Efficient synthesis and neuroprotective effect of substituted 1,3-diphenyl-2-propen-1-ones

Article abstract of DOI:10.1021/jm800221g

An efficient synthesis involving a key aldol reaction and biological properties of 1,3-diphenyl-2-propen-1-ones 8-20 is described. The in vitro activity for 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging of 10 and 11 was 2 times higher than that

Full text of DOI:10.1021/jm800221g

4054
J. Med. Chem. 2008, 51, 4054–4058
Efficient Synthesis and Neuroprotective Effect of Substituted 1,3-Diphenyl-2-propen-1-ones
Jae-Chul Jung,† Soyong Jang,† Yongnam Lee,‡ Dongguk Min,‡ Eunyoung Lim,‡ Heyin Jung,‡ Miyeon Oh,‡ Seikwan Oh,*,† and
Mankil Jung*,‡
Department of Neuroscience and Medical Research Institute, School of Medicine, Ewha Womans UniVersity, Seoul 158-710, Korea, and
Department of Chemistry, Yonsei UniVersity, Seoul 120-749, Korea
ReceiVed March 1, 2008
An efficient synthesis involving a key aldol reaction and biological properties of 1,3-diphenyl-2-propen-1-
ones 8-20 is described. The in vitro activity for 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging
of 10 and 11 was 2 times higher than that for resveratrol. Compounds 9 and 11 were the strongest in
suppression of in vitro nitric oxide (NO) generation and antiexcitotoxicity. Molecular modeling proposes
an electron-donating group at the para position of acetophenones that leads to a dramatic increase in the
suppression of NO production.
Introduction
1,3-Diarylpropenones (1, chalcones) constitute an important
group of natural products and serve as precursors for the
synthesis of different classes of various flavonoids, which
are common substances in plants that have an array of
biological activities.1,2 In addition, yakuchinone analogues
A and B (2 and 3) (Figure 1) have evoked much interest in
recent years because of their significant biological activities
in areas such as brain dysfunction,3 cancer,4,5 inflammation,6
and cardiovascular disease.7 Most of the phenolic natural
products are potentially useful intermediates for many
industrial products and agrochemical applications, including
food sciences. The phenolic natural products are closely
Figure 1. Structures of chalcones (1), yakuchinone A (2), and yakuchi-
none B (3).
related to free radicals, which play a major role in the
progression of many pathological disturbances.8 Furthermore,
free radical scavenging effects are a major cause in the
to develop and design new compounds with increased potency
deterioration of foods during processing and storage. In
and antioxidant and neuroprotective effects in terms of
addition, free radicals are related to antioxidation in foods
oxidative chalcone and its analogues, the substituted 1,3-
and biological systems.9 Recently, antioxidants have been
diphenyl-2-propen-1-ones were synthesized and their biologi-
shown to play an important role in biological defense
cal activities determined. Here, the one-pot synthesis of
mechanisms.10 In an ischemic condition, glutamate is released
substituted 1,3-diphenyl-2-propen-1-ones, which is an im-
excessively and then activates the glutamate receptor. Over-
provement made to previous routes,13,14 is described and the
free radical scavenging, anti-inflammatory, and antiexcito-
activation of the glutamate receptors may induce elevation
of intracellular Ca2+ levels, resulting in activation of Ca2+
-
toxic effects are established. Molecular modeling studies were
consequently described to investigate the chemical structural
characteristics required for the biological activities and
schematized delocalized form of electron density. Molecular
modeling can provide further information for exploring more
specific targets of related 1,3-diarylpropenones as a logical
starting point in studies of novel neurological disorders.
dependent proteases and kinases. Additionally, high intra-
cellular Ca2+ may activate nitric oxide synthase, resulting
in excessive production of nitric oxide (NOa) and cytotox-
icity.11 According to previous research, activated oxygen is
considered a major factor in cytotoxicity. Therefore, a search
for novel compounds with better neuroprotective effects and
less neurotoxicity based on antioxidative effects has been
undertaken.
In a preliminary communication,12 the authors of this study
reported the preparation of benzylideneacetophenone deriva-
tives and an evaluation of their biological activities. In order
Results and Discussion
Chemistry. A series of benzalacetophenone derivatives 8-20
were prepared from inexpensive vanillin (4, 4-hydroxy-3-
mehoxybenzaldehyde), isovanillin (5, 3-hydroxy-4-methoxy-
benzaldehyde), and o-vanillin (6, 2-hydroxy-3-methoxybenzal-
dehyde). Thus, treatment of various vanillins with commercially
available several acetophenones (7a, acetophenone, 7b, 3,4-
mehtylenedioxyacetophenone, 7c, 3,4,5-trifluoroacetophenone,
and 7d, 3-fluoro-4-methoxyacetophenone) in the presence of 2
equiv of lithium hydroxide (LiOH) as the most effective
coupling base in MeOH produced high yields of 1,3-diphenyl-
2-propen-1-ones (Scheme 1). The effectiveness of LiOH could
* To whom correspondence should be addressed. For S.O.: phone, +82-
2-2650-5749; fax, +82-2-2653-8891; e-mail, skoh@ewha.ac.kr. For M.J.:
phone, +82-2-2123-2648; fax, +82-2-364-7050; e-mail, mjung@
yonsei.ac.kr.
†
Ewha Womans University.
Yonsei University.
‡
a Abbreviations: DPPH, 2,2-diphenyl-1-picrylhydrazyl; NO, nitric oxide;
HOMO, highest occupied molecular orbital; LUMO, lowest unoccupied
molecular orbital; LPS, lipopolyssarcharide; WST, water soluble tetrazolium
salts; NMDA, N-methyl-D-aspartate.
10.1021/jm800221g CCC: $40.75
2008 American Chemical Society
Published on Web 06/03/2008

Brief Articles
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13 4055
Scheme 1. Aldol Condensation Reaction
Compound 15 exhibited the strongest activity among these
analogues. The increase of efficacy of vanillin moieties 8-11
is presumably due to the para position, which increased the
electron density of the hydroxyl group and lowered the
oxygen-hydrogen bonding energy. In addition, the moieties
(11, 15, and 19) of the attached 3-fluoro-4-methoxyacetophe-
none group were found to exhibit a significant improvement
in activity compared to other attached acetophenones (ac-
etophenone, 3,4-mehtylenedioxyacetophenone, 3,4,5-trifluo-
roacetophenone).
Molecular Modeling. The main object for molecular model-
ing was the determination of the effect of aromatic substitution
in the ortho and para positions of diphenylpropenones to the
free radical scavenging effect, LPS-induced NO generation, and
the neuroprotective effect. In the first part of the present study,
the synthesized compounds were divided into three vanillin
moieties and the structural characteristics of the three groups
were investigated. The results of the molecular modeling study
for 1,3-diphenyl-2-propen-1-ones 8-20 are shown in Table 3.
In the structure of acetophenones, the presence of the methoxy
group (11, 15, and 19) shows that their cell viability is as good
as that of other substituted groups and they indicate low dipole
moment values in our result. The neurotoxicity is probably
affected by the dipole moment, which can be a relevant
parameter for evaluating the interaction efficiency of ligand with
a receptor. In addition, the dipole moment indicates the strength
and orientation behavior of a molecule in an electrostatic field
in a CoMFA map.18 The electrostatic nature of the molecule
may lead to large variations of the biological activity. Particu-
larly, in the vanillin moieties 8-11, compounds 9 and 11 have
a small dipole moment while they have a high value in lowest
unoccupied molecular orbital (LUMO) energy compared with
8 and 10. Compounds 9 and 11 showed increased suppression
of NO production. At the para substituent of the acetophenones,
the electron-donating group (-OMe > -H > -F) was shown
to lead to a dramatic increase in the suppression of NO
generation. In addition, the weaker is the electron-donating
ability, the lower is the highest unoccupied molecular orbital
(HOMO) energy and the higher is the HOMO energy, implying
that the para substituent is a good electron donor. Molecules
with high HOMO can donate electrons with ease and are hence
relatively reactive compared to molecules with low HOMO.
Thus, HOMO measures the nucleophilicity of a molecule. This
fact reveals a close relation to the electron density based on the
resonance and inductive effect, which is represented in Figure
4. Further insight can be derived from some features of 8-11
by analyzing the frontier orbitals. In Figure 4, the HOMO
distribution of the compounds with 4′-H, 4′,5′-OCH2O-, 4′-F,
and 4′-OCH3 substituents is shown. The values of the activity
of these compounds are given to explain their correlation with
some features of the nucleophilic and electrophilic frontier
electron density distributions. As seen Figure 4, 9 and 11 are
much delocalized over entire structures in a π molecular orbital
and involve the electron-donating ability over the conjugated
framework. In the case of 9 and 11, the methylenedioxy group
of 9 and the methoxy group of 11 caused the potent biological
activities. A high radical scavenging effect for 1,3-diphenyl-2-
propen-1-ones can be expected because the LUMO energy
generated at the para-positioned electron-donating group could
be kinetically lowered through interaction with other external
radicals. These electronic descriptors (HOMO and LUMO) may
play an important role in the interaction of substituted 1,3-
diphenyl-2-propen-1-ones with the active sites. The relationship
of the ligand-receptor interactions could be explained by the
be explained in part by a lithium chelating effect. This aldol
condensation via a one-step reaction produced eight new
substituted 1,3-diphenyl-2-propen-1-ones (9-11, 13-15, and
18, 19) and five known derivatives (8,4 12,15 16,15 17,5 and
2016) as listed in Table 1.
Biology Evaluation. (A) Radical Scavenging Activity. 2,2-
Diphenyl-1-picrylhydrazyl (DPPH) is one of the few stable and
commercially available organic nitrogen radicals. DPPH radicals
are considered a representative method for the preliminary
screening of compounds capable of scavenging activated oxygen
species, since they are more stable and easier to handle than
oxygen free radicals. The radical scavenging activity of the 1,3-
diphenyl-2-propen-1-ones 8-20 was evaluated by the estab-
lished text method.17 All the compounds exhibited free radical
scavenging ability as shown in Table 2 at 10, 50, and 100 µM
compared with standard (control) material. Although prepared
compounds showed less DPPH radical scavenging activity than
resveratrol, the 1,3-diphenyl-2-propen-1-ones 10 and 11 showed
2-fold higher scavenging activity than resveratrol under lower
(10-50 µM) concentrations. However, 12, 14, 15, and 18-20
exhibited less activity than the standard material. Compound
10 exhibited the strongest radical scavenging activity among
the analogues. The vanillin analogues (8-11) showed a greater
rate of DPPH radical scavenging activity than o-vanillin
analogues (12-15) or isovanillin analogues (16-19). This
increase in activity may be attributed to the electronic distribu-
tion due to the generation of free radicals in the aromatic
conjugation system.
(B) Inhibition of NO Generation. The in vitro suppression
of NO production of 8-20 were evaluated in lipopolyssarcharide
(LPS) treated microglia cells, and the results are summarized
in Figure 2. All compounds showed a strong suppression of
NO generation on microglia cells with 11 being the strongest
at 10-20 µM. In addition, vanillin moieties 8-11 showed a
greater activity of NO generation than isovanillin moieties
12-15 or o-vanillin moieties 16-19. This result indicated that
the hydroxyl group at the para position of the benzene ring is
enhanced to delocalize the electron density based on a resonance
effect. Compounds with a hydroxyl group at the para position
of the benzene ring generally showed increased suppression of
NO production, while compounds with a hydroxyl group at the
ortho or meta position exhibited relatively weaker activity of
NO generation.
(C) Neuroprotective Activity. Inhibition of Glutamate-
Induced Neurotoxicity. The neuroprotective effect of 1,3-
diphenyl-2-propen-1-ones 8-20 on the inhibition of glutamate-
induced neurotoxicity in cultured cortical neurons was
examined (Figure 3). Most of the 1,3-diphenyl-2-propen-1-
ones 8-20 showed good antiexcitotoxicity at 10 µM.

4056 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13
Brief Articles
Table 1. Substituted 1,3-Diphenyl-2-propen-1-ones 8-20 Prepared via Aldol Condensation Reaction
entry
R1
R2
R3
R4
R5
R6
H
formula
product
yield(%)a
1
2
3
4
5
6
7
8
OH
OH
OH
OH
OMe
OMe
OMe
OMe
H
H
H
H
OMe
OMe
OMe
OMe
OMe
OH
OH
OH
OH
OMe
OMe
OMe
OMe
OMe
H
H
H
H
H
H
H
H
OH
OH
OH
OH
H
H
H
F
H
C16H14O3
C17H14O5
C16H11F3O3
C17H15FO4
C16H14O3
C17H14O5
C16H11F3O3
C17H15FO4
C16H14O3
C17H14O5
C16H11F3O3
C17H15FO4
C18H16O5
8
9
90
75
78
82
87
70
75
80
89
68
77
81
89
-OCH2O-
F
F
H
H
10
11
12
13
14
15
16
17
18
19
20
F
OMe
H
H
F
H
-OCH2O-
F
F
H
H
F
OMe
9
H
H
F
F
H
H
10
11
12
13
-OCH2O-
F
F
H
OMe
-OCH2O-
a Isolated yield including recovered starting material.
Table 2. Rate of DPPH Radical Scavenging of
1,3-Diphenyl-2-propen-1-ones 8-20
DPPH radical
scavenging activity (%)
compd
10 µM
50 µM
100 µM
200 µM
8
9
7.53
7.90
22.85
17.80
1.26
8.75
1.99
1.55
5.40
13.93
3.08
1.74
3.27
2.37
11.80
12.02
23.53
18.90
1.46
9.14
2.71
1.68
6.09
14.87
3.28
1.14
1.95
0.28
14.43
14.14
32.05
28.35
2.05
9.63
3.25
2.73
7.94
18.60
5.50
2.42
1.75
0.43
22.63
25.11
37.96
37.45
5.38
10.98
5.29
5.02
10.96
22.25
6.81
2.87
1.56
10
11
12
13
14
15
16
17
18
19
20
Figure 3. Inhibition of glutamate-induced neurotoxicity in cultured
cortical neurons. Glutamate (60 µM) and 8-20 were applied for 24 h
at 37 °C. After incubation of neurons with water soluble tetrazolium
salts WST-1 for 2 h, the compounds were quantified spectrophoto-
metrically. All values represent the mean ( SE of three independent
experiments performed in triplicate.
4-hydroxy-3-
10.56
methoxycinnamaldehydea
Troloxb
12.10
9.45
30.24
8.44
62.44
28.39
78.25
33.79
the substituted high radical scavenging 1,3-diphenyl-2-propen-
1-ones 8-20, particularly 11, could eventually be developed
as antioxidant and antiexcitotoxicity drug candidates.
resveratrolc
a A control material.12 b A standard material. c A standard material.
Conclusion
An efficient synthesis and biological evaluation of 1,3-
diphenyl-2-propen-1-ones 8-20 has been described. The syn-
thetic approach involves aldol condensation of aldehydes 4-6
and acetophenones 7 in the presence of LiOH to generate 1,3-
diphenyl-2-propen-1-ones in high yields. The prepared com-
pounds 8-20 were evaluated for free radical scavenging,
suppression of LPS-induced NO generation, and antiexcitotox-
icity in vitro. The activity for DPPH radical scavenging of 10,
11, and 17 was 6-10 times higher than 4-hydroxy-3-methoxy-
cinnamaldehyde in the in vitro concentration range of 10-100
µM. Compounds 10 and 11 were 2-fold higher than resveratrol
under lower (10-50 µM) concentrations. The compounds have
also exhibited a suppression effect on NO generation after LPS
stimulation in microglial cells and inhibitory action on glutamate-
induced neurotoxicity in cultured neurons. Among the 1,3-
diphenyl-2-propen-1-ones 8-20, compound 11 showed the most
potent neuroprotective effects compared with 1,3-diphenyl-2-
propen-1-ones 8, 10, 12-20. These results coupled with
Figure 2. Suppression of NO production in LPS-treated microglia.
The cells were treated with 1 µg/mL LPS only or LPS plus a different
concentration (10 or 20 µM) of 8-20 at 37 °C for 24 h. At the end
of incubation, 50 µL of the medium was removed to measure nitrite
production. All values represent the mean ( SE of three independent
experiments performed in triplicate.
observation that the regions of the molecules that contain a
greater HOMO contribution tend to be electron-donor to the
active site and that the regions that contain a greater LUMO
contribution tend to be electron-acceptor. On the basis of these
results and future in vivo evaluation of neuroprotective effects,

Brief Articles
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13 4057
Table 3. Calculated Chemical Descriptors and Biological Activities of 1,3-Diphenyl-2-propen-1-ones 8-20
nitritec
group
A
product
dipole moment (µ)
E LUMOa (eV)
E HOMOb (eV)
cell viabillity (%)
10 (µM)
20 (µM)
8
9
3.53
3.05
6.19
2.07
4.63
3.85
7.48
2.87
2.79
5.56
7.78
3.62
3.41
-1.95
-1.86
-2.27
-1.91
-1.90
-1.82
-2.22
-1.86
-2.10
-1.76
-2.16
-1.80
-1.96
-5.84
-5.69
-6.05
-5.81
-5.70
-5.60
-5.89
-5.68
-5.77
-5.65
-6.03
-5.81
-5.80
62
79
61
79
67
69
63
80
58
56
71
75
61
16.14
12.63
19.82
14.21
18.93
21.30
25.07
23.40
17.62
22.62
18.05
19.55
25.69
13.16
11.32
12.11
6.23
16.04
12.44
22.00
19.98
15.69
16.44
14.72
14.19
20.60
10
11
12
13
14
15
16
17
18
19
20
B
C
a Energy of lowest unoccupied molecular orbital (LUMO). b Energy of highest occupied molecular orbital (HOMO). c The amount of nitrite in the presence
of each compound (10 or 20 µM) in LPS-treated BV-2 microglia cells, presented as concentration of LPS-activated BV-2 microglia cells. A, B, and C
represent vanillin, isovanillin, and o-vanillin moieties, respectively.
(30% ethyl acetate/hexanes, v/v); IR (neat, NaCl) 3350, 3005, 2985,
1
2858, 1657, 1550, 1448, 1262, 1153, 1081 cm-1; H NMR (500
MHz, CDCl3) δ 7.83 (d, J ) 16.0 Hz, 1H), 7.66 (t, J ) 8.0 Hz,
2H), 7.22 (d, J ) 16.0 Hz, 1H), 7.20 (d, J ) 8.5 Hz, 1H), 7.15 (s,
1H), 6.93 (d, J ) 8.0 Hz, 1H), 3.90 (s, 3H, OMe); 13C NMR (125
MHz, CDCl3) δ 187.3, 151.0, 148.2, 146.5, 132.2, 128.3, 122.9,
121.7, 119.3, 113.1, 112.2, 111.9, 55.8. HRMS calculated for
C16H12F3O3: 309.0739 [M + H]+. Found: 309.0745. Anal.
(C16H11F3O3) C, H, O.
(E)-1-(3-Fluoro-4-methoxyphenyl)-3-(4-hydroxy-3-methoxyphe-
nyl)-2-propen-1-one (11). The title compound was obtained in 82%
yield from vanillin 4 and 3-fluoro-4-methoxyacetophenone (7d).
Rf ) 0.3 (40% ethyl acetate/hexanes, v/v); IR (neat, NaCl) 3359,
1
2987, 2875, 1662, 1578, 1455, 1278, 1164, 1086 cm-1; H NMR
(500 MHz, CDCl3) δ 7.85-7.72 (m, 3H), 7.33 (d, J ) 16.0 Hz,
1H), 7.15 (d, J ) 8.5 Hz, 1H), 7.13 (s, 1H), 7.04 (t, J ) 8.5 Hz,
1H), 6.91 (d, J ) 8.0 Hz, 1H), 3.96 (s, 3H), 3.91 (s, 3H, OMe);
Figure 4. Frontier orbital maps of vanillin moieties 8-11. Compounds
13C NMR (125 MHz, CDCl3) δ 189.4, 150.3, 148.7, 145.2, 132.4,
9 and 11 showed delocalization throughout all the structures of
129.6, 124.9, 123.1, 121.8, 119.5, 115.3, 113.2, 111.8, 56.8, 55.9.
HRMS calculated for C17H16FO4: 303.1033 [M + H]+. Found:
303.1020. Anal. (C17H15FO4) C, H, O.
substituted 1,3-diphenyl-2-propen-1-ones.
molecular modeling will be useful to further design and develop
potential antioxidant agents and neuroprotective compounds.
(E)-1-(Benzo[d][1,3]dioxol-5-yl)-3-(3-hydroxy-4-methoxyphenyl)-
2-propen-1-one (13). Rf ) 0.3 (40% ethyl acetate/hexanes, v/v);
Experimental Section
IR (neat, NaCl) 3340, 2969, 1671, 1460, 1265, 1176, 1055 cm-1
;
General Procedures for the Preparation of the Aldol
Condensation Products of Aldehyde with Acetophenones
(8-20). A stirred solution of acetophenones 7a-d (6.0 mmol) in
MeOH (30 mL) was added to LiOH (1.2 mmol), and the mixture
was stirred at room temperature for 1 h. The aldehydes 4-6 (6.0
mmol) were added to the mixture, and the resulting mixture was
stirred at room temperature for 148 h. The mixture was concentrated
under reduced pressure, and the residue was treated with water (35
mL). The aqueous mixture was neutralized by the addition of
aqueous 10% HCl solution and extracted with dichloromethane (2
× 30 mL). The organic phase was washed with aqueous saturated
NH4Cl solution (30 mL) and brine (30 mL). The organic layer was
separated and dried over anhydrous MgSO4, filtered, and concen-
trated under reduced pressure to give the crude product, which was
purified by flash silica chromatography to produce the pure
substituted 1,3-diphenyl-2-propen-1-ones 8-20.
1H NMR (500 MHz, CDCl3) δ 7.73 (d, J ) 15.5 Hz, 1H, vinyl),
7.64 (dd, J ) 1.7, 1.7 Hz, 1H, Ar-H), 7.52 (d, J ) 1.6 Hz, 1H,
Ar-H), 7.37 (d, J ) 15.5 Hz, 1H, vinyl), 7.32-7.26 (m, 1H,
Ar-H), 7.13 (dd, J ) 2.0, 2.0 Hz 1H, Ar-H), 6.89 (dd, J ) 3.8,
6.0 Hz, 2H, Ar-H), 6.05 (s, 2H, CH2), 5.69 (s, 1H, OH), 3.95 (s,
3H, OMe). HRMS calculated for C17H15O3: 299.0919 [M + H]+.
Found: 299.0910.
(E)-3-(3-Hydroxy-4-methoxyphenyl)-1-(3,4,5-trifluorophenyl)-2-
propen-1-one (14). The title compound was obtained in 75% yield
from isovanillin 5 and 3,4,5-trifluoroacetophenone (7c). Rf ) 0.3
(30% ethyl acetate/hexanes, v/v); IR (neat, NaCl) 3336, 2978, 1678,
1456, 1268, 1122, 1065 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.75
(d, J ) 15.5 Hz, 1H, vinyl), 7.60 (d, J ) 8.3 Hz, 2H, Ar-H),
7.36-7.16 (m, 2H, Ar-H), 7.14 (d, J ) 8.4 Hz, 1H, Ar-H), 6.87
(d, J ) 8.5 Hz, 1H, vinyl), 5.75 (s, 1H, OH), 3.95 (s, 3H, OMe).
HRMS calculated for C16H12F3O3: 309.0739 [M + H]+. Found:
309.0751. Anal. (C16H11F3O3) C, H, O.
(E)-1-(Benzo[d][1,3]dioxol-5-yl)-3-(4-hydroxy-3-methoxyphenyl)-
2-propen-1-one (9). Rf ) 0.3 (30% ethyl acetate/hexanes, v/v); IR
(neat, NaCl) 3349, 3007, 2955, 2876, 1645, 1554, 1477, 1243, 1186,
(E)-1-(3-Fluoro-4-methoxyphenyl)-3-(3-hydroxy-4-methoxyphe-
nyl)-2-propen-1-one (15). The title compound was obtained in 80%
yield from isovanillin 5 and 3-fluoro-4-methoxyacetophenone (7d).
Rf ) 0.3 (25% ethyl acetate/hexanes, v/v); IR (neat, NaCl) 3355,
1
1045 cm-1; H NMR (500 MHz, CDCl3) δ 7.11-6.72 (m, 6H),
6.59 (dd, J ) 7.5, 7.0 Hz, 1H), 6.38 (dd, J ) 7.0, 7.0 Hz, 1H),
6.05 (s, 2H), 3.88 (s, 3H, OMe); 13C NMR (125 MHz, CDCl3) δ
188.9, 151.1, 147.0, 146.3, 145.7, 138.3, 133.5, 127.9, 126.5, 125.4,
122.1, 121.4, 120.5, 112.1, 102.5, 55.9. HRMS calculated for
C17H15O5: 299.0919 [M + H]+. Found: 299.0928.
1
2976, 1682, 1458, 1276, 1120, 1076 cm-1; H NMR (500 MHz,
CDCl3) δ 7.95-7.78 (m, 2H, Ar-H), 7.76 (d, J ) 15.5 Hz, 1H,
vinyl), 7.39-7.27 (m, 2H, Ar-H), 7.15-7.04 (m, 2H, Ar-H), 6.84
(d, J ) 4.8 Hz, 1H, vinyl), 5.77 (s, 1H, OH), 3.97 (s, 3H, OMe),
3.94 (s, 3H, OMe); HRMS calculated for C17H16FO4: 303.1033
[M + H]+. Found: 303.1045. Anal. (C17H15FO4) C, H, O.
(E)-3-(4-Hydroxy-3-methoxyphenyl)-1-(3,4,5-trifluorophenyl)-2-
propen-1-one (10). The title compound was obtained in 78% yield
from vanillin 4 and 3,4,5-trifluoroacetophenone (7c). Rf ) 0.3

4058 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13
Brief Articles
evaluation studies on novel 1,3-diarylpropenones. Bioorg. Med. Chem.
2001, 9, 337–345.
(2) Kim, D. Y.; Kim, K. H.; Kim, N. D.; Lee, K. Y.; Han, C. K.; Yoon,
J. H.; Moon, S. K.; Lee, S. S.; Seong, B. L. Design and biological
evaluation of novel tubulin inhibitors as antimitotic agents using a
pharmacophore binding model with tubulin. J. Med. Chem. 2006, 49,
5664–5670.
(3) Ono, M.; Hori, M.; Haratake, M.; Tomiyama, T.; Mori, H.; Nakayama,
M. Structure-activity relationship of chalcones and related derivatives
as ligands for detecting of ꢀ-amyloid plaques in the brain. Bioorg.
Med. Chem. 2007, 15, 6388–6396.
(4) Konieczny, M. T.; Konieczny, W.; Sabisz, M.; Skladanowski, A.;
Wakiec, R.; Augustynowicz-Kopec, E.; Zwolska, Z. Synthesis of
isomeric, oxathiolone fused chalcones, and comparison of their activity
toward various microorganisms and human cancer cells line. Chem.
Pharm. Bull. 2007, 55, 817–820.
(E)-3-(2-Hydroxy-3-methoxyphenyl)-1-(3,4,5-trifluorophenyl)-2-
propen-1-one (18). The title compound was obtained in 77% yield
from o-vanillin 6 and 3,4,5-trifluoroacetophenone (7c). Rf ) 0.3
(30% ethyl acetate/hexanes, v/v); IR (neat, NaCl) 3405, 2987, 1675,
1540, 1455, 1247, 1130, 1060 cm-1; 1H NMR (500 MHz, CDCl3)
δ 7.99 (d, J ) 15.5 Hz, 1H, vinyl), 7.76 (d, J ) 7.5 Hz, 2H, Ar-H),
7.34 (d, J ) 15.5, Hz, 1H, vinyl), 7.23 (dd, J ) 3.5, 3.5 Hz, 1H,
Ar-H), 7.18 (d, J ) 6.5 Hz, 1H, Ar-H), 6.93 (d, J ) 7.5 Hz, 1H,
Ar-H), 5.54 (s, 1H, OH), 3.91 (s, 3H, OMe); HRMS calculated
for C16H12F3O3: 309.0739 [M + H]+. Found: 309.0722. Anal.
(C16H14F3O3) C, H, O.
(E)-1-(3-Fluoro-4-methoxyphenyl)-3-(2-hydroxy-3-methoxyphe-
nyl)-2-propen-1-one (19). The title compound was obtained in 81%
yield from o-vanillin 6 and 3-fluoro-4-methoxyacetophenone (7d).
Rf ) 0.3 (25% ethyl acetate/hexanes, v/v); IR (neat, NaCl) 3352,
(5) Gschwendt, M.; Kittstein, W.; Furstenberger, G.; Marks, F. The mouse
ear edema: a quantitatively evaluable assay for tumor promoting
compounds and for inhibitors of tumor promotion. Cancer Lett. 1984,
25, 177–185.
1
2979, 1687, 1466, 1285, 1122, 1084 cm-1; H NMR (500 MHz,
CDCl3) δ 8.20 (d, J ) 15.5 Hz, 1H, vinyl), 8.11-8.06 (m, 2H,
Ar-H), 7.96 (d, J ) 15.5 Hz, 1H, vinyl), 7.41 (dd, J ) 3.5, 3.5
Hz, 1H, Ar-H), 7.22 (t, J ) 8.4 Hz, 1H, Ar-H), 7.16-7.03 (m,
2H, Ar-H), 6.56 (s, 1H, OH), 4.21 (s, 3H, OMe), 4.17 (s, 3H,
OMe); HRMS calculated for C17H16FO4: 303.1033 [M + H]+.
Found: 303.1053. Anal. (C17H15FO4) C, H, O.
(6) Nowakowska, Z. A review of anti-infective and anti-inflammatory
chalcones. Eur. J. Med. Chem. 2007, 42, 125–137.
(7) Opletalova, V.; Jahodar, L.; Jun, D.; Opletal, L. Chalcones (1,3-
diarylpropen-1-ones) and their analogs as potential therapeutic agents
for diseases of the cardiovascular system. Ceska SloV. Farm. 2003,
52, 12–19.
(8) Afanas’ev, I. B. Signaling functions of free radicals superoxide & nitric
oxide under physiological & pathological conditions. Mol. Biotechnol.
2007, 37, 2–4.
(9) Esposito, E.; Capasso, M.; di Tomasso, N.; Corona, C.; Pellegrini,
F.; Uncini, A.; Vitaglione, P.; Fogliano, V.; Piantelli, M.; Sensi,
S. L. Antioxidant strategies based on tomato-enriched food or
pyruvate do not affect disease onset and survival in an animal model
of amyotrophic lateral sclerosis. Brain Res. 2007, 1168, 90–96.
(10) Foresti, R.; Hoque, M.; Monti, D.; Green, C. J.; Motterlini, R. Differential
activation of heme oxygenase-1 by chalcones and rosolic acid in
endothelial cells. J. Pharmacol. Exp. Ther. 2005, 312, 686–693.
(11) Kume, T.; Kawai, Y.; Yoshida, K.; Nakamizo, T.; Kanki, R.;
Sawada, H.; Katsuki, H.; Shimohama, S.; Sugimoto, H.; Akaike,
A. Protective effect of serofendic acid on glutamate-induced
neurotoxicity in rat cultured motor neurons. Neurosci. Lett. 2005,
383, 199–202.
(12) Oh, S.; Jang, S.; Kim, D.; Han, I. O.; Jung, J. C. Synthesis and
evaluation of biological properties of benzylideneacetophenone deriva-
tives. Arch. Pharm. Res. 2006, 29, 469–475.
(13) Arty, I. S.; Timmerman, H.; Samhoedi, M.; Sastrohamidjojo, S.;
Van der Goot, H. Synthesis of benzylideneacetophenones and their
inhibition of lipid peroxidation. Eur. J. Med. Chem. 2000, 35, 449–
457.
(14) Lawrence, N. J.; Patterson, R. P.; Ooi, L. L.; Cook, D.; Ducki, S.
Effects of R-substitutions on structure and biological activity of
anticancer chalcones. Bioorg. Med. Chem. Lett. 2006, 16, 5844
5848.
(15) Maiti, A.; Cuendet, M.; Croy, V. L.; Endringer, D. C.; Pezzuto, J. M.;
Cushman, M. Synthesis and biological evaluation of (()-abyssinone
II and its analogues as aromatase inhibitors for chemoprevention of
breast cancer. J. Med. Chem. 2007, 50, 2799–2806.
(16) Bhat, B. A.; Dhar, K. L.; Puri, S. C.; Saxena, A. K.; Shanmugavel,
M.; Qazi, G. N. Synthesis and biological evaluation of chalcones and
their derived pyrazoles as potential cytotoxic agents. Bioorg. Med.
Chem. Lett. 2005, 15, 3177–3180.
(17) Lawinski, M.; Sledzinski, Z.; Kubasik-Juraniec, J.; Spodnik, J. H.;
Wozniak, M.; Boguslawski, W. Does resveratrol prevent free radical-
induced acute pancreatitis? Pancreas 2005, 31, 43–47.
(18) Sivakumar, P. M.; Geetha Babu, S. K.; Mukesh, D. QSAR studies
on chalcones and flavonoids as anti-tuberculosis agents using
genetic function approximation (GFA) method. Chem. Pharm. Bull.
2007, 55, 44–49.
Measurement of Cell Viability. Cortical neuronal cell number
and viability were assessed by using the reagent WST-1 (Roche,
Indianapolis, IN). This colorimetric assay measures the metabolic
activity of viable cells based on cleavage of the tetrazolium salt
WST-1 substrate 4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-
tetrazolio-1,3-benzene disulfonate] into formazan by mitochon-
dria dehydrogenase in live cells. This was followed by incubation
with WST-1 reagent at a dilution of 1:10 in the original
conditioned media at 37 °C for 2 h. After thorough shaking, the
formazan produced by the metabolically active cells in each
sample was measured at a wavelength of 450 nm and a reference
wavelength of 650 nm. Absorbance readings were normalized
against control wells with untreated cells. Neuronal death was
analyzed 24 h later, and the percentage of neurons undergo-
ing actual neuronal death was normalized to the mean value
found after a 24 h exposure to 300 µM NMDA (defined as 0) or
a sham control (defined as 100).
Molecular Modeling. The lower energy conformers for 8-20
were searched by a molecular mechanics force field (MMFF)
analysis19 and were submitted to a geometry optimization and
energy calculations by density functional theories (DFT) model20
calculation at the B3LYP 6-31G** level. The HOMO, LUMO,
and dipole values of the selected conformers were also calcu-
lated. All calculations and graphical representations were
performed by using the SPARTAN 06 for Windows software
package.
Acknowledgment. This work was supported by a KOSEF
Brain Neurobiology grant (2007), Ewha Global Challenge
(BK21) grant, and Korean Research Foundation Grant funded
by the Korean Government (MOEHRD) (Grant KRF-2006-
312-C00267), the Republic of Korea. Y.L., D.M., H.J., and
M.O. appreciate the fellowship from the BK21 program from
the Ministry of Education and Human Resources Develop-
ment. Y.L. thanks the Seoul Science Fellowship Program and
Grant 20070301-034-026-007-04-00 from BioGreen 21 Pro-
gram, Rural Development Administration, Korea.
(19) Halgren, T. A. Merck molecular force field. I. Basis, form, scope,
parameterization, and performance of MMFF94. J. Comput. Chem.
1996, 17, 490–519.
Supporting Information Available: Spectral data of 8, 12, 16,
17, and 20, experimental procedures for synthesis, frontier orbital
maps of 8-20, and biological evaluations (radical scavenging test,
cell cultures, and DPPH bleaching kinetics). This material is
available free of charge via the Internet at http://pubs.acs.org.
(20) Kohn, W.; Becks, A. D.; Parr, R. G. Density functional theory of
electronic structure. J. Phys. Chem. 1996, 100, 12974–12980.
References
(1) Mukherjee, S.; Kumar, V.; Prasad, A. K.; Raj, H. G.; Bracke, M. E.;
Olsen, C. E.; Jain, S. C.; Parmar, V. S. Synthetic and biological activity
JM800221G