Synthesis and cytotoxic evaluation of alkoxylated chalcones

Article abstract of DOI:10.3390/molecules191117256

A series of chalcones a1-20 bearing a 4-OMe groups on the A-ring were initially synthesized and their anticancer activities towards HepG2 cells evaluated. Subsequently, a series of chalcones b1-42 bearing methoxy groups at the 2′ and 6′-positions of the B-ring were synthesized and their anticancer activities towards five human cancer cell lines (HepG2, HeLa, MCF-7, A549 and SW1990) and two non-tumoral human cell lines evaluated. The results showed that six compounds (b6, b8, b11, b16, b18, b22, b23 and b29) displayed promising activities, with compounds b22 and b29 in particular showing higher levels of activity than etoposide against all five cancer cell lines. Compound b29 showed a promising SI value compared with both HMLE and L02 (2.1-6.5 fold in HMLE and > 33 > 103.1 fold in L02, respectively).

Full text of DOI:10.3390/molecules191117256

Molecules 2014, 19, 17256-17278; doi:10.3390/molecules191117256
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis and Cytotoxic Evaluation of Alkoxylated Chalcones
Xiao-Guang Bai †, Chang-Liang Xu †, Shuang-Shuang Zhao, Hong-Wei He, Yu-Cheng Wang
and Ju-Xian Wang *
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union
Medical College, Beijing 100050, China; E-Mails: baixiaoguang130@126.com (X.-G.B.);
clxu1986@163.com (C.-L.X.); zhshsh1112@163.com (S.-S.Z.); hehwei@163.com (H.W.H.);
wyc9999@126.com (Y.-C.W.)
†
These authors contributed equally to this work.
* Author to whom correspondence should be addressed; E-Mail: imbjxwang@gmail.com;
Tel./Fax: +86-10-6316-5263.
External Editor: Derek J. McPhee
Received: 25 July 2014; in revised form: 26 September 2014 / Accepted: 17 October 2014 /
Published: 28 October 2014
Abstract: A series of chalcones a1–20 bearing a 4-OMe groups on the A-ring were initially
synthesized and their anticancer activities towards HepG2 cells evaluated. Subsequently, a
series of chalcones b1–42 bearing methoxy groups at the 2' and 6'-positions of the B-ring
were synthesized and their anticancer activities towards five human cancer cell lines
(HepG2, HeLa, MCF-7, A549 and SW1990) and two non-tumoral human cell lines
evaluated. The results showed that six compounds (b6, b8, b11, b16, b18, b22, b23 and
b29) displayed promising activities, with compounds b22 and b29 in particular showing
higher levels of activity than etoposide against all five cancer cell lines. Compound b29
showed a promising SI value compared with both HMLE and L02 (2.1–6.5 fold in HMLE
and > 33 > 103.1 fold in L02, respectively).
Keywords: alkoxylated chalcones; synthesis; cytotoxicity

Molecules 2014, 19
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1. Introduction
Chalcones (1,3-diaryl-2-propen-1-ones, Figure 1) are naturally occurring compounds that are widely
distributed in a variety of plant species. Compounds belonging to this structural class have been
identified as both intermediates and end products in the biosynthesis of flavonoids, and make significant
contributions to the medicinal value of herbs. The ease of preparation of these compounds, as well as
their potential for oral administration and safety, make them good candidates for use as therapeutic
agents in drug discovery [1]. For these reasons, chalcones have attracted considerable attention from
chemists and pharmacologists, and a large number of results have been reported in the literature
pertaining to the biological activities of both naturally occurring and synthetic chalcone compounds,
including their anti-inflammatory [2,3], antimicrobial [4–6], antifungal [7,8], antioxidant [9] and
anticancer activities [10–15].
Figure 1. General structure of chalcones.
The antitumor properties of chalcones have received considerable attention during the last few years,
because they operate via a similar mode of action to the structurally related combretastatin [16]. The
frequent occurrence of polymethoxyphenyl-type moieties in naturally occurring anticancer agents, such
as colchicine and combretastatin, has inspired scientists to investigate the synthesis and biological
evaluation of methoxylated chalcones, and the results of these studies have shown that methoxy groups
generally make a significant contribution to the cytotoxicity of these compounds [17–19].
To develop potential anticancer drugs based on chalcones, as well as improve our understanding of
the structure-activity relationships (SARs) of these compounds, we report herein the synthesis of a series
of alkoxylated chalcones. The cytotoxic activities of these 62 compounds have also been evaluated
against a panel of five cancer cell lines and two normal human cell lines, including HepG2, HeLa,
MCF-7, A549, SW1990, HMLE and L02 cells.
2. Results and Discussion
Compounds a1–20 bearing a 4-OMe on their A-ring (i.e., their 1-phenyl moiety) were initially
synthesized and evaluated in terms of their activity towards human liver carcinoma HepG2 cells using
a SRB assay. This evaluation was conducted to develop a better understanding of the structural-activity
relationship (SAR) of the B-ring of these compounds and the activity results (percentage rates at
concentration of 10 μM) are shown in Table 1.

Molecules 2014, 19
17258
Table 1. Inhibitory activities of the 4-methoxyl chalcones a1–20 against HepG2 cells (10 μM).
Compound
a1
R1
H
R2
H
R3
H
R4
H
R5
H
Inhibition (%) **
42.4 ± 2.0
37.6 ± 4.4
41.8 ± 5.9
41.2 ± 4.6
9.0 ± 5.6
a2
H
H
Br
H
H
a3
F
H
Br
H
H
a4 *
a5 *
a6
Br
H
F
H
H
Cl
H
Br
H
H
H
H
NO2
COOH
H
H
H
9.8 ± 5.0
a7
H
H
H
H
32.7 ± 3.0
61.4 ± 3.4
59.0 ± 2.9
27.7 ± 17.7
13.1 ± 8.4
66.3 ± 4.2
77.0 ± 2.2
78.1 ± 4.7
65.0 ± 17.6
70.6 ± 2.0
44.1 ± 6.2
31.8 ± 7.3
38.1 ± 10.3
71.1 ± 1.3
63.9 ± 0.1
a8
OCH3
H
H
H
H
a9
OCH3
H
H
H
H
a10
H
OCH3
OCH2CH3
H
H
H
a11
H
H
H
H
a12
OCH3
OCH3
OCH3
H
OCH3
H
H
H
a13
H
OCH3
H
H
a14 *
a15
H
H
OCH3
H
OCH3
OCH3
OCH2Ph
OCH3
H
OCH3
H
H
a16
H
OCH3
H
H
a17
H
OCH3
OCH3
OCH3
OCH3
H
a18
OCH3
OCH3
H
H
H
a19
OCH3
OCH3
H
a20
OCH3
H
Etoposide
*: Novel compound; **: The results are shown as the average percentage of the individual mean (±SD, standard
deviation) for three independent experiments.
The introduction of halogen atoms (i.e., compounds a2–5), a NO2 substituent (a6) and a COOH group
(a7) on the B-ring led to a decrease in the activity of these compounds compared with the parent
compound a1.Contrary to a2–7, compounds a8–20 which were substituted with electron donating
groups (i.e., OMe, OEt and OBn), generally exhibited moderate to high levels of inhibition. A single
OMe group substituted at the 2'-position (a8) or 3'-position (a9) led to much better inhibition than that
of the 4'-position (a10). A comparison of a10 vs. a11 and a15 vs. a17 revealed that bulky substituents
seemed to be poorly tolerated at the 3' and 4'-position. Interestingly, the substitution of the B ring with
two OMe groups (compounds a12–16) led to a general increase in the activity (inhibition 65.0%–78.1%),
with bis-substitution at the 2' and 6' positions (a14) providing the best results. The trimethoxy- substituted
chalcones synthesized in the current study (i.e., compound a18–20) showed weak anti-proliferative
activity towards HepG2 cells, except for the 3',4',5'-trimethoxy compound a20.
It is possible to draw some conclusions from the results in Table 1, including: (1) the introduction of
electron donating groups to the B-ring generally made a positive contribution to the cytotoxicity,
whereas electron withdrawing groups tended to have an adverse impact on the cytotoxicity;

Molecules 2014, 19
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(2) the position and size of the substituents might have a specific impact on the activity of these
compounds; and (3) the presence of two OMe moiety on the B-ring led to an remarkable increase in the
cytotoxic activity.
With a aim of identifying potential anticancer agents with enhanced levels of activity, as well as
verifying the conclusions provided above, we took a14 as a starting compound, and then designed and
synthesized a series of chalcones b1–42 bearing methoxy groups at the 2' and 6'-positions of the B-ring,
whilst varying the substituents on the A-ring. The cytotoxicities of the resulting chalcones were
evaluated in vitro against five human cancer cell lines and other two non-tumoral cell lines, including
HepG2, HeLa, MCF-7, A549, SW1990, HMLE and L02, and the results are shown in Table 2.
Compounds bearing electron donating groups (i.e., Me, OMe, OEt, OBn, OCH2O, CH2CH2O, Ph,
NH2 and OH) generally exhibited higher levels of anticancer activity than those with electron
withdrawing groups (i.e., F, Cl, Br, NO2, CN and CF3). Furthermore, chalcones substituted with alkoxyl
groups exhibited greater cytotoxic activities than those substituted with methyl, amino or hydroxyl
groups (e.g., the IC50 values of b6–11 were lower than those of b2–5 and b23–27). A comparison of
b2–4, b6–13 and b24–26 revealed that both the position and the size of the substituents had a significant
impact on the cytotoxic activities of the compounds, with the position effect appearing to be of the order
o > m > p (confirmed by b30–33), and the size contribution following the order OMe > OEt > OBn (b11
is an exception to this order).
A review of compounds b30 to b42 revealed that those with electron withdrawing groups exhibited
weak cytotoxic activity, and that the cytotoxic activities of these compounds were related to the
electrophilic nature of their substituents. For example, nearly all of the IC50 values for compounds b30
and b39–42, which had a CN, NO2 or CF3 group on their A-ring, were greater than 30 µM.
It’s noteworthy that compound b6, b8, b11, b16, b18, b22, b23 and b29 exhibited the most
outstanding activities among all the compounds tested in this study, with most of their in vitro IC50
values against the five human cancer lines being less than 10 µM. Compound b22 was 20.4- and
23.6-fold as potent than etoposide against HepG2 and SW1990 cells, respectively, and compound b29
was 11.5-fold more potent than etoposide against A549 cells. These two compounds displayed the best
activity and therefore are deserving of further investigation.
All compounds were also evaluated for their cytotoxic activity against two non-tumoral human cell
lines named human mammary epithelial cell (HMLE) and L02 (a human liver cell line) in Table 2 and
SI values between the CC50 in non-tumoral cell lines and IC50 in tumoral cells calculated. The data
indicate that about one third of the compounds (b8, b11–13, b16, b18–24, b28–29, b31–32, b34,
b36–38) exhibit more than 2-fold better SI between the CC50 in L02 and IC50 in tumoral cells, which is
similar to the value of etoposide. Among them, compounds b11, b16, b22, b23 exhibited over 5-fold
better SI toward L02. However, most compounds’ SI values between the CC50 in HMLE and IC50 in
tumoral cells are unsatisfactory, except for b11, b27, b29 and b31 (2–7 fold), which is also similar to
etoposide. Fortunately, compound b11, and especially b29, showed promising SI values compared with
both HMLE and L02 (2.1–6.5 fold in HMLE and >33–>103.1 fold, respectively).

Molecules 2014, 19
Table 2. Cytotoxicities of the 2',6'-dimethoxyl chalcones b1–b42 against five human cancer cell lines and two non-tumoral cell lines.
17260
Human Cancer Cell Lines, IC50 (µM) & SI
Normal Human Cell Lines, CC50 (µM) b
HepG2
HeLa
MCF7
A549
SW1990
Compound
R1
R2
R3
R4
a
a
a
a
a
IC50
IC50
IC50
IC50
IC50
HMLE
L02
SI c
20.98 ± 1.75
0.5 1.6 <0.3 <1.1
14.07 ± 1.84 18.40 ± 0.75 19.08 ± 2.11 25.47 ± 4.14
1.1 2.5 0.8 1.9 0.8 1.9 0.6 1.4
12.81 ± 0.50 13.28 ± 2.14 26.78 ± 4.26 20.69 ± 0.59
1.3 2.6 1.2 2.5 0.6 1.2 0.8 1.6
19.51 ± 1.28 18.60 ± 0.36 25.44 ± 0.15 22.07 ± 0.60
SI d SI e
SI f
SI g
28.18 ± 0.04
0.3 1.2
SI h
SI i
SI j
SI k
SI l
>30
>30
<0.3 <1.1
>30
>30
b1 #
b2
H
CH3
H
H
H
H
H
H
H
H
H
H
H
H
9.47 ± 0.39
14.98 ± 0.78
16.20 ± 0.19
13.77 ± 1.69
15.66 ± 0.76
4.01 ± 0.05
8.14 ± 0.53
3.28 ± 0.31
0.83 ± 0.21
9.58 ± 0.44
33.340.39e
35.87 ± 3.40
33.26 ± 1.61
59.59 ± 5.56
25.15 ± 2.71
8.78 ± 1.21
18.08 ± 5.82
8.87 ± 1.83
39.55 ± 7.53
17.42 ± 5.96
<0.3
<0.5
<1.1
<1.2
25.23 ± 2.00
b3
CH3
H
H
0.6
1.3
>30
>30
b4
H
CH3
CH3
H
0.7
26.79 ± 0.30 20.33 ± 1.01 30.31 ± 0.29
0.6 0.9 0.8 1.2 0.5 0.8
2.05 ± 0.22 5.00 ± 0.03 5.60 ± 0.17
2.0 4.3 0.8 1.8 0.7 1.6
6.97 ± 0.55 9.98 ± 0.37 6.37 ± 0.05
1.2 2.6 0.8 1.8 1.3 2.8
9.20 ± 0.31 12.42 ± 0.34 23.10 ± 0.79 21.18 ± 0.55
0.4 1.0 0.3 0.7 0.1 0.4 0.2 0.4
4.23 ± 0.09 8.72 ± 0.07 8.56 ± 0.17 7.36 ± 0.37
0.2 9.3 0.1 4.5 0.1 4.6 0.1 5.4
7.71 ± 0.21 12.16 ± 0.25 11.59 ± 0.07 13.22 ± 0.43
1.2 2.3 0.8 1.4 0.8 1.5 0.7 1.3
3.1
0.7
3.2
0.5
2.3
0.6
2.7
<0.5
<0.5
<2.0
<0.8
>30
b5
H
CH3
H
<0.5
<0.8
6.35 ± 0.32
0.6 1.4
14.02 ± 0.19
0.6 1.3
10.02 ± 0.14
b6 #
b7
OCH3
H
0.4
15.62
0.5
0.9
OCH3
H
1.2
17.80 ± 0.07
0.2 0.5
8.20 ± 0.12
0.1 4.8
10.68 ± 0.08
0.9 1.6
a16
b8
OCH3
H
OCH2CH3
H
H
H
H
b9
OCH2CH3
H

Molecules 2014, 19
17261
Table 2. Cont.
Human Cancer Cell Lines, IC50 (µM) & SI
Normal Human Cell Lines, CC50 (µM) b
HepG2
HeLa
MCF7
A549
SW1990
Compound
R1
R2
R3
R4
a
a
a
a
a
IC50
IC50
IC50
IC50
IC50
HMLE
L02
SI c
10.92 ± 0.46 14.36 ± 0.15 19.76 ± 0.69 22.72 ± 0.57 19.47 ± 0.23
1.3 3.4 1.0 2.6 0.7 1.9 0.6 1.6 0.7 1.9
2.76 ± 0.04 3.62 ± 0.07 4.15 ± 0.2 3.63 ± 0.13 7.43 ± 0.56
7.6 13.9 5.8 10.6 5.1 9.2 5.8 10.5 2.8 5.2
23.59 ± 0.84 25.59 ± 1.16 29.03 ± 0.09 13.25 ± 0.02 22.30 ± 0.07
SI d
SI e
SI f
SI g
SI h
SI i
SI j
SI k
SI l
b10
b11
H
H
H
OCH2CH3
H
H
H
13.81 ± 3.77
20.99 ± 1.26
31.40 ± 1.12
>100
36.66 ± 3.41
38.28 ± 5.63
>100
OCH2Ph
b12
H
OCH2Ph
H
H
H
1.3
>4.2 1.2
>3.9 1.1
>3.4
>30
2.4
>7.5
>30
1.4
>7.5
>30
21.75 ± 0.62
>4.6 >4.6
>30
>30
>30
>30
b13 #
b14
H
OCH2Ph
OCH3
OCH2Ph
OCH2CH3
OCH3
H
H
>100
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
>30
>30
>30
>30
>30
>30
OCH2Ph
H
H
>100
>100
-
-
>30
b15
H
OCH3
OCH3
H
H
>100
>100
-
-
4.14 ± 0.11
2.2 10.8
11.97 ± 0.23 8.54 ± 0.14
0.8 0.9 1.1 1.3
1.59 ± 0.15 4.56 ± 0.22
1.6 10.7 0.5 3.7
7.12 ± 0.67 9.26 ± 0.04 19.67 ± 0.20 13.62 ± 0.85 13.84 ± 0.06
1.5 5.6 1.1 4.3 0.5 2.0 0.8 2.9 0.8 2.9
17.46 ± 0.54 16.23 ± 0.95 22.54 ± 0.37 19.50 ± 0.90 25.85 ± 0.65
0.8 3.5 0.9 3.8 0.6 2.7 0.7 3.1 0.5 2.4
17.34 ± 0.23 21.57 ± 0.43 22.62 ± 2.10 22.26 ± 0.99 24.37 ± 0.60
0.8 3.3 0.7 2.7 0.6 2.5 0.7 2.6 0.6 2.4
5.02 ± 0.09
4.79 ± 0.13
1.9 9.3
7.74 ± 0.10
1.2 1.4
5.60 ± 0.06
0.4 3.0
5.78 ± 0.11
1.6 7.7
9.33 ± 0.30 10. 80 ± 0.50
1.0 1.2 0.8 1.0
4.16 ± 0.72 9.64 ± 0.18
0.6 4.1 0.3 1.8
7.67 ± 0.04
b16
H
H
9.15 ± 1.33
9.03 ± 0.80
2.48 ± 0.34
10.53 ± 0.41
14.21 ± 1.06
14.58 ± 0.81
44.70 ± 8.15
10.92 ± 0.42
16.97 ± 2.73
39.75 ± 6.32
60.90 ± 5.61
57.48 ± 13.57
1.8 8.9
1.2 5.8
b17
OCH2CH3
H
b18
OCH3
H
H
OCH3
H
b19 #
b20 #
b21
OCH3
OCH3
H
OCH2O
CH2CH2O
H
H
H

Molecules 2014, 19
17262
Table 2. Cont.
Human Cancer Cell Lines, IC50 (µM) & SI
Normal Human Cell Lines, CC50 (µM) b
HepG2
HeLa
MCF7
A549
SW1990
Compound R1
R2
R3
R4
a
a
a
a
a
IC50
IC50
IC50
IC50
IC50
HMLE
L02
SI c
SI d
SI e
0.87 ± 0.25
2.5 16.7
7.23 ± 0.07
1.6 6.0
13.38 ± 0.74
0.7 1.8
9.56 ± 0.33
0.7 2.1
12.73 ± 0.81
1.0 2.2
24.84 ± 0.17
>4.0 1.4
17.02 ± 0.65
1.0 >5.9
1.83 ± 0.08
SI f
SI g
2.40 ± 0.08
0.9 6.1
8.56 ± 0.75
1.3 5.0
10.68 ± 0.38
0.8 2.3
8.92 ± 0.25
0.7 2.2
20.24 ± 0.30
0.6 1.4
23.08 ± 0.82
>4.3 1.5
28.37 ± 1.25
0.6 >3.5
1.79 ± 0.20
SI h
SI i
1.75 ± 0.15
1.3 8.3
7.32 ± 0.29
1.6 5.9
8.64 ± 0.31
1.0 2.8
12.73 ± 0.28
0.5 1.5
23.75 ± 1.56
0.5 1.2
17.27 ± 0.76
>5.8 2.1
17.37 ± 0.97
0.9 >5.8
1.50 ± 0.07
SI j
SI k
1.24 ± 0.08
1.8 11.7
10.07 ± 0.03
1.1 4.3
16.11 ± 0.32
0.6 1.5
21.03 ± 0.43
0.3 0.9
20.76 ± 0.54
SI l
0.25 ± 0.03
b22
b23 #
b24 #
b25
H
H
H
NH2
H
Ph
H
H
H
H
H
H
H
H
H
H
H
H
2.21 ± 0.09
11.41 ± 0.76
8.96 ± 0.44
6.31 ± 0.13
12.55 ± 2.82
>100
14.54 ± 6.58
43.18 ± 11.74
24.22 ± 2.71
19.64 ± 1.29
28.16 ± 1.69
35.46 ± 5.72
>100
8.8
58.2
5.70 ± 0.09
2.0
7.6
7.77 ± 0.08
OH
H
H
1.2
3.1
7.27 ± 0.13
OH
H
H
0.9
2.7
14.38 ± 0.81
b26 #
b27
H
OH
OH
OCH3
OH
CN
H
0.9
2.0
0.6
1.4
17.39 ± 1.01
>30
OH
OH
H
H
>5.8
2.0
-
<1.2
19.52 ± 0.79
28.30 ± 0.26
0.6 >3.5
3.03 ± 0.05
b28 #
b29
H
16.25 ± 2.48
6.31 ± 0.13
12.55 ± 2.82
>100
0.8
0.97 ± 0.04
6.5 >103.1
20.45 ± 0.21
0.6 >4.9
17.98 ± 0.88
>5.1
OCH3
H
>100
3.4
>54.6
>30
3.5
>55.9
>30
4.2
>66.7
>30
2.1
<0.4
-
>33.0
>30
b30
H
>100
<0.4
-
<0.4
-
<0.4
-
-
23.33 ± 0.42
>4.3 >4.3
20.67 ± 0.78
0.6 3.5
23.51 ± 0.98
>4.3 >4.3
25.52 ± 0.78
0.5 2.8
27.44 ± 0.67
>3.6 >3.6
27.15 ± 1.39
0.4 2.7
>30
b31
F
H
>100
>5.6
>5.6
-
21.56 ± 0.97
28.38 ± 0.27
0.4 2.5
b32
H
F
H
11.91 ± 1.28
72.01 ± 12.10
0.6
3.3

Molecules 2014, 19
17263
Table 2. Cont.
Human Cancer Cell Lines, IC50 (µM) & SI
Normal Human Cell Lines, CC50 (µM) b
HepG2
HeLa
MCF7
A549
SW1990
Compound R1 R2
R3
R4
a
a
a
a
a
IC50
IC50
IC50
IC50
IC50
HMLE
L02
SI c
SI d
SI e
SI f
SI g
SI j
SI k
SI l
24.55 ± 0.36
17.41 ± 0.39
32.22 ± 1.34
>30
<0.4 <2.1
16.08
0.6 2.9
>30
<0.4 <2.1
21.44
0.4 2.2
b33
b34
H
H
H
H
Cl
H
H
H
H
H
H
Cl
F
H
H
H
12.73 ± 2.35
9.42 ± 1.21
17.71 ± 1.35
13.07 ± 1.21
19.82 ± 1.44
28.34 ± 3.74
>100
63.86 ± 13.78
46.87 ± 13.91
85.43 ± 6.86
61.24 ± 12.11
>100
0.5
0.7
2.6
13.45
3.5
0.7
0.6
3.7
16.55
2.8
0.4
2.0
21.97
2.1
0.4
27.09 ± 0.88
0.7 3.2
11.30 ± 1.45
1.2 5.4
11.73 ± 0.18
1.7 >8.5
18.58 ± 1.24
18.40 ± 0.06
1.0 4.6
13.38 ± 0.44
1.0 4.6
15.69 ± 1.09
1.3 >6.4
17.55 ± 2.01
29.76 ± 0.80
0.6 2.9
23.33 ± 0.79 25.03 ± 3.17
>30
>30
<0.6 <2.8
17.13 ± 0.57
0.8 3.6
15.36 ± 0.83
1.3 >6.5
26.16 ± 0.08
b35 #
b36
H
Cl
H
H
<0.6 <2.8
Br
H
0.6
30.35 ± 0.71
0.7 >3.3
2.6
0.5
2.4
>30
b37
H
Cl
Cl
H
H
<0.7
-
29.58 ± 2.13 27.63 ± 0.58
b38
Cl
H
>100
1.5
>5.4
1.6
>5.7
1.0
>3.4
>30
1.0
>3.6
1.1
>3.8
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
b39
NO2
H
H
>100
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
>30
>30
>30
>30
>30
b40
NO2
H
H
>100
>100
24.37 ± 5.87
29.07 ± 3.06
b41
CF3
CF3
H
>100
>100
>4.1
>4.1
>3.4
>3.4
>30
>30
b42
H
CF3
>100
>100
-
-
-
-
5.11 ± 0.45
1.3 >19.6
3.96 ± 0.17
1.6
20.57 ± 0.34
>4.9
3.23 ± 0.28
2.0 >31
29.32 ± 1.73
0.2 >3.4
Etoposide
6.42 ± 0.39
>100
>25.3 0.3
a
# Known compound; IC50 values were calculated by SigmaPlot 10.0 as the compounds concentrations producing half maximal inhibition after incubating the cells with increasing
concentrations up to 30 μM. Data are the mean ± SD of at least three independent experiments; b CC50 values were calculated by SigmaPlot 10.0 as the compounds concentrations producing
half maximal inhibition after incubating the cells with increasing concentrations up to 100 μM. Data are the mean ± SD of at least three independent experiments. SI = selectivity index, given
c
d
e
f
g
h
i
j
by (CC50HMLE/IC50HepG2); (CC50L02/IC50HepG2); (CC50HMLE/IC50Hela); (CC50L02/IC50Hela); (CC50HMLE/IC50MCF7); (CC50L02/IC50MCF7); (CC50HMLE/IC50A549); (CC50L02/IC50A549);
k (CC50HMLE/IC50SW1990) or l (CC50L02/IC50SW1990); “-” means SI value can’t be calculated.

Molecules 2014, 19
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3. Experimental
3.1. Chemistry
3.1.1. General Methods
All of the solvents and reagents used in the current study were purchased from commercial suppliers
and used without further purification. Melting points were determined in open capillaries and are
uncorrected. The reaction products were purified by crystallization or flash column chromatography
1
using a mixture of petroleum ether and ethyl acetate as the eluent. H-NMR spectra were recorded on
Varian Inova-400 MHz, Varian Inova-500 MHz and SYS-600 MHz instruments (Varian, Palo Alto, CA,
USA). 13C-NMR spectra were recorded on a 600 MHz Bruker ARX-600 spectrometer (Bruker
Bioscience, Billerica, MA, USA). The chemical shifts (δ) are reported in ppm relative to the internal
reference standard tetramethylsilane (TMS) and the coupling constants (J values) have been reported in
Hertz (Hz). MS data were obtained using time-of-flight mass spectrometer (TOF-MS) or Bruker
microTOF-Q instrument (Bruker, Billerica, MA, USA). High resolution mass spectra (HRMS) were
obtained on a Q-TOF Ultima ESI instrument (micrOTOF-Q II, Bruker Daltonics, Leipzig, Germany).
Analysis by thin layer chromatography (TLC) was performed on silica gel plates (Merck, Billerica, MA,
USA). Automated column chromatography was conducted over silica gel using a Companion Rf 200
automated chromatography system (Teledyne ISCO, Lincoln, NE, USA). The chalcones were prepared
according to methods previously described in the literature 6, 13–15 [20–22].
The chalcones evaluated in the current study were synthesized by the base catalyzed Claisen-Schmidt
condensation reaction of the appropriately substituted acetophenones and aldehydes (Scheme 1).
The chalcones prepared according to this method were formed predominantly with the (E)-configuration
(JH2-H3 = 15–16 Hz).
Scheme 1. Synthesis of compounds a1–20 and b1–42.
3.1.2. General Procedure for Synthesis of Chalcones
A 50 mL flask was charged with substituted acetophenone (5 mmol) and a solution of sodium
hydroxide (10 mmol) in a 4:1 (v/v) mixture of ethanol/H2O (25 mL), and the resulting mixture was
stirred at room temperature for 5 min. A substituted benzaldehyde (5 mmol) was then added to the
reaction, and the resulting mixture was stirred at room temperature. The reaction was then monitored by
TLC using ethyl acetate/petroleum ether (1:4 or 1:2 v/v) as the solvent system. Upon completion of the

Molecules 2014, 19
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reaction, the crude product was filtered off and recrystallized from a mixture of dichloromethane and
ethanol or purified by column chromatography over silica gel eluting with a mixture of petroleum ether
and ethyl acetate to give the pure product.
3.1.3. Characterization Data
(E)-1-(4-Methoxyphenyl)-3-phenylprop-2-en-1-one (a1). White solid (76%), mp: 104.1–105.3 °C ([23]
103–105 °C). 1H-NMR (400 MHz, DMSO-d6) δ 8.19–8.17 (m, 2H), 7.95 (d, J = 15.6 Hz, 1H), 7.91–7.86
(m, 2H), 7.72 (d, J = 15.6 Hz, 1H), 7.47–7.45 (m, 3H), 7.11–7.09 (m, 2H), 3.88 (s, 3H); MS (ESI)
m/z = 261 (M+Na)+; HRMS (ESI) m/z calcd. for C16H14O2 [M+Na] 261.0896, found 261.0875 [M+Na].
(E)-1-(4-Methoxyphenyl)-3-(4-bromophenyl)prop-2-en-1-one (a2). Yellow solid (84%), mp: 153.7–155.1 °C
1
([24] 157 °C). H-NMR (400 MHz, DMSO-d6) δ 8.18 (d, J = 8.8 Hz, 2H), 7.99 (d, J = 15.6 Hz, 1H),
7.86 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 15.6 Hz, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H),
3.88 (s, 3H); MS (ESI) m/z = 339 (M+Na)+; HRMS (ESI) m/z calcd. for C16H13BrO2 [M+Na] 338.9991,
found 338.9980 [M+Na].
(E)-1-(4-Methoxyphenyl)-3-(4-bromo-2-fluorophenyl)prop-2-en-1-one (a3). White solid (99%), mp:
1
122.2–123.6 °C. H-NMR (500 MHz, DMSO-d6) δ 8.16 (d, J = 9.0 Hz, 2H), 8.11 (m, 1H), 8.03 (d,
J = 15.5 Hz, 1H), 7.73 (d, J = 15.5 Hz, 1H), 7.71–7.68 (m, 1H), 7.56–7.54 (m, 1H), 7.10 (d, J = 9.0 Hz,
2H), 3.88 (s, 3H); MS (ESI) m/z = 357 (M+Na)+.
(E)-1-(4-Methoxyphenyl)-3-(2-bromo-4-fluorophenyl)prop-2-en-1-one (a4). White solid (63%), mp:
98.7–101.0 °C. 1H-NMR (400 MHz, DMSO-d6) δ 8.31–8.27 (m, 1H), 8.19 (d, J = 9.2 Hz, 2H), 7.96 (d,
J = 15.6 Hz, 1H), 7.92 (d, J = 15.6 Hz, 1H), 7.75–7.72 (m, 1H), 7.44–7.39 (m, 1H), 7.10 (d, J = 9.2 Hz,
13
2H), 3.88 (s, 3H); C-NMR (150 MHz, DMSO-d6): 187.5, 163.9, 139.8, 131.6, 131.4, 130.9, 130.6,
126.2, 125.3, 120.9, 116.2, 114.6, 56.1; MS (ESI) m/z = 357 (M+Na)+; HRMS (ESI) m/z calcd. for
C16H12BrFO2 [M+Na] 356.9897, found 356.9889 [M+Na].
(E)-1-(4-Methoxyphenyl)-3-(4-bromo-2-chlorophenyl)prop-2-en-1-one (a5). White solid (86%), mp:
145.3–146.4 °C. 1H-NMR (500 MHz, DMSO-d6) δ 8.20–8.18 (m, 3H), 8.05 (d, J = 15.5 Hz, 1H), 7.92
(d, J = 15.5 Hz, 1H), 7.87 (s, 1H), 7.68–7.67 (m, 1H), 7.10 (m, 2H), 3.88 (s, 3H); 13C-NMR (150 MHz,
DMSO-d6): δ 187.4, 164.0, 137.1, 135.6, 132.7, 132.3, 131.6, 131.2, 130.5, 130.4, 125.8, 124.4, 114.6,
56.1; MS (ESI) m/z = 351/353 (M+H)+.
(E)-1-(4-Methoxyphenyl)-3-(4-nitrophenyl)prop-2-en-1-one (a6). Yellow solid (63%), mp: 170.2–171.5 °C
1
([25] 168–169 °C). H-NMR (500 MHz, DMSO-d6) δ 8.30–8.28 (m, 2H), 8.21 (d, J = 9.0 Hz, 2H),
8.16–8.13 (m, 3H), 7.79 (d, J = 16.0 Hz, 1H), 7.11 (d, J = 9.0 Hz, 2H), 3.89 (s, 3H); MS (ESI) m/z = 284
(M+H)+; HRMS (ESI) m/z calcd. for C16H13NO4 [M+H] 284.0917, found 284.0916 [M+H].
(E)-1-(4-Methoxyphenyl)-3-(4-carbonylphenyl)prop-2-en-1-one (a7) [26]. Yellow solid (40%), mp:
>350 °C. 1H-NMR (400 MHz, DMSO-d6) δ 8.18 (d, J = 8.8 Hz, 2H), 7.92 (d, J = 15.6 Hz, 1H), 7.90 (d,
J = 8.0 Hz, 2H), 7.77 (d, J = 8.0 Hz, 2H), 7.71 (d, J = 15.6 Hz, 1H), 7.09 (d, J = 8.8 Hz, 2H), 3.88 (s,
3H); MS (ESI) m/z = 321 (M+K)+.

Molecules 2014, 19
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(E)-1-(4-Methoxyphenyl)-3-(2-methoxyphenyl)prop-2-en-1-one (a8). Yellow solid (82%). mp: 43.2–45.5 °C
1
([27] 44–45 °C). H-NMR (500 MHz, DMSO-d6) δ 8.16–8.14 (m, 2H), 8.05 (d, J = 15.5 Hz, 1H),
7.99–7.97 (m, 1H), 7.89 (d, J = 15.5 Hz, 1H), 7.47–7.44 (m, 1H), 7.13–7.09 (m, 3H), 7.06–7.03 (m, 1H),
3.91 (s, 3H), 3.88 (s, 3H); MS (ESI) m/z = 269 (M+H)+; HRMS (ESI) m/z calcd. for C17H16O3 [M+H]
269.1172, found 269.1177 [M+H].
(E)-1-(4-Methoxyphenyl)-3-(3-methoxyphenyl)prop-2-en-1-one (a9). Yellow solid (78%), mp: 95.7–97.0 °C
1
([28] 103–104 °C). H-NMR (500 MHz, DMSO-d6) δ 8.18 (d, J = 9.0 Hz, 2H), 7.95 (d, J = 15.5 Hz,
1H), 7.68 (d, J = 15.5 Hz, 1H), 7.48 (s, 1H), 7.44–7.43 (m, 1H), 7.38–7.35 (m, 1H), 7.10 (d, J = 9.0 Hz,
2H), 7.03–7.01 (m, 1H), 3.88 (s, 3H), 3.84 (s, 3H); MS (ESI) m/z = 269 (M+H)+; HRMS (ESI) m/z calcd.
for C17H16O3 [M+H] 269.1172, found 269.1179 [M+H].
(E)-1,3-bis(4-Methoxyphenyl)prop-2-en-1-one (a10). Yellow solid (72%), mp: 97.8–100.5 °C ([28]
103–104 °C). 1H-NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 9.2 Hz, 2H), 7.85 (d, J = 8.8 Hz, 2H), 7.81
(d, J = 15.6 Hz, 1H), 7.69 (d, J = 15.6 Hz, 1H), 7.08 (d, J = 9.2 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 3.87
(s, 3H), 3.83 (s, 3H); MS (ESI) m/z = 291 (M+Na)+; HRMS (ESI) m/z calcd. for C17H16O3 [M+Na]
291.0992, found 291.0998 [M+Na].
(E)-1-(4-Methoxyphenyl)-3-(4-ethoxyphenyl)prop-2-en-1-one (a11). White solid (83%), mp: 106.3–107.9 °C
([29] 109 °C). 1H-NMR (500 MHz, DMSO-d6) δ 8.15 (d, J = 8.5 Hz, 2H), 7.84–7.78 (m, 3H), 7.68 (d,
J = 15.5 Hz, 1H), 7.08 (d, J = 9.0 Hz, 2H), 7.00 (d, J = 8.5 Hz, 2H), 4.10 (q, J = 7.0 Hz, 2H), 3.87 (s,
3H), 1.35 (t, J = 7.0 Hz, 3H); MS (ESI) m/z = 283 (M+H)+; HRMS (ESI) m/z calcd. for C18H18O3 [M+H]
283.1329, found 283.1347 [M+H].
(E)-1-(4-Methoxyphenyl)-3-(2,3-dimethoxyphenyl)prop-2-en-1-one (a12). White solid (91%), mp:
99.8–102.0 °C ([30] 99.0–99.5 °C). 1H-NMR (500 MHz, DMSO-d6) δ 8.15 (d, J = 9.0 Hz, 2H), 7.96 (d,
J = 15.5 Hz, 1H), 7.89 (d, J = 15.5 Hz, 1H), 7.63–7.61 (m, 1H), 7.16–7.15 (m, 2H), 7.09 (d, J = 9.0 Hz,
2H), 3.88 (s, 3H), 3.85 (s, 3H), 3.80 (s, 3H); MS (ESI) m/z = 299 (M+H)+; HRMS (ESI) m/z calcd. for
C18H18O4 [M+H] 299.1278, found 299.1300 [M+H].
(E)-1-(4-methoxyphenyl)-3-(2,5-dimethoxyphenyl)prop-2-en-1-one (a13) [31]. Yellow solid (87%), mp:
1
54.7–56.3 °C. H-NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 8.8 Hz, 2H), 8.01 (d, J = 15.6 Hz, 1H),
7.91 (d, J = 15.6 Hz, 1H), 7.56–7.55 (m, 1H), 7.09 (d, J = 8.8 Hz, 2H), 7.07–7.00 (m, 2H), 3.87 (s, 3H),
3.85 (s, 3H), 3.80 (s, 3H); MS (ESI) m/z = 321 (M+Na)+; HRMS (ESI) m/z calcd. for C18H18O4 [M+Na]
321.1097, found 321.1098 [M+Na].
(E)-1-(4-Methoxyphenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (a14). Yellow solid (70%), mp:
1
123.7–125.7 °C. H-NMR (400 MHz, DMSO-d6) δ 8.10 (d, J = 15.6 Hz, 1H), 8.04–7.99 (m, 3H),
7.42–7.38 (m, 1H), 7.10–7.08 (m, 2H), 6.77–6.75 (m, 2H), 3.92 (s, 6H), 3.87 (s, 3H); 13C-NMR
(150 MHz, DMSO-d6): δ188.9, 163.4, 160.4, 134.5, 132.6, 131.4, 130.9, 124.1, 114.5, 112.1, 104.6,
56.5, 56.0; MS (ESI) m/z = 321 (M+Na)+; HRMS (ESI) m/z calcd. for C18H18O4 [M+Na] 321.1097,
found 321.1104 [M+Na].

Molecules 2014, 19
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(E)-1-(4-Methoxyphenyl)-3-(3,4-dimethoxyphenyl)prop-2-en-1-one (a15). Yellow solid (72%), mp:
104.9–106.4 °C ([32] 93–98 °C). 1H-NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 8.8 Hz, 2H), 7.83 (d,
J = 15.6 Hz, 1H), 7.68 (d, J = 15.6 Hz, 1H), 7.54–7.53 (m, 1H), 7.40–7.37 (m, 1H), 7.09 (d, J = 8.8 Hz,
2H), 7.03–7.01 (m, 1H), 3.87 (s, 6H), 3.82 (s, 3H); MS (ESI) m/z = 321 (M+Na)+; HRMS (ESI) m/z
calcd. for C18H18O4 [M+Na] 321.1097, found 321.1083 [M+Na].
(E)-1-(4-Methoxyphenyl)-3-(3,5-dimethoxyphenyl)prop-2-en-1-one (a16) [33]. Yellow solid (85%), mp:
1
87.6–89.1 °C. H-NMR (500 MHz, DMSO-d6) δ 8.19 (d, J = 9.0 Hz, 2H), 7.94 (d, J = 15.5 Hz, 1H),
7.64 (d, J = 15.5 Hz, 1H), 7.09 (d, J = 9.0 Hz, 2H), 7.07–7.06 (m, 2H), 6.59–6.58 (m, 1H), 3.88 (s, 3H),
13
3.82 (s, 6H); C-NMR (150 MHz, DMSO-d6): 187.9, 163.7, 161.2, 143.8, 137.2, 131.5, 130.9, 123.,
114.5, 107.1, 103.1, 56.0, 55.9; MS (ESI) m/z = 299 (M+H)+; HRMS (ESI) m/z calcd. for C18H18O4
[M+H]+ 299.1278, found 299.1298 [M+H].
(E)-1-(4-Methoxyphenyl)-3-(3-(benzyloxy)-4-methoxyphenyl)prop-2-en-1-one (a17). Yellow solid
1
(97%), mp: 115.0–118.2 °C. H-NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 8.8 Hz, 2H), 7.82 (d,
J = 15.2 Hz, 1H), 7.68–7.64 (m, 2H), 7.52–7.50 (m, 2H), 7.44–7.34 (m, 4H), 7.10 (d, J = 8.8 Hz, 2H),
7.06–7.04 (m, 1H), 5.19 (s, 2H), 3.87 (s, 3H), 3.83 (s, 3H); MS (ESI) m/z = 397 (M+Na)+; HRMS (ESI)
m/z calcd. for C22H24O4 [M+Na]+ 397.1410, found 397.1407 [M+Na].
(E)-1-(4-Methoxyphenyl)-3-(2,3,4-trimethoxyphenyl)prop-2-en-1-one (a18). Yellow solid (99%), mp:
1
94.4–96.5 °C ([34] 94 °C). H-NMR (500 MHz, DMSO-d6) δ 8.13 (d, J = 9.0 Hz, 2H), 7.88 (d,
J = 15.5 Hz, 1H), 7.81 (d, J = 15.5 Hz, 1H), 7.79–7.77 (m, 1H), 7.09 (d, J = 9.0 Hz, 2H), 6.94–6.92 (m,
1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.87 (s, 3H), 3.78 (s, 3H); MS (ESI) m/z = 351 (M+Na)+; HRMS (ESI)
m/z calcd. for C19H20O5 [M+Na]+ 351.1203, found 351.1216 [M+Na].
(E)-1-(4-Methoxyphenyl)-3-(2,4,5-trimethoxyphenyl)prop-2-en-1-one (a19). Yellow solid (94%), mp:
122.1–123.7 °C ([35] 107–110 °C). 1H-NMR (400 MHz, DMSO-d6) δ 8.14 (d, J = 8.8 Hz, 2H), 8.03 (d,
J = 15.6 Hz, 1H), 7.76 (d, J = 15.6 Hz, 1H), 7.52 (s, 1H), 7.08 (d, J = 8.8 Hz, 2H), 6.75 (s, 1H), 3.90 (s,
3H), 3.87 (s, 3H), 3.87 (s, 3H), 3.83 (s, 3H); MS (ESI) m/z = 351 (M+Na)+; HRMS (ESI) m/z calcd. for
C19H20O5 [M+Na]+ 351.1203, found 351.1194 [M+Na].
(E)-1-(4-Methoxyphenyl)-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (a20). Yellow solid (84%), mp:
1
109.7–111.5 °C ([36] 125 °C). H-NMR (500 MHz, DMSO-d6) δ 8.18 (d, J = 9.0 Hz, 2H), 7.88 (d,
J = 15.5 Hz, 1H), 7.66 (d, J = 15.5 Hz, 1H), 7.22 (m, 2H), 7.10 (d, J = 9.0 Hz, 2H), 3.88 (s, 3H), 3.87
(s, 6H), 3.72 (s, 3H); MS (ESI) m/z = 351 (M+Na)+; HRMS (ESI) m/z calcd. for C19H20O5 [M+Na]+
351.1203, found 351.1183 [M+Na].
(E)-1-Phenyl-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b1). Yellow solid (84%), mp: 52.6–54.7 °C
([37] 80 °C). 1H-NMR (500 MHz, DMSO-d6) δ 8.13 (d, J = 16.0 Hz, 1H), 8.03–7.98 (m, 3H), 7.67–8.65
(m, 1H), 7.59–7.56 (m, 2H), 7.43–7.39 (m, 1H), 6.77–6.75 (m, 2H), 3.92 (s, 6H); MS (ESI) m/z = 291
(M+Na)+; HRMS (ESI) m/z calcd. for C17H16O3 [M+Na] 291.0992, found 291.1007 [M+Na].
(E)-1-(2-Methylphenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b2). Yellow solid (91%), mp:
79.8–81.4 °C. 1H-NMR (500 MHz, DMSO-d6) δ 7.86 (d, J = 16.0 Hz, 1H), 7.51 (d, J = 16.0 Hz, 1H),

Molecules 2014, 19
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7.49–7.47 (m, 1H), 7.44–7.38 (m, 2H), 7.34–7.31 (m, 2H), 6.74–6.73 (m, 2H), 3.85 (s, 6H), 2.36 (s, 3H);
13C-NMR (150 MHz, DMSO-d6): 196.8, 160.3, 140.0, 136.4, 136.3, 133.0, 131.6, 130.8, 128.7, 128.3,
126.2, 111.6, 104.7, 56.5, 20.34; MS (ESI) m/z = 305 (M+Na)+; HRMS (ESI) m/z calcd. for C18H18O4
[M+Na] 305.1148, found 305.1134 [M+Na].
(E)-1-(3-Methylphenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b3). Yellow solid (94%), mp:
102.5–103.8 °C. 1H-NMR (500 MHz, DMSO-d6) δ 8.12 (d, J = 16.0 Hz, 1H), 7.98 (d, J = 16.0 Hz, 1H),
7.81–7.77 (m, 2H), 7.48–7.44 (m, 2H), 7.42–7.39 (m, 1H), 6.77–6.75 (m, 2H), 3.92 (s, 6H), 2.42 (s, 3H);
13C-NMR (150 MHz, DMSO-d6): 190.9, 160.5, 138.7, 138.6, 135.3, 133.9, 132.8, 129.2, 128.9, 125.9,
124.3, 112.0, 104.6, 56.5, 21.41; MS (ESI) m/z = 305 (M+Na)+; HRMS (ESI) m/z calcd. for C18H18O4
[M+Na] 305.1148, found 305.1155 [M+Na].
(E)-1-(4-Methylphenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b4). Yellow solid (74%), mp:
82.7–84.5 °C. 1H-NMR (500 MHz, DMSO-d6) δ 8.10 (d, J = 16.0 Hz, 1H), 7.99 (d, J = 16.0 Hz, 1H),
13
7.91–7.89 (m, 2H), 7.42–7.37 (m, 3H), 6.77–6.75 (m, 2H), 3.92 (s, 6H), 2.40 (s, 3H); C-NMR (150
MHz, DMSO-d6): 190.2, 160.4, 143.6, 136.1, 135.0, 132.8, 129.9, 128.7, 124.1, 112.0, 104.7, 56.5,
21.64; MS (ESI) m/z = 305 (M+Na)+; HRMS (ESI) m/z calcd. for C18H18O4 [M+Na] 305.1148, found
305.1135 [M+Na].
(E)-1-(3,4-Dimethylphenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b5). Yellow solid (90%), mp:
98.9–101.1 °C. 1H-NMR (500 MHz, DMSO-d6) δ 8.08 (d, J = 16.0 Hz, 1H), 7.98 (d, J = 16.0 Hz, 1H),
7.75–7.72 (m, 2H), 7.41–7.38 (m, 1H), 7.33–7.32 (m, 1H), 6.77–6.75 (m, 2H), 3.92 (s, 6H), 2.32 (s, 3H),
2.31 (s, 3H); 13C-NMR (150 MHz, DMSO-d6): 190.3, 160.4, 142.5, 137.4, 136.5, 134.9, 132.7, 130.3,
129.5, 126.4, 124.3, 112.0, 104.7, 56.6, 20.1, 19.9; MS (ESI) m/z = 319 (M+Na)+; HRMS (ESI) m/z
calcd. for C19H20O3 [M+Na] 319.1305, found 319.1302 [M+Na].
(E)-1-(2-Methoxyphenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b6) [38]. Yellow solid (84%),
mp: 109.0–111.4 °C. 1H-NMR (500 MHz, DMSO-d6) δ 7.91 (d, J = 16.5 Hz, 1H), 7.71 (d, J = 16.5 Hz,
1H), 7.56–7.46 (m, 2H), 7.39–7.18 (m, 2H), 7.07–7.04 (m, 1H), 6.74–6.72 (m, 2H), 3.88 (s, 3H), 3.86
(s, 6H); MS (ESI) m/z = 321 (M+Na)+; HRMS (ESI) m/z calcd. for C18H18O4 [M+Na] 321.1097, found
321.1080 [M+Na].
(E)-1-(3-Methoxyphenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b7). Yellow solid (93%), mp:
93.5–95.6 °C. 1H-NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 16.0 Hz, 1H), 7.97 (d, J = 16.0 Hz, 1H),
7.58–7.51 (m, 1H), 7.49–7.45 (m, 1H), 7.44–7.41 (m, 2H), 7.25–7.22 (m, 1H), 6.77–6.75 (m, 2H), 3.92
(s, 6H), 3.85 (s, 3H); 13C-NMR (150 MHz, DMSO-d6): 190.5, 160.5, 160.0, 140.1, 135.5, 132.9, 130.5,
124.2, 121.1, 119.3, 113.0, 111.9, 104.7, 56.6, 55.7; MS (ESI) m/z = 321 (M+Na)+. HRMS (ESI) m/z
calcd. for C18H18O4 [M+Na] 321.1097, found 321.1098 [M+Na].
(E)-1-(2-Ethoxyphenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b8). Yellow solid (94%). mp:
48.8–50.4 °C. 1H-NMR (400 MHz, DMSO-d6) δ 7.93 (d, J = 16.0 Hz, 1H), 7.74 (d, J = 16.0 Hz, 1H),
7.53–7.44 (m, 2H), 7.39–7.35 (m, 1H), 7.17–7.15 (m, 1H), 7.05–7.02 (m, 1H), 6.74–6.72 (m, 2H), 4.16
(q, J = 7.2 Hz, 2H), 3.86 (s, 6H), 1.31 (t, J = 7.2 Hz, 3H); 13C-NMR (150 MHz, DMSO-d6): 193.8, 160.3,

Molecules 2014, 19
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157.4, 133.5, 133., 132.5, 130.1, 130.0, 129.5, 121.0, 113.7, 111.9, 104.7, 64.4, 56.4, 14.9; MS (ESI)
m/z = 335 (M+Na)+; HRMS (ESI) m/z calcd. for C19H20O4 [M+Na] 335.1254, found 335.1248 [M+Na].
(E)-1-(3-Ethoxyphenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b9). Yellow solid (42%), mp:
63.1–64.8 °C. 1H-NMR (400 MHz, DMSO-d6) δ 8.11 (d, J = 16.0 Hz, 1H), 7.95 (d, J = 16.0 Hz, 1H),
7.57–7.55 (m, 1H), 7.50–7.46 (m, 1H), 7.44–7.38 (m, 2H), 7.24–7.18 (m, 1H), 6.77–6.75 (m, 2H), 4.12
(q, J = 7.2 Hz, 2H), 3.92 (s, 6H), 1.36 (t, J = 7.2 Hz, 3H); 13C-NMR (150 MHz, DMSO-d6): 190.5, 160.5,
159.2, 140.1, 135.5, 132.8, 130.4, 124.3, 120.9, 119.7, 113.5, 112.0, 104.6, 63.7, 56.5, 15.0; MS (ESI)
m/z = 335 (M+Na)+; HRMS (ESI) m/z calcd. for C19H20O4 [M+Na] 335.1254, found 335.1255 [M+Na].
(E)-1-(4-Ethoxyphenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b10). White solid (82%), mp:
99.0–101.2 °C. 1H-NMR (500 MHz, DMSO-d6) δ 8.09 (d, J = 15.5 Hz, 1H), 8.03–7.98 (m, 3H), 7.41–7.38
(m, 1H), 7.09–7.07 (m, 2H), 6.77–6.75 (m, 2H), 4.14 (q, J = 7.0 Hz, 2H), 3.92 (s, 6H), 1.37 (t, J = 7.0 Hz,
13
3H); C-NMR (150 MHz, DMSO-d6): 188.9, 162.7, 160.4, 134.5, 132.6, 131.2, 130.9, 124.0, 114.9,
112.1, 104.6, 64.0, 56.5, 15.0; MS (ESI) m/z = 335 (M+Na)+; HRMS (ESI) m/z calcd. for C19H20O4
[M+Na] 335.1254, found 335.1256 [M+Na].
(E)-1-(2-(Benzyloxy)phenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b11). Yellow solid (20%), mp:
94.6–97.9 °C. 1H-NMR (400 MHz, DMSO-d6) δ 7.92 (d, J = 16.0 Hz, 1H), 7.76 (d, J = 16.0 Hz, 1H),
7.53–7.47 (m, 2H), 7.45–7.35 (m, 3H), 7.25–7.21(m, 4H), 7.09–7.05 (m, 1H), 6.73–6.71 (m, 2H), 5.24
(s, 2H), 3.78 (s, 6H); 13C-NMR(150 MHz, DMSO-d6): 193.1, 157.6, 157.4, 137.4, 133.4, 131.7, 130.6,
129.9, 129.8, 128.9, 128.8, 128.1, 127.7, 120.7, 114.0, 113.7, 104.0, 70.11, 55.7; MS (ESI) m/z = 397
(M+Na)+; HRMS (ESI) m/z calcd. for C24H22O4 [M+Na] 397.1410, found 397.1395 [M+Na].
(E)-1-(3-(Benzyloxy)phenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b12). Yellow solid (81%), mp:
108.8–110.2 °C. 1H-NMR (400 MHz, DMSO-d6) δ 8.11 (d, J = 16.0 Hz, 1H), 7.95 (d, J = 16.0 Hz, 1H),
7.60–7.58 (m, 1H), 7.54–7.47 (m, 4H), 7.43–7.38 (m, 3H), 7.37–7.33 (m, 1H), 7.32–7.29 (m, 1H),
13
6.77–7.75 (m, 2H), 5.21 (s, 2H), 3.91 (s, 6H); C-NMR (150 MHz, DMSO-d6): 190.5, 160.5, 159.1,
140.1, 137.3, 135.5, 132.9, 130.5, 128.9, 128.4, 128.2, 124.2, 121.3, 120.2, 114.0, 111.9, 104.7, 69.8,
56.6; MS (ESI) m/z = 397 (M+Na)+; HRMS (ESI) m/z calcd. for C24H22O4 [M+Na] 397.1410, found
397.1394 [M+Na].
(E)-1-(4-(Benzyloxy)phenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b13) [39]. White solid (97%),
1
mp: 96.6–97.8 °C. H-NMR (500 MHz, DMSO-d6) δ 8.10 (d, J = 16.0 Hz, 1H), 8.04–7.98 (m, 3H),
7.49–7.47 (m, 2H), 7.44–7.33 (m, 4H), 7.18–7.16 (m, 2H), 6.77–6.75 (m, 2H), 5.23 (s, 2H), 3.92 (s, 6H);
MS (ESI) m/z = 375 (M+H)+; HRMS (ESI) m/z calcd. for C24H22O4 [M+H] 375.1591, found
375.1591 [M+H].
(E)-1-(2-(Benzyloxy)-4-methoxyphenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b14). Yellow solid
(75%), mp: 82.2–83.6 °C. 1H-NMR (400 MHz, DMSO-d6) δ 7.94 (d, J = 16.0, 1H), 7.90 (d, J = 16.0,
1H), 7.59–7.57 (m, 1H), 7.45–7.43 (m, 2H), 7.38–7.34 (m, 1H), 7.24–7.22 (m, 3H), 6.76–6.75 (m, 1H),
6.72–6.70 (m, 2H), 6.67–6.64 (m, 1H), 5.27 (s, 2H), 3.83 (s, 3H), 3.76 (s, 6H); MS (ESI) m/z = 427
(M+Na)+; HRMS (ESI) m/z calcd. for C25H24O5 [M+Na] 427.1516, found 427.1512 [M+Na].

Molecules 2014, 19
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(E)-1-(4-(Benzyloxy)-3-methoxyphenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b15). Yellow solid
1
(80%), mp: 112.8–114.1 °C. H-NMR (400 MHz, DMSO-d6) δ 8.09 (d, J = 16.0 Hz, 1H), 8.02 (d,
J = 16.0 Hz, 1H), 7.67–7.65 (m, 1H), 7.55–7.54 (m, 1H), 7.51–7.45 (m, 2H), 7.45–7.32 (m, 4H), 7.21–7.19
(m, 1H), 6.77–6.75 (m, 2H), 5.21 (s, 2H), 3.92 (s, 6H), 3.87 (s, 3H); 13C-NMR (150 MHz, DMSO-d6):
188.9, 160.4, 152.4, 149.5, 137.0, 134.5, 132.6, 131.7, 129.0, 128.5, 128.4, 124.1, 123.0, 112.9, 112.1,
111.2, 104.7, 70.4, 56.5, 56.0; MS (ESI) m/z = 405 (M+H)+; HRMS (ESI) m/z calcd. for C25H24O5 [M+H]
405.1697, found 405.1693 [M+H].
(E)-1-(4-Ethoxy-3-methoxyphenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b16). Yellow solid
1
(91%), mp: 105.3–107.2 °C. H-NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 16.0 Hz, 1H), 8.02 (d,
J = 16.0 Hz, 1H), 7.68–7.65 (m, 1H), 7.52–7.51 (m, 1H), 7.41–7.37 (m, 1H), 7.11–7.09 (m, 1H),
6.77–6.75 (m, 2H), 4.14 (q, J = 7.2 Hz, 2H), 3.92 (s, 6H), 3.86 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H);
13C-NMR (150 MHz, DMSO-d6): 188.9, 160.4, 152.7, 149.3, 134.3, 132.5, 131.3, 124.1, 123.1, 112.1,
112.0, 111.0, 104.7, 64.4, 56.5, 55.8, 15.0; MS (ESI) m/z = 365 (M+Na)+; HRMS (ESI) m/z calcd. for
C20H22O5 [M+Na] 365.1359, found 365.1350 [M+Na].
(E)-1-(2-Ethoxy-4-methoxyphenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b17). Yellow solid
1
(65%), mp: 98.7–100.2 °C. H-NMR (400 MHz, DMSO-d6) δ 7.95 (d, J = 16.0 Hz, 1H), 7.89 (d,
J = 16.0 Hz, 1H), 7.57–7.55 (m, 1H), 7.38–7.33 (m, 1H), 6.74–6.72 (m, 2H), 6.68–6.59 (m, 2H), 4.18
(q, J = 7.2 Hz, 2H), 3.87 (s, 6H), 3.84 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H); 13C-NMR (150 MHz,
DMSO-d6): 191.3, 164.1, 160.3, 159.7, 132.4, 132.3, 132.1, 129.8, 122.7, 112.3, 106.5, 104.6, 99.8,
64.5, 56.4, 56.0, 14.8; MS (ESI) m/z = 365 (M+Na)+; HRMS (ESI) m/z calcd. for C20H22O5 [M+Na]
365.1359, found 365.1357 [M+Na].
(E)-1-(2,5-Dimethoxyphenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b18). White solid (92%), mp:
121.0–122.0 °C. 1H-NMR (400 MHz, DMSO-d6) δ 7.91 (d, J = 16.0 Hz, 1H), 7.72 (d, J = 16.0 Hz, 1H),
7.40–7.36 (m, 1H), 7.16–7.08 (m, 2H), 7.02–7.01 (m, 1H), 6.73–6.71 (m, 2H), 3.87 (s, 6H), 3.82 (s, 3H),
3.75 (s, 3H); 13C-NMR (150 MHz, DMSO-d6): 193.1, 160.3, 153.6, 152.4, 134.1, 132.6, 130.3, 129.3,
118.8, 114.5, 114.4, 112.0, 104.7, 56.8, 56.5, 56.0; MS (ESI) m/z = 351 (M+Na)+; HRMS (ESI) m/z
calcd. for C19H20O5Na [M+Na] 351.1203, found 351.1189 [M+Na].
(E)-1-(3,4-Dimethoxyphenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b19) [15]. Yellow solid (80%),
mp: 120.5–122.7 °C. 1H-NMR (500 MHz, DMSO-d6) δ 8.08 (d, J = 16.0 Hz, 1H), 8.03 (d, J = 16.0 Hz,
1H), 7.69–7.67 (m, 1H), 7.52–7.51 (m, 1H), 7.40–7.38 (m, 1H), 7.13–7.11 (m, 1H), 6.77–7.75 (m, 2H),
3.92 (s, 6H), 3.87 (s, 3H), 3.85 (s, 3H); MS (ESI) m/z = 329 (M+H)+.
(E)-1-(Benzo[d][1,3]dioxol-5-yl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b20) [40]. White solid
1
(95%), mp: 138.6–140.4 °C. H-NMR (500 MHz, DMSO-d6) δ 8.08 (d, J = 16.0 Hz, 1H), 7.96 (d,
J = 16.0 Hz, 1H), 7.66–7.64 (m, 1H), 7.47–7.46 (m, 1H), 7.40–7.38 (m, 1H), 7.08–7.06 (m, 1H), 6.76–7.75
(m, 2H), 6.16 (s, 2H), 3.92 (s, 6H); MS (ESI) m/z = 313 (M+H)+; HRMS (ESI) m/z calcd. for C18H16O5
[M+H] 313.1071, found 313.1068 [M+H].

Molecules 2014, 19
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(E)-1-(2,3-Dihydrobenzofuran-5-yl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b21). Yellow solid
1
(99%), mp: 118.8–120.2 °C. H-NMR (400 MHz, DMSO-d6) δ 8.07 (d, J = 15.6 Hz, 1H), 7.98 (d,
J = 15.6 Hz, 1H), 7.91–7.90 (m, 1H), 7.87–7.84 (m, 1H), 7.41–7.37 (m, 1H), 6.91–6.89 (m, 1H),
6.77–6.75 (m, 2H), 4.65 (t, J = 8.8 Hz, 2H), 3.92 (s, 6H), 3.27 (t, J = 8.8 Hz, 2H); 13C-NMR (150 MHz,
DMSO-d6): 188.7, 164.3, 160.3, 134.3, 132.5, 131.7, 130.4, 128.9, 126.0, 124.2, 112.1, 109.4, 104.7,
72.6, 56.5, 28.9; MS (ESI) m/z = 333 (M+Na)+; HRMS (ESI) m/z calcd. for C19H18O4 [M+Na] 333.1097,
found 333.1098 [M+Na].
(E)-1-([1,1'-Biphenyl]-4-yl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b22). Yellow solid (70%), mp:
121.7–123.5 °C. 1H-NMR (500 MHz, DMSO-d6) δ 8.17 (d, J = 16.0 Hz, 1H), 8.10–8.08 (m, 2H), 8.06
(d, J = 16.0 Hz, 1H), 7.88–7.86 (m, 2H), 7.78–7.76 (m, 2H), 7.54–7.51 (m, 2H), 7.46–7.40 (m, 2H),
13
6.78–6.76 (m, 2H), 3.94 (s, 6H); C-NMR (150 MHz, DMSO-d6): 190.1, 160.5, 144.7, 139.5, 137.4,
135.4, 132.9, 129.6, 129.3, 128.8, 127.5, 127.4, 124.1, 112.0, 104.7, 56.6; MS (ESI) m/z = 345 (M+H)+;
HRMS (ESI) m/z calcd. for C23H20O3 [M+H] 345.1485, found 345.1478 [M+H].
(E)-1-(3-Aminophenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b23) [41]. Yellow solid (67%), mp:
148.6–150.3 °C. 1H-NMR (600 MHz, DMSO-d6) δ 8.06 (d, J = 16.2 Hz, 1H), 7.92 (d, J = 16.2 Hz, 1H),
7.41–7.38 (m, 1H), 7.21–7.17 (m, 2H), 7.13–7.12 (m, 1H), 6.84–6.80 (m, 1H), 6.77–6.75 (m, 2H), 5.39
(s, 2H), 3.92 (s, 6H); MS (ESI) m/z = 306 (M+Na)+; HRMS (ESI) m/z calcd. for C17H17NO3 [M+Na]
306.1101, found 306.1097 [M+Na].
(E)-1-(2-Hydroxyphenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b24) [42]. Yellow solid (83%), mp:
1
114.2–115.9 °C. H-NMR (400 MHz, DMSO-d6) δ 12.55 (s, 1H), 8.25 (d, J = 15.6 Hz, 1H), 8.13 (d,
J = 15.6 Hz, 1H), 7.96–7.94 (m, 1H), 7.59–7.52 (m, 1H), 7.45–7.41 (m, 1H), 7.03–6.99 (m, 2H), 6.78–6.76
(m, 2H), 3.94 (s, 6H); MS (ESI) m/z = 285 (M+H)+; HRMS (ESI) m/z calcd. for C17H16O4 [M+H]
285.1121, found 285.1133 [M+H].
(E)-1-(3-Hydroxyphenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b25). Yellow solid (70%), mp:
1
138.1–139.7 °C. H-NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 8.09 (d, J = 16.0 Hz, 1H), 7.94 (d,
13
J = 16.0 Hz, 1H), 7.46–7.33 (m, 4H), 7.05–7.02 (m, 1H), 6.77–6.75 (m, 2H), 3.92 (s, 6H); C-NMR
(150 MHz, DMSO-d6): 190.5, 160.5, 158.2, 140.0, 135.2, 132.8, 130.4, 124.2, 120.4, 119.5, 114.8,
112.0, 104.7, 56.6; MS (ESI) m/z = 307 (M+Na)+; HRMS (ESI) m/z calcd. for C17H16O4 [M+Na]
307.0941, found 307.0939 [M+Na].
(E)-1-(4-Hydroxyphenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b26) [43]. Yellow solid (82%), mp:
1
189.6–191.4 °C. H-NMR (500 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.06 (d, J = 16.0 Hz, 1H), 7.99 (d,
J = 16.0 Hz, 1H), 7.92–7.90 (m, 2H), 7.40–7.36 (m, 1H), 6.91–6.89 (m, 2H), 6.76–6.74 (m, 2H), 3.92
(s, 6H); MS (ESI) m/z = 307 (M+Na)+; HRMS (ESI) m/z calcd. for C17H16O4 [M+Na] 307.0941, found
307.0938 [M+Na].
(E)-1-(2,4-Dihydroxyphenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b27). Yellow solid (85%), mp:
218.7–220.2 °C. 1H-NMR (600 MHz, DMSO-d6) δ 13.51 (s, 1H), 10.70 (s, 1H), 8.21 (d, J = 15.6 Hz,
1H), 8.06 (d, J = 15.6 Hz, 1H), 7.88–7.86 (m, 1H), 7.43–7.40 (m, 1H), 6.77–6.76 (m, 2H), 6.46–6.44

Molecules 2014, 19
17272
(m, 1H), 6.30–6.29 (m, 1H), 3.93 (s, 6H); 13C-NMR (150 MHz, DMSO-d6): 192.8, 166.2, 165.4, 160.5,
135.1, 133.1, 132.7, 122.7, 113.6, 111.9, 108.9, 104.7, 103.2, 56.6; MS (ESI) m/z = 323 (M+Na)+;
HRMS (ESI) m/z calcd. for C17H16O5 [M+Na] 323.0890, found 323.0876 [M+Na].
(E)-1-(2-Hydroxy-4-methoxyphenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b28) Yellow solid
1
(74%), mp: 143.5–144.7 °Cs ([13] 140 °C). H-NMR (500 MHz, DMSO-d6) δ 13.55 (s, 1H), 8.21 (d,
J = 15.5 Hz, 1H), 8.10 (d, J = 15.5 Hz, 1H), 7.93–7.91 (m, 1H), 7.42–7.40 (m, 1H), 6.77–6.75 (m, 2H),
6.57–6.47 (m, 2H), 3.93 (s, 6H), 3.83 (s, 3H); MS (ESI) m/z = 315 (M+H)+; HRMS (ESI) m/z calcd. for
C18H18O5 [M+H] 315.1227, found 315.1243 [M+H].
(E)-1-(4-Hydroxy-3-methoxyphenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b29). Yellow solid
(40%), mp: 128.7–131.2 °C. 1H-NMR (500 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.06 (d, J = 16.0 Hz, 1H),
8.01 (d, J = 16.0 Hz, 1H), 7.59–7.57 (m, 1H), 7.53–7.52 (m, 1H), 7.40–7.36 (m, 1H), 6.94–6.92 (m, 1H),
6–6.74 (m, 2H), 3.92 (s, 6H), 3.86 (s, 3H); 13C-NMR (150 MHz, DMSO-d6): 188.6, 160.3, 152.1, 148.3,
134.0, 132.4, 130.4, 124.2, 123.5, 115.5, 112.2, 111.7, 104.6, 56.5, 56.0; MS (ESI) m/z = 337 (M+Na)+;
HRMS (ESI) m/z calcd. for C18H18O5 [M+Na] 337.1046, found 337.1042 [M+Na].
(E)-1-(4-Cyanophenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b30). Yellow solid (95%), mp:
1
144.3–145.9 °C. H-NMR (500 MHz, DMSO-d6) δ 8.16 (d, J = 16.0 Hz, 1H), 8.13–8.11 (m, 2H),
8.04–8.02 (m, 2H), 7.96 (d, J = 16.0 Hz, 1H), 7.45–7.42 (m, 1H), 6.78–6.76 (m, 2H), 3.92 (s, 6H);
13C-NMR (150 MHz, DMSO-d6): 190.1, 160.7, 142.0, 136.8, 133.4, 133.3, 129.2, 123.6, 118.7, 115.2,
111.7, 104.7, 56.6; MS (ESI) m/z = 294 (M+H)+; HRMS (ESI) m/z calcd. for C18H15NO3 [M+H]
294.1125, found 294.1130 [M+H].
(E)-1-(2-Fluorophenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b31). Yellow solid (93%), mp:
66.6–68.1 °C. 1H-NMR (500 MHz, DMSO-d6) δ 8.06–8.02 (m, 1H), 7.76–7.70 (m, 2H), 7.66–7.64 (m,
1H), 7.44–7.34 (m, 3H), 6.76–6.74 (m, 2H), 3.88 (s, 6H); 190.2, 160.52, 136.0, 134.5, 133.2, 130.9,
127.9, 125.3, 117.1, 111.6, 104.7, 56.5; MS (ESI) m/z = 287 (M+H)+; HRMS (ESI) m/z calcd. for
C17H15FO3 [M+H] 287.1078, found 287.1097 [M+H].
(E)-1-(3-Fluorophenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b32). Yellow solid (93%), mp:
105.4–107.3 °C. 1H-NMR (500 MHz, DMSO-d6) δ 8.15 (d, J = 16.0 Hz, 1H), 7.96 (d, J = 16.0 Hz, 1H),
7.86–7.84 (m, 1H), 7.72–7.70 (m, 1H), 7.64–7.62 (m, 1H), 7.53–7.51 (m, 1H), 7.43–7.41 (m, 1H),
13
6.78–7.76 (m, 2H), 3.93 (s, 6H); C-NMR (150 MHz, DMSO-d6): 189.6, 160.6, 140.9, 136.2, 133.2,
131.5, 124.8, 123.7, 120.2, 115.0, 111.8, 104.6, 56.6; MS (ESI) m/z = 287 (M+H)+; HRMS (ESI) m/z
calcd. for C17H15FO3 [M+H] 287.1078, found 287.1086 [M+H].
(E)-1-(4-Fluorophenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b33). Yellow solid (89%), mp:
1
108.2–109.6 °C. H-NMR (500 MHz, DMSO-d6) δ 8.13 (d, J = 16.0 Hz, 1H), 8.10–8.06 (m, 2H),
13
7.99 (d, J = 16.0 Hz, 1H), 7.44–7.36 (m, 3H), 6.77–6.75 (m, 2H), 3.92 (s, 6H); C-NMR (150 MHz,
DMSO-d6): 189.2, 160.5, 135.6, 135.2, 133.0, 131.6, 123.7, 116.4, 111.9, 104.7, 56.5. MS (ESI)
m/z = 309 (M+Na)+; HRMS (ESI) m/z calcd. for C17H15FO3 [M+Na] 309.0897, found 309.0890 [M+Na].

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(E)-1-(3-Chlorophenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b34). Yellow solid (96%), mp:
1
116.5–117.2 °C. H-NMR (500 MHz, DMSO-d6) δ 8.14 (d, J = 16.0 Hz, 1H), 7.96–7.92 (m, 3H),
7.75–7.71 (m, 1H), 7.63–7.60 (m, 1H), 7.44–7.41 (m, 1H), 6.77–6.75 (m, 2H), 3.92 (s, 6H); 13C-NMR
(150 MHz, DMSO-d6): 189.6, 160.6, 140.5, 136.3, 134.3, 133.2, 132.9, 131.3, 128.1, 127.3, 123.6,
111.8, 104.7, 56.6; MS (ESI) m/z = 303 (M+H)+; HRMS (ESI) m/z calcd. for C17H15ClO3 [M+H]
303.0782, found 303.0782 [M+H].
(E)-1-(4-Chlorophenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b35) [44]. Yellow solid (92%), mp:
107.9–109.7 °C. 1H-NMR (500 MHz, DMSO-d6) δ 8.14 (d, J = 16.0 Hz, 1H), 8.02–7.99 (m, 2H), 7.97
(d, J = 16.0 Hz, 1H), 7.65–7.61 (m, 2H), 7.44–7.40 (m, 1H), 6.77–6.75 (m, 2H), 3.92 (s, 6H); MS (ESI)
m/z = 325 (M+Na)+; HRMS (ESI) m/z calcd. for C17H15ClO3 [M+Na] 325.0602, found 325.0597 [M+Na].
(E)-1-(3-Bromophenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b36). Yellow solid (98%), mp:
1
135.7–138.2 °C. H-NMR (500 MHz, DMSO-d6) δ 8.14 (d, J = 16.0 Hz, 1H), 8.06–8.05 (m, 1H),
8.01–7.97 (m, 1H), 7.93 (d, J = 16.0 Hz, 1H), 7.87–7.85 (m, 1H), 7.56–7.53 (m, 1H), 7.44–7.40 (m, 1H),
13
6.77–6.75 (m, 2H), 3.92 (s, 6H); C-NMR (150 MHz, DMSO-d6): 189.5, 160.6, 140.7, 136.3, 135.8,
133.2, 131.6, 131.0, 127.7, 123.6, 122.8, 111.8, 104.7, 56.6; MS (ESI) m/z = 347 (M+H)+; HRMS (ESI)
m/z calcd. for C17H15BrO3 [M+H] 347.0277, found 347.0257 [M+H].
(E)-1-(2,4-Dichlorophenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b37). Yellow solid (99%), mp:
1
111.1–112.7 °C. H-NMR (500 MHz, DMSO-d6) δ 7.82 (d, J = 16.5 Hz, 1H), 7.78 (s, 1H), 7.59–7.54
13
(m, 2H), 7.45 (d, J = 16.5 Hz, 1H), 7.42–7.40 (m, 1H), 6.75–6.73 (m, 2H), 3.85 (s, 6H); C-NMR
(150 MHz, DMSO-d6): 193.6, 160.5, 138.5, 137.7, 135.9, 133.7, 131.6, 131.1, 130.1, 128.1, 128.0,
111.3, 104.7, 56.6; MS (ESI) m/z = 359 (M+Na)+; HRMS (ESI) m/z calcd. for C17H14Cl2O3 [M+Na]
359.0212, found 359.0215 [M+Na].
(E)-1-(3,4-Dichlorophenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b38). Yellow solid (98%), mp:
1
142.1–143.4 °C. H-NMR (500 MHz, DMSO-d6) δ 8.15 (d, J = 16.0 Hz, 1H), 8.12–8.10 (m, 1H),
7.97–7.95 (m, 1H), 7.93 (d, J = 16.0 Hz, 1H), 7.84–7.82 (m, 1H), 7.44–7.41 (m, 1H), 6.77–6.75 (m, 2H),
3.92 (s, 6H); 13C-NMR (150 MHz, DMSO-d6): 188.7, 160.6, 138.8, 136.6, 136.0, 133.3, 132.4, 131.7,
130.3, 128.7, 123.3, 111.8, 104.7, 56.6; MS (ESI) m/z = 359 (M+Na)+; HRMS (ESI) m/z calcd. for
C17H14Cl2O3 [M+Na] 359.0212, found 359.0189 [M+Na].
(E)-1-(3-Nitrophenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b39). Yellow solid (92%), mp:
1
172.3–173.7 °C. H-NMR (500 MHz, DMSO-d6) δ 8.66–8.63 (m, 1H), 8.49–8.47 (m, 1H), 8.44–8.42
(m, 1H), 8.20 (d, J = 16.0 Hz, 1H), 8.02 (d, J = 16.0 Hz, 1H), 7.89–7.86 (m, 1H), 7.46–7.42 (m, 1H),
13
6.77–6.75 (m, 2H), 3.93 (s, 6H); C-NMR (150 MHz, DMSO-d6): 189.0, 160.7, 148.6, 139.7, 136.9,
134.7, 133.5, 131.2, 127.5, 123.2, 122.9, 111.7, 104.7, 56.6; MS (ESI) m/z = 336 (M+Na)+; HRMS (ESI)
m/z calcd. for C17H15NO5 [M+Na] 336.0842, found 336.0825 [M+Na].
(E)-1-(4-Nitrophenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b40). Yellow solid (97%), mp:
1
147.3–148.6 °C. H-NMR (400 MHz, DMSO-d6) δ 8.39–8.36 (m, 2H), 8.21–8.16 (m, 3H), 7.98 (d,
J = 15.6 Hz, 1H), 7.46–7.42 (m, 1H), 6.78–6.76 (m, 2H), 3.93 (s, 6H); 13C-NMR (150 MHz,

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DMSO-d6): 189.9, 160.7, 150.1, 143.5, 136.9, 133.5, 130.0, 124.4, 123.7, 111.7, 104.7, 56.6; MS (ESI)
m/z = 314 (M+H)+; HRMS (ESI) m/z calcd. for C17H15NO5 [M+H] 314.1023, found 314.1022 [M+H].
(E)-1-(3-(Trifluoromethyl)phenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b41). Yellow solid (97%),
1
mp: 145.3–146.7 °C. H-NMR (500 MHz, DMSO-d6) δ 8.31–8.29 (m, 1H), 8.19 (s, 1H), 8.17 (d,
J = 16.0 Hz, 1H), 8.04–8.02 (m, 1H), 7.99 (d, J = 16.0 Hz, 1H), 7.85–7.82 (m, 1H), 7.45–7.41 (m, 1H),
13
6.77–6.75 (m, 2H), 3.93 (s, 6H); C-NMR (150 MHz, DMSO-d6): 189.7, 160.6, 139.3, 136.6, 133.3,
132.6, 130.8, 130.2, 129.9, 129.6, 124.8, 123.6, 111.8, 104.7, 56.6; MS (ESI) m/z = 337 (M+H)+; HRMS
(ESI) m/z calcd. for C18H15F3O3 [M+H] 337.1046, found 337.1039 [M+H].
(E)-1-(3,5-bis(Trifluoromethyl)phenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one (b42). Yellow solid
1
(99%), mp: 126.5–127.8 °C. H-NMR (500 MHz, DMSO-d6) δ 8.47 (s, 2H), 8.43 (s, 1H), 8.16 (d,
J = 16.0 Hz, 1H), 7.95 (d, J = 16.0 Hz, 1H), 7.46–7.43 (m, 1H), 6.77–6.75 (m, 2H), 3.91 (s, 6H);
13C-NMR (150 MHz, DMSO-d6): 188.9, 160.6, 140.6, 137.5, 133.6, 131.4, 131.2, 129.0, 126.4, 124.4,
123.6, 122.6, 111.7, 104.7, 56.6; MS (ESI) m/z = 405 (M+H)+; HRMS (ESI) m/z calcd. for C19H14F6O3
[M+H] 405.0920, found 405.0917 [M+H].
3.2. Biology
3.2.1. Cell Culture
HepG2 and MCF7 cells were grown in the Eagle’s minimum essential medium with Earle’s balanced
salts (MEM-EBSS) medium, HeLa, A549 and L02 cells were grown in Dulbecco’s Modified Eagle
Media (DMEM), SW1990 cells were grown in RPMI-1640 medium, and HMLE cell were grown in
DMEM/F-12 medium. The media were supplemented with 100 U/mL penicillin, 100 mg/mL
streptomycin and 10% fetal bovine serum (FBS), and incubated at 37 °C in a humidified atmosphere
containing 5% CO2.
3.2.2. In Vitro Anti-Proliferative Assay
Cells were seeded into 96-well plates (4000 cells/well) and incubated at 37 °C in a humidified 5%
CO2 atmosphere. After 24 h, the cells were treated with different concentrations of the compounds for
48 h in triplicate to generate dose-response curves. Cell viability was evaluated using the sulforhodamine
B (SRB) assay as previous described [45]. The IC50 values of the compounds were calculated using
SigmaPlot10.0 software, which defined the IC50 value as the concentration required to inhibit cell growth
by 50%. Etoposide was used as the positive control.
4. Conclusions
In summary, we have developed a class of alkoxylated chalcones and evaluated their cytotoxicities
in vitro against a panel of five different cancer cell lines and two non-tumoral cell lines. Most of the
chalcones displayed potent cytotoxic activities. The results of this study also revealed that chalcones
bearing electron donating alkoxy groups on their A- or B-ring generally exhibited good levels of
cytotoxicity, and that the position and size of the substituents had a significant impact on the cytotoxic

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activity, with ortho and meta substituents being beneficial to the activity and large substituents having
the opposite effect. The most potent compounds were b22 and b29, which had a 4-phenyl moiety and a
3-OMe-4-OH moiety, respectively. The SI values indicate that about one third of the compounds exhibit
more than a 2-fold SI between the CC50 in L02 and IC50 in tumoral cells, which is similar with etoposide.
Compounds b11, especially b29 showed promising SI values compared with both HMLE and L02
(2.1–6.5 fold in HMLE and over 33 fold in L02, respectively). These compounds are therefore worthy
of further investigation.
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/19/11/17256/s1.
Acknowledgments
This work was supported by the Natural Science Foundation of China (No. 81102376,
81302644), and the National S&T Major Special Project on Major New Drug Innovation
(No. 2012ZX09301002-001-023-03).
Author Contributions
Yu-Cheng Wang and Ju-Xian Wang designed the research; Xiao-Guang Bai, Chang-Liang Xu,
Shuang-Shuang Zhao and Hong-Wei He performed the experimental work; Xiao-Guang Bai and
Chang-Liang Xu wrote the manuscript.
Conflicts of Interest
The authors declare no conflict of interest.
References
1. Srinivasan, B.; Johnson, T.E.; Lad, R.; Xing, C. Structure-Activity Relationship Studies of
Chalcone Leading to 3-Hydroxy-4,3',4',5'-tetramethoxychalcone and Its Analogues as Potent
Nuclear Factor κB Inhibitors and Their Anticancer Activities. J. Med. Chem. 2009, 52, 7228–7235.
2. Lee, S.H.; Seo, G.S.; Kim, J.Y.; Jin, X.Y.; Kim, H.D.; Sohn, D.H. Heme oxygenase 1 mediates
anti-inflammatory effects of 2',4',6'-tris(methoxymethoxy) chalcone. Eur. J. Pharmacol. 2006, 532,
178–186.
3. Yang, H.M.; Shin, H.R.; Cho, S.H.; Bang, S.C.; Song, G.Y.; Ju, J.H.; Kim, M.K.; Lee, S.H.;
Ryu, J.C.; Kim, Y.; et al. Structural requirement of chalcones for the inhibitory activity of
interleukin-5. Bioorg. Med. Chem. 2007, 15, 104–111.
4. Nowakowska, Z. A review of anti-infective and anti-inflammatory chalcones. Eur. J. Med. Chem.
2007, 42, 125–137.
5. Fukai, T.; Marumo, A.; Kaitou, K.; Kanda, T.; Terada, S.; Nomura, T. Antimicrobial activity of
licorice flavonoids against methicillin-resistant Staphylococcus aureus. Fitoterapia 2002, 73,
536–539.

Molecules 2014, 19
17276
6. Chiaradia, L.D.; Martins, P.G.; Cordeiro, M.N.; Guido, R.V.; Ecco, G.; Andricopulo, A.D.;
Yunes, R.A.; Vernal, J.; Nunes, R.J.; Terenzi, H. Synthesis, biological evaluation, and molecular
modeling of chalcone derivatives as potent inhibitors of Mycobacterium tuberculosis protein
tyrosine phosphatases (PtpA and PtpB). J. Med. Chem. 2012, 55, 390–402.
7. Svetaz, L.; Tapia, A.; López, S.N.; Furlán, R.L.E.; Petenatti, E.; Pioli, R.; Schmeda-Hirschmann, G.;
Zacchino, S.A. Antifungal chalcones and new caffeic acid esters from Zuccagnia punctata acting
against soybean infecting fungi. J. Agric. Food Chem. 2004, 52, 3297–3300.
8. Lahtchev, K.L.; Batovska, D.I.; Parushev, S.P.; Ubiyvovk, V.M.; Sibirny, A.A. Antifungal activity
of chalcones: A mechanistic study using various yeast strains. Eur. J. Med. Chem. 2008, 43,
2220–2228.
9. Cheng, J.H.; Hung, C.F.; Yang, S.C.; Wang, J.P.; Won, S.J.; Lin, C.N. Synthesis and cytotoxic,
anti-inflammatory, and anti-oxidant activities of 2',5'-dialkoxylchalcones as cancer chemopreventive
agents. Bioorg. Med. Chem. 2008, 16, 7270–7276.
10. Modzelewska, A.; Pettit, C.; Achanta, G.; Davidson, N.E.; Huang, P.; Khan, S.R. Anticancer
activities of novel chalcone and bis-chalcone derivatives. Bioorg. Med. Chem. 2006, 14, 3491–3495.
11. Kachadourian, R.; Day, B.J.; Pugazhenti, S.; Franklin, C.C.; GenouxBastide, E.; Mahaffey, G.;
Gauthier, C.; di Pietro, A.; Boumendjel, A. A synthetic chalcone as a potent inducer of glutathione
biosynthesis. J. Med. Chem. 2012, 55, 1382–1388.
12. Achanta, G.; Modzelewska, A.; Feng, L.; Khan, S.R.; Huang, P. A boronic-chalcone derivative
exhibits potent anticancer activity through inhibition of the proteasome. Mol. Pharmacol. 2006, 70,
426–433.
13. Valdameri, G.; Gauthier, C.; Terreux, R.; Kachadourian, R.; Day, B.J.; Winnischofer, S.M.;
Rocha, M.E.; Frachet, V.; Ronot, X.; di Pietro, A.; et al. Investigation of Chalcones as Selective
Inhibitors of the Breast Cancer Resistance Protein: Critical Role of Methoxylation in both Inhibition
Potency and Cytotoxicity. J. Med. Chem. 2012, 55, 3193–3200.
14. Rangel, L.P.; Winter, E.; Gauthier, C.; Terreux, R.; Chiaradia-Delatorre, L.D.; Mascarello, A.;
Nunes, R.J.; Yunes, R.A.; Creczynski-Pasa, T.B.; Macalou, S.; et al. New structure—Activity
relationships of chalcone inhibitors of breast cancer resistance protein: Polyspecificity toward
inhibition and critical substitutions against cytotoxicity. Drug Des. Dev. Ther. 2013, 7, 1043–1052.
15. Winter, E.; Gozzi, G.J.; Chiaradia-Delatorre, L.D.; Daflon-Yunes, N.; Terreux, R.; Gauthier, C.;
Mascarello, A.; Leal, P.C.; Cadena, S.M.; Yunes, R.A.; et al. Quinoxaline-substituted chalcones as
new inhibitors of breast cancer resistance protein ABCG2: Polyspecificity at B-ring position.
Drug Des. Dev. Ther. 2014, 8, 609–619.
16. Kamal, A.; Shankaraiah, N.; Prabhakar, S.; Reddy, C.R.; Markandeya, N.; Reddy, K.L.; Devaiah, V.
Solid-phase synthesis of new pyrrolobenzodiazepine-chalcone conjugates: DNA-binding affinity
and anticancer activity. Bioorg. Med. Chem. Lett. 2008, 18, 2434–2439.
17. Jin, C.; Liang, Y.J.; He, H.; Fu, L. Synthesis and antitumor activity of novel chalcone derivatives.
Biomed. Pharmacother. 2013, 67, 215–217.
18. Shenvi, S.; Kumar, K.; Hatti, K.S.; Rijesh, K.; Diwakar, L.; Reddy, G.C. Synthesis, anticancer
and antioxidant activities of 2,4,5-trimethoxy chalcones and analogues from asaronaldehyde:
Structure-activity relationship. Eur. J. Med. Chem. 2013, 62, 435–442.

Molecules 2014, 19
17277
19. Boumendjel, A.; Boccard, J.; Carrupt, P.-A.; Nicolle, E.; Blanc, M.; Geze, A.; Choisnard, L.;
Wouessidjewe, D.; Matera, E.-L.; Dumontet, C. Antimitotic and antiproliferative activities of
chalcones: Forward structure-activity relationship. J. Med. Chem. 2008, 51, 2307–2310.
20. Kumar, V.; Kumar, S.; Hassan, M.; Wu, H.; Thimmulappa, R.K.; Kumar, A.; Sharma, S.K.;
Parmar, V.S.; Biswal, S.; Malhotra, S.V. Novel chalcone derivatives as potent Nrf2 activators in
mice and human lung epithelial cells. J. Med. Chem. 2011, 54, 4147–4159.
21. Hsieh, C.T.; Hsieh, T.J.; ElShazly, M.; Chuang, D.W.; Tsai, Y.H.; Yen, C.T.; Wu, S.F.; Wu, Y.C.;
Chang, F.-R. Synthesis of chalcone derivatives as potential anti-diabetic agents. Bioorg. Med.
Chem. Lett. 2012, 22, 3912–3915.
22. Lin, A.S.; NakagawaGoto, K.; Chang, F.R.; Yu, D.; MorrisNatschke, S.L.; Wu, C.C.; Chen, S.L.;
Wu, Y.C.; Lee, K.H. First total synthesis of protoapigenone and its analogues as potent cytotoxic
agents. J. Med. Chem. 2007, 50, 3921–3927.
23. Montes-Avila, J.; Diaz-Camacho, S.P.; Sicairos-Felix, J.; Delgado-Vargas, F.; Rivero, I.A.
Solution-phase parallel synthesis of substituted chalcones and their antiparasitary activity against
Giardia lamblia. Bioorg. Med. Chem. 2009, 17, 6780–6785.
24. Ashtekar, K.D.; Staples, R.J.; Borhan, B. Development of a Formal Catalytic Asymmetric [4 + 2]
Addition of Ethyl-2,3-butadienoate with Acyclic Enones. Org. Lett. 2011, 13, 5732–5735.
25. Braun, R.U.; Ansorge, M.; Müller, T.J.J. Coupling–Isomerization Synthesis of Chalcones. Chemistry
2006, 12, 9081–9094.
26. Dimmock, J.R.; Jha, A.; Zello, G.A.; Quail, J.W.; Oloo, E.O.; Nienaber, K.H.; Kowalczyk, E.S.;
Allen, T.M.; Santos, C.L.; de Clercq, E.; et al. Cytotoxic N-[4-(3-aryl-3-oxo-1 propenyl)
phenylcarbonyl]-3,5-bis(phenylmethylene)-4-piperidones and related compounds. Eur. J. Med. Chem.
2002, 37, 961–972.
27. Brown, B.R.; Cummings, W. Polymerisation of flavans. Part II. The condensation of 4[prime or
minute]-methoxyflavan with phenols. J. Chem. Soc. (Resum.) 1958, doi:10.1039/JR9580004172.
28. Kumar, A.; Sharma, S.; Tripathi, V.D.; Srivastava, S. Synthesis of chalcones and flavanones using
Julia–Kocienski olefination. Tetrahedron 2010, 66, 9445–9449.
29. Barnes, R.P.; Goodwin, T.C.; Cotten, T.W. A Study of the Direction of Enolization of
p-Methoxy-p'-bromodibenzoylmethane and p-Methoxy-p'-ethoxydibenzoylmethane. J. Am.
Chem. Soc. 1947, 69, 3135–3138.
30. Wu, J.; Li, J.; Cai, Y.; Pan, Y.; Ye, F.; Zhang, Y.; Zhao, Y.; Yang, S.; Li, X.; Liang, G. Evaluation
and Discovery of Novel Synthetic Chalcone Derivatives as Anti-Inflammatory Agents. J. Med. Chem.
2011, 54, 8110–8123.
31. D’Orazio, D.; de Saizieu, A.; Raederstorff, D.; Schueler, G.; Wang-Schmidt, Y.; Wehrli, C.; Wertz, K.;
Wolfram, S. Compounds for the Treatment of Non-Autoimmune Type 2 Diabetes Mellitus and/or
Syndrome X. WO Patent 2,006,136,429, 28 December 2006.
32. Shettigar, V.; Patil, P.S.; Naveen, S.; Dharmaprakash, S.M.; Sridhar, M.A.; Shashidhara Prasad, J.
Crystal growth and characterization of new nonlinear optical chalcone derivative:
1-(4-Methoxyphenyl)-3-(3, 4-dimethoxyphenyl)-2-propen-1-one. J. Cryst. Growth 2006, 295,
44–49.
33. Hwang, D.; Hyun, J.; Jo, G.; Koh, D.; Lim, Y. Synthesis and complete assignment of NMR data of
20 chalcones. Magn. Reson. Chem. 2011, 49, 41–45.

Molecules 2014, 19
17278
34. Russell, A. The constitution of tannins. Part I. Reduction products of chalkones and the synthesis of
a typical phlobatannin. J. Chem. Soc. (Resum.) 1934, doi:10.1039/JR9340000218.
35. Sharma, N.; Sharma, A.; Kumar, R.; Shard, A.; Sinha, A.K. One-Pot Two-Step Oxidative Cleavage
of 1,2-Arylalkenes to Aryl Ketones Instead of Arylaldehydes in an Aqueous Medium:
A Complementary Approach to Ozonolysis. Eur. J. Org. Chem. 2010, 31, 6025–6032.
36. Ducki, S.; Rennison, D.; Woo, M.; Kendall, A.; Chabert, J.F.D.; McGown, A.T.; Lawrence, N.J.
Combretastatin-like chalcones as inhibitors of microtubule polymerization. Part 1: Synthesis and
biological evaluation of antivascular activity. Bioorg. Med. Chem. 2009, 17, 7698–7710.
37. Simonis, H.; Danischewski, S. Über die Anwendung der Friedel-Craftsschen Reaktion zum Aufbau
der Flavone. Eur. J. Inorg. Chem. 1926, 59, 2914–2919.
38. Dietary Anticarcinogens and Antimutagens. Royal Society of Chemistry; Johnson, I.T.,
Fenwick, G.R., Eds.; Royal Society of Chemistry: England, UK, 2000; Volume 255, pp. 189–192.
39. Yong, K.; Lu, J.; Gu, H.; Chen, X. Process for Preparation of 4'-Hydroxy-2,6-
dimethoxydihydrochalcone. CN Patent 1,01,250,098, 27 August 2008.
40. Cohen, F.E.; McKerrow, J.H.; Kenyon, G.L.; Li, Z.; Chen, X.; Gong, B.; Li, R. Inhibitors of
Metazoan Parasite Proteases. U.S. Patent 5,739,170 A, 14 April 1998.
41. George, F.; Fellague, T. Preparation of Amino Substituted Chalcone Derivatives for Use
in Cosmetic Compositions as Sunscreens and Suntanning Agents. F.R. Patent 2,839,717, A1,
21 November 2003.
42. Song, L.L.; Kosmeder, J.W., II; Lee, S.K.; Gerhauser, C.; Lantvit, D.; Moon, R.C.; Moriarty, R.M.;
Pezzuto, J.M. Cancer chemopreventive activity mediated by 4'-bromoflavone, a potent inducer of
phase II detoxification enzymes. Cancer Res. 1999, 59, 578–585.
43. Nielsen, S.F.; Christensen, S.B.; Cruciani, G.; Kharazmi, A.; Liljefors, T. Antileishmanial
Chalcones: Statistical Design, Synthesis, and Three-Dimensional Quantitative Structure-Activity
Relationship Analysis. J. Med. Chem. 1998, 41, 4819–4832.
44. Sahu, N.K.; Bari, S.B.; Kohli, D.V. Molecular modeling studies of some substituted chalcone
derivatives as cysteine protease inhibitors. Med. Chem. Res. 2012, 21, 3835–3847.
45. Sun, H.X.; He, H.W.; Zhang, S.H.; Liu, T.G.; Ren, K.H.; He, Q.Y.; Shao, R.G. Suppression of
N-Ras by shRNA-expressing plasmid increases sensitivity of HepG2 cells to vincristine-induced
growth inhibition. Cancer Gene Ther. 2009, 16, 693–702.
Sample Availability: Samples of the compounds a1–20 and b1–42 are available from the authors.
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