Synthesis and radical scavenging activities of resveratrol analogs

Article abstract of DOI:10.1002/ardp.201300081

Highly substituted polyhydroxylated (E)-stilbenes were synthesized by Mizoroki-Heck reactions and tested for their ability to act as radical scavenger. One of the 56 stilbenes included in this study and investigated in DPPH assays gave an SC₅₀ value of 11.0 μM, hence exhibiting an about 9.3 times higher activity than resveratrol. As shown in a photometric SRB assay using mouse NiH 3T3 fibroblasts, this compound is not cytotoxic up to concentrations of <30 μM. Highly substituted polyhydroxylated (E)-stilbenes synthesized by Mizoroki-Heck reactions were tested for their ability to act as radical scavengers. One of the 56 stilbenes included exhibited about 9.3 times higher activity than resveratrol. At concentrations <30 μM, this compound was not cytotoxic.

Full text of DOI:10.1002/ardp.201300081

Arch. Pharm. Chem. Life Sci. 2013, 346, 1–7
1
Full Paper
Synthesis and Radical Scavenging Activities of Resveratrol
Analogs
René Csuk, Sabrina Albert, and Bianka Siewert
Martin-Luther-Universität Halle-Wittenberg, Bereich Organische Chemie, Halle (Saale), Germany
Highly substituted polyhydroxylated (E)-stilbenes were synthesized by Mizoroki–Heck reactions and
tested for their ability to act as radical scavenger. One of the 56 stilbenes included in this study and
investigated in DPPH assays gave an SC50 value of 11.0 mM, hence exhibiting an about 9.3 times higher
activity than resveratrol. As shown in a photometric SRB assay using mouse NiH 3T3 fibroblasts, this
compound is not cytotoxic up to concentrations of <30 mM.
Keywords: French paradox / Radical scavengers / Resveratrol analogs
Received: March 7, 2013; Revised: May 16, 2013; Accepted: May 24, 2013
DOI 10.1002/ardp.201300081
Introduction
phenolic compounds from Vitis vinifera cell cultures to act as
radical scavengers. Evidence from different studies suggests
that the ability of these natural phenolic compounds to act as
radical scavengers is one of the major reasons for the
phenomenon known as French paradox.
As previously shown, highly substituted stilbenes carrying
an (E) configurated double bond can be synthesized in good
yields using a two-step sequence consisting of a Wittig
olefination of substituted benzaldehydes to afford styrenes
followed by a Mizoroki–Heck reaction (Scheme 1). Recently,
we have accessed several different (E)-configurated stilbenes
and explored their antibacterial/antifungal as well as their
cytotoxic activity [20, 21]. Here, we describe the synthesis and
radical scavenger inhibitory activity of >50 substituted
stilbenes 1–56.
Resveratrol (1, (E)-3,5,40-trihydroxystilbene, Fig. 1) is a natural
phenol and phytoalexin. It is produced by >70 different plant
species, especially grapevines, pines, and legumes but also in
pomegranates, soy beans, and in peanuts [1]. Since its initial
discovery in 1940 [2] many biological activities have been
associated [1] with this compound, including antifungal [3],
antibacterial [4], antiviral [5], anticancer [6, 7], estrogenic [8],
platelet anti-aggregating [9], and heart protecting activi-
ties [10, 11].
Resveratrol inhibits cyclooxygenases [6, 12, 13], and, in
addition, is has been suggested that 1 is at least partly
responsible for the so-called French paradox. The French
paradox describes improved cardiovascular outcomes includ-
ing a low incidence of coronary heart diseases [10, 14] despite
the consumption of a high-fat diet by French people [15].
Although 1 is believed to be effective in preventing and
treating several chronic diseases, the number of structure–
activity relationships for 1 and analogs remained small. Thus,
several halogenated analogs of 1 have been investigated by
Chi and coworkers [16], and Kang et al. [17] evaluated several
derivatives as potential antioxidants. Glycosylated resveratrol
derivatives have been investigated by Orsini et al. [18], and
Fauconneau et al. [19] investigated the ability of natural
Results and discussion
Although the straightforward synthesis of stilbenes has been
carried out by many synthetic routes [22], the use of Mizoroki–
Heck reactions to synthesize (E)-configurated stilbenes from
styrenes results in short syntheses from commercially
available starting materials and good yields of the prod-
ucts [20, 21].
Thus, Wittig reaction of suitable substituted benzaldehydes
with methyl triphenylphosphonium iodide and tBuOK in THF
yielded styrenes [23] that were subjected to Mizoroki–Heck
coupling reactions. The use of triethanolamine (acting as well
as a base and as a solvent) allowed the economic synthesis of
compounds 1–56 [24, 25].
Correspondence: Dr. René Csuk, Bereich Organische Chemie, Martin-
Luther-Universität Halle-Wittenberg, Kurt-Mothes-Straße 2, D-06120 Halle
(Saale), Germany
E-mail: rene.csuk@chemie.uni-halle.de
Fax: þ49 345 5527030
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R. Csuk et al.
Arch. Pharm. Chem. Life Sci. 2013, 346, 1–7
Table 1. Radical scavenging activity (DPPH assay [26] SC50 in
mM); all experiments were carried out in triplicate on 96-well
microtiter plates and repeated three times. Variation was generally
ꢀ7%; cut-off: 130 mM.
Compound
SC50
IC50
Compound
SC50
IC50
(mM)
(mM)
(mM)
(mM)
1
2
3
4
5
6
7
8
102
105
129
50
>130
>130
89
>130
73
39
56
64
49
76
52
19
46
52
43
108
53
70
17
24
>130
26
>130
>130
>130
24.2
>30
>30
>30
>30
0.2
0.9
>30
1.5
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
>130
73
68
52
30
>130
>130
>130
>130
>130
>130
29
>30
7.5
9.6
8.2
7.2
Figure 1. Structure of resveratrol (1).
1,1-Diphenyl-2-picrylhydrazyl (DPPH) radical scavenging
effect assays were carried out for compounds 1–56 following
the procedure by Blois [26]. The results of these experiments
are summarized in Table 1 and Figs. 2–5.
29.8
>30
11.8
>30
>30
25.8
10.5
19.6
11.1
26.0
>30
14.8
>30
>30
>30
12.4
>30
0.2
9
Evaluation of the results showed that 3-hydroxy-4-methoxy
as well as 4-hydroxy-3-methoxy substituted stilbenes (Fig. 2)
gave low SC50 values as long as in the second ring hydroxyl
groups were present at positions 20,50 or 30,50. Compounds 7,
9–11 (having been synthesized starting from isovanilline)
exhibited higher SC50 values as compared to compounds
14–17 (having been synthesized starting from vanilline).
Figure 3 summarizes the SC50 values for 3,4-dimethoxy-
substituted stilbenes as well as for stilbenes having been
synthesized from syringaldehyde and for some fluorinated
stilbenes. 3,5-Dimethoxy-4-hydroxy substituted stilbenes
showed SC50 values <130 mM (130 mM being the cut-off in
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
>30
2.1
>30
17.4
15.0
>30
9.5
>30
15.0
10.8
10.6
>30
1.9
>30
>30
>30
4.5
12.2
11.5
6.9
52
22
>130
>130
>130
>130
>130
>130
22
118
>130
119
13
81
11
20.2
15.7
2.7
these experiments); for example, compounds 18 (SC50
¼
54
55
56
21.1
0.05
>30
n.d.
n.d.
52 mM) and 19 (SC50 ¼ 43 mM) possess significantly stronger
radical scavenging activity than compounds carrying a
3-hydroxy-4-methoxy substitution. Trifluoro compound 21
exhibits a lower SC50 value than 30,50-dimethoxy-4-fluoro-
stilbene 20 whereas compound 8 showed SC50 > 130 mM and
7 gave 89 mM.
Many (Fig. 4) of the 2-hydroxy, 3-hydroxy, and 4-hydroxy
stilbenes 27–33, 35–42, and 44–51, however, showed only low
activity as depicted in Fig. 4.
(þ)-Catechinꢁ
(ꢂ)-Epicatechinꢁ
Cytotoxicity (IC50 values (in mM) from SRB assays [27]; n.d. not
determined) for compounds 1–56 using mouse fibroblasts NiH
3T3 [21]. Values are derived from dose response curves obtained by
measuring the percentage of viable cells relative to untreated
controls after 96 h exposure of the test compounds to the cell
line. The IC50 value was estimated by linear regression between
the value before and after the 50% line is crossed in a dose–
response curve. Values are the average from at least five
independent experiments; cut-off: 30 mM, variation was generally
ꢀ7%.
Noteworthy seems compound 54 (Fig. 3) with an SC50
¼
13 mM. Finally, compound 56 (Fig. 5) has the lowest SC50 value
(SC50 ¼ 11.0 mM), which corresponds to the highest free
radical scavenging activity. Thus, this compound exhibited a
ca. 9.3 times higher activity than resveratrol (1) itself.
ꢁ
These values were taken from Ref. [16].
Scheme 1. General scheme for the synthesis of the stilbenes 1–56 by a sequence consisting of a Wittig olefination followed by a Mizoroki–
Heck reaction.
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Arch. Pharm. Chem. Life Sci. 2013, 346, 1–7
Radical Scavengers
3
Figure 2. Structures and SC50 values (in mM, from DPPH assay) for
compounds 1–4, 7–11, and 14–17.
Figure 3. SC50 values (in mM, from DPPH assay) for compounds
resveratrol (1), 5, 12, 13, 18–24, and 52–54.
Besides the stilbenes, several flavonoids are known for their
high free radical scavenging activities. Thus, for (þ)-catechin
and (ꢂ)-epicatechin SC50 values of 20.2 and 15.7 mM have been
reported [16]. Compounds 16, 23, 26, 29, and 43 showed
similar high activity. Compounds 54 and 56 showed an even
better radical scavenging activity.
As a prerequisite to extended biological testing of these
compounds, cytotoxicity has to be low. For all compounds
reported here, cytotoxicity has been determined using the
photometric SRB assay [27] employing the mouse fibroblast
cell line NiH 3T3 [21]. In this assay resveratrol (1) showed a
cytotoxicity IC50 ¼ 24.2 mM. Most active compounds 54 and
56 gave in this assay similar high IC50 values (IC50 ¼ 21.1 mM
for 54) or showed even less cytotoxicity (IC50 > 30 mM for 56).
These biological properties and activities make substituted
stilbenes interesting candidates for further biological evalua-
tion. Interestingly enough, the (Z) analog of 56 has been
suggested [28] as a cellular rejuvenation compound to be used
in skin cosmetics, and the bis(bibenzyl) analogs of 56 were
found to act as inhibitors of the nitric acid synthase [29].
Inhibition of this enzyme seems very important to control
inflammatory diseases. In addition, for some of the same class
of compounds antitrypanosomal activity [30] as well as the
induction of vasorelaxation [31] has been reported quite
recently. Thus, syntheses of analogs of 54 and 56 are currently
pursued, and further biological evaluation is in progress.
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Arch. Pharm. Chem. Life Sci. 2013, 346, 1–7
Figure 5. SC50 values (in mM, from DPPH assay) for compounds 1,
25, 26, 34, 43, and 56.
according to usual procedures. The purity of the compounds was
determined by HPLC and found to be >98%.
General procedure for the Mizoroki–Heck reactions
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 ꢃ 100 mL). The
organic phases were dried (Na2SO4), the solvents evaporated, and
the crude product subjected to chromatography (silica gel,
hexane/ethyl acetate mixtures). The synthesis of compounds 1–3,
6, 7, 9–11, 14, 16–20, 26–47, and 48–55 has already been described
[20, 21, 24, 32, 33].
Figure 4. SC50 values (in mM, from DPPH assay) for compounds
resveratrol (1) and 2-hydroxy-, 3-hydroxy- and 4-hydroxy-substitut-
ed stilbenes 27–33, 35–42, and 44–51.
Experimental
(E) 40-Fluoro-4-methoxy-3,30,50-trihydroxystilbene (4)
General
According to the general procedure from 3,5-dihydroxyiodoben-
Melting points are uncorrected (Leica hot stage microscope). NMR
spectra were recorded using the Varian spectrometers Gemini
200, Gemini 2000, or Unity 500 (d given in ppm, J in Hz, internal
Me4Si or CCl3F), IR spectra (film or KBr pellet) on a Perkin-Elmer
FT-IR spectrometer Spectrum 1000. MS spectra were taken on a
Finnigan MAT TSQ 7000 (electrospray, voltage 4.5 kV, sheath gas
nitrogen) instrument. TLC was performed on silica gel (Merck
5554, detection by UV absorption). The solvents were dried
zene and 4-fluoro-3,5-dihydroxybromobenzene compound
4
(72.3%) was obtained as an off-white solid; mp 177–179°C;
Rf ¼ 0.11 (silica gel, hexanes/ethyl acetate, 3:1); IR (KBr): n ¼ 3330
br, 1606m, 1539m, 1513m, 1438m, 1376m, 1267m, 1187m,
1128m, 1053m, 1025m cmꢂ1; UV–vis (methanol): lmax (log e)
¼ 239 (4.23), 343 (4.24) nm; 1H NMR (400 MHz, acetone-d6):
d ¼ 7.06 (d, 1H, J ¼ 1.7 Hz, CH (2)), 6.94 (dd, 1H, J ¼ 8.5, 2.0 Hz, CH
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Arch. Pharm. Chem. Life Sci. 2013, 346, 1–7
Radical Scavengers
5
–
(6)), 6.89 (d, 1H, Jtrans ¼ 16.4 Hz, CH (2)), 6.88 (d, 1H, J ¼ 8.5 Hz,
(63.7%) was obtained as a colorless solid; mp 166–168°C;
Rf ¼ 0.38 (silica gel, hexanes/ethyl acetate, 3:1); IR (KBr): n ¼ 3385
br, 2989w, 2845w, 1598w, 1518w, 1454w, 1423w, 1378w, 1331w,
–
CH (50)), 6.83 (d, 1H, J
¼ 16.4 Hz, CH (1)), 6.68 (d, 2H,
–
–
trans
4JH,F ¼ 7.5 Hz, CH (60) þ CH (20)), 3.82 (s, 3H, OCH3) ppm; 13C NMR
(100 MHz, acetone-d6): d ¼ 148.2 (C4.), 147.5 (C3), 146.5 (d,
1295w, 1264w, 1192w, 1160w, 1138w, 1052w, 1021w cmꢂ1
;
1
2JC,F ¼ 9.1 Hz, C30 þ C50), 141.4 (d, JC,F ¼ 237.0 Hz, C40), 134.4
UV–vis (methanol): lmax (log e) ¼ 236 (4.35), 341 (4.44) nm; 1H
(d, 4JC,F ¼ 4.1 Hz, C1 ), 131.6 (C1), 128.8 (CH ), 126.7 (CH ), 119.6
NMR (400 MHz, acetone-d6): d ¼ 7.22 (d, 1H, J ¼ 1.9 Hz, CH (2)),
4
0
–
–
–
–
3
3
(C5), 113.1 (C6), 112.3 (C2), 107.1 (C20 þ C60), 56.2 (OCH3) ppm;
19F NMR (188 MHz, CDCl3): d ¼ ꢂ163.7 (t, 4JF,H ¼ 7.5 Hz) ppm; MS
(ESI, MeOH): m/z ¼ 275.3 (100% [MꢂH]ꢂ), 320.9 (15% [MþHCO2]ꢂ);
550.7 (38% [2MꢂH]ꢂ); analysis for C15H13FO4 (276.26): C, 65.21; H,
4.74; found: C, 65.01; H, 4.93.
7.09 (d, 1H, Jtrans ¼ 16.6 Hz, CH (1)), 7.07 (dd, 1H, J ¼ 8.1 Hz,
–
–
4
J ¼ 1.9 Hz, CH (6)), 7.01–6.97 (m, 3H, CH (2) þ CH (20) þ CH
–
–
(60)), 6.93 (d, 1H, 3J ¼ 8.1 Hz, CH (5)), 3.45 (s, 3H, OCH3), 3.81 (s, 3H,
OCH3) ppm; 13C NMR (100 MHz, acetone-d6): d ¼ 153.2 (C4), 151.3
(C3), 150.6 (d, 2JC,F ¼ 11.9 Hz C30 þ C50), 140.0 (d, 1JC,F ¼ 243.0 Hz,
4
C40), 135.2 (d, JC,F ¼ 8.9 Hz, C1 ), 130.8 (C1) 130.6 (CH ), 125.4
0
–
–
3
–
–
(CH ), 121.7 (C6), 112.7 (C5 þ C2), 105.6 (d, JC,F ¼ 17.6 Hz,
(E) 1-(3,5-Dihydroxyphenyl)-2-(20-fluoro-50-hydroxy-40-
C20 þ C60), 56.0 (OCH3) ppm; 19F NMR (188 MHz, acetone-d6):
4
methoxyphenyl)ethene (5)
d ¼ ꢂ162.3 (t, JF,H ¼ 7.8 Hz); MS (ESI, MeOH): m/z ¼ 291.3 (100%
[MꢂH]ꢂ), 336.9 (20% [MþHCO2]ꢂ), 582.7 (77% [2MꢂH]ꢂ); analysis
According to the general procedure from dihydroxyiodobenzene
compound 5 (71.2%) was obtained as an off-white solid; mp
175–176°C; Rf ¼ 0.11 (silica gel, hexanes/ethyl acetate, 3:1); IR (KBr):
n ¼ 3345br, 2934m, 1699w, 1598s, 1513s, 1445s, 1339s, 1289s,
1195s, 1144s, 1014m cmꢂ1; UV–vis (methanol): lmax (log e) ¼ 218
(4.24), 331 (4.36) nm; 1H NMR (400 MHz, acetone-d6): d ¼ 8.22 (br s,
for C16H15FO4 (290.29): C, 66.20; H, 5.21; found: C, 66.17; H, 5.29.
(E) 20,50-Dihydroxy-3,4-dimethoxystilbene (13)
According to the general procedure from 2,5-dihydroxyiodoben-
zene and 3,4-dimethoxystyrene compound 13 (69.0%) was
obtained as an off-white solid; mp 178–179°C; Rf ¼ 0.63 (silica
gel, hexanes/ethyl acetate, 1:1); IR (KBr): n ¼ 3418br, 2945s, 2831s,
1845w, 1636m, 1600s, 1517s, 1452s, 1417s, 1384s, 1310m, 1265s,
1237s, 1193s, 1159s, 1139s, 1092w, 1039w, 1025s cmꢂ1; UV–vis
(methanol): lmax (log e) ¼ 227 (4.30), 314 (3.99), 367 (4.03) nm; 1H
NMR (400 MHz, acetone-d6): d ¼ 8.00 (br s, 1H, OH), 7.76 (br s, 1H,
4
3H, OH), 7.13 (d, 1H, JH,F ¼ 7.5 Hz, CH (60)), 7.08 (d, 1H,
3
3
–
–
–
–
Jtrans ¼ 16.6 Hz, CH (2)), 6.95 (d, 1H, Jtrans ¼ 16.6 Hz, CH (1)),
6.78 (d, 1H, JH,F ¼ 11.8 Hz, CH (30)), 6.55 (d, 2H, 4J ¼ 2.0 Hz CH
(2) þ CH (6)), 6.29 (s, 1H, CH (4)), 3.86 (s, 3H, OCH3) ppm; 13C NMR
(100 MHz, acetone-d6): d ¼ 158.7 (C3 þ C5), 153.5 (d, 1JC,F ¼ 236.9 Hz,
3
3
4
C20), 147.9 (d, JC,F ¼ 10.6 Hz, C40), 143.0 (d, JC,F ¼ 2.0 Hz, C50),
3
4
139.6 (C10), 128.7 (d, JC,F ¼ 4.8 Hz, CH ), 119.9 (d, J ¼ 3.9 Hz,
–
–
–
OH), 7.33 (d, 1H, 3Jtrans ¼ 16.4 Hz, CH (1)), 7.18 (d, 1H,
C,F
–
2
3
CH ), 116.6 (d, J ¼ 12.5 Hz, C10), 111.5 (d, JC,F ¼ 4.8 Hz, C60),
–
–
4J ¼ 1.9 Hz, CH (2)), 7.06 (d, 1H, Jtrans ¼ 16.4 Hz, CH (2)),
3
–
–
C,F
2
104.9 (C2 þ C6), 102.2 (C4), 99.8 (d, JC,F ¼ 28.8 Hz, C30), 55.7 (s,
7.06–7.04 (m, 2H, CH (6) þ CH (60)), 6.91 (d, 1H, 3J ¼ 8.3 Hz, CH
OCH3) ppm; 19F NMR (188 MHz, acetone-d6): d ¼ ꢂ128.8 (dd,
(5)), 6.72 (d, 1H, J ¼ 8.8 Hz, CH (30)), 6.58 (dd, 3J ¼ 8.8 Hz,
4
4JF,H ¼ 7.5 Hz, JF,H ¼ 11.8 Hz); MS (ESI, MeOH): m/z ¼ 275.5 (79%
3
4J ¼ 1.9 Hz, CH (40)), 3.85 (s, 3H, OCH3), 3.80 (s, 3H, OCH3) ppm; 13C
[MꢂH]ꢂ), 321.3 (100% [MþHCO2]ꢂ), 550.9 (70% [M(MꢂH)]ꢂ); analysis
NMR (100 MHz, acetone-d6): d ¼ 151.3 (C50), 150.5 (C3), 150.1
0
0
for C15H13FO4 (276.26): C, 65.21; H, 4.74; found: C, 64.99; H, 4.83.
–
–
–
–
(C3 ), 148.7 (C4), 132.1 (C1), 128.9 (CH ), 126.0 (C1 ) 122.5 (CH ),
120.5 (C2), 117.3 (C30), 116.0 (C40), 113.0 (C5 þ C60), 110.3 (C2),
56.1 (OCH3), 56.0 (OCH3); MS (ESI, MeOH): m/z ¼ 271.4 (41%
[MꢂH]ꢂ); 317.2 (74% [MþHCO2]ꢂ); 542.9 (100% [2MꢂH]ꢂ); analysis
for C16H16O4 (272.30): C, 70.57; H, 5.92; found: C, 70.38; H, 6.09.
(E) 3-Hydroxy-4-methoxy-30,40,50-trifluorostilbene (8)
According to the general procedure from 3,4,5-tribromofluor-
obenzene and 3-hydroxy-5-methoxystyrene compound 8 (85.6%)
was obtained as a colorless solid; mp 137–138°C; Rf ¼ 0.29 (silica
gel, hexanes/ethyl acetate, 9:1); IR (KBr): n ¼ 3528br, 3030m,
1616w, 1604m, 1582w, 1528m, 1508m, 1459m, 1441m, 1367w,
1341w, 1307w, 1293w, 1263m, 1238m, 1205m, 1158w, 1180w,
1158w, 1128m, 1039m, 1022m cmꢂ1; UV–vis (methanol): lmax
(log e) ¼ 204 (4.34), 326 (4.41) nm; 1H NMR (400 MHz, CDCl3):
d ¼ 7.09 (d, 1H, 4J ¼ 2.1 Hz, CH (2)), 7.05–7.01 (m, 2H, CH
(E) 4-Hydroxy-20,3,50-trimethoxystilbene (15)
According to the general procedure from 2,5-dimethoxyiodoben-
zene and 4-hydroxy-3-methoxystyrene compound 15 (68.6%) was
obtained as an off-white solid; mp 75–77°C; Rf ¼ 0.25 (silica gel,
hexanes/ethyl acetate, 8:2); IR (KBr): n ¼ 3418br, 2938m, 2834m,
2062w, 1594m, 1514s, 1463s, 1427s, 1372m, 1218s, 1161m,
1120s, 1045s cmꢂ1; UV–vis (methanol): lmax (log e) ¼ 339 (4.21)
nm; 1H NMR (400 MHz, CDCl3): d ¼ 7.26 (d, 1H, 3Jtrans ¼ 16.6 Hz,
(20) þ CH (60)), 6.93 (dd, 1H, 3J ¼ 8.3 Hz, 4J ¼ 2.1 Hz, CH (6)), 6.88
(d, 1H, 3Jtrans ¼ 16.2 Hz, CH (1)), 6.81 (d, 1H, J ¼ 8.3 Hz, CH (5)),
3
–
–
4
4
0
–
CH (1)), 7.11 (d, 1H, J ¼ 2.9 Hz, CH (6 )), 7.04 (d, 1H, J ¼ 2.0 Hz,
3
–
3
–
–
6.74 (d, 1H, Jtrans ¼ 16.2 Hz, CH (2)), 5.60 (br s, 1H, OH), 3.89
CH (2)), 7.02 (dd, 1H, 3J ¼ 8.0 Hz, 4J ¼ 2.0 Hz, CH (6)), 7.00 (d, 1H,
(s, 3H, OCH3) ppm; 13C NMR (100 MHz, CDCl3): d ¼ 151.7
3
–
Jtrans ¼ 16.6 Hz, CH (2)), 6.87 (d, 1H, J ¼ 8.0 Hz, CH (5)), 6.81 (d,
–
1
(m, JC,F ¼ 214.0 Hz, C30 þ C50), 146.9 (C4), 145.9 (C3), 138.7
1H, 3J ¼ 8.9 Hz, CH (30)), 6.75 (dd, 1H, 3J ¼ 8.9 Hz, 4J ¼ 2.9 Hz CH
(m, 1JC,F ¼ 247.7 Hz, C4 ), 133.8 (m, C1 ), 130.6 (CH ), 129.9 (C1),
0
0
–
–
(40)), 3.93 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 3.80 (s, 3H, OCH3) ppm;
0
0
–
–
124.0 (CH ), 119.7 (C6), 111.8 (C2), 110.6 (C5), 109.8 (C2 þ C6 ),
13C NMR (100 MHz, CDCl3) d ¼ 153.8 (C50), 151.3 (C20), 146.7 (C3),
55.9 (OCH3), 56.1 (OCH3), 55.7 (OCH3) ppm; 19F NMR (188 MHz,
CDCl3): d ¼ ꢂ135.2 (m, ꢂF (40)), ꢂ160.5 (m, ꢂF (30;50)) ppm; MS
(ESI, MeOH): m/z ¼ 279.3 (100% [MꢂH]ꢂ), 325.0 (12% [MþHCO2]ꢂ),
558.9 (12% [2MꢂH]ꢂ); analysis for C15H11F3O2 (280.24): C, 64.29; H,
3.96; found: C, 64.13; H, 4.09.
0
–
–
–
–
145.5 (C4), 130.5 (C1), 129.4 (CH ), 127.5 (C1 ), 121.0 (CH ), 120.6
(C6), 114.5 (C5), 113.3 (C40), 112.3 (C30), 111.5 (C2), 108.4 (C60), 56.3
(OCH3), 56.0 (OCH3), 55.8 (OCH3) ppm; MS (ESI, MeOH):
m/z ¼ 285.3 (100% [MꢂH]ꢂ); analysis for C17H18O4 (286.32): C,
71.31; H, 6.34; found: C, 71.15; H, 6.54.
(E) 30,50-Dimethoxy-3,4-dihydroxy-40-fluorostilbene (12)
According to the general procedure from 2,5-dihydroxy-4-
fluorobromobenzene and 3,4-dimethoxystyrene compound 12
(E) 4-Hydroxy-20,3,40-trimethoxystilbene (17)
According to the general procedure from 2,4-dimethoxyiodoben-
zene and 4-hydroxy-3-methoxystyrene compound 17 (62.7%) was
ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

6
R. Csuk et al.
Arch. Pharm. Chem. Life Sci. 2013, 346, 1–7
obtained as a beige colored solid; mp 98–100°C; Rf ¼ 0.25 (silica
gel, hexanes/ethylacetate 8:2 þ 0.01% acetic acid); IR (KBr):
n ¼ 3405br, 2940w, 1607w, 1576w, 1513w, 1455w, 1417w,
was obtained as a colorless solid; mp 121–122°C; Rf ¼ 0.13 (silica
gel, hexanes/ethyl acetate, 8:2 þ 0.01% acetic acid); IR (KBr):
n ¼ 3445br, 2999w, 2941w, 2840w, 1602m, 1574w, 1515m,
1462m, 1426w, 1359w, 1332w, 1314w, 1293m, 1250w, 1199m,
1163w, 1110m, 1024w cmꢂ1; UV–vis (methanol): lmax (log e) ¼ 214
(4.36), 241 (4.24), 332 (4.47) nm; 1H NMR (400 MHz, CDCl3): d ¼ 7.45
1365w, 1336w, 1264w, 1202w, 1155w, 1118w, 1034w cmꢂ1
;
UV–vis (methanol): lmax (log e) ¼ 207 (4.61), 292 (4.40), 331 (4.58)
nm; 1H NMR (400 MHz, CDCl3): d ¼ 7.47 (d, 1H, 3J ¼ 8.4 Hz, CH (60)),
4
3
3
7.22 (d, 1H, 3Jtrans ¼ 16.4 Hz, CH (1)), 7.03 (d, 1H, J ¼ 1.6 Hz, CH
(d, 1H, J ¼ 8.6 Hz, CH (60)), 7.20 (d, 1H, Jtrans ¼ 16.4 Hz, CH (2)),
–
–
–
–
(2)), 7.00 (dd, 1H, 3J ¼ 8.2 Hz, 4J ¼ 1.6 Hz, CH (6)), 6.93 (d, 1H,
6.90 (d, 1H, 3Jtrans ¼ 16.4 Hz, CH (1)), 6.72 (s, 2H, CH (2) þ CH (6)),
–
–
3
3
4
Jtrans ¼ 16.4 Hz, CH (2)), 6.88 (d, 1H, J ¼ 8.2 Hz, CH (5)), 6.51 (dd,
6.49 (dd, 1H, 3J ¼ 8.6 Hz, J ¼ 2.5 Hz, CH (50)), 6.46 (d, 1H,
–
–
3
4
1H, J ¼ 8.4 Hz, J ¼ 2.3 Hz, CH (40)), 6.47 (d, 1H, 4J ¼ 2.3 Hz, CH
4J ¼ 2.5 Hz, CH (30)), 3.92 (s, 6H, OCH3), 3.86 (s, 3H, OCH3), 3.83
13
(30)), 3.95 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 3.83 (s, 3H, OCH3) ppm;
(s, 3H, OCH3) ppm; C NMR (100 MHz, CDCl3): d ¼ 160.3 (C40),
13C NMR (100 MHz, CDCl3): d ¼ 160.2 (C40), 157.8 (C20), 146.6 (C3),
157.9 (C2 ), 147.1 (C3 þ C5) 134.4 (C4), 129.9 (C1), 127.3 (CH ), 127.0
0
–
–
0
0
0
–
–
–
–
–
–
145.0 (C4), 131.0 (C1), 127.1 (CH ), 126.9 (C6 ), 121.1 (CH ), 120.1
(C6, CH), 121.5 (CH ), 119.6 (C1 ), 104.9 (C5 ), 103.2 (C2 þ C6), 98.5
(C6), 119.8 (C10), 114.4 (C5), 108.1 (C2), 104.9 (C50), 98.5 (C30), 55.9
(OCH3), 55.5 (OCH3), 55.4 (OCH3) ppm; MS (e.i. 70 eV): m/z (%) ¼ 286
(100); 274 (37), 243 (26), 228 (11), 211 (14), 150 (16), 137 (19); analysis
for C17H18O4 (286.32): C, 71.31; H, 6.34; found: C, 71.08; H, 6.55.
(C30), 56.3 (OCH3), 55.4 (OCH3), 54.8 (OCH3) ppm; MS (e.i. 70 eV): m/z
(%) ¼ 316 (100), 273 (14), 241 (10), 180 (14), 137 (7); analysis for
C
18H20O5 (316.35): C, 68.34; H, 6.37; found: C, 68.13; H, 6.54.
(E) 30,50-Dihydroxy-40-fluoro-4-methoxystilbene (25)
According to the general procedure from 3,5-dihydroxy-4-fluoro-
bromobenzene and 4-methoxystyrene compound 25 (62.3%) was
obtained as a colorless solid; mp 173–174°C; Rf ¼ 0.38 (silica gel,
hexanes/ethyl acetate, 3:1); IR (KBr): n ¼ 3424s, 1601m, 1575w,
1539s, 1510m, 1452w, 1417w, 1378m, 1365m, 1329w, 1301m,
1247m, 1177s, 1112w, 1051s, 1013m, 1003m cmꢂ1; UV–vis
(methanol): lmax (log e) ¼ 217 (4.45), 305 (4.57) nm; 1H NMR
(E) 3,5-Dimethoxy-4-hydroxy-,30,40,50-trifluorstilbene (21)
According to the general procedure from 3,4,5-trifluorobromo-
benzene and 3,5-dimethoxy-4-hydroxystyrene compound 21
(75.3%) was obtained as a colorless solid; mp 161–162°C;
Rf ¼ 0.09 (silica gel, hexanes/ethyl acetate, 9:1); IR (KBr): n ¼ 3511
br, 2950w, 2847w, 1609m, 1529s, 1518s, 1458m, 1441m, 1425w,
1353m, 1372m, 1351s, 1257s, 1329m, 1259w, 1220m, 1160w,
1107s, 1046m cmꢂ1; UV–vis (methanol): lmax (log e) ¼ 244 (4.20),
326 (4.39) nm; 1H NMR (400 MHz, CDCl3): d ¼ 7.04 (dt, 1H,
(400 MHz, methanol-d4): d ¼ 7.41 (d, 2H, 3J ¼ 8.7 Hz, CH (2) þ CH
3
–
(6)), 6.89 (d, 1H, 3Jtrans ¼ 16.4 Hz, CH (1)), 6.88 (d, 2H, J ¼ 8.7 Hz,
–
3JH,F ¼ 8.3 Hz, JH,F ¼ 2.2 Hz, CH (20) þ CH (60)), 6.89 (d, 1H,
CH (3) þ CH (5)), 6.78 (d, 1H, 3Jtrans ¼ 16.4 Hz, CH (2)), 6.55 (d, 2H,
4
–
–
3
3
–
–
–
Jtrans ¼ 16.2 Hz, CH (1)), 6.75 (d, 1H, J
¼ 16.4 Hz, CH (2)),
4JH,F ¼ 7.1 Hz, CH (20) þ CH (60)), 4.82 (br s, 2H, OH), 3.79 (s, 3H,
–
trans
6.70 (s, 2H, CH (2) þ CH (6)), 5.60 (br s, 1H, OH), 3.92 (s, 6H, OCH3)
ppm; 13C NMR (100 MHz, CDCl3): d ¼ 151.4 (ddd, 1JC,F ¼ 249.0 Hz,
2JC,F ¼ 10.1 Hz, 3JC,F ¼ 4.3 Hz, C30 þ C50), 147.3 (C3 þ C5), 138.7
OCH3) ppm; 13C NMR (100 MHz, methanol-d4): d ¼ 160.8 (C4),
2
1
147.0 (d, JC,F ¼ 11.0 Hz, C30 þ C50), 142.1 (d, JC,F ¼ 236.6 Hz,
4
C40), 134.8 (d, JC,F ¼ 4.6 Hz, C1 ), 131.5 (C1), 128.7 (CH ), 128.6
0
–
0
–
1
3
0
(m, JC,F ¼ 251.9 Hz, C40), 135.5 (C4), 133.8 (dd, JC,F ¼ 12.4 Hz,
(C2 þ C6, CH), 127.1 (CH ), 115.1 (C3 þ C5, CH), 107.3 (C2 þ C6 ,
–
–
4
5
JC,F ¼ 7.6 Hz, C10), 131.1 (d, JC,F ¼ 2.4 Hz, CH ), 127.8 (C1), 123.7
CH), 55.7 (OCH3) ppm; 19F NMR (188 MHz, CDCl3): d ¼ ꢂ165.1 (t,
4JF,H ¼ 7.1 Hz); MS (ESI MeOH): m/z ¼ 259.3 (100%, [MꢂH]ꢂ), 304.9
(19% [MþHCO2]ꢂ), 518.8 (71% [2MꢂH]ꢂ); analysis for C15H13FO3
(260.26): C, 69.22; H, 5.03; found: C, 68.97; H, 5.15.
–
–
4
2
3
–
–
(d, JC,F ¼ 2.8 Hz, CH ), 109.8 (dd, J ¼ 16.8 Hz, JC,F ¼ 4.9 Hz,
C,F
C20 þ C60), 103.6 (C2 þ C6), 56.3 (OCH3) ppm; 19F NMR (188 MHz,
3
3
CDCl3): d ¼ ꢂ135.1 (dd, JF,F ¼ 25.6 Hz, JF,H ¼ 8.3 Hz, F (30) þ F
(50)), ꢂ162.5 (tt, 3JF,F ¼ 25.6 Hz, 4JF,H ¼ 2.2 Hz, F (40)) ppm; MS (ESI,
MeOH): m/z ¼ 309.5 (100% [MꢂH]ꢂ); analysis for C16H13F3O3
(310.27): C, 61.94; H, 4.22; found: C, 61.75; H, 4.44.
(E) 40-Fluoro-2,30,50-trihydroxystilbene (48)
According to the general procedure from 3,5-dihydroxy-4-fluoro-
bromobenzene and 2-hydroxystyrene compound 48 (69.8%) was
obtained as an off-white solid; mp 193–194°C; Rf ¼ 0.21 (silica
gel, hexanes/ethyl acetate, 3:1); IR (KBr): n ¼ 3395br, 1638w,
1604m, 1576m, 1523s, 1486m, 1457w, 1369m, 1340m, 1292m,
1261m, 1191s, 1135m, 1088w, 1055s cmꢂ1; UV–vis (methanol):
lmax (log e) ¼ 236 (4.30), 291 (4.30), 325 (4.36) nm; 1H NMR
(400 MHz, methanol-d4): d ¼ 7.46 (d, 1H, 3J ¼ 7.7 Hz, CH (6)), 7.24
(E) 3,5-Dimethoxy-4,20,50-trihydroxystilbene (23)
According to the general procedure from 2,5-dihydroxyiodoben-
zene and 3,5-dimethoxy-4-hydroxystyrene compound 23 (65.3%)
was obtained as a colorless solid; mp 89–91°C; Rf ¼ 0.45 (silica
gel, hexanes/ethyl acetate, 1:1); IR (KBr): n ¼ 3421br, 2938w,
1610w, 1517w, 1458w, 1339w, 1215w, 1113w cmꢂ1; UV–vis
(methanol): lmax (log e) ¼ 218 (4.45), 309 (4.05) nm; 1H NMR
–
(d, 1H, 3Jtrans ¼ 16.6 Hz, CH (1), 7.04–7.01 (m, 1H, CH (4)), 6.90 (d,
–
(400 MHz, acetone-d6): d ¼ 7.21 (d, 1H, 3Jtrans ¼ 16.6 Hz, CH (1)),
1H, 3Jtrans ¼ 16.6 Hz, CH (2)), 6.79–6.77 (m, 2H, CH (3) þ CH (5)),
–
–
–
–
7.02 (d, 1H, 3Jtrans ¼ 16.6 Hz, CH (2)), 6.96 (d, 1H, J ¼ 2.9 Hz, CH
6.55 (d, 2H, JH,F ¼ 8.0 Hz, CH (20) þ CH (60)) ppm; 13C NMR
4
4
–
–
(60)), 6.83 (s, 2H, CH (2) þ CH (6)), 6.68 (d, 1H, 3J ¼ 8.7 Hz, CH (30)),
6.55 (dd, 3J ¼ 8.7 Hz, 4J ¼ 2.9 Hz, CH (40)), 3.86 (s, 6H, OCH3) ppm;
13C NMR (100 MHz, acetone-d6): d ¼ 149.9 (C50), 147.9 (C3 þ C5),
(100 MHz, methanol-d4): d ¼ 156.0 (C2), 146.9 (d, 2JC,F ¼ 10.7 Hz,
1
4
C30 þ C50), 142.1 (d, JC,F ¼ 236.8 Hz, C40), 135.2 (d, JC,F ¼ 4.4
0
–
–
Hz, C1 ), 129.3 (C6, CH) 128.7 (CH ), 127.4 (C4, CH), 125.7 (C1),
0
0
–
–
–
–
147.6 (C2 ), 135.1 (C4), 131.6 (CH ), 129.54 (C1), 125.2 (C1 ), 120.9
124.4 (CH ), 120.7 (C5), 116.6 (C3), 107.4 (d,
3
JC,F ¼ 4.5 Hz,
0
0
0
–
–
(CH ), 116.0 (C3 ), 114.7 (C4 ), 111.3 (C6 ), 103.4 (C2 þ C6), 55.3
C20 þ C60) ppm; 19F NMR (188 MHz, acetone-d6): d ¼ ꢂ165.0 (t,
4JF,H ¼ 8.0 Hz) ppm; MS (ESI, MeOH): m/z ¼ 245.6 (100% [MꢂH]ꢂ);
291.5 (60% [MþHCO2]ꢂ);491.3 (52% [2MꢂH]ꢂ); analysis for
C14H11FO3 (246.23): C, 68.29; H, 4.50; found: C, 68.01; H, 4.73.
(OCH3) ppm; MS (ESI, MeOH): m/z ¼ 287.2 (100% [MꢂH]ꢂ), 332.9
(15% [MþHCO2]ꢂ); analysis for C16H16O5 (288.30): C, 66.66; H, 5.59;
found: C, 66.43; H, 5.71.
(E) 4-Hydroxy-20,3,40,5-tetramethoxystilbene (24)
According to the general procedure from 2,4-dimethoxyiodoben-
zene and 3,5-dimethoxy-4-hydroxystyrene compound 24 (72.8%)
(E) 20,50,3,4-Tetrahydroxystilbene (56)
According to the general procedure from 3,4-dihydroxystyrene
and 2,5-dihydroxyiodobenzene compound 56 (62.4%) was
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Arch. Pharm. Chem. Life Sci. 2013, 346, 1–7
Radical Scavengers
7
obtained as an off-white solid; mp 162–164°C; Rf ¼ 0.47 (silica
gel, hexanes/ethyl acetate, 1:1); IR (KBr): n ¼ 3356br, 1601w,
1523m, 1453m, 1363w, 1190m, 1109w cmꢂ1; UV–vis (methanol):
[10] J. M. Wu, Z. R. Wang, T. C. Hsieh, J. L. Bruder, J. G. Zou, Y. Z.
Huang, Int. J. Mol. Med. 2001, 8, 3–17.
[11] H. Babich, A. G. Reisbaum, H. L. Zuckerbraun, Toxicol. Lett.
2000, 114, 143–153.
lmax (log e) ¼ 294 (4.15), 347 (4.21) nm; 1H NMR (400 MHz,
3
–
methanol-d4): d ¼ 7.17 (d, 1H, Jtrans ¼ 16.4 Hz, CH (1)), 6.99 (d,
–
[12] K. Subbaramaiah, W. J. Chung, P. Michaluart, N. Telang,
T. Tanabe, H. Inoue, M. S. Jang, J. M. Pezzuto, A. J. Dannenberg,
J. Biol. Chem. 1998, 273, 21875–21882.
4
4
1H, J ¼ 1.9 Hz, CH (2)), 6.93 (d, 1H, J ¼ 2.9 Hz, CH (60)), 6.90 (d,
3
3
4
–
–
1H, Jtrans ¼ 16.4 Hz, CH (2)), 6.83 (dd, J ¼ 8.1 Hz, J ¼ 1.9 Hz,
CH (6)), 6.72 (d, 1H, 3J ¼ 8.1 Hz, CH (5)), 6.63 (d, 1H, 4J ¼ 8.7 Hz, CH
(30)), 6.51 (dd, 3J ¼ 8.7 Hz, J ¼ 2.9 Hz, CH (40) ppm; 13C NMR
4
[13] K. Subbaramaiah, P. Michaluart, W. J. Chung, A. J.
Dannenberg, Pharm. Biol. 1998, 36, 35–43.
(100 MHz, methanol-d4): d ¼ 151.3 (C50 ), 148.9 (C20), 146.4 (C4),
.
0
–
–
–
–
[14] M. Frombaum, S. Le Clanche, D. Bonnefont-Rousselot,
146.2 (C3), 131.8 (C1 ), 129.3 (CH ), 126.9 (C1) 121.8 (CH ), 120.0
(C6), 117.4 (C30), 116.4 (C5), 115.9 (C40), 113.8 (C2), 112.7 (C60)
ppm; MS (ESI, MeOH): m/z ¼ 243.4 (48% [MꢂH]ꢂ); 487.0 (100%
[2MꢂH]ꢂ); analysis for C14H12O4 (244.24): C, 68.85; H, 4.95; found:
C, 68.74; H, 5.07.
D. Borderie, Biochimie 2012, 94, 269–276.
[15] B. Catalgol, S. Batirel, Y. Taga, N. K. Ozer, Front. Cardiovasc.
Smooth Muscle Pharmacol. 2012, 3, 1–18.
[16] H. J. Lee, J. W. Seo, B. H. Lee, K. H. Chung, D. Y. Chi, Bioorg. Med.
Chem. Lett. 2004, 14, 463–466.
Biological testing
[17] S. S. Kang, M. Cuendet, D. C. Endringer, V. L. Croy, J. M.
Pezzuto, M. A. Lipton, Bioorg. Med. Chem. 2009, 17, 1044–
1054.
DPPH assays [26] were performed in 96-well microtiter plates
(Nunc) using a Spectrafluorplus instrument (Tecan) at 25°C and
l ¼ 518 nm. Thus, 100 mL of the sample solution was added to
900 mL of an ethanolic solution of DPPH (10ꢂ4 M) and incubated
at 25°C for 30 min. Then the absorbance of this solution was
determined at l ¼ 518 nm, and the respective SC50 values (in mM)
were calculated. All experiments were carried out in triplicate
and repeated three times. The cytotoxicity assay (SRB) [27] was
performed as previously described [21].
[18] F. Orsini, F. Pelizzoni, L. Verotta, T. Aburjai, C. B. Rogers, J.
Nat. Prod. 1997, 60, 1082–1087.
[19] B. Fauconneau, P. Waffo-Teguo, F. Huguet, L. Barrier, A. Decendit,
J.-M. Merillon, Life Sci. 1997, 61, 2103–2110.
[20] S. Albert, R. Horbach, H. B. Deising, B. Siewert, R. Csuk,
Bioorg. Med. Chem. 2011, 19, 5155–5166.
[21] R. Csuk, S. Albert, B. Siewert, S. Schwarz, Eur. J. Med. Chem.
2012, 54, 669–678.
We are grateful to the Hans-Böckler Stiftung (Düsseldorf) for a scholarship
to S.A. Many thanks are due to Dr. R. Kluge for the measurement of the MS
spectra and to Dr. D. Ströhl for recording the NMR spectra. Support by the
“Gründerwerkstatt – Biowissenschaften” is gratefully acknowledged. The cell
line was kindly provided by Dr. T. Müller (Dept. of Haematology/Oncology,
Univ. Halle).
[22] G. Likhtenshtein, Stilbenes – Applications in Chemistry, Life
Sciences and Material Science, Wiley-VCH, Weinheim 2010,
pp. 1–41.
[23] A. J. Fisher, F. Kerrigan, Synth. Commun. 1998, 28, 2959–2968.
[24] R. Csuk, S. Albert, Z. Naturforsch. 2011, 66b, 311–316.
[25] H. J. Li, I. Wang, Eur. J. Org. Chem. 2006, 5099–5102.
[26] M. S. Blois, Nature 1958, 181, 1199–1200.
The authors have declared no conflict of interest.
[27] P. Skehan, R. Storeng, D. Scudiero, A. Monks, J. McMahon,
D. Vistica, J. T. Warren, H. Bokesch, S. Kenny, M. R. Boyd, J.
Nat. Cancer Inst. 1990, 82, 1107–1112.
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ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com