Resveratrol derived butyrylcholinesterase inhibitors

Article abstract of DOI:10.1002/ardp.201300051

Novel polyhydroxylated (E)-stilbenes were synthesized by Mizoroki-Heck reactions and tested for their ability to inhibit the enzymes acetyl- and butyrylcholinesterase. Several of them are good inhibitors of butyrylcholinesterase; one of them carrying an extra fluorine substituent is a 94-fold stronger inhibitor of butyrylcholinesterase than of acetylcholinesterase. Novel polyhydroxylated (E)-stilbenes synthesized by Mizoroki-Heck reactions were tested for their ability to inhibit the enzymes acetyl- and butyrylcholinesterase. Several of them were found to be good inhibitors of butyrylcholinesterase. One of them carrying an extra fluorine substituent is a 94-fold stronger inhibitor of butyrylcholinesterase than of acetylcholinesterase.

Full text of DOI:10.1002/ardp.201300051

Arch. Pharm. Chem. Life Sci. 2013, 346, 499–503
499
Full Paper
Resveratrol Derived Butyrylcholinesterase Inhibitors
´
Rene Csuk, Sabrina Albert, Ralph Kluge, and Dieter Strohl
¨
¨
Bereich Organische Chemie, Martin-Luther-Universitat Halle-Wittenberg, Halle (Saale), Germany
Novel polyhydroxylated (E)-stilbenes were synthesized by Mizoroki–Heck reactions and tested for their
ability to inhibit the enzymes acetyl- and butyrylcholinesterase. Several of them are good inhibitors of
butyrylcholinesterase; one of them carrying an extra fluorine substituent is a 94-fold stronger
inhibitor of butyrylcholinesterase than of acetylcholinesterase.
Keywords: Acetylcholinesterase / Alzheimer disease / Butyrylcholinesterase / Resveratrol analogs
Received: February 7, 2013; Revised: April 3, 2013; Accepted: April 12, 2013
DOI 10.1002/ardp.201300051
Introduction
cal’’ ACE inhibitors often suffer from side effects like nausea
and vomiting. These side effects have been attributed to an
accompanying undesirable inhibition of butyrylcholine
esterase (BCE) [5, 6]. In addition, the concentration of AcCh
seems to be controlled by the action of ACE and BCE, since
during AD the activity of ACE is decreased while that of BCE is
high. Hence, it was suggested that BCE may in vivo also
catalyze the hydrolysis of AcCh during this stage of disease.
In summary, a specific inhibition of the BCE can raise the
level of AcCh and improve recognition [7].
Neurodegenerative diseases are the sixth-leading cause of
death in Europe and North-America. Worldwide up to 40
million people suffer from these diseases. Up to 8–10% of
all elderly people have some sort of dementia, and dementia
prevalence doubles for every five years of age starting at the
age of 60 [1]. However, there are only a handful of drugs
available for treating dementia, especially for the treatment
of Alzheimer’s disease (AD). AD strikes nearly a half million
new patients each year; by 2050 approximately 115–116
million people will be affected by AD or another neurodege-
nerative disease. For a new drug to reduce memory loss
annual sales exceeding $ 5 billion are expected. None of
the drugs presently used, however, stops the underlying
disease or delays the cell damage. Each of these drugs works
by slowing down the disease progress by breaking down the
key neurotransmitter acetylcholine (AcCh) or by regulating
the activity of glutamate [2, 3].
Phenols like curcumin (1) [8–10] and resveratrol (2, Fig. 1)
[11–13] have been in the focus of scientific interest for to treat
AD for several years, and stilbenes [14–17] seem of particular
interest because these molecules are known for their various
biological activities. Recently, we have accessed several differ-
ent (E)-configurated stilbenes and explored their antibacte-
rial/antifungal as well as their cytotoxic activity [18, 19]. Here,
we describe the synthesis and cholinesterase inhibitory
activity of several substituted resveratrol analogs.
AD patients suffer from an impaired memory, and the
decline in memory and cognition is accompanied by a pro-
gressive deposition of aggregated amyloid beta-peptides (Ab-
peptides) forming amyloid plaques. This leads to neuronal
degeneration and cholinergic dysfunctions in the brain [4].
The application of reversible acetylcholine esterase (ACE)
inhibitors seems helpful in restoring AcCh levels and there-
fore cholinergic brain activity. Patients treated with ‘‘classi-
Results and discussion
The straightforward synthesis of stilbenes has been carried
out by many synthetic routes [20]. As previously shown, the
use of Mizoroki–Heck reactions to synthesize (E)-configurated
stilbenes from styrenes seems most rewarding [18, 19].
Thus, Wittig reaction of suitable substituted aldehydes
t
with methyl triphenylphosphonium iodide and BuOK in
THF yielded styrenes [21] that were subjected to Mizoroki–
Heck coupling reactions to yield the stilbenes. The use of
triethanolamine (acting as well as a base and as a solvent)
allows the economic synthesis of these compounds
(Scheme 1) [22, 23].
´
Correspondence: Prof. Rene Csuk, Bereich Organische Chemie, Martin-
Luther-Universitat Halle-Wittenberg, Kurt-Mothes-Strasse 2, D-06120
Halle (Saale), Germany
E-mail: rene.csuk@chemie.uni-halle.de
Fax: þ49 345 5527030
¨
ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

500
R. Csuk et al.
Arch. Pharm. Chem. Life Sci. 2013, 346, 499–503
Figure 1. Structures of curcumine (1) and resveratrol (2).
Scheme 1. Synthesis of the stilbenes by Mizoroki–Heck reactions; yields: 60–85% (cf. [18, 19, 23]).
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Arch. Pharm. Chem. Life Sci. 2013, 346, 499–503
Butyrylcholinesterase Inhibitors
501
Table 1. IC50 values (in mM) for compounds 4–25 inhibiting ACE or
BCE [from Ellman’s assay [28], averaged from three independent
measurements each performed at least in triplicate; error ꢁ 10%;
selectivity ¼ IC50 (ACE)/IC50 (BCE); internal standards a-pinene
(IC50 for ACE ¼ 0.51 mM) and testosterone (IC50 ¼ 0.06 mM for
BCE) and galantamine hydrobromide (IC50 ¼ 0.60 mM for ACE and
IC50 ¼ 1.55 mM for BCE)].
Only (E) configurated stilbenes were obtained from these
reactions. The coupling constant 3JH,H for the olefinic protons
was found to be approx. 16 Hz for all products, thus showing
a trans configuration of the double bond.
To screen the compounds for an inhibitory activity towards
acylcholine esterase, Ellman’s method was applied [24]. Thus,
acetyl- or butyrylthiocholine iodide was used as a substrate
for the corresponding esterase. On incubation of the substrate
with the enzyme, thiocholine is released which can be
measured by its reaction with Ellman’s reagent, 5,50-dithio-
bis(nitrobenzoic acid) leading to the subsequent formation
of yellow 5-thio-2-nitrobenzoate. ACE from the electric eel
and BCE from equine serum were used as enzymes. The enzyme
BCE from equine serum shows high homology with human
BCE; it was estimated that the rate of evolution for this enzyme
was about 2.2 million years for 1% amino acid change [25]. The
ACE from the electric eel shows high homology with the
human nerve system ACE subtype. Thus, it has been widely
established as a model of CNS-located inhibition of human ACE
(which can be obtained only at very high costs) [7, 26].
For comparison, a-pinene (for the ACE), galantamine
hydrobromide (for ACE and BCE) and testosterone (for the
BCE) were used as known inhibitors in these assays. a-Pinene
is a component of essential oils; many of them are known to
have some beneficial effects on memory disorders or depres-
sion [29, 30]. Evaluation of the results (Table 1) showed that
only a few stilbenes act as inhibitors for the enzymes.
Compounds 18 and 19 were found to be good inhibitors for
the ACE; they are weaker inhibitors for the BCE. Compounds
7, 10, and 24 are excellent inhibitors for the BCE. Common
feature of these compounds is the presence of one free
hydroxyl group at the ortho-position. Comparing the results
from both assays for compound 10 shows this compound a
94-fold stronger inhibitor for the BCE than for the ACE.
Testing of the compounds in photometric SRB assays [27]
for cytotoxic activity (using a panel of several human tumor
cell lines as well as mouse fibroblasts) gave IC50 values
>30 mM for each cell line, therefore indicating that only a
low cytotoxicity can be established for these compounds.
In summary, several of the stilbenes show noteworthy differ-
ences concerning the inhibition of ACE and BCE. Thus, fluoro-
substituted 10 is a >90-fold stronger inhibitor for BCE than for
ACE. The compounds possess only low cytotoxicity. These bio-
logical properties and activities make substitutes stilbenes
interesting candidates for further biological evaluation especi-
ally with respect to AD.
Compound IC50 (mM, ACE)
IC50 (mM, BCE)
4
5
6
7
8
9
0.37
0.51
0.90
0.56
>1
0.80
0.22
>1
0.01
0.85
0.40
0.01
0.46
0.50
0.44
0.41
0.51
0.29
0.13
0.33
0.23
0.35
0.21
0.10
0.15
0.01
0.24
>1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
0.94
0.21
>1
>1
0.58
0.55
0.34
0.25
0.06
0.08
0.32
0.33
0.37
0.41
0.56
0.16
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 according to usual procedures. The purity of the
compounds was determined by HPLC and found to be >98%.
Biological testing
Ellman’s assay [24] was performed in 96-well microtiter plates
(Nunc) using a Spectrafluorplus instrument (Tecan) at 378C and
l ¼ 405 nm as outlined by Rhee et al. [28]. ACE (from electric eel,
Electrophorus electricus) and BCE (from equine serum) were
obtained from Sigma. In short, the lyophilized enzyme was
dissolved in buffer (50 mM Tris–HCl, pH 8) to make a 1000 U/mL
stock solution. This stock solution was further diluted (50 mM
Tris–HCl, pH 8, containing 0.1% bovine serum albumine) to get
0.22 U/mL enzyme for the microtiter plate assay. For this assay
the concentration of the substrate was 15 mM in water, for
Ellman’s reagent 3 mM in buffer (50 mM Tris–HCl, pH 8, con-
taining 0.1 M NaCl and 0.02 M MgCl2 ꢀ 6H2O). In the 96-well
microtiter plates 25 mL of 15 mM substrate in water, 125 mL
of 3 mM Ellman’s reagent in buffer, 50 mL of additional buffer
(50 mM Tris–HCl, pH 8, containing 0.1% bovine serum albu-
mine), 25 mL of sample (10 mg/mL in MeOH diluted ten times
with 50 mM Tris–HCl buffer, pH 8 to give a concentration of
1 mg/mL) were added, and the absorbance was measured at
Experimental
General
Melting points are uncorrected (Leica hot stage microscope),
NMR spectra were recorded using the Varian spectrometers
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Arch. Pharm. Chem. Life Sci. 2013, 346, 499–503
l ¼ 405 nm every 12 s for five times. After 25 mL of 0.22 U/mL of
the enzyme solution was added, the absorbance was again read
every 12 s for ten times. The rates of reactions were calculated
using JMP7 and GraphPad Prism 5 software. The results are
averaged from three independent measurements each per-
formed at least in triplicate. The cytotoxicity assay (SRB) was
performed as previously described [18, 19].
3JC,F ¼ 4.5 Hz, C20 þ C60, CH) ppm; 19F NMR (188 MHz,
MeOH): m/z ¼ 245.6 (100% [MꢃH]ꢃ); 291.5 (60% [MþHCO2]ꢃ);
491.3 (52% [2MꢃH]ꢃ); analysis for C14H11FO3 (246.23): C, 68.29;
H, 4.50; found C, 68.01; H, 4.73.
4
acetone-d6): d ¼ ꢃ165.0 (t, JF,H ¼ 8.0 Hz, F) ppm; MS (ESI,
(E)-30,50-Dihydroxy-40-fluoro-4-methoxystilbene (11)
According to the general procedure, from 4-methoxystyrene,
3,5-dihydroxy-4-fluoro-bromobenzene 11 (82.3%) was obtained
as a colorless solid; mp 173–1748C; 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 cmꢃ1; UV–Vis (MeOH): lmax
(log e) ¼ 217 (4.45), 305 (4.57) nm; 1H NMR (400 MHz, MeOH-d4):
d ¼ 7.41 (d, 2 H, 3J ¼ 8.7 Hz, CH (2) þ CH (6)), 6.89 (d, 1 H, 3J
(trans) ¼ 16.4 Hz, CH ¼ (1)), 6.88 (d, 2 H, 3J ¼ 8.7 Hz, CH (3) þ CH
(5)), 6.78 (d, 1 H, 3J (trans) ¼ 16.4 Hz, CH ¼ (2)), 6.55 (d, 2 H,
4JH,F ¼ 7.1 Hz, CH (20) þ CH (60)), 4.82 (br s, 2 H, OH), 3.79 (s,
3 H, OCH3) ppm; 13C NMR (100 MHz, MeOH-d4): d ¼ 160.8 (C4,
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 1008C for 24 h. The reaction was
cooled to 258C, 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 product subjected to chromatography (silica gel, hex-
ane/ethyl acetate mixtures).
(E)-1-(3,5-Dihydroxyphenyl)-2-(20-fluoro-50-hydroxy-40-
methoxyphenyl)ethene (5)
2
Cquart.), 147.0 (d, JC,F ¼ 11.0 Hz, C30 þ C50, Cquart.), 142.1 (d,
4
1JC,F ¼ 236.6 Hz, C40, Cquart.), 134.8 (d, JC,F ¼ 4.6 Hz, C10,
According to the general procedure, from 6-fluoro-3-hydroxy-4-
methoxystyrene, 3,5-dihydroxyiodobenzene
–
Cquart.), 131.5 (C1, Cquart.), 128.7 (CH ), 128.6 (C2 þ C6, CH),
–
5 (81.2%) was
0
0
–
–
127.1 (CH ), 115.1 (C3 þ C5, CH), 107.3 (C2 þ C6 , CH), 55.7
obtained as an off-white solid; mp 175–1768C; 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 cmꢃ1; UV–Vis (MeOH): lmax (log e) ¼ 218 (4.24), 331
(4.36) nm; 1H NMR (400 MHz, acetone-d6): d ¼ 8.22 (br s, 3 H,
(OCH3) ppm; 19F NMR (188 MHz, CDCl3): d ¼ ꢃ165.1 (t,
4JF,H ¼ 7.1 Hz, -F) ppm; MS (ESI, MeOH): m/z ¼ 259.3 (100%
[MꢃH]ꢃ), 304.9 (19% [MþHCO2]ꢃ), 518.8 (71% [2MꢃH]ꢃ); analysis
for C15H13FO3 (260.26): C, 69.22; H, 5.03; found C, 68.97; H, 5.15.
4
OH), 7.13 (d, 1 H, JH,F ¼ 7.5 Hz, CH (60)), 7.08 (d, 1 H, 3J
(E)-20,50-Dihydroxy-3,4-dimethoxystilbene (14)
(trans) ¼ 16.6 Hz, CH ¼ (2)), 6.95 (d, 1 H, 3J (trans) ¼ 16.6 Hz,
3
CH ¼ (1)), 6.78 (d, 1 H, JH,F ¼ 11.8 Hz, CH (30)), 6.55 (d, 2 H,
According to the general procedure, from 3,4-dimethoxystyrene,
2,5-dihydroxyiodobenzene 14 (79.0%) was obtained as an off-
white solid; mp 178–1798C; 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 cmꢃ1; UV–Vis (MeOH): 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, 1 H, OH), 7.76 (br s, 1 H, OH), 7.33 (d,
4J ¼ 2.0 Hz, CH (2) þ CH (6)), 6.29 (s, 1 H, CH (4)), 3.86 (s, 3 H,
OCH3) ppm; 13C NMR (100 MHz, acetone-d6): d ¼ 158.7 (C3 þ C5,
1
Cquart.), 153.5 (d, JC,F ¼ 236.9 Hz, C20, Cquart.), 147.9 (d,
4
3JC,F ¼ 10.6 Hz, C40, Cquart.), 143.0 (d, JC,F ¼ 2.0 Hz, C50,
3
Cquart.), 139.6 (C10, Cquart.), 128.7 (d, JC,F ¼ 4.8 Hz, CH ), 119.9
–
–
4
2
(d, JC,F ¼ 3.9 Hz, CH ), 116.6 (d, JC,F ¼ 12.5 Hz, C10, Cquart.),
–
–
3
111.5 (d, JC,F ¼ 4.8 Hz, C60, CH), 104.9 (C2 þ C6, CH), 102.2
3
4
2
(C4, CH), 99.8 (d, JC,F ¼ 28.8 Hz, C30, CH), 55.7 (s, OCH3) ppm;
1 H, J (trans) ¼ 16.4 Hz, CH ¼ (1)), 7.18 (d, 1 H, J ¼ 1.9 Hz, CH
(2)), 7.06 (d, 1 H, 3J (trans) ¼ 16.4 Hz, CH ¼ (2)), 7.06–7.04 (m, 2 H,
CH (6) þ CH (60)), 6.91 (d, 1 H, 3J ¼ 8.3 Hz, CH (5)), 6.72 (d, 1 H,
19F NMR (188 MHz, acetone-d6): d ¼ ꢃ128.8 (dd, JF,H ¼ 7.5,
4
3JF,H ¼ 11.8 Hz, -F) ppm; MS (ESI, MeOH): m/z ¼ 275.5 (79%
[MꢃH]ꢃ); 321.3 (100% [MþHCO2]ꢃ); 550.9 (70% [2MꢃH)]ꢃ);
analysis for C15H13FO4 (276.26): C, 65.21; H, 4.74; found C,
64.99; H, 4.83.
4
4J ¼ 8.8 Hz, CH (30)), 6.58 (dd, 3J ¼ 8.8 Hz, J ¼ 1.9 Hz, CH (40)),
3.85 (s, 3 H, OCH3), 3.80 (s, 3H, OCH3) ppm; 13C NMR (100 MHz,
acetone-d6): d ¼ 151.3 (C50, Cquart.), 150.5 (C3, Cquart.), 150.1 (C30,
–
Cquart.), 148.7 (C4, Cquart.), 132.1 (C1, Cquart.), 128.9 (CH ), 126.0
–
(C10, Cquart.) 122.5 (CH ), 120.5 (C2, CH), 117.3 (C3 , CH), 116.0
0
–
–
(E)-40-Fluoro-2,30,50-trihydroxystilbene (10)
(C40, CH), 113.0 (C5 þ C60, CH), 110.3 (C2, CH), 56.1 (OCH3), 56.0
(OCH3) ppm; MS (ESI, MeOH): m/z ¼ 271.4 (41% [MꢃH]ꢃ); 317.2
(74% [MþHCO2]ꢃ); 542.9 (100% [2MꢃH]ꢃ); analysis for C16H16O4
(272.30): C, 70.57; H, 5.92; found C, 70.38; H, 6.09.
According to the general procedure, from 2-hydroxystyrene,
3,5-dihydroxy-4-fluorobromobenzene 10 (69.8%) was obtained
as a beige-colored solid; mp 193–1948C; 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 cmꢃ1; UV–Vis (MeOH): lmax
(log e) ¼ 236 (4.30), 291 (4.30), 325 (4.36) nm; 1H NMR (400 MHz,
MeOH-d4): d ¼ 7.46 (d, 1 H, 3J ¼ 7.7 Hz, CH (6)), 7.24 (d, 1 H, 3J
(trans) ¼ 16.6 Hz, CH ¼ (1), 7.04–7.01 (m, 1 H, CH (4)), 6.90 (d,
1 H, 3J (trans) ¼ 16.6 Hz, CH ¼ (2)), 6.79–6.77 (m, 2 H, CH
(E)-3,5-Dimethoxy-4,20,50-trihydroxystilbene (17)
According to the general procedure, from 3,5-dimethoxy-4-
hydroxystyrene, 2,5-dihydroxyiodobenzene 17 (65.3%) was
obtained as a colorless solid; mp 89–918C; Rf ¼ 0.45 (silica gel,
hexanes/ethyl acetate, 1:1); IR (KBr): n ¼ 3421br, 2938w, 1610w,
1517w, 1458w, 1339w, 1215w, 1113w cmꢃ1; UV–Vis (MeOH): lmax
(log e) ¼ 218 (4.45), 309 (4.05) nm; 1H NMR (400 MHz, acetone-
d6): d ¼ 7.21 (d, 1 H, 3J (trans) ¼ 16.6 Hz, CH ¼ (1)), 7.02 (d, 1 H, 3J
4
(3) þ CH (5)), 6.55 (d, 2 H, JH,F ¼ 8.0 Hz, CH (20) þ CH (60))
ppm; 13C NMR (100 MHz, MeOH-d4): d ¼ 156.0 (C2, Cquart.),
146.9 (d, 2JC,F ¼ 10.7 Hz, C30 þ C50, Cquart.), 142.1 (d,
4
(trans) ¼ 16.6 Hz, CH ¼ (2)), 6.96 (d, 1 H, J ¼ 2.9 Hz, CH (60)),
4
1JC,F ¼ 236.8 Hz, C40, Cquart.), 135.2 (d, JC,F ¼ 4.4 Hz, C10,
6.83 (s, 2 H, CH (2) þ CH (6)), 6.68 (d, 1 H, 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, 6 H, OCH3) ppm; 13C
–
Cquart.), 129.3 (C6, CH), 128.7 (CH ), 127.4 (C4, CH), 125.7 (C1,
–
–
Cquart.), 124.4 (CH ), 120.7 (C5, CH), 116.6 (C3, CH), 107.4 (d,
–
ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Arch. Pharm. Chem. Life Sci. 2013, 346, 499–503
Butyrylcholinesterase Inhibitors
503
NMR (100 MHz, acetone-d6): d ¼ 149.9 (C50, Cquart.), 147.9
(C3 þ C5, Cquart.), 147.6 (C20, Cquart.), 135.1 (C4, Cquart.), 131.6
[12] T. S. Anekonda, Brain Res. Rev. 2006, 52, 316–324.
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37277–37382.
(CH ), 129.54 (C1, Cquart.), 125.2 (C10, Cquart.), 120.9 (CH ), 116.0
–
–
–
–
(C30, CH), 114.7 (C40, CH), 111.3 (C60, CH), 103.4 (C2 þ C6, CH),
55.3 (OCH3) ppm; MS (ESI, MeOH): m/z ¼ 287.2 (100% [MꢃH]ꢃ),
332.9 (15% [MþHCO2]ꢃ); analysis for C16H16O5 (288.30): C, 66.66;
H, 5.59; found C, 66.43; H, 5.71.
[14] N. Gacar, O. Mutlu, T. Utkan, I. K. Celikyurt, S. S. Gocmez, G.
Ulak, Pharmacol. Biochem. Behav. 2011, 99, 316–323.
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Res. Bull. 2010, 82, 251–258.
[16] P. K. Mukherjee, N. Satheeshkumar, P. Venkatesh, M.
Venkatesh, Mini Rev. Med. Chem. 2011, 11, 247–262.
We are grateful to the Hans-Bo¨ckler Stiftung (Du¨sseldorf) for a scholarship
to S. Albert. Many thanks are due to Dr. R. Kluge for the measurement of the
MS spectra, Dr. D. Stro¨hl for recording the NMR spectra and to B. Siewert
for the measurement of the SRB assays. Support by the ‘‘Gru¨nderwerkstatt
– Biowissenschaften’’ is gratefully acknowledged. The cell lines were kindly
provided by Dr. T. Mu¨ller (Dept. of Haematology/Oncology, Univ. Halle).
[17] C. Riviere, T. Richard, L. Quentin, S. Krisa, J.-M. Merillon, J.-P.
Monti, Bioorg. Med. Chem. 2007, 15, 1160–1167.
[18] S. Albert, R. Horbach, H. B. Deising, B. Siewert, R. Csuk,
Bioorg. Med. Chem. 2011, 19, 5155–5166.
[19] R. Csuk, S. Albert, B. Siewert, S. Schwarz, Eur. J. Med. Chem.
2012, 54, 669–678.
The authors declare that there are no conflicts of interest.
[20] G. Likhtenshtein, Stilbenes – Applications in Chemistry, Life
Sciences and Material Science, Wiley-VCH, Weinheim 2010,
pp. 1–41
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