Discovery of a novel benzenesulfonamide analogue that inhibits proliferation and metastasis against ovarian cancer OVCAR-8 cells

Article abstract of DOI:10.2147/DDDT.S225201

Background: Ovarian cancer has been a salient public health concern in the world. It is necessary to develop novel antitumor drugs to treat ovarian cancer. Purpose: This study investigated the synthesis, antiproliferation ability, antitumor mechanisms in

Full text of DOI:10.2147/DDDT.S225201

Drug Design, Development and Therapy
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O R I G I N A L R E S E A R C H
Discovery of a Novel Benzenesulfonamide
Analogue That Inhibits Proliferation and Metastasis
Against Ovarian Cancer OVCAR-8 Cells
This article was published in the following Dove Press journal:
Drug Design, Development and Therapy
Background: Ovarian cancer has been a salient public health concern in the world. It is
Yanyan Jia
Meijuan Li
Yuan Cao
Wenlong Feng
Xueru Li
Wenhua Xue
Huirong Shi
necessary to develop novel antitumor drugs to treat ovarian cancer.
Purpose: This study investigated the synthesis, antiproliferation ability, antitumor mechan-
isms in vitro and in vivo of a novel benzenesulfonamide derivative.
Methods: The novel benzenesulfonamide-1,2,3-triazole hybrid 7c was synthesized from 4-fluor-
obenzenesulfonyl chloride, prop-2-yn-1-amine and 1-(azidomethyl)-3-phenoxybenzene. The struc-
1
ture of this benzenesulfonamide-1,2,3-triazole hybrid 7c was confirmed by 13C NMR, and H
NMR. Compound 7c was evaluated for its antitumor effects in vitro and in vivo against ovarian
Department of Gynecology and
cancer OVCAR-8 cells.
Obstetrics, The First Affiliated Hospital
of Zhengzhou University, Zhengzhou
450052, People’s Republic of China
Results: We discovered that the benzenesulfonamide hybrid 7c potently inhibited cell pro-
liferation against ovarian cancer. Especially, it inhibited cell proliferation with an IC50 value of
0.54μM against OVCAR-8 cells. It could inhibit migration and invasion against OVCAR-8
cells in a concentration-dependent and time-dependent manner. In addition, compound 7c
affected the Wnt/β-catenin/GSK3β pathway against ovarian cancer OVCAR-8 cells. In vivo
study suggested that compound 7c inhibited tumor growth remarkably without obvious
toxicity.
Conclusion: In conclusion, benzenesulfonamide hybrid 7c could be a lead compound for
further antitumor drug discovery to treat ovarian cancer.
Keywords: benzenesulfonamide, proliferation, migration, invasion, in vivo
Introduction
Ovarian cancer as a salient public health concern remains the deadliest form of
gynaecological malignancy.1,2 According to the world health organization, an
estimated total of 226,000 cases of ovarian cancer will be diagnosed and 140,200
patients will succumb to this disease every year in the world, representing the
seventh most common form of cancer in women.3,4 Therefore, discovery of potent
drugs against ovarian cancer is very necessary.
Benzenesulfonamide has become a biologically important object since its pre-
sence in the therapeutic application as the antitumor agent.5,6 Benzenesulfonamide
derivative 1 (Figure 1) was known as a potent receptor tyrosine kinase inhibitor to
treat renal cell carcinoma.7 Benzenesulfonamide derivative 2 was found to have a
significant effect on the inhibition of antiapoptotic proteins Bcl2 and BclxL against
HT-29 cells and SW620 cells.8 Benzenesulfonamide derivative 2 as a histone deace-
tylase inhibitor has been directed to treat peripheral T-cell lymphoma.9 In addition,
Correspondence: Yanyan Jia
Department of Gynecology and
Obstetrics, The First Affiliated Hospital of
Zhengzhou University, Jianshe East Road,
Zhengzhou 450052, People’s Republic of
China
Email jiayy2019@163.com
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207
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you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For
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Figure 1 Anticancer benzenesulfonamide derivatives and 1,2,3-triazole derivatives.
1,2,3-triazole-based heterocycles have been reported to CuSO4.5H2O (0.2 mmol) and sodium ascorbate (0.1 mmol)
possess the anticancer activity.10,11 1,2,3-Triazole 4 could were dissolved in acetone/H2O (4 mL/4 mL) and stirred for 10
arrest cell cycle at the G0/G1 phase in MCF-7 cells.12 1,2,3- hrs at room temperature. Upon completion of the reactions, the
Triazole 5 arrested the cell cycle in the G1/S phase and precipitated product 7c was purified with column chromato-
induced apoptosis against A549 cells.13 1,2,3-Triazole 6 graphy on silica gel (hexane/EtOAc = 9/1). The chemical route
exhibited the antiproliferative activity against acute mye- and NMR data were shown in the Supporting information.
loid leukemia cells by inhibiting histone deacetylases and
tubulin acetylation.14 Based on these interesting findings,
Cell Culture
we hypothesised that the benzenesulfonamide-1,2,3-tria-
Cancer cell lines (MCF7, MGC803, EC109, HepG-2, PC-3,
zole hybrid may display the antiproliferative activity.
A549, OC-314, KYSE-450 and SK-N-SH) were purchased
In continuation of our effort to obtain the bioactive
from GeneChem (Shanghai, China), cancer cell lines
benzenesulfonamide derivative with potent antitumor abil-
(OVCAR-8, SKOV3 and Caov-3) were purchased from
ities, we reported a novel benzenesulfonamide analogue
Type Culture Collection of the Chinese Academy of
containing the 1,2,3-triazole moiety, and furthermore
Sciences (Shanghai, China). All cells were cultured in RPMI
examined its cytotoxic effect against ovarian cancer. We
1640 (Hyclone, Logan, UT, USA), supplemented with 10%
also revealed that this benzenesulfonamide-1,2,3-triazole
foetal bovine serum (Hyclone, Logan, UT, USA) in a humi-
hybrid as an antitumor agent could suppress OVCAR-8
dified CO2 (5%) incubator at 37°C.
cells proliferation, migration and invasion via Wnt/β-cate-
nin/GSK3β pathway.
Cell Viability Assay
1.0 × 105 cells per well were seeded in the 96-well plates.
Materials and Methods
Following treatment with the compound, the cell viability
Synthesis of the Benzenesulfonamide
was detected using the cell proliferation assay kit (Promega
Corporation, Madison, WI) according to the manufacturer’s
Derivative
protocol. The absorbance at 570 nm was examined by a
Reagents and solvents were purchased from commercial
microplate reader to analysize the IC50 values.
sources. 4-Fluorobenzenesulfonyl chloride (2 mmol) was
reacted with prop-2-yn-1-amine (3 mmol) in the presence of
sodium hydroxide (2.5 mmol) and dichloromethane (10 mL) Migration Assay
to obtain the intermediate 7b without the further purification.15 OVCAR-8 cell line was seeded and grown in a migration
Alkyne intermediate 7b (1 mmol), azide derivative (1 mmol), plate (Corning, USA). 20% FBS media or a vehicle was
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Jia et al
added in the upper bottom for 24 hrs. Fresh medium contain- 45%.16 It is necessary to develop the potent anticancer
ing the compound was added to the plates. Images were taken
using an inverted microscope (Nikon, Japan).
against ovarian cancer. In addition, benzenesulfona-
mide and 1,2,3-triazole have been reported to possess
the antitumor activity.5,17 In this investigation, we
synthesized a novel benzenesulfonamide-1,2,3-triazole
hybrid and explored its anticancer mechanisms against
ovarian cancer.
Invasion Assay
OVCAR cells were seeded in a transwell plate with the inva-
sion membrane (LKT labs, USA). 20% FBS media or a vehicle
was added in the upper bottom for 24 hrs. Fresh medium
containing the compound was added for 48 hrs. Images were
taken using an inverted microscope (Nikon, Japan).
Chemical Synthesis of the
Benzenesulfonamide Hybrid 7c
The novel benzenesulfonamide-1,2,3-triazole hybrid 7c
was synthesized in Scheme 1. 4-Fluorobenzenesulfonyl
chloride 7a was reacted with prop-2-yn-1-amine in the
presence of sodium hydroxide to obtain 7b without the
purification.18,19 Compound 7c was readily synthesized
from the crude product 7b and the 1-(azidomethyl)-3-phe-
noxybenzene via click reaction in the presence of copper
(II) sulfate pentahydrate. The NMR data of this benzene-
sulfonamide-1,2,3-triazole hybrid 7c were shown in the
Supporting information.
Western Blotting Analysis
OVCAR cells were treated with the compound for 48 hrs.
Proteins in the cell lysates were resolved by sodium dodecyl
sulfate-polyacrylamide gel electrophoresis, and then trans-
ferred to polyvinylidene fluoride membrane. Then, the mem-
branes were incubated with the primary antibodies overnight
at 4°C. The protein signals were visualized using the chemi-
luminescent substrate (KPL, Guildford, UK).
Xenograft Study
Animals were treated according to protocols established by
the ethics committee of Zhengzhou University and the in
vivo experiments were carried out in accordance with the
approved guidelines and approved by the ethics committee of
Zhengzhou University. Nude mice were maintained under
specific pathogen-free conditions according to the
Zhengzhou university committee protocol. OVCAR cells
were subcutaneously injected into the right flanks of nude
mice. Then, the mice were randomly assigned to the control
group and the treatment group. The control group received
the vehicle (0.9% NaCl) alone, and the treatment group
received the compound for 21 days. The body weight and
tumor size of each mouse was measured every other day. All
data were analysized by GraphPad software.
Benzenesulfonamide Hybrid 7c Was a
Potential Antiproliferative Agent Against
Various Cancer Cell Lines
In order to investigate the antiproliferation ability of
compound 7c, MCF7 cells (breast cancer cells),
MGC803 (gastric cancer cells), EC109 (esophagus can-
cer cells), HepG-2 (liver cancer cells), PC-3 (prostate
cancer cells), A549 (lung cancer cells), OC-314 (ovarian
cancer cells), KYSE-450 (esophagus cancer cells), and
SK-N-SH (neuroblastic cancer cells) were treated with
compound 7c at different concentrations (control, 2μM,
4μM, and 8μM). From the results of Figure 2, com-
pound 7c displayed the potential antiproliferative activ-
ity against all these cancer cell lines. Among them,
compound 7c showed the most potent antiproliferation
efficiency around 70% and 80% for 48 hrs and 72 hrs at
Results and Discussion
Globally, ovarian cancer is the seventh most common
cancer in women and the eighth most common cause of
cancer death, with five-year survival rates below 4μM concentration against ovarian cancer OC-314 cells.
O
S
O
O
S
O
O
S
O
N
b
NH
N
N
NH
Cl
a
F
F
F
O
7a
7b
7c
Scheme
1 Reagents and conditions: (a) sodium hydroxide, prop-2-yn-1-amine, dichloromethane, rt.; (b) 1-(azidomethyl)-3-phenoxybenzene, sodium ascorbate,
CuSO4.5H2O, acetone/H2O = 1:1.
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MGC803
EC109
MCF7
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control
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HepG-2
A549
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OC-314
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72 hours
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*
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M
4 μ
M
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M
control
control
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8 μ
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M
8 μM
Figure 2 Antiproliferative ability of compound 7c at different concentrations (control, 2μM, 4μM, and 8μM) for 48 hrs and 72 hrs against various cancer cell lines. The data
were presented as the mean SEM. *P < 0.05, **P < 0.01.
Benzenesulfonamide Hybrid 7c Potently
Inhibited Cell Proliferation Against
Ovarian Cancer
Benzenesulfonamide Hybrid 7c Inhibited
Migration Against Ovarian Cancer
OVCAR-8 Cells
Based on the preliminary experimental results, concentra- To investigate the effects of benzenesulfonamide hybrid 7c
in endothelial cell migration against ovarian cancer
OVCAR-8 cells, the migration assay was explored accord-
ing to the previous reference.20 As shown in Figure 4A and
C, the migration rates with the treatment of 7c for 48 hrs at
0.25μM, 0.5μM and 1μM were 62.4%, 37.5% and 7.3%,
respectively. From the migration results of Figure 4B and D,
the migration rates with the treatment of 7c at 0.25μM for
24 hrs, 48 hrs and 72 hrs were 73.3%, 61.4%, and 20.8%,
respectively. All these illustrated that benzenesulfonamide-
1,2,3-triazole hybrid 7c could inhibit OVCAR-8 cells
migration in a concentration-dependent manner.
tions of 0.5μM, 1μM, 2μM, and 4μM were chosen to test
the proliferation effects of compound 7c on the cell viabi-
lity of ovarian cancer cells (OC-314, OVCAR-8, SKOV3,
and Caov-3). We added the 5-Fluorouracil as a positive
control to do the cytotoxicity assays in cancer cell lines
(OC-314, OVCAR-8, SKOV3, and Caov-3). The IC50
values of 5-Fluorouracil against OC-314, OVCAR-8,
SKOV3, and Caov-3 cells were 3.12μM, 2.24μM,
22.5μM and 10.7μM, respectively. As shown in Figure 3,
OVCAR-8 cells displayed a marked loss in cell viability
following the treatment at 2μM and 4μM for 48 hrs. From
the results of Figure 3, compound 7c inhibited cell prolif-
eration with IC50 values of 1.82μM, 0.54μM, 3.91μM, and
2.13μM against OC-314, OVCAR-8, SKOV3, and Caov-3
cell lines. These findings supported that the benzenesulfo-
namide hybrid 7c potently inhibited cell proliferation
against ovarian cancer in a concentration-dependent
manner.
Benzenesulfonamide Hybrid 7c Could
Suppress OVCAR-8 Cells Invasion
In addition, the invasion ability of benzenesulfonamide-
1,2,3-triazole hybrid 7c against OVCAR-8 cells was also
evaluated by matrigel-coated transwell. Based on the inva-
sion results of Figure 5A and C, the invasion rates with the
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Figure 3 Benzenesulfonamide 7c potently inhibited cell proliferation against ovarian cancer cell lines (OC-314, OVCAR-8, SKOV3, and Caov-3) in a concentration-
dependent manner. The data were presented as the mean SEM. **P < 0.01, ***P < 0.001.
Control
0.25 μM
0.5 μM
1 μM
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1 μM
Control
24 hours
48 hours
72 hours
Figure 4 (A and C): OVCAR-8 cells were treated with 7c for 48 hrs at 0.25μM, 0.5μM and 1μM to evaluate the migration rates. (B and D): OVCAR-8 cells were treated
with 7c at 0.25μM for 24 hrs, 48 hrs and 72 hrs to evaluate the migration rates. **P < 0.01 and ***P < 0.001 were considered statistically significant compared with the
control.
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A
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Control
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24hours
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1 μM
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1 μM
Figure 5 (A and C): OVCAR-8 cells were treated with 7c for 48 hrs at 0.25μM, 0.5μM and 1μM to evaluate the invasion effects. (B and D): OVCAR-8 cells were treated
with 7c at 0.5μM for 24 hrs, 48 hrs and 72 hrs to evaluate the invasion effects. **P < 0.01 and *P < 0.05 were considered statistically significant compared with the control.
treatment of 7c for 48 hrs at 0.25μM, 0.5μM and 1μM extracellular matrix were involved.22 Based on the migration
were 76.1%, 60.2% and 20.3%, respectively. When and invasion effects of benzenesulfonamide-1,2,3-triazole
OVCAR-8 cells were treated with 7c at 0.5μM, the inva- hybrid 7c against OVCAR-8 cells, the expression levels of
sion rates for 24 hrs, 48 hrs and 72 hrs were 60.6%, EMT related markers (E-cadherin, N-cadherin and Snail-1)
30.4%, and 9.1%, respectively. The matrigel offered a were evaluated by Western blot methods. As shown in
simulant biologicalstroma, and ovarian cancer OVCAR-8 Figure 6, benzenesulfonamide-1,2,3-triazole hybrid 7c
cells were blocked to invade by the benzenesulfonamide could decrease the expression levels of N-cadherin and
hybrid 7c in a concentration-dependent and time-depen- Snail-1, and increase the expression level of E-cadherin in a
dent manner.
concentration-dependent manner.
Benzenesulfonamide Hybrid 7c Affected
the Epithelial-Mesenchymal Transition
Related Markers
Benzenesulfonamide Hybrid 7c Affected
the Wnt/β-Catenin/GSK3β Pathway
Against Ovarian Cancer OVCAR-8 Cells
The phenomenon that epithelial cells acquire mesenchymal Wnt/β-catenin is a conserved cell-signaling system that is
traits, termed as epithelial-mesenchymal transition (EMT), involved numerous biological processes such as organo-
has been observed in physiological and pathological pro- genesis in multicellular organisms cancer pathogenesis and
cesses, including cancer progression.21 Loss of E-cadherin the epithelial-mesenchymal transition (EMT) process.23
and increase of N-cadherin expression levels were consid- Some 1,2,3-triazoles recently described as inhibitors of
ered key events in an EMT process where the cell polarity- the wnt/β-catenin signaling pathway.24 In addition, cele-
related cytoskeleton, cell-cell contacting modulators and coxib as a sulfonamide selective COX-2 inhibitor inhibited
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Control
0.25
0.5
1 (μM)
N-Cadherin
N-Cadherin
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**
Snail-1
β-tubulin
Control
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1 μM
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1 μM
Control
0.25 μM
0.5 μM
1 μM
Figure 6 OVCAR-8 cells were treated with 7c for 48 hrs at 0.25μM, 0.5μM and 1μM to test the expression levels of EMT related markers (E-cadherin, N-cadherin, and
Snail-1). **P < 0.01 and *P < 0.05 were considered statistically significant compared with the control.
human colon cancer cell proliferation by suppressing the proteins Wnt 3a, β-catenin, C-Myc, Cyclin-D, Axin2,
Wnt/β-catenin signaling pathway.25 Because of the same
and TCF4 were significantly downregulated after 48 hrs
treatment.
1,2,3-triazole scaffold in the hybrid 7c, we also explored
its effects on the wnt/β-catenin signaling pathway.
Glycogen synthase kinase-3β (GSK3β) as a serine/threo-
nine protein kinase has been implicated in a wide range of
diseases including cancer.26 The inhibition of GSK-3β
could lead to β-catenin activation and tumor cell
proliferation.27 There is increasing evidence to show that
GSK3β was aberrantly activated in various cancer types
and related to tumor invasion.28 To further investigate
whether compound 7c inhibited OVCAR-8 cells migration
and invasion via a wnt/β-catenin signaling pathway, seven
wnt/β-catenin pathway-related proteins of Wnt 3a, β-cate-
nin, GSK3β, C-Myc, Cyclin-D, Axin2 and TCF4 were
tested in OVCAR-8 cells and examined by Western blot
analysis. Western blot analysis showed that the expression
level of GSK3β was significantly enhanced after treatment
of OVCAR-8 cells with compound 7c compared with the
In vivo Antitumor Study of
Benzenesulfonamide Hybrid 7c
To elucidate the antitumor effects of benzenesulfonamide-
1,2,3-triazole hybrid 7c in vivo, OVCAR-8 xenograft
models were used. Tumor-bearing mice were then ran-
domly assigned to two groups (control and 100 mg/kg
7c) with 5 mice per group. The treatment group received
intragastric administration of 7c per day for a period of 21
days. The results showed that benzenesulfonamide 7c sup-
pressed OVCAR-8 subcutaneous tumor growth (Figure 8).
The average tumor weights of control and benzenesulfo-
namide-1,2,3-triazole hybrid 7c groups were 1.23 0.30 g
and 0.47 0.20 g (inhibitory rate: 61.79%), respectively.
The relative tumor volume in the benzenesulfonamide 7c
group (100 mg/kg) was reduced. Benzenesulfonamide 7c
control group (Figure 7). The results exhibited that treatment did not significantly decrease the mouse body
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Control
0.25
0.5
1
(μM)
Wnt 3a
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β-catenin
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**
Wnt 3a
β-catenin
GSK3β
**
**
**
**
1 μM
****
Control 0.25 μM
0.5 μM
Control 0.25 μM
0.5 μM
1 μM
C-Myc
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GSK3β
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Cyclin-D
Axin2
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TCF4
**
Control 0.25 μM 0.5 μM
1 μM
Control
0.25 μM
0.5 μM
1 μM
β-tubulin
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****
1 μM
Control
0.25 μM
0.5 μM
1 μM
Control
0.25 μM
0.5 μM
Control
0.25 μM
0.5 μM
1 μM
Figure 7 OVCAR-8 cells were treated with 7c for 48 hrs at 0.25μM, 0.5μM and 1μM to explore the expression levels (Wnt 3a, β-catenin, GSK3β, C-Myc, Cyclin-D, Axin2
and TCF4). **P < 0.01 and ****P < 0.0001 were considered statistically significant compared with the control.
A
B
D
C
Normal
100mg/kg
Figure 8 In vivo antitumor effects of compound 7c. (A): Tumor volume. (B): Tumor weight. (C): Body weight. (D): Representative tumor size after treatment with
compound 7c. **P < 0.01 were considered statistically significant compared with the controls.
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weight compared with that of the control. As shown in
Figure 8, compound 7c inhibited tumor growth remark-
ably, suggesting its antitumor efficacy.
Conclusion
In this work, we synthesized a novel benzenesulfonamide-
1,2,3-triazole hybrid, and furthermore examined its cytotoxic
effect against nine cancer cell lines (MCF7, MGC803, EC109,
HepG-2, PC-3, A549, OC-314, KYSE-450, and SK-N-SH).
Among them, compound 7c showed the most potent antipro-
liferation effects against ovarian cancer OC-314 cells with
percentages of 32.3% and 20.7% for 48 hrs and 72 hrs at
4μM concentration. In addition, compound 7c inhibited cell
proliferation with IC50 values of 1.82μM, 0.54μM, 3.91μM,
and 2.13μM against OC-314, OVCAR-8, SKOV3, and Caov-
3 cell lines, investigating that compound 7c displayed the
potent antiproliferation effects against ovarian cancer.
Furthermore, benzenesulfonamide-1,2,3-triazole hybrid
7c potently inhibited migration and invasion against ovar-
ian cancer OVCAR-8 cells in a concentration-dependent
and time-dependent manner. It could decrease the expres-
sion levels of Wnt 3a, β-catenin, C-Myc, Cyclin-D, Axin2,
TCF4, N-cadherin and Snail-1, and increase the expression
levels of E-cadherin and GSK3β. All these results revealed
that compound 7c affected the Wnt/β-catenin/GSK3β path-
way against ovarian cancer OVCAR-8 cells. Importantly,
compound 7c inhibited tumor growth remarkably, while
the body weight was almost unchanged, suggesting the
antitumor efficacy and low global toxicity. Collectively,
we identify that compound 7c could be a lead compound
for further antitumor drug discovery to treat ovarian
cancer.
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synthesis and biological evaluation of novel uracil derivatives bearing
1, 2, 3-triazole moiety as thymidylate synthase (TS) inhibitors and as
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Acknowledgment
The authors thank the support from First Affiliated
Hospital of Zhengzhou University.
14. Ashwini N, Garg M, Mohan CD, et al. Synthesis of 1,2-benzisox-
azole tethered 1,2,3-triazoles that exhibit anticancer activity in acute
myeloid leukemia cell lines by inhibiting histone deacetylases, and
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Disclosure
The authors report no conflicts of interest in this work.
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and antiproliferative evaluation of novel sulfanilamide derivatives as
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