼ 3505m, 3005w, 2961w,
hexanes/ethyl acetate, 3:1); IR (KBr):
n
¼ 3417br, 2936w, 1702w,
2938w, 2841w, 1608m, 1516s, 1462m, 1429w, 1373w, 1348m, 1252w,
1608m, 1517m, 1457w, 1425w, 1344w, 1257w, 1214w, 1147w, 1111m
1219m, 1161w, 1127s, 1108s cmꢀ1; UVevis (methanol): lmax (log
cmꢀ1; UVevis (methanol): lmax (log ε) ¼ 224 (4.38), 326 (4.42) nm;
ε) ¼ 214 (4.19), 319 (4.30) nm; 1H NMR (400 MHz, CDCl3):
d
¼ 7.43

674
R. Csuk et al. / European Journal of Medicinal Chemistry 54 (2012) 669e678
(d, 2H, 3J ¼ 8.7 Hz, CH (2) þ CH (6)), 6.94 (d, 1H, 3J (trans) ¼ 16.4 Hz,
2835s, 1607s, 1575m, 1510s, 1454s, 1418m, 1320m, 1247s, 1207s,
1173s, 1158s, 1118s, 1028s cmꢀ1; UVevis (methanol): lmax (log
ε) ¼ 210 (4.44), 294 (4.37), 329 (4.44) nm; 1H NMR (400 MHz,
3
CH] (1)), 6.88 (d, 2H, J ¼ 8.7 Hz, CH (3) þ CH (5)), 6.85 (d, 1H, 3J
(trans) ¼ 16.4 Hz, CH] (2)), 6.71 (d, 2H, 4JH,F ¼ 7.1 Hz, CH (20) þ CH
(60)), 3.91 (s, 6H, OCH3), 3.81 (s, 3H, OCH3) ppm; 13C NMR (100 MHz,
CDCl3):
d
¼ 7.46 (d, 1H, 3J ¼ 8.5 Hz, CH (60)), 7.42 (d, 2H, 3J ¼ 8.5 Hz,
2
CDCl3):
d
¼ 159.4 (C4, Cquart.), 148.4 (d, JC,F ¼ 9.1 Hz, C30 þ C50,
CH (2) þ CH (6)), 7.24 (d, 1H, 3J (trans) ¼ 16.4 Hz, CH] (1)), 6.94
(d, 1H, 3J (trans) ¼ 16.4 Hz, CH] (2)), 6.86 (d, 2H, 3J ¼ 8.5 Hz, CH
Cquart.), 142.1 (d, 1JC,F ¼ 244.9 Hz, C40, Cquart.), 133.1 (d, 4JC,F ¼ 4.8 Hz,
C10, Cquart.), 129.8 (C1, Cquart.), 128.2 (CH]), 127.6 (C2 þ C6, CH),
126.0 (CH]), 114.1 (C3 þ C5, CH), 103.9 (C20 þ C60, CH), 56.5 (OCH3),
4
(3) þ CH (5)), 6.49 (dd, 1H, 3J ¼ 8.5 Hz, J ¼ 2.3 Hz, CH (50)) 6.45
3
(d, 1H, J ¼ 2.3 Hz, CH (30)), 3.85 (s, 3H, OCH3), 3.81 (s, 3H, OCH3),
55.3 (OCH3) ppm; 19F NMR (188 MHz, CDCl3):
d
¼ ꢀ159.2
3.80 (s, 3H, OCH3) ppm; 13C NMR (100 MHz, CDCl3):
d
¼ 160.2 (C40,
(t, 4JF,H ¼ 6.7 Hz, eF) ppm; MS (i.e., 70 eV): m/z (%) ¼ 288 (100), 276
(33), 257 (5), 242 (5), 230 (5), 214 (5); analysis for C17H17FO3
(288.31): C, 70.82; H, 5.94; found: C, 70.59; H, 6.18.
Cquart.), 158.8 (C4, Cquart.), 157.8 (C20, Cquart.), 131.2 (C1, Cquart.), 127.5
(C2 þ C6, CH), 126.9 (C60, CH), 126.1 (CH]), 121.2 (CH]), 119.9 (C10,
Cquart.), 113.9 (C3 þ C5, CH), 104.9 (C50, CH), 98.5 (C30, CH), 55.5
(OCH3), 55.3 (OCH3), 55.2 (OCH3) ppm; MS (i.e., 70 eV): m/z
(%) ¼ 256 (100), 213 (44), 181 (24), 152 (16), 137 (26); analysis for
C17H18O3 (270.32): C, 75.53; H, 6.71; found: C, 75.43; H, 6.98.
4.16. (E) 20,4,50-trimethoxystilbene (18)
Following the general procedure, 18 was obtained from
4-methoxystyrene and 2,5-dimethoxyiodobenzene; yield: 56.0%;
colorless solid; mp 59e61 ꢁC (lit.: 61.9e62.7 ꢁC [53], 67e68 ꢁC
[54]); RF ¼ 0.55 (silica gel, hexanes/ethyl acetate, 8:2); IR (KBr):
4.19. (E) 30,50-dimethoxy-4-hydroxystilbene (21)
Following the general procedure, 21 was obtained from 4-
hydroxystyrene and 3,5-dimethoxyiodobenzene; yield: 55.0%;
colorless solid; mp 83e84 ꢁC (lit.: 88 ꢁC [56], 86e88 ꢁC [57],
55e64 ꢁC [58]); RF ¼ 0.16 (silica gel, hexanes/ethyl acetate, 3:1). IR
n
¼ 2999m, 2935m, 2835m, 1603m, 1573w, 1511s, 1488m, 1458m,
1425m, 1319w, 1305m, 1281m, 1250s, 1237m, 1211m, 1175m, 1160w,
1119m, 1049m, 1022m cmꢀ1; UVevis (methanol): lmax (log ε) ¼ 207
(4.42), 295 (4.33), 341 (4.26) nm; 1H NMR (400 MHz, CDCl3):
(KBr):
n
¼ 3406br, 2932w, 1598w, 1511w, 1449w, 1415w, 1233w,
d
¼ 7.46 (d, 2H, 3J ¼ 8.7 Hz, CH (2) þ CH (6)), 7.30 (d, 1H, 3J
1171w, 1120w cmꢀ1; UVevis (methanol): lmax (log ε) ¼ 209 (4.43),
(trans) ¼ 16.4 Hz, CH] (1)), 7.12 (d, 1H, 4J ¼ 2.9 Hz, CH (60)), 7.03 (d,
1H, 3J (trans) ¼ 16.4 Hz, CH] (2)), 6.88 (d, 2H, 3J ¼ 8.7 Hz, CH
326 (4.41) nm; 1H NMR (400 MHz, CDCl3):
d
¼ 7.37 (d, 2H,
3J ¼ 8.7 Hz, CH (2) þ CH (6)), 6.97 (d, 1H, 3J (trans) ¼ 16.1 Hz, CH]
(1)), 6.88 (d, 1H, 3J (trans) ¼ 16.1 Hz, CH] (2)), 6.80 (d, 2H,
3J ¼ 8.7 Hz, CH (3) þ CH (5)), 6.67 (d, 2H, 4J ¼ 2.1 Hz, CH (20) þ CH
3
(3) þ CH (5)), 6.82 (d, 1H, J ¼ 9.0 Hz, CH (30)), 6.76 (dd, 1H,
3J ¼ 9.0 Hz, J ¼ 2.9 Hz, CH (60)), 3.83 (s, 3H, OCH3), 3.81 (s, 3H,
4
OCH3), 3.80 (s, 3H, OCH3) ppm; 13C NMR (100 MHz, CDCl3):
(60)), 6.38 (t, 1H, J ¼ 2.1 Hz, CH (40)), 3.74 (s, 6H, OCH3) ppm; 13C
4
d
¼ 159.2 (C4, Cquart.), 153.8 (C50, Cquart.), 151.3 (C20, Cquart.), 130.6 (C1,
NMR (100 MHz, CDCl3):
d
¼ 158.5 (C30 þ C50, Cquart.), 155.2 (C4,
Cquart.), 128.9 (CH]), 127.8 (C2 þ C6, CH), 127.6 (C10, Cquart.), 121.2
(CH]), 114.0 (C3 þ C5, CH), 113.2 (C40, CH), 112.3 (C30, CH), 111.5
(C60, CH), 56.3 (OCH3), 55.8 (OCH3), 55.3 (OCH3) ppm; MS (i.e.,
70 eV): m/z (%) ¼ 270 (100), 255 (60), 227 (76), 152 (31), 115 (34);
analysis for C17H18O3 (270.32): C, 75.53; H, 6.71; found: C, 75.42; H,
6.95.
Cquart.),138.5 (C10, Cquart.) 130.3 (C1, Cquart.),127.8 (C2 þ C6, CH),127.7
(CH]), 126.9 (CH]), 115.6 (C3 þ C5, CH), 104.3 (C20 þ C60, CH), 99.6
(C40, CH), 55.8 (OCH3) ppm; MS (i.e., 70 eV): m/z (%) ¼ 256 (100), 241
(14), 228 (9), 213 (43), 198 (15), 181 (25), 152 (22), 133 (26); analysis
for C16H16O3 (256.30): C, 74.78; H, 6.29; found: C, 74.77; H, 6.48.
4.20. (E) 30,4,50-trihydroxystilbene (22)
4.17. (E) 20,50-dihydroxy-4-methoxystilbene (19)
Following the general procedure, 22 was obtained from 4-
hydroxystyrene and 3,5-dihydroxyiodobenzene; yield: 41.4%;
colorless solid; mp >260 ꢁC (lit.: 275e276 ꢁC [59], 260 ꢁC [60],
256e258 ꢁC [61], 254e255 ꢁC [62]); RF ¼ 0.46 (silica gel, hexanes/
Following the general procedure, 19 was obtained from
4-methoxystyrene and 2,5-dihydroxyiodobenzene; yield: 52.8%;
colorless solid; mp 141e142 ꢁC; RF ¼ 0.30 (silica gel, hexanes/ethyl
acetate, 3:1); IR (KBr):
n
¼ 3227br, 3030m, 2835w, 1862w, 1605m,
ethyl acetate, 1:1). IR (KBr):
n
¼ 3287br, 1606m, 1587m, 1512m,
1574w, 1513s, 1451s, 1360w, 1304w, 1290w, 1250m, 1189s, 1176m,
1111w, 1094w, 1032w cmꢀ1; UVevis (methanol): lmax (log ε) ¼ 293
1462w,1443m,1383m,1325m,1300w,1265w,1248m, 1175w,1148m,
1105w, 1010w cmꢀ1; UVevis (methanol): lmax (log ε) ¼ 217 (4.36),
(4.30), 345 (4.19) nm; 1H NMR (400 MHz, DMSO-d6):
d
¼ 8.95 (br s,
305 (4.48) nm; 1H NMR (400 MHz, CD3CN):
d
¼ 7.38 (d, 2H,
1H, OH), 8.71 (br s, 1H, OH), 7.45 (d, 2H, 3J ¼ 8.5 Hz, CH (2) þ CH (6)),
7.19 (d, 1H, 3J (trans) ¼ 16.4 Hz, CH] (1)), 6.99 (d, 1H, 3J
3J ¼ 8.7 Hz, CH (2) þ CH (6)), 7.00 (d, 1H, 3J (trans) ¼ 16.4 Hz, CH]
(1)), 6.85 (d, 1H, 3J (trans) ¼ 16.4 Hz, CH] (2)), 6.79 (d, 2H,
3J ¼ 8.7 Hz, CH (3) þ CH (5)), 6.48 (d, 2H, 4J ¼ 2.1 Hz, CH (20) þ CH
4
(trans) ¼ 16.4 Hz, CH] (2)), 6.92 (d, 1H, J ¼ 2.7 Hz, CH (60)), 6.90
4
(d, 2H, 3J ¼ 8.7 Hz, CH (3) þ CH (5)), 6.65 (d, 1H, 3J ¼ 8.5 Hz, CH (30)),
(60)), 6.16 (t, 1H, J ¼ 2.1 Hz, CH (40)) ppm; 13C NMR (100 MHz,
4
6.50 (dd, 1H, 3J ¼ 8.5 Hz, J ¼ 2.7 Hz, CH (40)), 3.75 (s, 3H,
CD3CN):
d
¼ 159.1 (C30 þ C50, Cquart.), 157.7 (C4, Cquart.), 141.0 (C10,
OCH3) ppm; 13C NMR (100 MHz, DMSO-d6):
d
¼ 158.8 (C4, Cquart.),
Cquart.) 130.0 (C1, Cquart.), 129.3 (CH]), 128.7 (C2 þ C6, CH), 126.5
(CH]), 116.3 (C3 þ C5, CH), 105.7 (C20 þ C60, CH), 102.5 (C40,
CH) ppm; MS (ESI, MeOH): m/z ¼ 227.4 (100% [M ꢀ H]ꢀ), 273.0 (38%
[M þ HCO2]ꢀ), 454.9 (26% [2M ꢀ H]ꢀ); analysis for C14H12O3
(228.24): C, 73.67; H, 5.30; found: C, 73.46; H, 5.51.
150.1 (C50, Cquart.), 147.7 (C20, Cquart.), 130.4 (C1, Cquart.), 127.6
(C2 þ C6, CH), 127.2 (CH]), 124.6 (C10, Cquart.), 121.6 (CH]), 116.6
(C30, CH), 115.5 (C40, CH), 114.3 (C3 þ C5, CH), 111.7 (C60, CH), 55.2
(OCH3) ppm; MS (ESI, MeOH): m/z (%) ¼ 241.3 (78% [M ꢀ H]ꢀ), 287.1
(100% [M þ HCO2]ꢀ), 482.9 (45% [2M ꢀ H]ꢀ); analysis for C15H14O3
(242.27): C, 74.36; H, 5.82; found: C, 74.18; H, 6.09.
4.21. (E) 30,50-dimethoxy-40-fluoro-4-hydroxystilbene (23)
4.18. (E) 20,4,40-trimethoxystilbene (20)
Following the general procedure, 23 was obtained from
4-hydroxystyrene and 3,5-dimethoxy-4-fluorobromobenzene;
yield: 47.6%; off-white solid; mp 123e125 ꢁC; RF ¼ 0.49 (silica gel,
Following the general procedure, 20 was obtained from
4-methoxystyrene and 2,4-dimethoxyiodobenzene; yield: 57.3%;
off-white solid; mp 87e90 ꢁC (lit.: 86e89 ꢁC [55], 94e95 ꢁC [56]);
RF ¼ 0.75 (silica gel, hexanes/ethyl acetate, 3:1). IR (KBr): ¼ 2966s,
hexanes/ethyl acetate, 3:1); IR (KBr):
n
¼ 3419br, 2940w, 1606m,
1585w, 1519m, 1455w, 1420w, 1330w, 1265w, 1249w, 1219w, 1171w,
n
1124m cmꢀ1; UVevis (methanol): lmax (log ε) ¼ 209 (4.49), 306

R. Csuk et al. / European Journal of Medicinal Chemistry 54 (2012) 669e678
675
(4.53) nm; 1H NMR (400 MHz, CDCl3):
d
¼ 7.37 (d, 2H, 3J ¼ 8.5 Hz, CH
296 (4.16), 345 (4.09) nm; 1H NMR (400 MHz, DMSO-d6):
d
¼ 9.53
(2) þ CH (6)), 6.92 (d,1H, 3J (trans) ¼ 16.2 Hz, CH] (1)), 6.84 (d,1H, 3J
(trans) ¼ 16.2 Hz, CH] (2)), 6.81 (d, 2H, 3J ¼ 8.5 Hz, CH (3) þ CH (5)),
6.70 (d, 2H, 4JH,F ¼ 7.1 Hz, CH (20) þ CH (60)), 3.91 (s, 6H, OCH3) ppm;
(br s, 1H, OH), 8.93 (br s, 1H, OH), 8.71 (br s, 1H, OH), 7.33 (d, 2H,
3J ¼ 8.5 Hz, CH (2) þ CH (6)), 7.12 (d, 1H, 3J (trans) ¼ 16.6 Hz, CH]
(1)), 6.93 (d, 1H, 3J (trans) ¼ 16.6 Hz, CH] (2)), 6.89 (d, 1H,
4J ¼ 2.8 Hz, CH (60)), 6.73 (d, 2H, 3J ¼ 8.5 Hz, CH (3) þ CH (5)), 6.63 (d,
13C NMR (100 MHz, CDCl3):
d
¼ 155.3 (C4, Cquart.), 148.4 (d,
2JC,F ¼ 8.8 Hz, C30 þ C50, Cquart.), 142.1 (d, 1JC,F ¼ 245.8 Hz, C40, Cquart.),
1H, J ¼ 8.5 Hz, CH (30)), 6.48 (dd, 1H, 3J ¼ 8.5 Hz, 4J ¼ 2.8 Hz, CH
3
4
133.0 (d, JC,F ¼ 5.0 Hz, C10, Cquart.) 130.0 (C1, Cquart.), 128.1 (CH]),
(40)) ppm; 13C NMR (100 MHz, DMSO-d6):
d
¼ 157.4 (C4, Cquart.),
127.8 (C2 þ C6, CH),126.1 (CH]),115.6 (C3þ C5, CH),103.9 (C20 þ C60,
150.4 (C50, Cquart.), 147.9 (C20, Cquart.), 129.2 (C1, Cquart.), 128.0
(C2 þ C6, CH), 127.9 (CH]), 125.1 (C10, Cquart.), 121.0 (CH]), 116.9
(C30, CH), 115.9 (C3 þ C5, CH), 115.5 (C40, CH), 111.9 (C60, CH) ppm;
MS (ESI, MeOH): m/z (%) ¼ 227.3 (100% [M ꢀ H]ꢀ), 272.9 (17%
[M þ HCO2]ꢀ), 454.8 (26% [2M ꢀ H]ꢀ); analysis for C14H12O3
(228.24): C, 73.67; H, 5.30; found: C, 73.51; H, 5.32.
CH), 56.5 (OCH3) ppm; 19F NMR (188 MHz, CDCl3):
d
¼ ꢀ159.1 (t,
4JF,H ¼ 7.1 Hz, eF) ppm; MS (ESI, MeOH): m/z (%) ¼ 273.6 (100%
[M ꢀ H]ꢀ), 319.2 (10% [M þ HCO2]ꢀ), 547.0 (17% [2M ꢀ H]ꢀ); analysis
for C16H15FO3 (274.28): C, 70.06; H, 5.51; found: C, 69.85; H, 5.62.
4.22. (E) 4-hydroxy-30,40,50-trifluorostilbene (24)
4.25. (E) 20,50-dihydrox-3-methoxystilbene (27)
Following the general procedure, 24 was obtained from
4-hydroxystyrene and 3,4,5-trifluorobromobenzene; yield: 56.9%;
colorless solid; mp 149e151 ꢁC; RF ¼ 0.30 (silica gel, hexanes/ethyl
Following the general procedure, 27 was obtained from
3-methoxystyrene and 2,5-dihydroxyiodobenzene; yield: 54.5%;
slightly yellow solid; mp 139e140 ꢁC; RF ¼ 0.78 (silica gel, hexanes/
acetate, 9:1); IR (KBr):
n
¼ 3266br, 2361w,1889w,1638w,1594s,1529s,
1508s, 1442s, 1360m, 1321m, 1269m, 1231s, 1174m, 1131w, 1106w,
ethyl acetate, 1:1); IR (KBr):
n
¼ 3300br, 2836m, 1862w, 1718w,
1043s cmꢀ1; UVevis (methanol): lmax (log ε) ¼ 230 (4.19), 321
1602m, 1576m, 1515w, 1487m, 1455s, 1374w, 1328w, 1265s, 1235s,
1199s, 1152s, 1095w, 1048m cmꢀ1; UVevis (methanol): lmax (log
ε) ¼ 214 (4.74), 291 (4.60), 346 (4.45) nm; 1H NMR (400 MHz,
(4.50) nm; 1H NMR (400 MHz, CDCl3):
d
¼ 7.36 (d, 2H, 3J ¼ 8.5 Hz, CH
(2) þ CH(6)), 7.03(dt,1H, 3JH,F ¼ 9.2 Hz,4JH,F ¼ 6.6 Hz, CH(20)þ CH(60)),
6.92 (d, 1H, 3J (trans) ¼ 16.2 Hz, CH] (1)), 6.81 (d, 2H, 3J ¼ 8.5 Hz, CH
(3) þ CH (5)), 6.75 (d,1H, 3J (trans) ¼ 16.2 Hz, CH] (2)) ppm; 13C NMR
DMSO-d6):
d
¼ 9.03 (br s, 1H, OH), 8.74 (br s, 1H, OH), 7.30 (d, 1H, 3J
(trans) ¼ 16.4 Hz, CH] (1)), 7.22 (t, 1H, 3J ¼ 7.8 Hz, CH (5)), 7.07
(d, 1H, 3J ¼ 7.8 Hz, CH (6)), 7.03 (s, 1H, CH (2)), 7.01 (d, 1H, 3J
(trans) ¼ 16.4 Hz, CH] (2)), 6.90 (d,1H, 4J ¼ 2.9 Hz, CH (60)), 6.77 (dd,
1H, 3J ¼ 7.8 Hz, 4J ¼ 2.3 Hz, CH (4)), 6.64 (d, 1H, 3J ¼ 8.5 Hz, CH (30)),
6.51 (dd,1H, 3J ¼ 8.5 Hz, 4J ¼ 2.9 Hz, CH (40)), 3.74 (s, 3H, OCH3) ppm;
(100 MHz, CDCl3):
d
¼ 155.8 (C4, Cquart.), 151.4 (ddd, 1JC, F ¼ 252.3 Hz,
2JC,F ¼ 10.1 Hz, 3JC,F ¼ 4.3 Hz, C30 þ C50, Cquart.),138.7 (m,1JC,F ¼ 250.7 Hz,
C40, Cquart.), 133.9 (dd, 3JC,F ¼ 12.2 Hz, 4JC,F ¼ 7.7 Hz, C10, Cquart.), 130.4
(d, 5JC,F ¼ 2.4 Hz, CH]),129.2 (C1, Cquart.),128.2 (C2 þ C6, CH),123.6 (d,
4JC,F ¼ 2.8 Hz, CH]), 115.7 (C3 þ C5, CH), 109.8 (dd, JC,F ¼ 16.8 Hz,
13C NMR (100 MHz, DMSO-d6):
d
¼ 159.7 (C3, Cquart.), 150.0 (C50,
2
3JC,F ¼ 4.9 Hz, C20 þ C60, CH) ppm; 19F NMR (188 MHz, CDCl3):
Cquart.), 147.9 (C20, Cquart.), 139.2 (C1, Cquart.), 129.8 (C5, CH), 127.5
(CH]), 124.2 (CH]), 124.1 (C10, Cquart.), 118.7 (C6, CH), 116.7 (C30,
CH),116.1 (C40, CH),113.1 (C4, CH),112.0 (C60, CH),111.5 (C2, CH), 56.3
(OCH3) ppm; MS (ESI, MeOH): m/z (%) ¼ 241.3 (46% [M ꢀ H]ꢀ), 287.0
(100% [M þ HCO2]ꢀ), 482.8 (52% [2M ꢀ H]ꢀ); analysis for C15H14O3
(242.27): C, 74.36; H, 5.82; found: C, 74.11; H, 6.04.
d
¼ ꢀ135.2 (dd, 3JF,F ¼ 19.7 Hz, 3J F,H ¼ 9.2 Hz, F (30) þ F (50)), ꢀ161.7 (tt,
4
3JF,F ¼ 19.7 Hz, JF,H ¼ 6.6 Hz, F (40)) ppm; MS (ESI, MeOH): m/z
(%) ¼ 249.6 (55% [M ꢀ H]ꢀ), 498.9 (100% [2M ꢀ H]ꢀ); analysis for
C14H9F3O (250.22): C, 67.20; H, 3.63; found: C, 66.98; H, 3.83.
4.23. (E) 20,50-dimethoxy-4-hydroxystilbene (25)
4.26. (E) 30,50-dimethoxy-40-fluoro-3-hydroxystilbene (28)
Following the general procedure, 25 was obtained from
4-hydroxystyrene and 2,5-dimethoxyiodobenzene; yield: 52.2%;
off-white solid; mp 81e82 ꢁC; RF ¼ 0.27 (silica gel, hexanes/ethyl
Following the general procedure, 28 was obtained from
3-hydroxystyrene and 3,5-dimethoxy-4-fluorobromobenzene;
yield: 53.3%; off-white solid; mp 108e111 ꢁC; RF ¼ 0.59 (silica gel,
acetate, 8:2 þ acetic acid (0.1%)); IR (KBr):
n
¼ 3341br, 2867m,
1605m, 1515m, 1497m, 1460m, 1436m, 1416w, 1359w, 1316w, 1299w,
1271w, 1215m, 1172m, 1099w, 1039m, 1009w cmꢀ1; UVevis (meth-
anol): lmax (log ε) ¼ 208 (4.41), 284 (4.34), 341 (4.30) nm; 1H NMR
hexanes/ethyl acetate, 3:1); IR (KBr):
n
¼ 3241br, 2944w, 1743w,
1601m,1518m,1457m,1420m,1336m,1279w,1247m,1225m,1184w,
1159m, 1149m, 1131s cmꢀ1; UVevis (methanol): lmax (log ε) ¼ 214
(400 MHz, CDCl3):
d
¼ 7.40 (d, 2H, 3J ¼ 8.5 Hz, CH (2) þ CH (6)), 7.28
(4.41), 319 (4.44) nm; 1H NMR (400 MHz, CDCl3):
d
¼ 7.21 (t, 1H,
(d,1H, 3J (trans) ¼ 16.4 Hz, CH] (1)), 7.11 (d, 1H, 4J ¼ 2.9 Hz, CH (60)),
7.00 (d,1H, 3J (trans) ¼ 16.4 Hz, CH] (2)), 6.81 (d,1H, 3J ¼ 9.0 Hz, CH
(30)), 6.79 (d, 2H, 3J ¼ 8.5 Hz, CH (3) þ CH (5)), 6.76 (dd,1H, 3J ¼ 9.0 Hz,
4J ¼ 2.9 Hz, CH (40)), 4.92 (br s,1H, OH), 3.82 (s, 3H, OCH3), 3.80 (s, 3H,
3J ¼ 7.7 Hz, CH (5)), 7.05 (d, 1H, 3J ¼ 7.7 Hz, CH (6)), 6.97 (d, 1H,
4J ¼ 2.3 Hz, CH (2)), 6.96 (d, 1H, 3J (trans) ¼ 16.2 Hz, CH] (1)), 6.90
(d, 1H, 3J (trans) ¼ 16.2 Hz, CH] (2)), 6.74 (dd, 1H, 3J ¼ 7.7 Hz,
4J ¼ 2.3 Hz, CH (4)), 6.72 (d, 2H, 4JH,F ¼ 7.1 Hz, CH (20) þ CH (60)), 3.91
OCH3) ppm; 13C NMR (100 MHz, CDCl3):
d
¼ 155.1 (C4, Cquart.), 153.8
(s, 6H, OCH3) ppm; 13C NMR (100 MHz, CDCl3):
d
¼ 155.8 (C3,
2
(C50, Cquart.), 151.3 (C20, Cquart.), 130.8 (C1, Cquart.), 128.9 (CH]), 128.0
(C2 þ C6, CH), 127.6 (C10, Cquart.), 121.2 (CH]), 115.5 (C3 þ C5, CH),
113.3 (C40, CH), 112.4 (C30, CH), 111.5 (C60, CH), 56.3 (OCH3), 55.8
(OCH3) ppm; MS (i.e., 70 eV): m/z (%) ¼ 256 (100), 241 (16), 213 (56),
198 (11),181 (16),169 (9); analysis for C16H16O3 (256.30): C, 74.98; H,
6.29; found: C, 74.85; H, 6.51.
Cquart.), 148.4 (d, JC,F
¼
8.6 Hz, C30
þ
C50, Cquart.), 142.1
1
(d, JC,F ¼ 243.1 Hz, C40, Cquart.), 138.8 (C1, Cquart.), 132.7 (d,
4JC,F ¼ 5.0 Hz, C10, Cquart.), 129.9 (C5, CH), 128.6 (CH]), 128.3 (CH]),
119.4 (C6, CH), 114.8 (C4, CH), 112.9 (C2, CH), 104.4 (C20 þ C60, CH),
56.7 (OCH3) ppm; 19F NMR (188 MHz, CDCl3):
d
¼ ꢀ158.3
(t, 4JF,H ¼ 7.1 Hz, eF) ppm; MS (i.e., 70 eV): m/z (%) ¼ 274 (100), 242
(10), 228 (10), 199 (15), 170 (9); analysis for C16H15FO3 (274.28): C,
70.06; H, 5.51; found: C, 69.84; H, 5.73.
4.24. (E) 20,4,50-trihydroxystilbene (26)
Following the general procedure, 26 was obtained from
4-hydroxystyrene and 2,5-dihydroxyiodobenzene; yield: 48.7%;
off-white solid; mp 198e200 ꢁC; RF ¼ 0.13 (silica gel, hexanes/ethyl
4.27. (E) 20,3,50-trihydroxystilbene (29)
Following the general procedure, 29 was obtained from
3-hydroxystyrene and 2,5-dihydroxyiodobenzene; yield: 47.9%; off-
white solid; mp 208e210 ꢁC; RF ¼ 0.13 (silica gel, hexanes/ethyl
acetate, 3:1); IR (KBr):
n
¼ 3278br, 1605w, 1513w, 1451w, 1362w,
1253w, 1188w cmꢀ1; UVevis (methanol): lmax (log ε) ¼ 209 (4.22),

676
R. Csuk et al. / European Journal of Medicinal Chemistry 54 (2012) 669e678
acetate, 3:1); IR (KBr):
n
¼ 3300br, 1613w, 1582w, 1505w, 1457m,
acetate, 3:1); IR (KBr):
n
¼ 3052m, 2918m, 2900m, 2841m, 1643m,
1377w, 1305w, 1254w, 1199w, 1156w, 1095w cmꢀ1; UVevis (meth-
anol): lmax (log ε) ¼ 211 (4.57), 291 (4.42), 345 (4.31) nm; 1H NMR
1609s, 1599s, 1572s, 1503s, 1468m, 1463s, 1437m, 1423m, 1415m,
1341s, 1320m, 1289s, 1259s, 1244s, 1201s, 1185s, 1158s, 1119s, 1039s
cmꢀ1; UVevis (methanol): lmax (log ε) ¼ 212 (4.21), 294 (4.12), 331
(400 MHz, DMSO-d6):
d
¼ 9.44 (br s,1H, OH), 9.07 (br s,1H, OH), 8.81
(br s, 1H, OH), 7.27 (d, 1H, 3J (trans) ¼ 16.4 Hz, CH] (1)), 7.13 (t, 1H,
3J ¼ 7.8 Hz, CH (5)), 6.96 (d, 1H, 3J (trans) ¼ 16.4 Hz, CH] (2)),
6.94e6.92 (m, 3H, CH (2) þ CH (6) þ CH (60)), 6.66 (d, 1H, 3J ¼ 8.5 Hz,
CH (30)), 6.64 (d, 1H, 3J ¼ 7.8 Hz, CH (4)), 6.53 (dd, 1H, 3J ¼ 8.5 Hz,
(4.30) nm; 1H NMR (400 MHz, CDCl3):
d
¼ 7.60 (d,1H, 3J ¼ 7.7 Hz, CH
(6)), 7.54 (d, 1H, 3J ¼ 8.5 Hz, CH (60)), 7.37 (d, 1H, 3J (trans) ¼ 16.8 Hz,
CH] (1)), 7.33 (d, 1H, 3J (trans) ¼ 16.8 Hz, CH] (2)), 7.18 (t, 1H,
3J ¼ 7.7 Hz, CH (4)), 6.93 (t, 1H, 3J ¼ 7.7 Hz, CH (5)), 6.86 (d, 1H,
3J ¼ 7.7 Hz, CH (3)), 6.50 (dd,1H, 3J ¼ 8.5 Hz, 4J ¼ 2.5 Hz, CH (50)), 6.44
(d,1H, 4J ¼ 2.5 Hz, CH (30)), 3.86 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 3.82
4J ¼ 2.9 Hz, CH (40)) ppm; 13C NMR (100 MHz, DMSO-d6):
¼ 157.7
d
(C3, Cquart.), 150.2 (C50, Cquart.), 148.0 (C20, Cquart.), 139.2 (C1, Cquart.),
129.9 (C5, CH), 127.7 (CH]), 124.3 (C10, Cquart.), 123.7 (CH]), 117.8
(C6, CH),116.8 (C30, CH),116.1 (C40, CH),114.8 (C4, CH),112.7 (C60, CH),
112.0 (C2, CH) ppm; MS (ESI, MeOH): m/z (%) ¼ 227.4 (25% [M ꢀ H]ꢀ),
273.1 (100% [M þ HCO2]ꢀ), 454.9 (27% [2M ꢀ H]ꢀ); analysis for
C14H12O3 (228.24): C, 73.67; H, 5.30; found: C, 73.49; H, 5.35.
(s, 3H, OCH3) ppm; 13C NMR (125 MHz, CDCl3):
d
¼ 160.3 (C40, Cquart.),
157.9 (C20, Cquart.), 156.7 (C2, Cquart.), 127.9 (C4, CH), 127.4 (C1, Cquart.),
127.1 (C60, CH), 126.1 (C6, CH), 123.4 (CH]), 121.5 (CH]), 120.7 (C5,
CH), 120.3 (C10, Cquart.), 110.8 (C3, CH), 104.9 (C50, CH), 98.4 (C30, CH),
55.5 (OCH3), 55.4 (OCH3), 55.2 (OCH3) ppm; MS (i.e., 70 eV): m/z
(%) ¼ 270 (100), 240 (8), 225 (12), 164 (10), 151 (27); analysis for
C17H18O3 (270.32): C, 75.53; H, 6.71; found: C, 75.32; H, 6.98.
4.28. (E) 20,40-dimethoxy-3-hydroxystilbene (30)
Following the general procedure, 30 was obtained from
3-hydroxystyrene and 2,4-dimethoxyiodobenzene; yield: 53.7%;
off-white solid; mp 106e108 ꢁC; RF ¼ 0.30 (silica gel, DCM/hexanes,
4.31. (E) 30,50-dimethoxy-40-fluoro-2-hydroxystilbene (33)
Following the general procedure, 33 was obtained from
2-hydroxystyrene and 3,5-dimethoxy-4-fluorobromobenzene;
yield: 51.1%; colorless solid; mp 63e65 ꢁC; RF ¼ 0.16 (silica gel,
3:1); IR (KBr):
n
¼ 3397br, 2945m, 1603m, 1577m, 1505m, 1468m,
1434w, 1419w, 1296m, 1277m, 1200m, 1152m, 1107w, 1023 cmꢀ1
;
UVevis (methanol): lmax (log ε) ¼ 213 (4.34), 326 (4.36) nm; 1H
hexanes/ethyl acetate, 8:2); IR (KBr):
n
¼ 3418br, 2940m, 2842w,
3
NMR (400 MHz, CDCl3):
d
¼ 7.47 (d, 1H, J ¼ 8.5 Hz, CH (60)), 7.35
1704m, 1605s, 1519s, 1455s, 1421s, 1349s, 1243s, 1128s, 1042m cmꢀ1
;
(d, 1H, 3J (trans) ¼ 16.4 Hz, CH] (1)), 7.18 (t, 1H, 3J ¼ 7.9 Hz, CH (5)),
7.05 (d, 1H, 3J ¼ 7.9 Hz, CH (6)), 6.97 (d, 1H, 4J ¼ 1.7 Hz, CH (2)), 6.92
(d, 1H, 3J (trans) ¼ 16.4 Hz, CH] (2)), 6.68 (dd, 1H, 3J ¼ 7.9 Hz,
UVevis (methanol): lmax (log ε) ¼ 290 (4.12), 326 (4.18) nm; 1H NMR
(400 MHz, CDCl3):
d
¼ 7.48 (d, 1H, 3J ¼ 7.7 Hz, CH (6)), 7.28 (d, 1H, 3J
(trans) ¼ 16.4 Hz, CH] (1)), 7.11 (t,1H, 3J ¼ 7.7 Hz, CH (4)), 7.01 (d,1H,
3J (trans) ¼ 16.4 Hz, CH] (2)), 6.92 (t,1H, 3J ¼ 7.7 Hz, CH (5)), 6.80 (d,
1H, 3J ¼ 7.7 Hz, CH (3)), 6.74 (d, 2H, 4JH,F ¼ 7.0 Hz, CH (20) þ CH (60))
4J ¼ 1.7 Hz, CH (4)), 6.50 (dd, 1H, 3J ¼ 8.5 Hz, J ¼ 2.3 Hz, CH (50)),
4
4
6.46 (d, 1H, J ¼ 2.3 Hz, CH (30)), 3.85 (s, 3H, OCH3), 3.82 (s, 3H,
OCH3) ppm; 13C NMR (100 MHz, CDCl3):
d
¼ 160.7 (C40, Cquart.),158.1
3.88 (s, 6H, OCH3) ppm; 13C NMR (100 MHz, CDCl3):
d
¼ 153.3 (C2,
2
(C20, Cquart.),155.7 (C3, Cquart.),140.0 (C1, Cquart.),129.7 (C5, CH),127.3
(C60, CH), 126.5 (CH]), 123.8 (CH]), 119.4 (C10, Cquart.), 119.3 (C6,
CH), 114.0 (C4, CH), 112.6 (C2, CH), 105.6 (C50, CH), 98.5 (C30, CH),
55.5 (OCH3), 55.4 (OCH3) ppm; MS (ESI, MeOH): m/z (%) ¼ 255.3
(100% [M ꢀ H]ꢀ), 510.8 (21% [2M ꢀ H]ꢀ); analysis for C16H16O3
(256.30): C, 74.98; H, 6.29; found: C, 74.69; H, 6.42.
Cquart.), 148.3 (d, JC,F ¼ 8.7 Hz, C30 þ C50, Cquart.), 142.2 (d,
1JC,F ¼ 245.7 Hz, C40, Cquart.), 133.3 (d, 4JC,F ¼ 4.8 Hz, C10, Cquart.) 129.1
(CH]),128.8 (C4, CH),127.0 (C6, CH),124.4 (C1, Cquart.),123.3 (CH]),
121.0 (C5, CH),116.0 (C3, CH),104.3 (C20 þ C60, CH), 56.5 (OCH3) ppm;
19F NMR (188 MHz, CD3CN):
d
¼ ꢀ158.8 (t, 4JF,H ¼ 7.0 Hz, F) ppm; MS
(ESI, MeOH): m/z (%) ¼ 273.3 (100% [M ꢀ H]ꢀ); 319.0 (16.3%
[M þ HCO2]ꢀ); 546.8 (52% [2M ꢀ H]ꢀ); analysis for C16H15FO3
(274.28): C, 70.06; H, 5.51; found: C, 69.89; H, 5.71.
4.29. (E) 20,50-dihydroxy-2-methoxystilbene (31)
Following the general procedure, 31 was obtained from
2-methoxystyrene and 2,5-dihydroxyiodobenzene; yield: 51.7%;
colorless solid; mp 163e165 ꢁC; RF ¼ 0.67 (silica gel, hexanes/ethyl
4.32. (E) 2,20,50-trihydroxystilbene (34)
Following the general procedure, 34 was obtained from
2-hydroxystyrene and 2,5-dihydroxyiodobenzene; yield: 49.8%; off-
white solid; mp 218e220 ꢁC; RF ¼ 0.67 (silica gel, hexanes/ethyl
acetate, 1:1); IR (KBr):
n
¼ 3284br, 2984w, 1598w, 1511w, 1489w,
1466m, 1449m, 1362w, 1328w, 1289w, 1244m, 1195m, 1163w, 1105w,
1051w, 1023w cmꢀ1; UVevis (methanol): lmax (log ε) ¼ 210 (4.35),
acetate, 1:1); IR (KBr):
n
¼ 3287br, 2362w, 1603w, 1581w, 1508w,
287 (4.09), 341 (4.07) nm; 1H NMR (400 MHz, DMSO-d6):
d
¼ 9.00 (br
1455w, 1376w, 1236w, 1197w, 1156w, 1097w cmꢀ1; UVevis (meth-
anol): lmax (log ε) ¼ 284 (4.17), 341 (4.24) nm; 1H NMR (400 MHz,
s,1H, OH), 8.74 (brs,1H, OH), 7.54 (d,1H, 3J ¼ 7.7Hz, CH(6)), 7.29 (d,1H,
3J (trans) ¼ 16.8 Hz, CH] (1)), 7.25 (d, 1H, 3J (trans) ¼ 16.8 Hz, CH]
(2)), 7.19 (t,1H, 3J ¼ 7.5 Hz, CH (4)), 6.96 (d,1H, 3J ¼ 7.5 Hz, CH (3)), 6.91
(t, 1H, 3J ¼ 7.5 Hz, CH (5)), 6.89 (d,1H, 4J ¼ 2.7 Hz, CH (60)), 6.64 (d,1H,
3J ¼ 8.7 Hz, CH (30)), 6.50 (dd,1H, 3J ¼ 8.7 Hz, 4J ¼ 2.7 Hz, CH (40)), 3.79
methanol-d4):
d
¼ 7.52 (d, 1H, 3J ¼ 7.7 Hz, CH (6)), 7.40 (d, 1H, 3J
(trans) ¼ 16.4 Hz, CH] (1)), 7.35 (d,1H, 3J (trans) ¼ 16.4 Hz, CH] (2)),
7.03 (t,1H, 3J ¼ 7.4 Hz, CH (4)), 7.01 (d,1H, 4J ¼ 2.9 Hz, CH (60)), 6.81 (t,
1H, 3J ¼ 7.4 Hz, CH (5)), 6.78 (d, 1H, 3J ¼ 7.4 Hz, CH (3)), 6.64 (d, 1H,
3J ¼ 8.5 Hz, CH (30)), 6.53 (dd,1H, 3J ¼ 8.5 Hz, 4J ¼ 2.9 Hz, CH (40)), 4.81
(s, 3H, OCH3) ppm; 13C NMR (100 MHz, DMSO-d6):
d
¼ 156.7 (C2,
Cquart.),150.4 (C50, Cquart.),148.1 (C20, Cquart.),128.9 (C4, CH),126.5 (C10,
Cquart.), 126.1 (C6, CH), 125.0 (C1, Cquart.), 124.4 (CH]), 122.2 (CH]),
121.1 (C5, CH),117.1 (C30, CH),116.1 (C40, CH),112.0 (C60, CH),111.8 (C3,
CH), 55.9 (OCH3) ppm; MS (ESI, MeOH): m/z (%) ¼ 241.3 (46%
[Mꢀ H]ꢀ), 287.1 (100%[Mþ HCO2]ꢀ), 482.8(41%[2M ꢀ H]ꢀ);analysis
for C15H14O3 (242.27): C, 74.36; H, 5.82; found: C, 74.21; H, 5.91.
(br s, 3H, OH) ppm; 13C NMR (100 MHz, methanol-d4):
d
¼ 155.8 (C2,
Cquart.),151.2 (C50, Cquart.),148.9 (C20, Cquart.),129.0 (C4, CH),127.1 (C10,
Cquart.), 127.0 (C6, CH), 126.4 (C1, Cquart.), 124.0 (CH]), 123.8 (CH]),
120.7 (C5, CH), 117.4 (C30, CH), 116.5 (C3, CH), 116.1 (C40, CH), 112.7
(C60, CH) ppm;MS (ESI, MeOH): m/z (%) ¼ 227.4 (48% [M ꢀ H]ꢀ), 273.1
(58% [M þ HCO2]ꢀ), 455.0 (100% [2M ꢀ H]ꢀ); analysis for C14H12O3
(228.24): C, 73.67; H, 5.30; found: C, 73.56; H, 5.44.
4.30. (E) 2,20,40-trimethoxystilbene (32)
4.33. (E) 40,6-difluoro-3-hydroxy-30,4, 50-trimethoxystilbene (35)
Following the general procedure, 32 was obtained from
2-methoxystyrene and 2,4-dimethoxyiodobenzene; yield: 56.4%;
colorless solid; mp 91e92 ꢁC; RF ¼ 0.74 (silica gel, hexanes/ethyl
Following the general procedure, 35 was obtained from
6-fluoro-3-hydroxy-4-methoxystyrene and 3,5-dimethoxy-4-

R. Csuk et al. / European Journal of Medicinal Chemistry 54 (2012) 669e678
677
fluorobromobenzene; yield: 56.0%; colorless solid; mp 149e151 ꢁC;
RF 0.39 (silica gel, hexanes/ethyl acetate, 3:1); IR (KBr):
CH]), 116.8 (C40, CH), 116.5 (d, 2JC,F ¼ 13.2 Hz, C1, Cquart.), 115.8 (C30,
3
¼
CH), 115.3 (C60, CH), 111.7 (d, JC,F ¼ 4.7 Hz, C2, CH), 100.6 (d,
n
¼ 3517br, 3006w, 2944m, 2845w, 1630m, 1606m, 1518s, 1467m,
2JC,F ¼ 28.0 Hz, C5, CH), 56.1 (OCH3) ppm; 19F NMR (188 MHz, DMSO-
1447m, 1424m, 1375m, 1333m, 1291m, 1275s, 1252m, 1226m, 1197s,
1168m, 1152m, 1128s, 1017m cmꢀ1; UVevis (methanol): lmax (log
d6):
d
¼ ꢀ128.2 (dd, 3JF,H ¼ 12.2 Hz, 4JF,H ¼ 8.9 Hz, F) ppm; MS (ESI,
MeOH):m/z ¼ 275.3 (45% [M ꢀ H]ꢀ), 321.2 (100%[Mþ HCO2]ꢀ), 550.8
(16% [2M ꢀ H]ꢀ); analysis for C15H13FO4 (276.26): C, 65.21; H, 4.74;
found: C, 65.03; H, 4.96.
ε) ¼ 210 (4.79), 300 (4.54), 331 (4.59) nm; 1H NMR (400 MHz,
4
CDCl3):
d
¼ 7.10 (d, 1H, JH,F ¼ 7.3 Hz, CH (2)), 7.05 (d, 1H, 3J
(trans) ¼ 16.4 Hz, CH] (1)), 6.98 (d, 1H, 3J (trans) ¼ 16.4 Hz, CH]
4
(2)), 6.71 (d, 2H, JH,F ¼ 7.1 Hz, CH (20) þ CH (60)), 6.61 (d, 1H,
4.36. (E) 6-fluoro-3-hydroxy-20,4,40-trimethoxystilbene (38)
Following the general procedure, 38 was obtained from
3JH,F ¼ 11.4 Hz, CH (5)), 5.32 (br s, 1H, OH), 3.91 (s, 6H, OCH3), 3.88
(s, 3H, OCH3) ppm; 13C NMR (100 MHz, CDCl3):
d
¼ 154.3
1
2
(d, JC,F ¼ 227.3 Hz, C6, Cquart.), 148.4 (d, JC,F ¼ 8.8 Hz, C30 þ C50,
Cquart.), 146.6 (d, 3JC,F ¼ 9.1 Hz, C4, Cquart.), 142.3 (d, 1JC,F ¼ 241.4 Hz,
C40, Cquart.), 141.9 (d, 4JC,F ¼ 1.0 Hz, C3, Cquart.), 132.9 (d, 4JC,F ¼ 1.8 Hz,
6-fluoro-3-hydroxy-4-methoxystyrene
and
2,
4-
dimethoxyiodobenzene; yield: 51.6%; off-white solid; mp
127e130 ꢁC; RF ¼ 0.50 (silica gel, hexanes/ethyl acetate, 3:1); IR
2
C10, Cquart.), 128.3 (CH]), 120.4 (CH]), 117.0 (d, JC,F ¼ 12.1 Hz, C1,
(KBr):
n
¼ 3543br, 2961w, 1609w, 1513w, 1451w, 1420w, 1369w,
3
Cquart.), 110.9 (d, JC,F ¼ 2.2 Hz, C2, CH), 104.1 (C20 þ C60, CH), 99.4
1327w, 1294w, 1278w, 1262w, 1197w, 1160w, 1119w, 1097w, 1041w,
1015w cmꢀ1; UVevis (methanol): lmax (log ε) ¼ 210 (4.43), 288
(d, 2JC,F ¼ 25.4 Hz, C5, CH), 56.6 (OCH3), 56.2 (OCH3) ppm; 19F NMR
3
4
(188 MHz, CDCl3):
d
¼ ꢀ126.1 (dd, JF,H ¼ 11.4 Hz, JF,H ¼ 7.3 Hz, F
(4.22), 335 (4.37) nm; 1H NMR (400 MHz, CDCl3):
d
¼ 7.48 (d, 1H,
4
(6)), ꢀ158.7 (t, JF,H ¼ 7.1 Hz, F (40)) ppm; MS (ESI, MeOH): m/z
(%) ¼ 321.6 (71% [M ꢀ H]ꢀ), 643.2 (100% [2M ꢀ H]ꢀ); analysis for
C17H16F2O4 (322.30): C, 63.35; H, 5.00; found: C, 63.54; H, 5.57.
3J ¼ 8.5 Hz, CH (60)), 7.26 (d, 1H, 3J (trans) ¼ 16.6 Hz, CH] (2)), 7.17
(d, 1H, 4JH,F ¼ 7.2 Hz, CH (2)), 7.06 (d, 1H, 3J (trans) ¼ 16.6 Hz, CH]
(1)), 6.58 (d, 1H, JH,F ¼ 9.4 Hz, CH (5)), 6.49 (dd, 1H, 3J ¼ 8.5 Hz,
3
4J ¼ 2.5 Hz, CH (50)), 6.44 (d, 1H, J ¼ 2.5 Hz, CH (30)), 3.86 (s, 3H,
4
4.34. (E) 6-fluoro-3-hydroxy-20,4,50-trimethoxystilbene (36)
OCH3), 3.85 (s, 3H, OCH3), 3.81 (s, 3H, OCH3) ppm; 13C NMR
(100 MHz, CDCl3):
d
¼ 160.8 (C40, Cquart.), 157.9 (C20, Cquart.), 153.4
Following the general procedure, 36 was obtained from 6-fluoro-
3-hydroxy-4-methoxystyrene and 2,5-dimethoxyiodobenzene;
yield: 56.8%; off-white solid; mp 132e134 ꢁC; RF ¼ 0.19 (silica gel,
(d, 1JC,F ¼ 241.3 Hz, C6, Cquart.), 146.0 (d, JC,F ¼ 10.1 Hz, C4, Cquart.),
3
4
141.7 (d, JC,F
¼
2.4 Hz, C3, Cquart.), 127.1 (C60, CH), 123.3
4
3
(d, JC,F ¼ 3.8 Hz, CH]), 119.7 (C10, Cquart.), 118.4 (d, JC,F ¼ 3.8 Hz,
CH]), 118.3 (d, 2JC,F ¼ 12.6 Hz, C1, Cquart.), 110.7 (d, 3JC,F ¼ 4.8 Hz, C2
CH), 104.9 (C50, CH), 99.3 (d, 2JC,F ¼ 28.8 Hz, C5, CH), 98.5 (C30, CH),
56.2 (OCH3), 55.5 (OCH3), 55.4 (OCH3) ppm; 19F NMR (188 MHz,
hexanes/ethyl acetate, 8:2); IR (KBr):
n
¼ 3519br, 2999m, 2942m,
2835m, 1630m, 1610m, 1582m, 1504s, 1469s, 1444s, 1429m, 1369m,
1331m,1311s,1285s,1243s,1215s,1191s,1170s,1123m,1101m,1046s,
1018s cmꢀ1; UVevis (methanol): lmax (log ε) ¼ 213 (4.39), 286 (4.18),
acetone-d6):
d
¼ ꢀ127.1 (dd, 3JF,H ¼ 9.4 Hz, 4JF,H ¼ 7.2 Hz, F) ppm; MS
343 (4.33) nm; 1H NMR (400 MHz, acetone-d6):
d
¼ 7.59 (br s, 1H,
(ESI, MeOH): m/z (%) ¼ 303.3 (100% [M ꢀ H]ꢀ), 349.0 (11%
[M þ HCO2]ꢀ), 606.8 (28% [2M ꢀ H]ꢀ); analysis for C17H17FO4
(304.31): C, 67.10; H, 5.63; found: C, 66.97; H, 5.89.
OH), 7.36 (d, 1H, 3J (trans) ¼ 16.6 Hz, CH] (1)), 7.23 (d, 1H, 3J
4
(trans) ¼ 16.6 Hz, CH] (2)), 7.21 (d, 1H, J ¼ 3.1 Hz, CH (60)), 7.14
(d,1H, 4JH,F ¼ 7.6 Hz, CH (2)), 6.93 (d,1H, 3J ¼ 9.0 Hz, CH (30)), 6.82 (dd,
1H, 3J ¼ 9.0 Hz, 4J ¼ 3.1 Hz CH (40)), 6.80 (d,1H, 3JH,F ¼ 11.9 Hz, CH (5)),
3.88 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 3.79 (s, 3H, OCH3) ppm; 13C
Acknowledgments
1
NMR (100 MHz, acetone-d6):
d
¼ 155.0 (d, JC,F ¼ 240.6 Hz, C6,
Cquart.), 154.8 (C50, Cquart.), 152.3 (C20, Cquart.), 148.8 (d, 3JC,F ¼ 10.6 Hz,
C4, Cquart.),143.8 (d, 4JC,F ¼ 2.7 Hz, C3, Cquart.),128.0 (C10, Cquart.),124.2
Many thanks are due to Dr. R. Paschke and Dr. H. Kommera,
Biozentrum (Biosolutions GmbH, Halle) for assistance with the
biological screening of the compounds, and to Dr. Th. Müller, Dept.
of Haematology/Oncology (Univ. of Halle), for providing the cell
lines. We are grateful to the Hans Böckler Stiftung for a personal
scholarship to Sabrina Albert. We like to thank Dr. Dieter Ströhl for
recording the NMR spectra and Dr. Ralph Kluge (Martin-Luther
Universität, Halle-Wittenberg, Organische Chemie) for numerous
MS spectra. Support by “Gründerwerkstatt e Biowissenschaften” is
gratefully acknowledged.
4
3
(d, JC,F ¼ 3.0 Hz, CH]), 121.7 (d, JC,F ¼ 3.4 Hz, CH]), 118.0
2
(d, JC,F ¼ 13.2 Hz, C1, Cquart.), 114.7 (C40, CH), 113.4 (C30, CH), 112.4
(d, 3JC,F ¼ 4.7 Hz, C2, CH), 112.2 (C60, CH), 100.8 (d, 2JC,F ¼ 28.0 Hz, C5,
CH), 56.6 (OCH3), 56.5 (OCH3), 55.9 (OCH3) ppm; 19F NMR (188 MHz,
acetone-d6):
d
¼ ꢀ128.6 (dd, 3JF,H ¼ 11.9 Hz, 4JF,H ¼ 7.6 Hz, F) ppm; MS
(ESI, MeOH): m/z (%) ¼ 303.1 (100% [M ꢀ H]ꢀ), 348.9 (8%
[M þ HCO2]ꢀ), 606.7 (30% [2M ꢀ H]ꢀ); analysis for C17H17FO4
(304.31): C, 67.10; H, 5.63; found: C, 66.85; H, 5.55.
4.35. (E) 6-fluoro-4-methoxy-20,3,50-trihydroxystilbene (37)
References
Following the general procedure, 37 was obtained from 6-fluoro-
3-hydroxy-4-methoxystyrene and 2,5-dihydroxyiodobenzene;yield:
44.4%; off-white solid; mp 158e160 ꢁC; RF ¼ 0.08 (silica gel, hexanes/
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ethyl acetate, 3:1); IR (KBr):
n
¼ 3383br, 2942w,1627w,1508w,1448w,
1384w, 1303w, 1195w, 1094w, 1017w cmꢀ1; UVevis (methanol): lmax
(log ε) ¼ 291 (4.11), 349 (4.06) nm; 1H NMR (400 MHz, DMSO-d6):
d
¼ 7.16 (d, 1H, 3J (trans) ¼ 16.4 Hz, CH] (1)), 7.01 (d, 1H, 3J
(trans) ¼ 16.4 Hz, CH] (2)), 6.88 (d, 1H, 4J ¼ 2.3 Hz, CH (60)), 6.82 (d,
1H, 3JH,F ¼ 12.2 Hz, CH (5)), 6.73 (d,1H, 3J ¼ 8.7 Hz, CH (30)), 6.65 (d,1H,
4JH,F ¼ 8.9 Hz, CH (2)), 6.51 (dd,1H, 3J ¼ 8.7 Hz, 4J ¼ 2.3 Hz, CH (40)), 3.77
(s, 3H, OCH3) ppm; 13C NMR (100 MHz, DMSO-d6):
d
¼ 153.3 (d,
1JC,F ¼ 244.3 Hz, C6, Cquart.), 150.1 (C50, Cquart.), 148.1 (d, 3JC,F ¼ 11.3 Hz,
C4, Cquart.), 147.8 (C20, Cquart.), 143.1 (d, 4JC,F ¼ 2.2 Hz, C3, Cquart.), 124.3
4
3
(C10, Cquart.), 123.7 (d, JC,F ¼ 3.0 Hz, CH]), 119.2 (d, JC,F ¼ 3.4 Hz,

678
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