Synthesis and antiproliferative evaluation of 3-phenylquinolinylchalcone derivatives against non-small cell lung cancers and breast cancers

Article abstract of DOI:10.1016/j.ejmech.2012.11.027

Certain 3-phenylquinolinylchalcone derivatives were synthesized and evaluated for their antiproliferative activities. Among them, (E)-3-(3-(4-methoxyphenyl)quinolin-2-yl)-1-phenylprop-2-en-1-one (6a) and (E)-1-(5-bromothiophen-2-yl)-3-(3-(4-methoxyphenyl)

Full text of DOI:10.1016/j.ejmech.2012.11.027

European Journal of Medicinal Chemistry 59 (2013) 274e282
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and antiproliferative evaluation of 3-phenylquinolinylchalcone
derivatives against non-small cell lung cancers and breast cancers
Chih-Hua Tseng a, Yeh-Long Chen a, Chih-Yao Hsu a, Tzu-Chiang Chen a, Chih-Mei Cheng b,
,
Hsien-Cheng Tso c, Yan-Jia Lu c, Cherng-Chyi Tzeng a
*
a Department of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung City 807, Taiwan
b Department of Biomedical Science and Environmental Biology, College of Life Science, Kaohsiung Medical University, Kaohsiung City 807, Taiwan
c Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung City 807, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
Certain 3-phenylquinolinylchalcone derivatives were synthesized and evaluated for their anti-
proliferative activities. Among them, (E)-3-(3-(4-methoxyphenyl)quinolin-2-yl)-1-phenylprop-2-en-1-
one (6a) and (E)-1-(5-bromothiophen-2-yl)-3-(3-(4-methoxyphenyl)quinolin-2-yl)prop-2-en-1-one
(11) were identified as potential lead compounds for further development. Compound 6a was active
Received 23 August 2012
Received in revised form
19 November 2012
Accepted 19 November 2012
Available online 24 November 2012
against the growth of H1299 and SKBR-3 with IC50 values of 1.41 and 0.70
more active than the positive topotecan (IC50 values of 6.02 and 8.91 M respectively). Compound 11
exhibited an IC50 value of less than 0.10 M against the growth of MDA-MB231, and non-cytotoxic to the
mM respectively which was
m
m
Keywords:
normal mammary epithelial cell (H184B5F5/M10). Mechanism studies indicated that compound 11
induced cell cycle arrest at G2/M phase followed by activation of caspase-3, cleavage of PARP, and
consequently caused the cell death.
Chalcone derivatives
3-Phenylquinolinylchalcones
Antiproliferative activities
Ó 2012 Elsevier Masson SAS. All rights reserved.
1. Introduction
synthesized certain 2,3-diarylquinoline derivatives whose struc-
tures are resemble to 1 in which the ethylene bridge was replaced
Chalcones are natural products which have displayed a wide
variety of biological activities, including anti-malarial, anti-proto-
zoal, anti-inflammatory, immunomodulatory, nitric oxide inhibi-
tion, tyrosinase inhibition, and anticancer activities [1e9]. Due to
their abundance in plants and ease of synthesis, the chalcone class
of compounds have attracted extensive studies. On the other hand,
quinoline skeleton is one of the key building elements for a large
number of natural and synthetic heterocycles which possess a wide
variety of biological effects such as antimalarials, bactericidal,
antitumor, anti-inflammatory, antiproliferative, and antiviral
activities [10e20]. Therefore, a series of chalcone derivatives in
which an aryl moiety was replaced with quinoline nucleus have
been synthesized and evaluated for their biological activities
[21,22].
with quinoline. Among them, 6-fluoro-2,3-bis{4-[2-(piperidin-1-
yl)ethoxy]phenyl}quinoline (2) which possesses the aminoalkyl
side chain, was one of the most active derivative against the growth
of Hep 3B, H1299, and MDA-MB-231 with a GI50 value of 0.71, 1.46,
and 0.72 mM respectively [34].
Herein, we report the synthesis of certain 3-phenyl-
quinolinylchalcone derivatives whose structures can be considered
as 2,3-diarylquinoline derivatives in which an
a,b-unsaturated
carbonyl moiety is inserted between quinoline and the C-2 phenyl
group. They can also be considered as hybrids of 3-phenylquinolines
and chalcones. These 3-phenylquinolinylchalcone derivatives were
evaluated in vitro against three non-small cell lung cancer cells
(H1299, H460, and A549), three breast cancer cells (MCF-7, MDA-
MB-231, and SKBR-3), and a normal mammary epithelial cell
(H184B5F5/M10). These cancers are common malignancies in the
world, and especially are the leading cause of cancer deaths in Asian
countries including Taiwan [35e39].
Combretastatin A-4 (1; Fig. 1) is a natural product with potent
anticancer activity [23e27]. Its mechanism of action involves
reversible, high affinity binding in the colchicine site of tubulin
[28]. The novel anticancer properties exhibited by 1 have led to the
extensive structural optimization [29e33]. Recently, we have
2. Chemistry
Thermal decarboxylation of 3-(4-methoxyphenyl)-2-methylqu-
inoline-4-carboxylic acid (3) [40] gave 3-(4-methoxyphenyl)-2-
* Corresponding author. Tel.: þ886 7 3121101x2684; fax: þ886 7 3125339.
E-mail address: tzengch@kmu.edu.tw (C.-C. Tzeng).
0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2012.11.027

C.-H. Tseng et al. / European Journal of Medicinal Chemistry 59 (2013) 274e282
275
assay [43]. The concentration that inhibited the growth of 50% of
cells (IC50) was determined from the linear portion of the curve by
calculating the concentration of tested agent that reduced absor-
bance in treated cells, compared to control cells, by 50%.
The IC50 results of these 3-phenylquinolinylchalcone derivatives
are summarized in Table 1. 3-(4-Methoxyphenyl)quinoline-2-
carbaldehyde (5) was inactive while its chalcone derivative, (E)-
3-(3-(4-methoxyphenyl)quinolin-2-yl)-1-phenylprop-2-en-1-one
(6a) was active against the growth of H1299, MDA-MB-231, and
OMe
OMe
OMe
O
O
N
N
F
N
OMe
OH
Combretastatin A-4 (1)
2
SKBR-3 with IC50 values of 1.41, 0.86, and 0.70
Although the positive topotecan was active against MDA-MB-231
with an IC50 of <0.1 M, it was only weakly active against H1299
and SKBR-3 with IC50 values of 6.02 and 8.91 M respectively. The
mM respectively.
OMe
Ar
m
m
antiproliferative activity against H1299 was increased by the
introduction of an electron-withdrawing group such as 4-F or 4-
NO2 at C-1 phenyl moiety in which (E)-1-(4-fluorophenyl)-3-(3-
(4-methoxyphenyl)quinolin-2-yl)prop-2-en-1-one (6b) and (E)-3-
(3-(4-methoxyphenyl)quinolin-2-yl)-1-(4-nitrophenyl)prop-2-en-
N
O
O
Chalcone
Target compounds
Fig. 1. Structures of combretastin A-4 (1), 6-fluoro-2,3-bis{4-[2-(piperidin-1-yl)-
ethoxy]phenyl}quinoline (2), chalcone, and target compounds.
1-one (7) exhibited IC50 values of 0.82 and 0.77 mM respectively.
However, introduction of an electron-donating group such as 4-
OH, 4-OMe, or 4-NH2 at C-1 phenyl moiety decreased anti-
proliferative activity in which compounds 6c, 6d, and 6i were
inactive against all the cell lines tested. For the dimethoxyphenyl
derivatives 6eeh, 2,4-dimethoxy derivative 6e, 2,6-dimethoxy
derivative 6f, and 3,4-dimethoxy derivative 6g were inactive
while 3,5-dimethoxy derivative 6h was active against the growth of
H1299, MDA-MB-231, and SKBR-3 with IC50 values of 0.93, 0.92,
methylquinoline (4) which was then reacted with selenium oxide
to afford 3-(4-methoxyphenyl)quinoline-2-carbaldehyde (5) as
described in Scheme 1. The desired 3-phenylquinolinylchalcones
6e16 were synthesized by the ClaiseneSchmidt condensation
reaction of 5 and appropriately substituted acetophenones as
outlined in Scheme 2. Due to the strong electron-withdrawing
effect of NO2 group, (E)-3-(3-(4-methoxyphenyl)quinolin-2-yl)-1-
(4-nitrophenyl)prop-2-en-1-one (7) can only be synthesized by
using acid catalyst while other compounds 6aei and 8e16 were
obtained using base catalyst. These 3-phenylquinolinylchalcones
were obtained as geometrically pure and with trans-configuration
(J HaeHb ¼ 15.50e15.60 Hz) [41] of the sole (E)-form isomers.
Structure of 6e was unambiguously determined by X-ray crys-
tallographical analysis (Fig. 2). The structure was solved and refined
by direct methods Shelxs 97 [42] suite of programs. Yellow single
crystal (0.25 ꢀ 0.20 ꢀ 0.20 mm3) of 6e was obtained by slow
evaporation from MeOH/CH2Cl2 (30/70) solution: orthorhombic,
and 0.47 mM respectively which is approximately equal potent to
the parent compound 6a. Substitution of an electron-donating
group at ortho or para position of the phenyl moiety is unfavor-
able to the antiproliferative activity while the influence of meta
substitution was not apparent.
In order to establish the structureeactivity relationship, C-1
phenyl group was replaced with various heterocyclic rings. The
replacement of C-1 phenyl with furan-2-yl, thiophen-2-yl, or pyr-
idin-2-yl ring enhanced antiproliferative activity in which
(E)-1-(furan-2-yl)-3-(3-(4-methoxyphenyl)quinolin-2-yl)prop-2-
en-1-one (8), (E)-3-(3-(4-methoxyphenyl)quinolin-2-yl)-1-(thio-
phen-2-yl)prop-2-en-1-one (9), and (E)-3-(3-(4-methoxyphenyl)
quinolin-2-yl)-1-(pyridin-2-yl)prop-2-en-1-one (10) were more
active than 6a. Substitution of a 5-Br group at the furan moiety
improved antiproliferative activity against MDA-MB-231 in which
(E)-1-(5-bromothiophen-2-yl)-3-(3-(4-methoxyphenyl)quinolin-
2-yl)prop-2-en-1-one (11) exhibited an IC50 value of less than
ꢀ
ꢀ
space group P b c a, a ¼ 13.6844(5) A, b ¼ 17.8924(7) A,
3
ꢁ
ꢀ
c ¼ 18.0314(7) angst;,
a
¼ 90ꢁ,
b
¼ 90ꢁ,
g
¼ 90 , V ¼ 4414.9(3) A ,
Z ¼ 8,
d
(calcd) ¼ 1.280 Mg mꢂ3, FW ¼ 425.46 for C27H23NO4,
F(000) ¼ 1792. Complete crystallographic data for the structural
analysis have been deposited with the Cambridge Crystallographic
Data Centre, CCDC 877658 for compound 6e. Copies of this infor-
mation may be obtained free of charge from the Director, Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cambridge,
CB2 1EZ, UK. (Fax: þ44-1223-336033, e-mail: deposit@ccdc.cam.ac.
uk or via www.ccdc.cam.ac.uk).
0.10
mM. Compound 11 was also active against the growth of H1299,
MCF-7, and SKBR-3 with an IC50 value of 0.71, 0.91, and 0.52
mM
respectively. (E)-3-(3-(4-Methoxyphenyl)quinolin-2-yl)-1-(thio-
phen-3-yl)prop-2-en-1-one (12) was less active than 9 indicated
the furan-3-yl substituent at C-1 position was less favorable than
the furan-2-yl substituent. Replacement of the thiophen-3-yl group
with the pyrrol-3-yl resulted in a loss of antiproliferative activity in
which compound 12 was active against the growth of H1299, MDA-
3. Results and discussion
All the synthesized 3-phenylquinolinylchalcone derivatives
were evaluated in vitro against a panel of six cancer cell lines
including three non-small cell lung cancer cells (H1299, H460, and
A549), three breast cancer cells (MCF-7, MDA-MB-231, and SKBR-3),
and a normal mammary epithelial cell (H184B5F5/M10) using XTT
MB-231, and SKBR-3 with an IC50 value of less than 1.22
mM
respectively while 13 was inactive.
Although compound 9 was active against the growth of most of
the cancer cells tested, its 3-amino derivative 14 was inactive. Both
Scheme 1. Reagents and conditions: (i) Dowtherm A, 280 ꢁC, 4 h; (ii) SeO2, 100 ꢁC, 2 h.

276
C.-H. Tseng et al. / European Journal of Medicinal Chemistry 59 (2013) 274e282
Scheme 2. Reagents and conditions: (i) KOH, EtOH, rt, 2 h; (ii) catalytic H2SO4, HOAc, reflux, 4 h.
pyrimidine derivative 15 and indole derivative 16 were inactive.
Compound 11 was found to be especially active (IC50 < 0.10 M)
against the growth of MDA-MB-231 and was inactive
(IC50 9.38 M) against normal mammary epithelial cell
(H184B5F5/M10), and therefore, was selected for further mecha-
nism studies. MDA-MB231 cells were treated with 0.1e5.0 M of
compound 11 for 12, 24, 36 and 48 h and the number of viable cells
was counted by XTT method.
Compound 11 inhibited the growth ofMDA-MB231 cells in a dose-
and time-dependent manner as shown in Fig. 3A. In addition, it was
found to be less toxic on normal breast H184B5F5/M10 cells as shown
in Fig. 3B. Compound 11 was also selected for further evaluation on its
effects of cell cycle distribution by flowcytometric analysis. It induced
cell cycle arrest in a concentration dependent manner as shown in
Fig. 4 and Table 2. The proportion of cells was decreased in the G1 and
accumulated in G2/M phase after 24 h treatment of 11, while the
hypodiploid (sub-G0/G1 phase) cells increased (Table 2).
Apoptosis can be characterized by morphological and
biochemical changes in the cell nucleus, including chromatin
condensation and nuclear shrinking. Morphological changes of
cells treated with 11 can be visually observed with light microscopy
(Fig. 5). We found that the MDA-MB231 cells treated with 11 at
m
¼
m
m
0.5
mM for 24 h became shrinked. Such morphological changes
were not apparent in the control cells.
To understand the mechanism of 11-induced apoptosis, we
examined the changes of the intracellular proteins related to
apoptosis, such as caspase-3, and PARP in cells treated with 11.
Caspases play a crucial role in apoptotic cell death. Caspase-3 in
particular, could be activated by the proteolytic processing of pro-
caspase 3 in response to exogenous apoptosis inducers [44].
Caspase-3 is an executioner caspase whose activation leads to the
cleavage of key cellular proteins including DNA repair enzyme poly-
(ADP-ribose) polymerase (PARP). PARP is involved in DNA repair
predominantly in response to environmental stress, and is important
for the maintenance of cell viability [45]. Our results indicated that
caspase-3 was activated and PARP was cleaved from 116 kDa intact
form into 85 kDa fragment after the treatment of 11 for 24 h in
a concentration-dependent manner (Fig. 6). Thus, compound 11
induced cell cycle arrest at G2/M phase followed by activation of
caspase-3, cleavage of PARP, and consequently caused the cell death.
4. Conclusion
We have synthesized a number of 3-phenylquinolinylchalcone
derivatives and evaluated in vitro for their activities against
Fig. 2. ORTEP view of (E)-1-(2,4-dimethoxyphenyl)-3-(3-(4-methoxyphenyl)quinolin-
2-yl)prop-2-en-1-one (6e).

C.-H. Tseng et al. / European Journal of Medicinal Chemistry 59 (2013) 274e282
277
Table 1
Antiproliferative activities of 3-phenylquinolinylchalcones (IC50
, mM).
Compd.
Cell lines
H1299
H460
A549
MCF-7
MDA-MB-231
SKBR-3
H184B5F5/M10
5
>10
>10
>10
>10
>10
>10
>10
6a
6b
6c
6d
6e
6f
6g
6h
6i
1.41 ꢃ 0.13
0.82 ꢃ 0.06
8.97 ꢃ 0.86
6.42 ꢃ 0.13
3.77 ꢃ 1.24
4.71 ꢃ 0.15
1.05 ꢃ 0.08
0.93 ꢃ 0.17
6.51 ꢃ 0.10
0.77 ꢃ 0.13
0.73 ꢃ 0.08
0.72 ꢃ 0.06
0.66 ꢃ 0.12
0.71 ꢃ 0.03
1.22 ꢃ 0.14
>10
6.67 ꢃ 0.14
6.99 ꢃ 0.58
6.93 ꢃ 0.07
>10
7.41 ꢃ 0.08
8.32 ꢃ 0.21
7.44 ꢃ 0.21
8.50 ꢃ 0.59
7.99 ꢃ 0.72
7.41 ꢃ 0.51
8.86 ꢃ 1.34
9.52 ꢃ 0.38
7.53 ꢃ 0.19
6.31 ꢃ 0.31
6.13 ꢃ 0.05
0.92 ꢃ 0.16
6.14 ꢃ 0.04
6.25 ꢃ 0.09
8.21 ꢃ 0.96
>10
4.04 ꢃ 0.18
5.45 ꢃ 0.21
6.71 ꢃ 0.07
7.38 ꢃ 0.12
6.26 ꢃ 0.06
4.52 ꢃ 0.04
6.03 ꢃ 0.88
3.23 ꢃ 0.05
6.92 ꢃ 0.03
4.11 ꢃ 0.04
0.71 ꢃ 0.04
1.03 ꢃ 0.05
0.81 ꢃ 0.08
0.91 ꢃ 0.09
6.01 ꢃ 0.07
>10
0.86 ꢃ 0.07
0.83 ꢃ 0.05
6.35 ꢃ 0.09
7.54 ꢃ 0.05
3.21 ꢃ 0.21
5.63 ꢃ 0.09
4.79 ꢃ 0.50
0.92 ꢃ 0.57
7.51 ꢃ 0.07
0.84 ꢃ 0.07
0.63 ꢃ 0.02
0.41 ꢃ 0.03
0.74 ꢃ 0.03
<0.1
0.70 ꢃ 0.14
0.81 ꢃ 0.09
3.88 ꢃ 0.11
9.28 ꢃ 0.04
2.26 ꢃ 0.08
3.83 ꢃ 0.14
3.26 ꢃ 0.26
0.47 ꢃ 0.62
8.561 ꢃ 0.16
0.59 ꢃ 0.21
0.64 ꢃ 0.14
0.80 ꢃ 0.04
0.37 ꢃ 0.09
0.52 ꢃ 0.05
0.66 ꢃ 0.24
>10
8.56 ꢃ 0.32
>10
5.69 ꢃ 0.13
>10
7.04 ꢃ 0.05
6.63 ꢃ 0.08
7.54 ꢃ 0.38
7.52 ꢃ 0.37
7.40 ꢃ 0.06
6.47 ꢃ 0.19
6.43 ꢃ 0.04
5.44 ꢃ 0.55
6.26 ꢃ 0.15
5.17 ꢃ 0.18
7.08 ꢃ 0.15
>10
6.11 ꢃ 0.11
4.47 ꢃ 0.06
7.24 ꢃ 0.90
6.66 ꢃ 0.95
9.29 ꢃ 0.12
6.10 ꢃ 0.15
6.24 ꢃ 0.33
7.03 ꢃ 0.23
4.14 ꢃ 0.36
9.38 ꢃ 0.22
6.39 ꢃ 0.18
>10
7
8
9
10
11
12
13
14
15
16
Topa
1.06 ꢃ 0.12
>10
>10
>10
>10
6.02 ꢃ 0.20
>10
>10
>10
>10
>10
4.81 ꢃ 0.72
>10
>10
>10
5.97 ꢃ 1.03
>10
>10
>10
<0.1
>10
>10
>10
>10
>10
>10
8.01 ꢃ 1.61
3.45 ꢃ 0.03
7.29 ꢃ 1.01
8.91 ꢃ 3.03
a
Top: topotecan.
a panel of six cancer cell lines and a normal mammary epithelial
cell. Results indicated that 3-(4-methoxyphenyl)quinoline-2-
carbaldehyde (5) was inactive while its chalcone derivative, (E)-
3-(3-(4-methoxyphenyl)-quinolin-2-yl)-1-phenylprop-2-en-1-one
(6a) was active against the growth of H1299 and SKBR-3 with IC50
values of 1.41 and 0.70 M respectively. The antiproliferative
m
activity against H1299 was increased by the introduction of an
electron-withdrawing group (such as 4-F or 4-NO2) but was
decreased by the introduction of an electron-donating group (such
as 4-OH, 4-OMe, or 4-NH2) at the C-1 phenyl moiety. In order to
establish the structureeactivity relationship, C-1 phenyl group was
replaced with various heterocyclic rings. The replacement of C-1
phenyl with furan-2-yl, thiophen-2-yl, or pyridin-2-yl ring
enhanced antiproliferative activity. Among them, (E)-1-(5-
bromothiophen-2-yl)-3-(3-(4-methoxyphenyl)quinolin-2-yl)prop-
2-en-1-one (11) was the most active which exhibited an IC50 value
of less than 0.10 mM against the growth of MDA-MB-231 and was
Fig. 3. Compound 11 suppresses the viability of breast cancer cell line MDA-MB-231
(A), and the normal mammary epithelial cell line H184B5F5/M10 (B). MDA-MB-231
cells were treated with DMSO, 0.1, 0.5, 1.0 and 5.0
were treated with DMSO, 0.1, 1.0, 5.0 and 10.0 M of 11. At 12, 24, 36 and 48 h after
treatment, 50 L XTT reaction solution were added to each well for an additional 4 h of
incubation. The absorbance at 492 nm was measured on a microtiter plate reader. The
results represent the mean ꢃ SD (n ¼ 4).
m
M of 11; H184B5F5/M10 cells
Fig. 4. Flow cytometric analysis of MDA-MB-231 cells. Cells were treated with DMSO
(A), compound 11 at 0.1 M (B), 0.5 M (C) or 1.0 M (D) in MB-231 cells; 24 h later the
cells were harvested, fixed, and stained with propidium iodide as described in
Experimental Section prior to analysis by flow cytometry. The percentage of cells in
each cell cycle phase was quantified (Table 2).
m
m
m
m
m

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C.-H. Tseng et al. / European Journal of Medicinal Chemistry 59 (2013) 274e282
Table 2
Effects of 11 on MDA-MB-231 cell cycle progression.
Concentration (
m
M)
Cell cycle distribution (%)a
Sub G1
G1
S
G2/M
DMSO
0.1
0.5
3.3 ꢃ 1.5
8.1 ꢃ 2.1
63.1 ꢃ 2.7
54.3 ꢃ 3.4
39.6 ꢃ 1.9
30.1 ꢃ 1.7
12.4 ꢃ 2.1
13.1 ꢃ 3.5
10.1 ꢃ 2.9
7.2 ꢃ 2.4
22.1 ꢃ 3.1
25.7 ꢃ 1.7
28.3 ꢃ 1.8
30.1 ꢃ 1.5
23.5 ꢃ 2.4
33.4 ꢃ 3.2
1.0
a
Values representative mean ꢃ SD from three experiments.
non-cytotoxic to the normal mammary epithelial cell (H184B5F5/
M10) with an IC50 value of 9.38 M. Compound 11 was also active
against the growth of H1299, MCF-7, and SKBR-3 with an IC50 value
of 0.71, 0.91, and 0.52 M respectively. Mechanism studies indi-
m
m
cated that compound 11 induced cell cycle arrest at G2/M phase
followed by activation of caspase-3, cleavage of PARP, and conse-
quently caused the cell death. Further studies on the structure
optimization are ongoing.
Fig. 6. Immunoblot analysis of the expression of pro-caspase 3, caspase-3, and PARP in
MDA-MB-231 cells. Cells were incubated with compound 11 (0.1e1.0 M) and the
expression of the apoptosis-related proteins pro-caspase 3, caspase-3, and PARP was
determined at 24 h by western blot. Protein loading was normalized to the expression
m
5. Experimental
of b-actin. A representative experiment is shown of three performed.
5.1. General
crystallized from EtOH to give 4 (0.97 g, 78%) as a brown solid. Mp:
71e72 ꢁC (EtOH). 1H NMR (CDCl3): 2.68 (s, 3H, CH3), 3.88 (s, 3H,
OMe), 6.99e7.03 (m, 2H, 30-H), 7.32e7.35 (m, 2H, 20-H), 7.47e7.51
(m, 1H, 6-H), 7.66e7.70 (m, 1H, 7-H), 7.78 (d, 1H, J ¼ 8.4 Hz, 8-H),
7.94 (s,1H, 4-H), 8.06 (d,1H, J ¼ 8.4 Hz, 5-H).13C NMR (CDCl3): 24.60,
55.33,113.84 (2C),125.96,126.93,127.37,128.34,129.16,130.34 (2C),
132.20, 135.39, 136.02, 146.86, 127.68, 159.14. Anal. Calcd for
C17H15NO: C 81.90, H 6.06, N 5.62; found: C 81.92, H 6.18, N 5.50.
Melting points were determined on a Electrothermal IA9100
melting point apparatus and are uncorrected. Nuclear magnetic
resonance (1H and 13C) spectra were recorded on a Varian Gemini
200 spectrometer or Varian-Unity-400 spectrometer. Chemical
shifts were expressed in parts per million (d) with tetramethylsilane
(TMS) as an internal standard. Thin-layer chromatography was
performed on silica gel 60 F-254 plates purchased from E. Merck and
Co. The elemental analyses were performed in the Instrument
Center of National Science Council at National Cheng-Kung Univer-
sityand National Taiwan University using Heraeus CHNeO Rapid EA,
and all values are within ꢃ0.4% of the theoretical compositions.
5.1.2. 3-(4-Methoxyphenyl)quinoline-2-carbaldehyde (5)
A mixture 4 (0.75 g, 3.0 mmol) and selenium dioxide (0.66 g,
6.0 mmol) in 1,4-dioxane (50 mL) was heated at 100 ꢁC for 2 h (TLC
monitoring). After cooling, the mixture was treated with 5%
NaHCO3 aqueous (80 mL), extracted with CH2Cl2 (50 mL ꢀ 3), the
organic layer was collected, dried over MgSO4, and evaporated. The
crude product was crystallized with EtOH to give 5 (0.62 g, 78%) as
a yellow solid. Mp: 106e107 ꢁC (EtOH). 1H NMR (CDCl3): 3.89 (s, 3H,
OMe), 7.01e7.05 (m, 2H, 30-H), 7.35e7.39 (m, 2H, 20-H), 7.67e7.71
5.1.1. 3-(4-Methoxyphenyl)-2-methylquinoline (4)
3-(4-Methoxyphenyl)-2-methylquinoline-4-carboxylic acid (3,
1.47 g, 5.0 mmol) in 10 mL DowthermÒ Awas heated at 280 ꢁC for 4 h
(TLC monitoring). After cooled to room temperature, hexane (50 mL)
was added and the resulting precipitate was collected, purified by
flash chromatography on silica gel (hexane/CH2Cl2 1/1), and
Fig. 5. Induction of morphological change in MDA-MB-231 cells. Cells were treated with DMSO or compound 11 (0.1e1.0
m
M) for 24 h at 37 ꢁC and photographed under
a microscope.

C.-H. Tseng et al. / European Journal of Medicinal Chemistry 59 (2013) 274e282
279
(m, 1H, 6-H), 7.79e7.83 (m, 1H, 7-H), 7.90 (d, 1H, J ¼ 8.4 Hz, 8-H),
8.19 (s, 1H, 4-H), 8.31 (d, 1H, J ¼ 8.4 Hz, 5-H), 10.27 (s, 1H, CHO). 13C
NMR (CDCl3): 55.35, 113.99 (2C), 127.51, 128.97, 129.07, 129.36,
130.30, 130.49, 130.77 (2C), 135.52, 138.47, 146.89, 149.90, 159.70,
192.58. Anal. Calcd for C17H13NO2: C 77.55, H 4.98, N 5.32; found: C
77.45, H 5.06, N 5.26.
2H, AreH), 7.55e7.59 (m, 1H, 6-H), 7.72e7.77 (m, 1H, 7-H), 7.83 (d,
1H, J ¼ 8.4 Hz, 5-H), 8.00 (d, 1H, J ¼ 14.8 Hz, CH]CHeCO), 8.10 (s,
1H, 4-H), 8.12e8.16 (m, 2H, AreH), 8.19 (d, 1H, J ¼ 8.4 Hz, 8-H), 8.39
(d, 1H, J ¼ 14.8 Hz, CH]CHeCO). 13C NMR (CDCl3): 55.37, 55.47,
113.81 (2C), 114.17 (2C), 127.35 (2C), 127.46, 128.19, 129.57, 129.71,
130.50, 130.95, 131.04 (2C), 131.13 (2C), 136.20, 136.89, 140.52,
147.18, 151.74, 159.54, 163.57, 188.55. Anal. Calcd for C26H21NO3: C
78.95, H 5.36, N 3.54; found: C 78.63, H 5.32, N 3.49.
5.2. General procedure for the preparation of quinolinyl chalcones
6aee and 8e16
5.2.5. (E)-1-(2,4-Dimethoxyphenyl)-3-[3-(4-methoxyphenyl)
quinolin-2-yl]prop-2-en-1-one (6e)
Compound 5 (0.53 g, 2.0 mmol) and appropriate acetophenone
(2.0 mmol) were stirred at 0 ꢁC for 15 min. Aqueous solution of KOH
(6 equiv) was added and the mixture was stirred at room temper-
ature for 12 h (TLC monitoring). After the reaction reached
completion, the resulting mixture was added 1 M HCl until pH 3
resulted and extracted with ethyl acetate (50 mL ꢀ 3). The organic
layer was collected, dried over MgSO4 and concentrated in vacuo.
The crude product was purified and crystallized with EtOH to give
quinolinyl chalcones 6aei and 8e16.
Yield 83%; mp 151.9e152.3 ꢁC (EtOH). 1H NMR (CDCl3): 3.87 (s,
3H, OMe), 3.89 (s, 3H, OMe), 3.94 (s, 3H, OMe), 6.49 (d, 1H,
J ¼ 2.4 Hz, AreH), 6.54 (dd, 1H, J ¼ 8.8, 2.4 Hz, AreH), 7.01e7.03 (m,
2H, AreH), 7.36e7.39 (m, 2H, AreH), 7.55 (m, 1H, 6-H), 7.72 (m, 1H,
7-H), 7.78e7.82 (m, 2H, 5-H and AreH), 7.88 (d, 1H, J ¼ 15.2 Hz,
CH]CHeCO), 8.07 (s, 1H, 4-H), 8.14 (d, 1H, J ¼ 8.4 Hz, 8-H), 8.30 (d,
1H, J ¼ 15.2 Hz, CH]CHeCO). 13C NMR (CDCl3): 55.37, 55.52,
55.75, 98.60, 105.18, 114.11 (2C), 122.15, 127.12, 127.40, 128.08,
129.50, 129.67, 130.70, 131.02 (2C), 132.62, 133.03, 136.12, 136.67,
138.72, 147.23, 152.27, 159.49, 160.85, 164.35, 190.27. Anal. Calcd
for C27H23NO4: C 76.22, H 5.45, N 3.29; found: C 76.28, H 5.46,
N 3.16.
5.2.1. (E)-3-[3-(4-Methoxyphenyl)quinolin-2-yl]-1-phenylprop-2-
en-1-one (6a)
Yield 92%. Mp: 147e148 ꢁC (EtOH). 1H NMR (CDCl3): 3.89 (s, 3H,
OMe), 7.02e7.06 (m, 2H, 30-H), 7.35e7.39 (m, 2H, 20-H), 7.49e7.62
(m, 4H, 6- & ArH), 7.73e7.77 (m, 1H, 7-H), 7.83 (d, 1H, J ¼ 8.4 Hz,
8-H), 8.02 (d, 1H, J ¼ 15.2 Hz, CH]CHeCO), 8.11e8.14 (m, 3H, 4- &
AreH), 8.19 (d, 1H, J ¼ 8.4 Hz, 5-H), 8.39 (d, 1H, J ¼ 15.2 Hz, CH]
CHeCO). 13C NMR (CDCl3): 55.38, 114.176 (2C), 127.36, 127.46 (2C),
128.24, 128.59 (2C), 128.77 (2C), 129.62, 129.77, 130.43, 131.04 (2C),
132.99, 136.24, 136.92, 137.90, 141.30, 147.19, 151.51, 159.56, 190.32.
Anal. Calcd for C25H19NO2: C 82.15, H 5.25, N 3.83; found: C 82.07, H
5.16, N 3.63.
5.2.6. (E)-1-(2,6-Dimethoxyphenyl)-3-[3-(4-methoxyphenyl)
quinolin-2-yl]prop-2-en-1-one (6f)
Yield 73%; mp 173.1e173.5 ꢁC (EtOH). 1H NMR (CDCl3): 3.75 (s,
6H, OMe ꢀ2), 3.87 (s, 3H, OMe), 6.53 (d, 2H, J ¼ 8.4 Hz, AreH), 6.92e
6.99 (m, 2H, AreH), 7.23e7.30 (m, 3H, AreH), 7.54 (m, 1H, 6-H), 7.59
(d, 1H, J ¼ 15.6 Hz, CH]CHeCO), 7.67 (d, 1H, J ¼ 15.6 Hz, CH]CHe
CO), 7.69e7.73 (m, 1H, 7-H), 7.79 (d, 1H, J ¼ 8.0 Hz, 5-H), 8.04 (s, 1H,
4-H), 8.12 (d, 1H, J ¼ 8.4 Hz, 8-H). 13C NMR (CDCl3): 55.40, 55.84
(2C), 103.62, 103.94 (2C), 113.67, 113.91 (2C), 127.35 (2C), 128.08,
129.64, 129.73, 130.50, 130.68, 130.95 (2C), 133.66, 135.86, 136.60,
141.38, 147.25, 151.59, 157.48, 159.37 (2C), 195.17. Anal. Calcd for
C27H23NO4: C 76.22, H 5.45, N 3.29; found: C 76.19, H 5.48, N 3.23.
5.2.2. (E)-1-(4-Fluorophenyl)-3-[3-(4-methoxyphenyl)quinolin-2-
yl]prop-2-en-1-one (6b)
Yield 44%. Mp: 153e154 ꢁC (EtOH). 1H NMR (400 MHz, CDCl3):
3.89 (s, 3H, OMe), 7.02e7.06 (m, 2H, AreH), 7.15e7.21 (m, 2H, Are
H), 7.35e7.38 (m, 2H, AreH) 7.58 (m, 1H, 6-H), 7.76 (m, 1H, 7-H),
7.83 (d, 1H, J ¼ 8.0 Hz, 8-H), 8.02 (d, 1H, J ¼ 15.2 Hz, CH]CHeCO),
8.11 (s, 1H, 4-H), 8.13e8.20 (m, 3H, 5- and AreH), 8.36 (d, 1H,
J ¼ 15.2 Hz, CH]CHeCO). 13C NMR (100 MHz, DMSO-d6): 55.39,
114.20 (2C), 115.72 (2C, J ¼ 22.0 Hz), 126.92, 127.48, 127.52, 128.27,
129.62, 129.80, 130.41, 131.04 (2C), 131.39 (2C, J ¼ 9.1 Hz), 134.31,
136.28, 136.95, 141.50, 147.21, 151.38, 159.62, 165.75 (J ¼ 253.9 Hz),
188.67. Anal. Calcd for C25H18FNO2: C 78.31, H 4.73, N 3.65; found: C
78.37, H 4.74, N 3.49.
5.2.7. (E)-1-(3,4-Dimethoxyphenyl)-3-[3-(4-methoxyphenyl)
quinolin-2-yl]prop-2-en-1-one (6g)
Yield 78%; mp 189.8e190.0 ꢁC (EtOH). 1H NMR (CDCl3): 3.87 (s,
3H, OMe), 3.96 (s, 3H, OMe), 3.98 (s, 3H, OMe), 6.95 (d, 1H,
J ¼ 8.4 Hz, AreH), 7.02e7.05 (m, 2H, AreH), 7.35e7.39 (m, 2H, Are
H), 7.57 (m, 1H, 6-H), 7.66 (d, 1H, J ¼ 2.0 Hz, AreH), 7.75 (m, 1H, 7-
H), 7.82e7.86 (m, 2H, 5-H and AreH), 8.01 (d, 1H, J ¼ 14.8 Hz, CH]
CHeCO), 8.11 (s, 1H, 4-H), 8.19 (d, 1H, J ¼ 8.4 Hz, 8-H), 8.39 (d, 1H,
J ¼ 14.8 Hz, CH]CHeCO). 13C NMR (CDCl3): 55.37, 56.02, 56.08,
110.01, 110.81, 114.18 (2C), 123.69, 127.18, 127.37, 127.48, 128.21,
129.57, 129.72, 130.52, 131.05 (2C), 131.18, 136.20, 136.89, 140.58,
147.21, 149.23, 151.77, 153.48, 159.59, 188.48. Anal. Calcd for
C27H23NO4$0.1 H2O: C 75.90, H 5.47, N 3.28; found C 75.69, H 5.50, N
3.23.
5.2.3. (E)-1-(4-Hydroxyphenyl)-3-[3-(4-methoxyphenyl)quinolin-
2-yl]prop-2-en-1-one (6c)
Yield 75%. Mp: 239e240 ꢁC (EtOH). 1H NMR (DMSO-d6): 3.87 (s,
3H, OMe), 6.92e6.95 (m, 2H, AreH), 7.12e7.16 (m, 2H, AreH), 7.43e
7.47 (m, 2H, AreH), 7.65e7.69 (m, 1H, 6-H), 7.76 (d, 1H, J ¼ 14.8 Hz,
CH]CHeCO), 7.82e7.86 (m, 1H, 7-H), 7.97e8.00 (m, 2H, AreH),
8.04 (d, 1H, J ¼ 8.4 Hz, 8-H), 8.16 (d, 1H, J ¼ 8.4 Hz, 5-H), 8.28 (d,
5.2.8. (E)-1-(3,5-Dimethoxyphenyl)-3-[3-(4-methoxyphenyl)
quinolin-2-yl]prop-2-en-1-one (6h)
1H, J ¼ 14.8 Hz, CH]CHeCO), 8.36 (s, 1H, 4-H), 10.54 (s, 1H, OH). 13
C
Yield 87%; mp 162.1e162.5 ꢁC (EtOH). 1H NMR (CDCl3): 3.87 (s,
6H, OMe ꢀ2), 3.89 (s, 3H, OMe), 6.68 (t, 1H, J ¼ 2.4 Hz, AreH), 7.02e
7.06 (m, 2H, AreH), 7.25e7.26 (m, 2H, AreH), 7.35e7.39 (m, 2H, Are
H), 7.58 (m, 1H, 6-H), 7.75 (m, 1H, 7-H), 7.83 (d, 1H, J ¼ 8.0 Hz, 5-H),
8.00 (d, 1H, J ¼ 15.2 Hz, CH]CHeCO), 8.11 (s, 1H, 4-H), 8.19 (d, 1H,
J ¼ 8.4 Hz, 8-H), 8.29 (d, 1H, J ¼ 15.2 Hz, CH]CHeCO). 13C NMR
(CDCl3): 55.37, 56.63 (2C), 105.40, 106.61 (2C), 114.20 (2C), 127.45,
127.48 (2C), 128.24, 129.68, 129.77, 130.48, 130.92, 131.05 (2C),
136.22, 136.90, 139.94, 141.51, 147.22, 151.51, 159.60, 160.90 (2C),
190.02. Anal. Calcd for C27H23NO4$0.1 H2O: C 75.90, H 5.47, N 3.28;
found C 75.78, H 5.48, N 3.16.
NMR (DMSO-d6): 55.28, 114.15 (2C), 115.63 (2C), 127.06, 127.61,
127.85, 127.93, 128.81, 129.00, 130.02, 130.20, 131.12 (2C), 131.19
(2C), 135.65, 137.08, 139.35, 146.51, 150.78, 159.20, 162.49, 187.34.
Anal. Calcd for C25H19NO3$1H2O: C 75.17, H 5.30, N 3.51; found: C
74.97, H 5.22, N 3.16.
5.2.4. (E)-1-(4-Methoxyphenyl)-3-[3-(4-methoxyphenyl)quinolin-
2-yl]prop-2-en-1-one (6d)
Yield 85%. Mp: 160e161 ꢁC (EtOH). 1H NMR (CDCl3): 3.89 (s, 3H,
OMe), 3.90 (s, 3H, OMe), 6.97e7.04 (m, 4H, AreH), 7.35e7.39 (m,

280
C.-H. Tseng et al. / European Journal of Medicinal Chemistry 59 (2013) 274e282
5.2.9. (E)-1-(4-Aminophenyl)-3-[3-(4-methoxyphenyl)quinolin-2-
yl]prop-2-en-1-one (6i)
1H, 6-H), 7.74 (m, 1H, 7-H), 7.82 (dd, 1H, J ¼ 1.6, 8.0 Hz, 5-H), 7.87
(dd, 1H, J ¼ 1.6, 7.6 Hz, pyridinyleH), 8.10e8.16 (m, 3H, 4-,
pyridinyleH and CH]CHeCO), 8.23 (d, 1H, J ¼ 8.4 Hz, 8-H), 8.79e
Yield 40%; mp 198.2e201 ꢁC (EtOH). 1H NMR (400 MHz, CDCl3):
3.88 (s, 3H, OMe), 4.20 (br s, 2H, NH2), 6.68e6.71 (m, 2H, AreH),
7.01e7.05 (m, 2H, AreH), 7.35e7.39 (m, 2H, AreH), 7.56 (m, 1H, 6-
H), 7.73 (m, 1H, 7-H), 7.82 (d, 1H, J ¼ 8.4 Hz, 5-H), 7.97 (d, 1H,
J ¼ 15.2 Hz, CH]CHeCO), 8.00e8.04 (m, 2H, AreH), 8.09 (s, 1H, 4-
H), 8.19 (d, 1H, J ¼ 8.4 Hz, 8-H), 8.37 (d, 1H, J ¼ 15.2 Hz, CH]CHe
CO). 13C NMR (100 MHz, CDCl3): 55.37, 113.89 (2C), 114.16 (2C),
127.22, 127.45, 127.67, 128.13, 128.46, 129.55, 129.63, 130.61, 131.40
(2C), 131.41 (2C), 136.15, 136.83, 139.74, 147.20, 151.25, 152.02,
159.51, 187.91. Anal. Calcd for C25H20N2O2: C 78.93, H 5.30, N 7.36;
found: C 78.67, H 5.27, N 7.01.
8.81 (m, 1H, pyridinyleH), 8.96 (d, 1H, J ¼ 15.2 Hz, CH]CHeCO). 13
C
NMR (100 MHz, CDCl3): 55.39, 114.13 (2C), 122.87, 126.91, 126.94,
127.38, 127.42, 128.23, 129.64, 129.88, 130.57, 131.11 (2C), 136.24,
136.75, 136.91, 141.58, 147.28, 149.03, 151.71, 154.19, 159.54, 190.06.
Anal. Calcd for C24H18N2O2: C 78.67, H 4.95, N 7.65; found: C 78.42,
H 4.82, N 7.59.
5.2.14. (E)-1-(5-Bromothiophen-2-yl)-3-[3-(4-methoxyphenyl)
quinolin-2-yl]prop-2-en-1-one (11)
Yield 77%; mp 169.3e169.6 ꢁC (EtOH). 1H NMR (400 MHz,
CDCl3): 3.89 (s, 3H, OMe), 7.02e7.06 (m, 2H, AreH), 7.16 (d, 1H,
J ¼ 4.0 Hz, thiophenyleH), 7.33e7.37 (m, 2H, AreH), 7.58 (m, 1H, 6-
H), 7.73e7.78 (m, 2H, 7- and thiophenyleH), 7.82 (d, 1H, J ¼ 8.0 Hz,
5-H), 8.02 (d, 1H, J ¼ 15.2 Hz, CH]CHeCO), 8.11 (s, 1H, 4-H), 8.14
5.2.10. (E)-3-[3-(4-Methoxyphenyl)quinolin-2-yl]-1-(4-
nitrophenyl)prop-2-en-1-one (7)
A solution 5 (0.53 g, 2.0 mmol), 4-nitroacetophenone (0.33 g，
2.00 mmol) and 99% H2SO4 (0.2 mL) in acetic acid (15 mL) were
refluxed for 4 h. The cooled mixture was triturated with water and
the resulting precipitate was collected and crystallized with EtOH
to give 0.38 g (46%) of 7 as a yellow solid. mp 214.7e216.5 ꢁC
(EtOH). 1H NMR (400 MHz, CDCl3): 3.90 (s, 3H, OMe), 7.03e7.07
(m, 2H, AreH), 7.34e7.38 (m, 2H, AreH), 7.60 (m, 1H, 6-H), 7.77
(m, 1H, 7-H), 7.84 (d, 1H, J ¼ 8.0 Hz, 5-H), 8.05 (d, 1H, J ¼ 15.2 Hz,
CH]CHeCO), 8.14 (s, 1H, 4-H), 8.19 (d, 1H, J ¼ 8.4 Hz, 8-H), 8.22e
8.25 (m, 2H, AreH), 8.33e8.37 (m, 3H, CH]CHeCO and AreH).
13C NMR (100 MHz, CDCl3): 55.41, 114.19, 114.23 (2C), 123.82 (2C),
126.35, 127.52, 127.82, 128.41, 129.65 (2C), 129.98, 130.20, 131.04
(2C), 136.43, 137.08, 142.63, 143.13, 147.20, 150.16, 150.82, 159.70,
188.83. Anal. Calcd for C25H18N2O4$0.5H2O: C 71.59, H 4.56, N 6.68;
found: C 71.63, H 4.22, N 6.66.
(d, 1H, J ¼ 15.2 Hz, CH]CHeCO), 8.18 (d, 1H, J ¼ 8.4 Hz, 8-H). 13
C
NMR (100 MHz, CDCl3): 55.40, 114.21 (2C), 123.35, 126.02, 127.49,
127.59, 128.30, 129.57, 129.85, 130.26, 131.04 (2C), 131.44, 132.58,
136.35, 136.99, 141.15, 147.16, 147.22, 151.10, 159.62, 181.12. Anal.
Calcd for C23H16BrNO2S: C 61.34, H 3.58, N 3.11; found: C 61.37, H
3.54, N 2.98.
5.2.15. (E)-3-[3-(4-Methoxyphenyl)quinolin-2-yl]-1-(thiophen-3-
yl)prop-2-en-1-one (12)
Yield 51%; mp 163.5e164 ꢁC (EtOH). 1H NMR (400 MHz, CDCl3):
3.89 (s, 3H, OMe), 7.02e7.06 (m, 2H, AreH), 7.35e7.38 (m, 3H, Ar-
and thiophenyleH), 7.58 (m, 1H, 6-H), 7.71 (dd, 1H, J ¼ 1.6, 5.2 Hz,
thiophenyleH), 7.75 (m, 1H, 7-H), 7.83 (dd, 1H, J ¼ 1.2, 8.0 Hz, 5-H),
8.01 (d, 1H, J ¼ 15.2 Hz, CH]CHeCO), 8.11 (s, 1H, 4-H), 8.19 (d, 1H,
J ¼ 8.4 Hz, 8-H), 8.23 (d, 1H, J ¼ 15.2 Hz, CH]CHeCO), 8.31 (dd, 1H,
J ¼ 1.2, 2.8 Hz, thiophenyleH). 13C NMR (100 MHz, CDCl3): 55.39,
114.19 (2C), 126.41, 127.46, 127.48, 127.52, 128.15, 128.24, 129.57,
129.78, 130.42, 131.04 (2C), 132.92, 136.25, 136.93, 140.65, 143.14,
147.19, 151.49, 159.59, 183.89. Anal. Calcd for C23H17NO2S: C 74.37, H
4.61, N 3.77; found: C 74.06, H 4.56, N 3.61.
5.2.11. (E)-1-(Furan-2-yl)-3-[3-(4-methoxyphenyl)quinolin-2-yl]
prop-2-en-1-one (8)
Yield 41%; mp 164.6e165.3 ꢁC (EtOH). 1H NMR (400 MHz,
CDCl3): 3.89 (s, 3H, OMe), 6.61 (dd, 1H, J ¼ 1.6, 3.6 Hz, furanyleH),
7.02e7.06 (m, 2H, AreH), 7.34e7.38 (m, 2H, AreH), 7.42 (dd, 1H,
J ¼ 0.8, 3.6 Hz, furanyleH), 7.58 (m, 1H, 6-H), 7.68 (dd, 1H, J ¼ 0.8,
1.6 Hz, furanyleH), 7.75 (m, 1H, 7-H), 7.83 (d, 1H, J ¼ 8.4 Hz, 5-H),
8.06 (d, 1H, J ¼ 15.2 Hz, CH]CHeCO), 8.11 (s, 1H, 4-H), 8.18 (d, 1H,
J ¼ 8.4 Hz, 8-H), 8.22 (d, 1H, J ¼ 15.2 Hz, CH]CHeCO). 13C NMR
(100 MHz, CDCl3): 55.40, 112.48, 114.21 (2C), 118.30, 126.99, 127.46,
127.49, 128.27, 129.64, 129.76, 130.39, 131.06 (2C), 136.27, 136.93,
140.64, 146.94, 147.19, 151.36, 153.71, 159.62, 177.98. Anal. Calcd for
C23H17NO3: C 77.73, H 4.82, N 3.94; found: C 77.52, H 4.79, N 3.87.
5.2.16. (E)-3-[3-(4-Methoxyphenyl)quinolin-2-yl]-1-(1H-pyrrol-2-
yl)prop-2-en-1-one (13)
Yield 70%; mp 165.3e167.5 ꢁC (EtOH). 1H NMR (400 MHz,
DMSO): 3.86 (s, 3H, OMe), 6.31 (m, 1H, pyrrolyleH), 7.12e7.16 (m,
2H, AreH), 7.22e7.24 (m, 2H, pyrrolyleH), 7.43e7.46 (m, 2H, AreH),
7.65 (m, 1H, 6-H), 7.77 (d, 1H, J ¼ 14.8 Hz, CH]CHeCO), 7.84 (m, 1H,
7-H), 8.04 (d, 1H, J ¼ 7.6 Hz, 5-H), 8.10 (d, 1H, J ¼ 14.8 Hz, CH]CHe
CO), 8.16 (d, 1H, J ¼ 7.6 Hz, 8-H), 8.36 (s, 1H, 4-H), 12.05 (br s, 1H,
NH). 13C NMR (100 MHz, DMSO): 55.27, 110.53, 114.15 (2C), 117.58,
127.11, 127.50, 127.75, 127.90, 128.06, 128.98, 130.13 (2C), 131.09
(2C), 132.90, 135.52, 137.05, 137.52, 146.51, 150.89, 159.18, 177.41.
Anal. Calcd for C23H18N2O2: C 77.95, H 5.12, N 7.90; found: C 77.98, H
5.10, N 7.86.
5.2.12. (E)-3-[3-(4-Methoxyphenyl)quinolin-2-yl]-1-(thiophen-2-
yl)prop-2-en-1-one (9)
Yield 94%; mp 167.4e167.8 ꢁC (EtOH). 1H NMR (400 MHz, CDCl3):
3.89 (s, 3H, OMe), 7.02e7.06 (m, 2H, AreH), 7.20 (dd, 1H, J ¼ 3.6,
4.8 Hz, thiophenyleH), 7.35e7.38 (m, 2H, AreH), 7.58 (m, 1H, 6-H),
7.70 (dd,1H, J ¼ 1.2, 4.8 Hz, thiophenyleH), 7.76 (m,1H, 7-H), 7.83 (d,
1H, J ¼ 8.0 Hz, 5-H), 8.01 (dd,1-H, J ¼ 1.2, 3.6 Hz, thiophenyleH), 8.03
(d, 1H, J ¼ 15.2 Hz, CH]CHeCO), 8.11 (s, 1H, 4-H), 8.19 (d, 1H,
J ¼ 8.4 Hz, 8-H), 8.24 (d, 1H, J ¼ 15.2 Hz, CH]CHeCO). 13C NMR
(100 MHz, CDCl3): 55.40,114.22 (2C),127.21,127.49 (2C),128.28 (2C),
129.62, 129.78, 130.39, 131.06 (2C), 132.53, 134.29, 136.31, 136.94,
140.69, 145.72, 147.20, 151.37, 159.61, 182.28. Anal. Calcd for
C23H17NO2S: C 74.37, H 4.61, N 3.77; found: C 74.04, H 4.49, N 3.60.
5.2.17. (E)-1-(3-Aminothiophen-2-yl)-3-[3-(4-methoxyphenyl)
quinolin-2-yl]prop-2-en-1-one (14)
Yield 77%; mp 171.3e172.5 ꢁC (EtOH). 1H NMR (400 MHz,
CDCl3): 3.88 (s, 3H, OMe), 6.40 (br s, 2H, NH2), 6.58 (d,1H, J ¼ 5.2 Hz,
thiophenyleH), 7.01e7.05 (m, 2H, AreH), 7.35e7.39 (m, 2H, AreH),
7.40 (d,1H, J ¼ 5.2 Hz, thiophenyleH), 7.56 (m, 1H, 6-H), 7.73 (m,1H,
7-H), 7.82 (d, 1H, J ¼ 8.4 Hz, 5-H), 7.95 (s, 2H, CH]CHeCO), 8.08 (s,
1H, 4-H), 8.19 (d, 1H, J ¼ 8.4 Hz, 8-H). 13C NMR (100 MHz, CDCl3):
55.35, 112.94, 114.13 (2C), 119.71, 127.22, 127.38, 128.07, 129.63 (2C),
130.01, 130.63, 131.01 (2C), 132.99, 136.09, 136.83, 138.34, 147.18,
151.72, 155.84, 159.47, 182.57. Anal. Calcd for C23H18N2O2S: C 71.48,
H 4.69, N 7.25, S 8.30; found: C 71.29, H 4.77, N 7.08, 8.04.
5.2.13. (E)-3-[3-(4-Methoxyphenyl)quinolin-2-yl]-1-(pyridin-2-yl)
prop-2-en-1-one (10)
Yield 20%; mp 143.8e144.4 ꢁC (EtOH). 1H NMR (400 MHz,
CDCl3): 3.90 (s, 3H, OMe), 7.02e7.06 (m, 2H, AreH), 7.37e7.41 (m,
2H, AreH), 7.49 (ddd, 1H, J ¼ 1.2, 4.8, 7.6 Hz, pyridinyleH), 7.57 (m,

C.-H. Tseng et al. / European Journal of Medicinal Chemistry 59 (2013) 274e282
281
5.2.18. (E)-1-(2-Amino-4-methylpyrimidin-5-yl)-3-[3-(4-
methoxyphenyl)quinolin-2-yl]prop-2-en-1-one (15)
were suspended in 1 mL of propidium iodide (PI) solution con-
taining 20 g/ L of PI, 0.2 mg/mL RNase, and 0.1% (v/v) Trition X-
m
m
Yield 40%; mp 151.3e152.5 ꢁC (EtOH). 1H NMR (400 MHz,
DMSO): 2.51 (s, 3H, CH3), 3.86 (s, 3H, OMe), 7.12e7.14 (m, 2H, Are
H), 7.43e7.47 (m, 2H, AreH), 7.49 (br s, 2H, NH2), 7.66 (d, 1H,
J ¼ 14.8 Hz, CH]CHeCO), 7.68 (m, 1H, 6-H), 7.82 (M, 1H, 7-H), 8.02
(d, 1H, J ¼ 8.4 Hz, 5-H), 8.05 (d, 1H, J ¼ 14.8 Hz, CH]CHeCO), 8.13
(d,1H, J ¼ 8.4 Hz, 8-H), 8.36 (s,1H, 4-H), 8.82 (s,1H, pyrimidinyleH).
13C NMR (100 MHz, DMSO): 24.48, 55.29, 114.15 (2C), 119.91, 127.62,
127.83, 127.91, 129.03, 129.38, 129.97, 130.18, 131.10 (2C), 135.59,
137.05, 139.28, 146.49, 150.68, 159.19, 160.68, 163.18, 169.78, 188.15.
Anal. Calcd for C24H20N4O2$1.5H2O: C 68.07, H 5.47, N 13.23; found:
C 68.01, H 5.58, N 13.06.
100. Cell samples were incubated at room temperature in the dark
for at least 30 min and analyzed by a flow cytometer (Coulter Epics).
Data recording was made using Epics software and cell cycle data
were analyzed using Multicycle software (coulter).
5.3.3. DNA fragmentation assay
DNA fragmentation was determined by agarose gel electro-
phoresis. Cells were treated with various concentrations of
compound 11 (0.1, 0.5, 1.0 mM) for 24 h and then washed twice with
PBS. Total DNA was isolated using a commercial kit (genomic DNA
purification kit, Fermentas Life Sciences). DNA agarose electro-
phoresis was executed at 100 V on a 2.0% agarose gel in 1ꢀ TAE
buffer (40 mmol/L of Tris, 2 mmol/L of EDTA, 20 mmol/L of acetic
acid). DNA ladder marker (0.2e14.0 kb; GeneMark) was added to
gel as a reference for the analysis of internucleosomal DNA frag-
5.2.19. (E)-1-(1H-Indol-3-yl)-3-[3-(4-methoxyphenyl)quinolin-2-
yl]prop-2-en-1-one (16)
Yield 27%; mp 278e279.4 ꢁC (EtOH). 1H NMR (400 MHz, DMSO):
3.88 (s, 3H, OMe), 7.14e7.17 (m, 2H, AreH), 7.21e7.29 (m, 2H,
indolyleH), 7.44e7.48 (m, 2H, AreH), 7.52 (d, 1H, J ¼ 7.2 Hz,
indolyleH), 7.66 (dd,1H, J ¼ 1.2, 8.0 Hz, 6-H), 7.79 (d,1H, J ¼ 14.8 Hz,
CH]CHeCO), 7.84 (m, 1H, 7-H), 8.05 (d, 1-H, J ¼ 7.2 Hz, 5-H), 8.18
(d, 1H, J ¼ 8.4 Hz, 8-H), 8.24 (d, 1H, J ¼ 14.8 Hz, CH]CHeCO). 8.28
(dd, 1H, J ¼ 1.6, 7.8 Hz, indolyleH), 8.35 (s, 1H, 4-H), 8.66 (s, 1H,
indolyleH), 12.20 (br s, 1H, NH). 13C NMR (100 MHz, DMSO): 55.29,
112.34, 114.16 (2C), 117.59, 121.69, 122.07, 123.33, 125.80, 127.37,
127.72, 127.94, 128.92, 129.53, 130.08, 130.29, 131.09 (2C), 134.96,
135.57, 136.65, 136.97 (2C), 146.56, 151.32, 159.19, 183.40. Anal.
Calcd for C27H20N2O2$0.2H2O: C 79.47, H 5.04, N 6.86; found: C
79.29, H 4.92, N 6.58.
mentation. The gel was stained with ethidium bromide (20
and photographed under ultraviolet illumination.
mg/mL)
5.3.4. Immunoblot analysis
After treatment, cells were collected and washed twice with
cold PBS. The cells were then lysed in lysis buffer (50 mM TriseHCl,
pH 7.5, 150 mM NaCl, 1% Nonidet P-40, 2 mM EDTA, 1 mM EGTA,
1 mM NaVO3, 10 mM NaF, 1 mM DTT, 1 mM PMSF, 25
mg/mL
aprotinin, and 25 mg/mL leupeptin) and kept on ice for 30 min. The
lysates were then centrifuged at 12,000 g at 4 ꢁC for 20 min; the
supernatants were stored at ꢂ70 ꢁC until use. The protein
concentration was determined by the Bradford method. 20
mg
protein was separated by 8e12% SDS-PAGE and transferred onto
a PVDF membrane using a glycine transfer buffer (192 mM glycine,
25 mM TriseHCl, pH 8.8, and 20% methanol [v/v]). After blocking
with 5% non-fat dried milk, the membrane was incubated for 2 h
with primary antibodies, followed by 30 min with secondary
antibodies in milk containing Tris-buffered saline (TBS) and 0.5%
Tween. Anti-human-PARP, pro-caspase 3 and caspase-3 antibodies
were used at a 1:1000 dilution as the primary antibodies, while
horseradish peroxidase-conjugated horse anti-rabbit IgG (Vector
Laboratories, Burlingame, CA, USA) was used at a 1:5000 dilution as
the secondary antibody. The membrane was then exposed to X-ray
film. Protein bands were detected using the enhanced chem-
iluminescence blotting detection system (Amersham, USA).
5.3. Pharmacological methods
5.3.1. Antiproliferative assay
Cancer cells (H460, A549, H1299, MCF-7, MDA-MB-231, SKBR-3)
and normal mammary epithelial cell (H184B5F5/M10) were
purchased from Bioresources Collection and Research Center, Taiwan.
Cell lines were maintained in the same standard medium and grown
as a monolayer in DMEM (Gibco, USA) and supplemented with 10%
fetal bovine serum (FBS) and antibiotics i.e. 100 IU/mL penicillin,
0.1 mg/mL streptomycin and 0.25 mg/mL amphotericin. Culture was
maintained at 37 ꢁC with 5% CO2 in a humidified atmosphere.
Cells (5 ꢀ 103 cells/well) were treated as indicated for 72 h in
medium containing 10% FBS. Cell viability was quantitated with the
use of sodium 30-[1-(phenylamino-carbonyl)-3,4-tetrazolium}-
bis(4-methoxy-6-nitro)benzene sulfonic acid hydrate (XTT) color-
imetric assay (Biological Industries, Beit-Haemek, Israel). XTT
labeling reagent (1 mg/mL) was mixed with electron-coupling
Acknowledgments
Financial support of this work by the National Science Council of
the Republic of China (NSC 99-2320-B-037-011-MY3) is gratefully
acknowledged. We also thank National Center for High-
Performance Computing for providing computer resources and
chemical database services.
reagent, following the manufacturer’s instructions, and 50
mL of
the mixture was added directly to the cells. The plates were further
incubated at 37 ꢁC for 4 h. Color was measured spectrophotomet-
rically in a microtiter plate reader at 492 nm and used as a relative
measure of viable cell number. The number of viable cells following
treatment was compared to solvent and untreated control cells and
Appendix A. Supplementary data
used to determine the percent of control growth as (Abtreated
/
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2012.11.027.
Abcontrol) ꢀ 100, where Ab represents the mean absorbance (n ¼ 3).
The concentration that killed 50% of cells (GI50) was determined
from the linear portion of the curve by calculating the concentra-
tion of agent that reduced absorbance in treated cells, compared to
control cells, by 50%.
References
[1] M. Liu, P. Wilairat, S.L. Cropft, A.L.C. Tan, M.L. Go, Structureeactivity rela-
tionships of antileishmanial and antimalarial chalcones, Bioorg. Med. Chem.
11 (2003) 2729e2738.
5.3.2. Cell cycle analysis
[2] M. Liu, P. Wilairat, M.L. Go, Antimalarial alkoxylated and hydroxylated chal-
cones: structureeactivity relationship analysis, J. Med. Chem. 44 (2001)
4443e4452.
MDA-MB-231 cells treated with DMSO and compound 11 at
different concentration (0.1, 0.5, 1.0 mM) for 24 h were harvested,
rinsed in PBS, resuspended and fixed in 70% ethanol and store cells
[3] J.F. Ballesteros, M.J. Sanz, A. Ubeda, M.A. Miranda, S. Iborra, M. Paya,
at ꢂ20 ꢁC in fixation buffer until ready for analysis. Then the pellets
M. Alcaraz, Synthesis and pharmacological evaluation of 20-hydroxychalcones

282
C.-H. Tseng et al. / European Journal of Medicinal Chemistry 59 (2013) 274e282
and flavones as inhibitors of inflammatory mediators generation, J. Med.
Chem. 38 (1995) 2794e2797.
[4] L. Barford, K. Kemp, M. Hansen, A. Kharazmi, Chalcones from Chinese liquorice
inhibit proliferation of T cells and production of cytokines, Int. Immunopharm.
2 (2002) 545e550.
[23] G.R. Pettit, G.M. Cragg, D.L. Herald, J.M. Schmidt, P. Lobavanijaya, Anti-
neoplastic agents. 84. Isolation and structure of Combretastatin, Can. J. Chem.
60 (1982) 1347e1376.
[24] N.H. Nam, Combretastatin A-4 analogues as antimitotic antitumor agents,
Curr. Med. Chem. 10 (2003) 1697e1722.
[5] J. Rajas, M. Paya, J.N. Dominguez, M.L. Ferrandiz, The synthesis and effect of
fluorinated chalcone derivatives on nitric oxide production, Bioorg. Med.
Chem. Lett. 12 (2002) 1951e1954.
[25] Y. Xia, Z.Y. Yang, P. Xia, K.F. Bastow, Y. Tachibana, S.C. Kuo, E. Hamel, T. Hackl,
K.H. Lee, Antitumor agents. 181. Synthesis and biological evaluation of
6,7,20,30,40-substituted-1,2,3,4-tetrahydro-2-phenyl-4-quinolones as
a new
[6] O. Nerya, R. Musa, S. Khatib, S. Tamir, O. Jacob, Chalcones as potent tyrosinase
inhibitors: the effect of hydroxyl positions and numbers, Phytochemistry 65
(2004) 1389e1395.
[7] J.R. Dimmock, N.M. Kandepu, M. Hetherington, J.W. Quail, U. Pugazhenthi,
A.M. Sudom, M. Chamankhah, P. Rose, E. Pass, T.M. Allen, S. Halleran,
J. Szydlowski, B. Mutus, M. Tannous, E.K. Manavathu, T.G. Myers, E.D. Clercq,
J. Balzarini, Cytotoxic activities of Mannich bases of chalcones and related
compounds, J. Med. Chem. 41 (1998) 1014e1026.
class of antimitotic antitumor agents, J. Med. Chem. 41 (1998) 1155e1162.
[26] A.A. El-Zayat, D. Degen, S. Drabek, G.M. Clark, G.R. Pettit, D.D. Von Hoff, In vitro
evaluation of the antineoplastic activity of Combretastatin-A-4, a natural product
from Combretum-Caffrum (acid shrub), Anti-Cancer Drugs 4 (1993) 19e25.
[27] K. Ohsumi, R. Nakagava, Y. Fukuda, T. Hatanaka, Y. Morinaga, U. Nihei,
K. Ohishi, Y. Suga, Y. Akiyama, T. Tsuji, Novel combretastatin analogues
effective against murine solid tumors: design and structureꢂactivity rela-
tionships, J. Med. Chem. 41 (1998) 3022e3032.
[8] Y.Z. Yang, P. Xia, K.F. Bastow, Y. Nakanishi, K.H. Lee, Antitumor agents. Part
202: novel 20-amino chalcones: design, synthesis and biological evaluation,
Bioorg. Med. Chem. Lett. 10 (2000) 699e701.
[9] A.T. Dinkova-Kostova, C. Abeygunawardana, P. Talalay, Chemoprotective
properties of phenylpropenoids, bis(benzylidene)cycloalkanones, and related
[28] C.M. Lin, H.H. Ho, G.R. Pettit, E. Hamel, Antimitotic natural products com-
bretastatin A-4 and combretastatin A-2: studies on the mechanism of their
inhibition of the binding of colchicine to tubulin, Biochemistry 28 (1989)
6984e6991.
[29] M.L. Edwards, D.M. Stemerick, P.S. Sunkara, Chalcones: a new class of anti-
mitotic agents, J. Med. Chem. 33 (1990) 1948e1954.
Michael reaction acceptors: correlation of potencies as phase
2 enzyme
inducers and radical scavengers, J. Med. Chem. 41 (1998) 5287e5296.
[10] M.E. Wall, M.C. Wani, C.E. Cook, K.H. Palmer, A.T. McPhail, G.A. Sim, Plant anti-
tumor agents-I. The isolation and structure of CPT, a novel alkaloidal leukemia
and tumor inhibitor from Camptotheca acuminate, J. Am. Chem. Soc. 88 (1966)
3888e3890.
[11] K.A. Werbovetz, A.K. Bhattacharjee, J.J. Brendle, J.P. Scovill, Analysis of ster-
eoelectronic properties of camptothecin analogues in relation to biological
activity, Bioorg. Med. Chem. 8 (2000) 1741e1747.
[12] A. Chilin, G. Marzaro, C. Marzano, L.D. Via, M.G. Ferlin, G. Pastorini, A. Guiotto,
Synthesis and antitumor activity of novel amsacrine analogs: the critical role
of the acridine moiety in determining their biological activity, Bioorg. Med.
Chem. 17 (2009) 523e529.
[13] C.M. Lu, Y.L. Chen, H.L. Chen, C.A. Chen, P.J. Lu, C.N. Yang, C.C. Tzeng, Synthesis
and antiproliferative evaluation of certain indolo[3,2-c]quinoline derivatives,
Bioorg. Med. Chem. 18 (2010) 1948e1957.
[14] N. Ahmed, K.G. Brahmbhatt, S. Sabde, D. Mitra, I.P. Singh, K.K. Bhutani,
Synthesis and anti-HIV activity of alkylated quinoline 2,4-diols, Bioorg. Med.
Chem. 18 (2010) 2872e2879.
[15] R.S. Upadhayaya, J.K. Vandavasi, R.A. Kardile, S.V. Lahore, S.S. Dixit,
H.S. Deokar, P.D. Shinde, M.P. Sarmah, J. Chattopadhyaya, Novel quinoline and
naphthalene derivatives as potent antimycobacterial agents, Eur. J. Med.
Chem. 45 (2010) 1854e1867.
[30] G.R. Pettit, S.B. Singh, M.R. Boyd, E. Hamel, R.K. Pettit, J.M. Schmidt, F. Hogan,
Antineoplastic agents. 291. Isolation and synthesis of combretastatins A-4, A-
5, and A-6(1a), J. Med. Chem. 38 (1995) 1666e1672.
[31] G.R. Pettit, S.B. Singh, M.L. Niven, E. Hamel, J.M. Schmidt, Isolation, structure,
and synthesis of combretastatins A-1 and B-1, potent new inhibitors of
microtubule assembly, derived from combretum caffrum, J. Nat. Prod. 50
(1987) 119e131.
[32] G.R. Pettit, S.B. Singh, E. Hamel, C.M. Lin, D.S. Alberts, D. Garcia-Kendall,
Isolation and structure of the strong cell growth and tubulin inhibitor com-
bretastatin A-4, Experientia 45 (1989) 209e211.
[33] C.M. Lin, S.B. Singh, P.S. Chu, R.O. Dempcy, J.M. Schmidt, G.R. Pettit, E. Hamel,
Interactions of tubulin with potent natural and synthetic analogs of the
antimitotic agent combretastatin: a structureeactivity study, Mol. Pharmacol.
34 (1988) 200e208.
[34] C.H. Tseng, Y.L. Chen, K.Y. Chung, C.H. Wang, S.I. Peng, C.M. Cheng, C.C. Tzeng,
Synthesis and antiproliferative evaluation of 2,3-diarylquinoline derivatives,
Org. Biomol. Chem. 9 (2011) 3205e3216.
[35] M.M.Lee,I.Y.Chang,C.F.Chang,J.S. Cheng, S.H. Cheng,A.Huang, Breastcancer and
dietary factors in Taiwanese women, Cancer Causes Control 16 (2005) 929e937.
[36] S.H. Cheng, C.M. Chen, J.J. Jian, S.Y. Tsai, W.T. Liu, M.C. Liu, C.M. Chen, H.H. Lin,
Breast-conserving surgery and radiotherapy for early breast cancer in Taiwan,
J. Formos. Med. Assoc. 95 (1996) 372e377.
[16] V.R. Solomon, C. Hu, H. Lee, Design and synthesis of anti-breast cancer agents
from 4-piperazinylquinoline: a hybrid pharmacophore approach, Bioorg. Med.
Chem. 18 (2010) 1563e1572.
[17] S. Eswaran, A.V. Adhikari, R.A. Kumar, New 1,3-oxazolo[4,5-c]quinoline
derivatives: synthesis and evaluation of antibacterial and antituberculosis
properties, Eur. J. Med. Chem. 45 (2010) 957e966.
[18] S. Eswaran, A.V. Adhikari, N.K. Pal, I.H. Chowdhury, Design and synthesis of
some new quinoline-3-carbohydrazone derivatives as potential anti-
mycobacterial agents, Bioorg. Med. Chem. Lett. 20 (2010) 1040e1044.
[19] F.S. Chang, W.C. Chen, C.H. Wang, C.C. Tzeng, Y.L. Chen, Synthesis and anti-
[37] Y.S. Lu, S.H. Kuo, C.S. Huang, Recent advances in the management of primary
breast cancers, J. Formos. Med. Assoc. 103 (2004) 579e598.
[38] Y.C. Ko, J.L. Wang, C.C. Wu, W.T. Huang, M.C. Lin, Lung cancer at a medical
center in southern Taiwan, Chang Gung Med. J. 28 (2005) 387e395.
[39] Y.H. Kuo, Z.Z. Lin, Y.Y. Yang, Y.Y. Shao, W.Y. Shau, R.N. Kuo, J.C. Yang, M.S. Lai,
Survival of patients with small cell lung carcinoma in Taiwan, Oncology 82
(2012) 19e24.
[40] M.H. Palmer, P.S. McIntyre, The Pfitzinger reaction with unsymmetrical
ketones, J. Chem. Soc. B 5 (1969) 539e543.
[41] M.P. Neves, S. Cravo, R.T. Lima, M.H. Vasconcelos, M.S. Nascimento, A.M. Silva,
M. Pinto, H. Cidade, A.G. Corrêa, Solid-phase synthesis of 20-hydroxychalcones.
Effects on cell growth inhibition, cell cycle and apoptosis of human tumor cell
lines, Bioorg. Med. Chem. 20 (2012) 25e33.
proliferative
evaluations
of
certain
2-phenylvinylquinoline
(2-
styrylquinoline) and 2-furanylvinylquinoline derivatives, Bioorg. Med.
Chem. 18 (2010) 124e133.
[20] S. Eswaran, A.V. Adhikari, N.S. Shetty, Synthesis and antimicrobial activities of
novel quinoline derivatives carrying 1,2,4-triazole moiety, Eur. J. Med. Chem.
44 (2009) 4637e4647.
[21] V. Kotra, S. Ganapaty, S.R. Adapa, Synthesis of a new series of quinolinyl
chalcones as anticancer and anti-inflammatory agents, Indian J. Chem. 49B
(2010) 1109e1116.
[22] L. Gupta, C. Karthikeyan, P. Trivedi, Synthesis and characterization of some
quinolinyl chalcones as anti-HIV agents, Int. J. Pharmaceut. Appl. Sci. 1 (2010)
109e113.
[42] G.M. Sheldrick, SHELXS 97, Program Crystal Structure Solution, University of
Göttingen, Germany, 1997.
[43] N.W. Roehm, G.H. Rodgers, S.M. Hatfield, A.L. Glasebrook, An improved
colorimetric assay for cell proliferation and viability utilizing the tetrazolium
salt XTT, J. Immunol. Methods 142 (1991) 257e265.
[44] G. Nunez, M.A. Benedict, Y. Hu, N. Inohara, Caspases: the proteases of the
apoptotic pathway, Oncogene 17 (1998) 3237e3245.
[45] M.S. Satoh, T. Lindahl, Role of poly(ADP-ribose) formation in DNA repair,
Nature 356 (1992) 356e358.