Design, synthesis and antiproliferative activity studies of 1,2,3-triazole-chalcones

Article abstract of DOI:10.1039/c6md00169f

A series of 1,2,3-triazole-chalcone hybrids were designed, synthesized and evaluated for their antiproliferative activity against three selected cancer cell lines (SK-N-SH, HepG-2 and MGC-803). Most of the synthesized compounds exhibited moderate to good activity against all the cancer cell lines selected. Particularly, compound 12k showed the most excellent antiproliferative activity with an IC₅₀ value of 1.53 μM against SK-N-SH cancer cells. The mechanism studies revealed that compound 12k inhibited the proliferation of SK-N-SH cancer cells by inducing apoptosis and arresting the cell cycle at the G1 phase.

Full text of DOI:10.1039/c6md00169f

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Design, synthesis and antiproliferative activity studies of
†
1
,2,3ꢀtriazoleꢀchalcones
1
a
1a
a
b
a
Dong-Jun Fu , Sai-Yang Zhang , Ying-Chao Liu , Xiao-Xin Yue , Jun-Ju Liu , Jian
a
a
a
a
*a
Song , Ruo-Han Zhao , Feng Li , Hui-Hui Sun , Yan-Bing Zhang , and Hong-Min
*a
Liu
a
Collaborative Innovation Center of New Drug Research and Safety Evaluation,
School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR
China
Henan Medical College, Zhengzhou 450001, PR, China
These authors contributed equally
b
1
†
The authors declare no competing interests
Abstract: A series of 1,2,3ꢀtriazoleꢀchalcone hybrids were designed,
synthesized and evaluated for their antiproliferative activity against three
selected cancer cell lines (SK-N-SH, HepG-2 and MGC-803). Most of the
synthesized compounds exhibited moderate to good activity against all
the cancer cell lines selected. Particularly, compound 12k showed the
most excellent antiproliferative activity with an IC value of 1.53 µM
50
against SK-N-SH cancer cells. The mechanism studies revealed that
compound 12k inhibited the proliferation of SK-N-SH cancer cells by
inducing apoptosis and arresting the cell cycle at G1 phase.
Key words: 1,2,3ꢀtriazoleꢀchalcones; antiproliferative; apoptosis; G1
phase
Cancer, being one of the leading causes of death globally, causes a
great burden to both single human lives and the society as a whole.
Although there have been progresses in the development of treatment and
prevention of cancer, the successful treatment of cancer remains a
1
challenge. Therefore, there is still an urgent need to search for novel
anticancer agents that have broader spectrum of cytotoxicity to tumor
2
cells.
Chalcones, important constituents of natural products, are abundant
in edible plants where they are considered to be the precursors of
3
flavonoids and isoflavonoids. There is a growing interest in the
pharmacological potential of chalcones, which constitute an important
group of natural and synthetic products that have been screened for their
4
, 5
6, 7
wide range of pharmacological activities as antibacterial, antitumor,
8, 9
10, 11
antiinflammatory, antifungal and antioxidant agents.
For example,
compound (1), a combretastatin-like chalcone as the inhibitor of
microtubule polymerization, exhibited the excellent cytotoxic activity
12
against K562 cells with an IC of 1.1 µM. A novel boronic acid
5
0
chalcone (2) was reported by Kumar et al. as a putative MDM2
13
antagonist with antitumor activity against cultured tumor cells (Fig. 1).
On the other hand, 1,2,3-triazole is a privileged scaffold in drug
14
discovery with a wide array of biological activities as anti-fungal, anti-

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1
5
16
17
18
bacterial,
anti-allergic,
anti-HIV,
anti-tubercular
and anti-
19
inflammatory agents. Recent research of its pharmacological effects
became much more appealing and promising for the design of anticancer
20
agents.
N-((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl) arylamide was
identified as a proprietary small molecule scaffold for potential antitumor
agents by M.J. Miller group and compound (3) exhibited an IC of 46
5
0
21
nM against MCF-7 cancer cell line. Compound (4), a 1,2,3-triazol-
naphthalimide hybrid, inhibited MCF-7 and SMMC-7721 cell lines with
2
2
IC values of 0.348 and 0.258 µM, respectively(Fig. 1).
5
0
Fig. 1 Structures of chalcone and 1,2,3-triazole derivatives as
antiproliferative agents previously reported
The study of new hybrid systems in which 1,2,3-triazole and
23-27
chalcone are combined comprises an interesting field of research.
We
have previously reported some 1,2,3-triazole-pyrimidine hybrids with
2
8
good antiproliferative activity. These findings have encouraged us to
investigate the potential synergistic effect of 1,2,3-triazole and chalcone
scaffolds. Herein, we report the hybridization of these two
pharmacophores and their antiproliferative ability against the three
selected tumor cell lines.
Azide intermediates 5aꢀe (Scheme 1) and chalcones 6aꢀc (Scheme 2)
29
were efficiently prepared following our previous described method. The
general route for the synthesis of the target 1,2,3-triazole-chalcone
analogues (9aꢀg and 12aꢀn) was depicted in Scheme 3. Commercially
available propargyl bromide reacted with p-acetylphenol or p-
aminoacetophenone in the presence of potassium carbonate to form
compound 7 or 10, which was subjected to click reaction with
appropriately azide intermediates to afford 8 or 11aꢀe with good yields. 8
and 11aꢀe reacted with substituted aromatic aldehyde at room
temperature in a NaOH/EtOH solution to afford target compounds.

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Scheme 1. Synthesis of azide intermediates 5aꢀe. Reagents and
conditions: (a) NaN , TBAB, acetonitrile, reflux.
3
Scheme 2. Synthesis of chalcone intermediates 6aꢀc. Reagents and
conditions: (a) substituted aromatic aldehyde, NaOH, EtOH, rt.
Scheme 3. Synthesis of 1,2,3-triazole-chalcone analogues. Reagents and
conditions: (a) K CO , p-acetylphenol, acetone, reflux; (b) azide
2
3
.
intermediates 5aꢀe, CuSO 5H O, sodium ascorbate, THF-H O (1:1), rt;
4
2
2
(
c) substituted aromatic aldehyde, NaOH, EtOH, rt; (d) K CO , p-
2
3
aminoacetophenone, acetone, reflux.
All synthesized compounds were evaluated for their antiproliferative
activity against three cancer cell lines, MGC-803 (human gastric cancer
cell line), SK-N-SH (human neuroendocrine cancer cell line), and HepG-
2
(human hepatocellular cancer cell line) using the MTT assay. The well-
3
0
known anticancer drug 5-fluorouracil was used as the control.
In order to investigate the effect of 1,2,3-trizole for inhibitory
activity, non-1,2,3-triazole chalcones 6aꢀc and 1,2,3-triazole chalcones
1
2hꢀj were examined for antiproliferative activity and the results are
summarized in Table 1. Removing the 1,2,3-triazole was clearly
detrimental for the inhibitory activity against three cancer cell lines, such

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as compound 6a vs 12h, compound 6b vs 12i, compound 6c vs 12j.
These modifications revealed that 1,2,3-triazole moiety may play a
critical role in determining activity.
Table 1. Inhibitory results of preliminary evaluation against three cancer
cell lines for the target compounds.
a
Comp.
R
R1
IC (µM)
50
SK-N-SH
HepG-2
MGC-803
6
a
-
H
-
48.90 ± 1.03
＞64
＞64
1
2h
39.18 ± 0.89 42.46 ± 0.63 37.26 ± 0.75
＞64 ＞64 ＞64
6
b
1
2i
p-Cl
30.88 ± 0.88 39.22 ± 0.46 29.64 ± 0.48
58.22 ± 1.18 55.64 ± 1.07 61.23 ± 1.24
6
c
-
1
2j
m-OCH3 21.22 ± 0.77 34.66 ± 0.98 38.63 ± 0.46
10.32 ± 0.74 10.30 ± 0.83 7.22 ± 1.04
Inhibitory activity was assayed by exposure for 72 h to substances and
expressed as concentration required to inhibit tumor cell proliferation by
5
-Fu
-
-
a
5
0% (IC ). Data are presented as the means ± SDs of three independent
50
experiments.
To complete the SAR study, a series of 1,2,3-triazole-chalcone
hybrids were prepared and evaluated for their antiproliferative activity.
The antiproliferative activity of compounds 9a−h and 12dꢀg against three
cancer cells were determined initially and the IC values are shown in
50
Table 2. Among them, compound 9g showed the most potent activity
with an IC of 5.47 µM against HepG-2 cells. We found that the
5
0
substitution on the phenyl ring was important for the activity showing
over 5-fold activity loss, when the o, p-diCl group was replaced with the
m-F-p-(p-CH -pierazine) group (compound 9d vs 9g). In addition,
3
compounds 9c and 12f with electron-donating trimethoxy group on the
phenyl ring had more potent inhibitory effect (9.35 and 10.39 µM,

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respectively) against HepG-2 cells than compounds (9aꢀb, 12dꢀe and 12g)
IC > 18 µM) with electron-withdrawing groups.
(
50
Table 2. Antiproliferative activity of the 1,2,3-triazole-chalcone
derivatives
a
Comp. X
R
IC (µM)
5
0
SK-N-SH
HepG-2
MGC-803
9
9
9
a
b
c
O
O
O
o-F
p-Cl
28.58 ± 1.47 18.44 ± 0.73 50.57 ± 1.20
17.50 ± 1.24 21.01 ± 1.32 43.23 ± 0.94
o, m, p-trimethoxy 14.53 ± 1.12 9.35 ± 0.73 37.25 ± 1.05
9
d
O
o,p-diCl
o-OCH3
36.35 ± 1.56 27.86 ± 1.45
26.65 ± 1.36 24.84 ± 1.40
＞64
9
e
O
O
＞64
9
f
p-NO2
m-F-p-(p-CH3-
pierazine)
11.55 ± 0.90 24.35 ± 0.40 29.83 ± 1.19
6.44 ± 0.42 5.47 ± 0.74 11.56 ± 1.38
19.63 ± 1.29 24.02 ± 1.38
＞64
20.48 ± 0.68 23.44 ± 0.54 16.78 ± 0.98
＞64
27.34 ± 0.93 23.48 ± 0.46
6.26 ± 0.32 10.39 ± 0.75 6.26 ± 0.32
42.38 ± 0.73 38.78 ± 0.63 40.18 ± 0.95
10.32 ± 0. 74 10.30 ± 0.83 7.22 ± 1.04
9
g
O
9
h
O
m-Cl
1
2d
2e
2f
2g
-Fa u
N
N
m, m-diCl
m, m-diF
1
1
1
5
N
N
o, o, p- trimethoxy
p-F
Inhibitory activity was assayed by exposure for 72 h to substances and
expressed as concentration required to inhibit tumor cell proliferation by
5
0% (IC ). Data are presented as the means ± SDs of three independent
50
experiments.
To determine whether the benzene ring and heterocycles have an
effect on the activity, compounds with 4-pyridine ring (9i and 12b), 3-
pyridine ring (9j and 12c), 2-furan ring (12h) were synthesized and their
antiproliferative activity results were shown in Table 3. Replacing the
trimethoxy phenyl scaffold of compound 12f with 2-furan ring (12h) led
to a loss of the activity. However, changing the trimethoxy phenyl ring
(
compound 12f) to 3-pyridine ring (compound 12c) led to a significant
improvement of the activity against the tested cell lines. Among the
pyridine-chalcones, compounds with 3-pyridine ring had better
antiproliferative activity than compounds with 4-pyridine ring (compound

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9
j vs 9i, compound 12b vs 12c). All the results indicated that the
heterocycles may play an important role for their inhibitory activity.
Furthermore, the importance of heteroatom between chalcone and
1
,2,3-trizole was investigated (Table 3). When the oxygen atom was
replaced with a nitrogen atom (compound 9i vs 12b, compound 9j vs
2c), their antiproliferative activity were improved, indicating the
1
significance of the nitrogen atom for their inhibitory activity.
These findings have encouraged us to synthesize more pyridine-
chalcone derivatives with nitrogen atom (compound 12k-n, Table 3).
With all the selected three cancer cell lines, compound 12k-n were more
potent than 5-fluorouracil in the single-digit micromolar range. Especially,
compound 12k showed excellent inhibitory effect against the three tested
human cancer cell lines with the IC value ranging from 1.53 to 2.73 µM.
5
0
Compound 12k with electron-donating methoxy group on the phenyl ring
had more potent inhibitory effect (1.53 µM) against SK-N-SH cells than
compounds (12l-n) (IC > 4 µM) with electron-withdrawing groups.
5
0
Table 3. Antiproliferative activity of the 1,2,3-triazole-heteroaryl
chalcones
O
Hetero
X
N
N
R
N
a
Comp.
R
X
Hetero
IC (µM)
5
0
SK-N-SH
HepG-2
MGC-803
9
i
H
H
H
O
NH
O
7.43 ± 0.87 11.39 ± 1.06 26.13 ± 1.20
1
2b
5.23 ± 0.68
6.37 ± 0.15
5.15 ± 0.49
7.02 ± 0.68 17.13 ± 0.57
5.22 ± 0.37 10.16 ± 1.54
9
j
1
2c
H
H
NH
NH
4.37 ± 0.38
3.43 ± 0.56
1
1
2h
39.18 ± 0.88 42.46 ± 0.63 37.26 ± 0.75
2k m-OCH3 NH
2l
o-CF3 NH
1.53 ± 0.13
7.29 ± 0.10
2.21 ± 0.44
6.92 ± 0.46
2.73 ± 0.46
3.15 ± 0.53
1

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1
2m p-CF3
NH
7.26 ± 0.30
4.36 ± 0.43
9.24 ± 0.36
9.32 ± 0.87
7.19 ± 0.25
7.03 ± 0.48
1
2n
p-Cl
NH
-
5
-Fu
-
10.32 ± 0.74 10.30 ± 0.83 7.22 ± 1.04
a
Inhibitory activity was assayed by exposure for 72 h to substances and
expressed as concentration required to inhibit tumor cell proliferation by
0% (IC ). Data are presented as the means ± SDs of three independent
5
50
experiments.
Compounds 12k and 12l were further examined for possible toxicity
against GES-1 (normal human gastric epithelial cell line). As can be seen
in Table 4, we found that compounds 12k and 12l exhibited no
significant toxicity against GES-1 (31.13 and 54.70 µM, respectively).
However, compounds 12k and 12l exhibited remarkable toxicity against
MGC-803 cancer cell line (2.73 and 3.15 µM, respectively). The results
indicated that compounds 12k and 12l had good selectivity between
cancer and normal cells.
Table 4. Inhibitory results of 1,2,3-triazole-chalcones against GES-1 cell
line.
a
Comp.
2k
2l
-Fu
R
m-OCH3
o-CF3
-
IC (µM)
5
0
1
1
5
31.13 ± 1.56
54.70 ± 1.35
7.22 ± 1.04
a
Inhibitory activity was assayed by exposure for 72 h to substances and
expressed as concentration required to GES-1 cell proliferation by 50%
IC ). Data are presented as the means ± SDs of three independent
(
50
experiments.
Apoptosis defects in cancer cells are the primary obstacle that limits
the therapeutic efficacy of anticancer agents, hence the development of
novel agents targeting programmed cell death has become an imperative
3
1
mission for clinical application. Due to the excellent cytotoxic activity
against all tested cancer cell lines, compound 12k was chosen to be
further investigated regarding its mechanism of action. After 24 h
incubation with 12k at indicated concentrations, characteristic apoptotic
morphological changes were observed by fluorescence microscope,
including cell rounding, chromatin shrinkage, and formation of apoptotic

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bodies (Fig. 2). To characterize the mode of cell death induced by
compound 12k, the apoptotic analysis was also performed with Annexin
3
2
V-FITC/PI double staining and quantitated by flow cytometry.
Treatment of S-KN-SH cells with compound 12k increased, in
concentration-dependent manner, the percentage of the apoptotic cells
was up to 6.9%, 7.9%, 12.1%, 50.7% and 97.4%, respectively, compared
to control (8.8%) (Fig. 3A and 3B).
Fig. 2 Apoptosis analysis with Hoechst-33258 staining after a 24 h
treatment of compound 12k in S-KN-SH cells.

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Fig. 3 Compound 12k induced apoptosis in S-KN-SH cells (3A and 3B).
Quantitative analysis of apoptotic cells using Annexin V-FITC/PI double
staining and flow-cytometry calculation. ***P < 0.01 was considered
statistically significant. Dates are mean ± SD. All experiments were
carried out at least three times.
To have a better understanding of the mechanism of action of
cytotoxic activity of compound 12k, the effect of compound 12k on the
cell cycle was investigated by treating S-KN-SH cells with different
26
concentrations (2.5, 5, 10 µM). After treatment S-KN-SH cells for 24 h,
it was observed that the percentage of cells in G1 phase at different
concentrations were 67.06%, 71.27%, and 81.80%, respectively (Fig. 4).
The results suggested that 12k caused an obvious G1 arrest in a
concentration-dependent manner with a concomitant decrease in terms of
the number of cells in other phases of the cell cycle.

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Fig. 4 Effect of compound 12k on the cell cycle of S-KN-SH cells
At the same time, S-KN-SH cells were cultured with different
concentrations of compound 12k for 24 h, both adherent and floating
cells were collected and then Western blot analysis was performed (Fig.
5
). At the same time, the promising compound 12k decreased the level of
pro-caspase 3 and increased the level of active-caspase 3 and p53, which
was consistent with the result of flow cytometry analysis in inducing
apoptosis.

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Fig. 5 Compound 12k regulated related protein expression in S-KN-SH
cells. Equal amounts of protein from whole-cell extracts were separated
by SDS-PAGE.
In summary, we have discovered a new class of 1,2,3-triazole-
chalcone hybrids displaying good inhibitory. Compound 12k was more
potent than 5-FU against three human cancer cell lines. Further
investigation indicated that compound 12k induced cell apoptosis and
arrested cell cycle at G1 phase. Further mechanism investigations are
underway and will be reported in due course.
Acknowledgments
We are grateful for the financial support from the Natural Science
Foundation of China (No. 21372206; 81430085; 81273393), the
Development Foundation of Priority, Ministry of Education (No.
2
0134101130001).
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MedChemComm
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DOI: 10.1039/C6MD00169F
1
2k exhibited an IC value of 1.53 µM against SK-N-SH cells by inducing apoptosis
50
and arresting the cell cycle at G1 phase.