Synthesis and biological evaluation of novel fluorinated anticancer agents incorporating the indolin-2-one moiety

Article abstract of DOI:10.1039/c5ra19617e

A series of novel fluorinated anticancer agents containing the indolin-2-one moiety were designed, synthesized and evaluated for their anticancer activities in vitro. Among them, compounds 6, 7, 9, 12 and 13 showed potent activities against the tested human cancer cell lines. Notably, compound 6 showed significant activities against A549, Bel7402, HepG2, HCT116 and HeLa cancer cell lines, which were comparable to those of sunitinib. Further study on its mechanisms demonstrated that compound 6 can be used as a potential anticancer agent for inhibiting proliferation and inducing apoptosis of HepG2 cells, along with inhibiting angiogenesis of HUVECs.

Full text of DOI:10.1039/c5ra19617e

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Synthesis and Biological Evaluation of Novel Fluorinated
Anticancer Agents Incorporating Indolin-2-One Moiety
Received 00th January 20xx,
Accepted 00th January 20xx
Shuai-Yu Wang†, Li-Jun Wang†, Bo Jiang, Ning Wu, Xiang-Qian Li, Jiao Luo, Bao-Chen Wang, Ren-
Shuai Zhang, Qi Xu, and Da-Yong Shi*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A series of novel fluorinated anticancer agents containing indolin-2-one analogs have aroused great attention for their
indolin-2-one moiety were designed, synthesized and evaluated anticancer activities and were developed as anticancer drugs,
for their anticancer activities in vitro. Among them, compounds 6, such as SU5416, SU5402, SU6668, SU14813, SU11248
7, 9, 12 and 13 showed potent activities against the tested human (sunitinib), SU11274 and PHA665752 (Fig. 1).12,13 Based on the
cancer cell lines. Notably, compound 6 showed significant anticancer pharmacophore moiety of natural bromophenol
activities against A549, Bel7402, HepG2, HCT116 and HeLa cancer and indolin-2-one,
a series of bromophenol derivatives
cell lines, which were comparable to those of sunitinib. The containing indolin-2-one moiety were designed and
further study on its mechanisms demonstrated that compound 6 synthesized. Seven compounds showed potent activity against
can be used as a potential anti-cancer agent for inhibiting the tested fives human cancer cell lines. Among of them,
proliferation and inducing apoptosis of HepG2 cells, along with compound WLJ18 (Fig. 1) was demonstrated that inactivated
inhibiting angiogenesis of HUVECs.
invasion and metastasis by inhibiting the migration of cancer
cells.14
ancer is a one of the most serious diseases and has
gradually become a major public health problem all over the
world. It is accounted for 8.2 million cancer-related deaths
occurred in 2012 according to the WHO report. The incidence
of cancer has been increasing in most regions of the world and
new cancer cases will further increase to 19.3 million per year
by 2025.1 Although many effective chemotherapeutic agents
have been approved to treat cancer, therapies for it are less
satisfactory due to side effects. Therefore, searching for and
developing novel effective agents for treating this disease are
still urgently needed today. Various studies have been
conducted to synthesize and find novel effective anticancer
agents.2-9
Bromophenols possess various potent activities including
protein tyrosine phosphatase 1B inhibitory, antioxidative,
antimicrobial, proteintyrosine kinase (PTK) inhibitory,
anticancer, antithrombotic, and antiinflammatory.10 In our
previous study, a series bromophenols isolated from marine
algae with potent anticancer activities were reported.11 The Fig. 1 Structures of indolinone derivatives as anticancer agents in preclinical
structural scaffold of indolin-2-one is proven as a core or clinical trials and compound WLJ18
.
structure in anticancer active compounds. Those potent
Introduction of fluorine into drug has positive effects on
several properties of molecules including: drug–target
interactions and specificity, metabolic stability, acidity or
basicity, membrane permeability and toxicity.15-18 Based on
structure–activity relationships (SARs) of bromophenol
derivatives containing indolin-2-one moiety and F atom’s
important role in drug design, we designed and synthesized a
a.Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese
Academy of Sciences. Author to whom correspondence should be addressed; E-
Mail: shidayong@qdio.ac.cn; Tel.: +86-0532-8289-8719; Fax: +86-0532-8289-
8741.
†
These authors contributed equally to this work.
Electronic Supplementary Information
DOI: 10.1039/x0xx00000x
(ESI)
available:
See
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series of fluorinated derivatives displaced Br using F atom in our continuing research for novel anticancer agents.
H
O
N
S
O
O
O
Br
N
H
O
N
3
O
N
SO2Cl
S
a
b
O
O
O
N
N
N
H
H
H
N
1
2
4
N
N
O
N
S
O
O
N
H
5
Br
N
N
O
O
O
O
N
N
N
H
R3
S
R3
S
R3
O S
O
O
R2
R1
R2
R1
R2
R1
c
NH
NH
NH
O
O
O
12 14
-
6-8
9 11
-
No.
R1
R2
R3
6 9 12
, ,
CF3
H
CF3
7 10 13
,
,
F
F
F
OH
H
H
8 11 14
,
,
Scheme 1. Synthesis of compounds 6–14. Reagents and conditions: (a) ClSO3H, 65 °C, 1 h; (b) R1R2NH, THF, reflux; (c) EtOH, aldehyde, piperidine, reflux.
The general synthetic methods of compounds were bond in compounds
6
-
14 was assigned to E based on the
shown in Scheme 1, which were performed as our prvious spectra of H NMR and referenced with Ref 19 and 20.
report.14 Firstly, oxindole (
) was reacted with ClSO3H to yield Physicochemical properties (including cLogP-calculated
compound . And then, compound and amines were heated logarithm of partition coefficient between n-octanol and water,
for 3h in THF at 80 oC to afford 5-substituted-indolin-2-one (
TPSA-polar surface area, Ha-hydrogen bond acceptor, Hd-
). At last, the reaction between 5-substituted-indolin-2-one hydrogen bond donor) and toxicity profiles (including
) and the aldehydes was performed under the condition of mutagenic effect, tumorigenic effect, irritating effect and
1
1
2
2
3-
5
(3-5
Knoevenagel condensation in ethanol with a catalytic amount reproductive effect) of these compounds were calculated and
of piperidine to give the desired derivatives 6-14 in good yields. predicted using OSIRIS Property Explorer software at URL
All of the synthesized derivatives were purified and their http://www.organic-chemistry.org/prog/peo/.21
The
structures were characterized by spectroscopic means (1H, 13C calculation of physicochemical properties and prediction of
NMR, MS and HRMS). The configuration of the double toxicity risks were shown in table 1.
Table 1 Calculated physicochemical properties and predicted toxicity of compounds 6-14
Toxicity Risks e
M/T/I/R
Compd
cLogPa
TPSA(Å2)b
Ha c
Hdd
2 | RSC. Adv., 2015, 00, 1-3
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WLJ18
3.88
4.99
3.49
3.05
3.01
1.51
1.06
3.42
1.92
1.47
102.1
83.65
83.65
103.8
84.09
84.09
104.3
103.8
103.8
124.1
7
5
5
6
6
6
7
8
8
9
2
2
2
3
1
1
2
1
1
2
L/L/L/H
L/L/L/H
L/L/L/H
L/L/L/H
L/L/L/H
L/L/L/H
L/L/L/H
L/L/L/H
L/L/L/H
L/L/L/H
6
7
8
9
10
11
12
13
14
acLogP, calculated logarithm of partition coefficient between n-octanol and water; b TPSA, polar surface area; c Ha, hydrogen bond acceptor; dHd, hydrogen
bond donor; e Toxicity risks: M, mutagenic effect; T, tumorigenic effect; I, irritating effect; R, reproductive effect; L, low; M, medium; H, high.
All the newly synthesized compounds were investigated HeLa; human colon cancer cell line, HCT116) by using MTT
for their in vitro anti-cancer activity against five human cancer assay and sunitinib as a positive control. The preliminary
cell lines (human lung cancer cell line, A549; human hepatoma results of inhibited ration of compounds
cell lines, Bel-7402 and HepG2; human cervical cancer cell line, summarized in Fig.2.
6-14 were
Fig.2 Newly synthesized compounds inhibit human cancer cell lines proliferation.
As shown in Fig.2, the synthesized compounds 6, 7, 9, 12
,
HepG2, HCT116 and HeLa cancer cell lines with IC50 values of
and 13 exhibited potent anticancer activity against the tested 5.10 ± 0.64, 4.40 ± 0.78, 3.30 ± 0.14, 4.40 ± 1.09 and 4.30 ±
human cancer cell lines at 10 μg/mL, respectively. Notably, 0.77 μg/mL, repectively, which better than that of our previous
compound
HepG2, HCT116 and HeLa cancer cell lines with the inhibition activities of compound
rate of 96.6%, 97.5%, 98.4%, 91.7% and 98.0% at 10 μg/mL, HCT116 and HeLa cancer cell lines were comparable to those
which were comparable to those of sunitinib. Compounds of sunitinib under the same conditions. Compound showed
and showed better anticancer activity against A549, Bel7402, potential inhibitory activity against HeLa cancer cell line with
HCT116 and HeLa cancer cell lines than that of HepG2 cancer IC50 value 7.3 ± 0.87 μg/mL. Compound displayed better
6
showed significant activity against A549, Bel7402, reported compound WLJ18. The results also testify that
6
against A549, Bel7402, HepG2,
7
7
9
9
cell line at 10 μg/mL. Compounds 12 and 13 exhibited selective anticaner activity against A549, Bel7402, HCT116 and HeLa
cytotoxicity to HCT116 cell line with 59.1% and 66.9% growth cancer cell lines with IC50 values 7.2 ± 0.64 μg/mL, 8.86 ± 2.17
inhibitions at 10 μg/mL, and with under 50.0% inhibitions to μg/mL, 5.23 ± 0.57 μg/mL, 5.3 ± 1.21 μg/mL than that of
A549, Bel7402, HepG2 and HeLa cancer cell lines, respectively. HepG2 cancer cell line (IC50 = 15.2
± 1.76 μg/mL. Compounds
Based on the preliminary bioassay results, the IC50 values 12 and 13 exhibited selective cytotoxicity to HCT116 cell line
were evaluated in order to investigate the potential anticancer with IC50 values of 7.3 ± 1.26 μg/mL and 4.3 ± 0.82 μg/mL. The
activities. The IC50 values of the target compounds are other compounds showed weak anticancer activities against
presented in table 2. As shown in table 2, compound
6
the tested cancer cell lines.
exhibited excellent anticancer activities against A549, Bel7402,
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Table 2 IC50 values of compounds
6-
14 against five human cancer cell lines.
IC50 (µg/mL)a
Compd
A549
Bel7402
9.2± 0.84
4.40± 0.78
15.8± 3.17
NA
HepG2
13.2±2.42
3.30± 0.14
36.4± 0.74
NA
Hct116
9.1± 0.13
4.40± 1.09
11.3± 1.21
NA
Hela
WLJ18
6.6± 0.82
7.4± 0.22
4.30± 0.77
7.3± 0.87
NA
6
5.10± 0.64
15.1± 2.13
NAb
7
8
9
7.2± 0.64
NA
8.86± 2.17
NA
15.2± 1.76
NA
5.23± 0.57
NA
5.3± 1.21
NA
10
11
12
NA
NA
NA
NA
NA
23.2 ± 3.11
15.0 ± 1.26
NA
14.5 ± 0.45
11.2± 2.03
27.1± 3.15
4.5± 0.56
24.6 ± 1.78
12.6 ± 3.36
NA
7.3 ± 1.26
4.3 ± 0.82
NA
10.9 ± 1.53
11.3 ± 1.36
NA
13
14
Sunitinibc
11.7± 1.22
4.9± 0.62
3.4± 1.26
2.6± 0.42
a IC50: Concentration of the compound producing 50% cell growth inhibition after 48 h of drug exposure, as determined by the MTT assay. Each experiment
b
was run at least three times, and the results are presented as average values ± standard deviation; NA: Compound showing IC50 value > 50μg/mL;
cSunitinib as the positive control.
From above results, the preliminary SARs of these benefit for their anticancer activity; (III) the fluorinated moiety
compounds can been drawn as the follows (Fig.3.): (I) the played a crucial role in maintaining anticancer activities of the
types of amino groups at 5-position of indolin-2-one could conjugated derivatives.
influence the activities; (II) the hydrophobic parameter was
Fig. 3 Structure–Activity relationships of compounds 6-14.
Along with proliferation inhibition of cancer cells, the HepG2 cells were stained and photographed. As shown in
induction of apoptosis is an important strategy in cancer Fig. 4, compound induced apoptosis of HepG2 cells in a dose-
therapy. Thus, we checked the apoptotic effect of compound dependent manner. Compound , at the concentration of 12
by using a Hoechst33342 staining assay. After treated with μg/mL, was able to induce 25.75% cell apoptosis compared to
compound (0 μg/mL, 3μg/mL, 6μg/mL, 12μg/mL) for 12 h, the untreated one.
6
6
6
6
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Fig. 4 Effect of compound
6
on apoptotic cell death by Hoechst33342 assay. (a)The cancer cells were treated with compound
6
for 12 h, and then stained
with Hoechst 33342 solution. (b) The apoptotic cells were counted. The data shown in the graphs are the mean ± SD values of at least three individual
experiments. ** p< 0.01 versus control.
To reveal the underlying mechanisms of apoptosis drugs. For further understand the anticancer activity of
induced by compound
compound at the indicated doses (0-12 μg/mL) for 12 h, and Before we started the angiogenesis assays, we checked the
the apoptosis-related proteins were checked by cytotoxicity of compound on HUVECs. As shown in Fig. 6,
immunoblotting assay. Compound increased the pro- compound significantly induced cytotoxicity on HUVECs at
apoptotic protein expression of p53, Bax, cleaved caspase 9 12 µg/mL concentration. Thus, we used and µg/mL of
6, HepG2 cells were treated with compound 6, we performed angiogenic assays in HUVECs.
6
6
6
6
3
6
and cleaved caspase 3. In contrast, compound
anti-apoptotic protein expression of Bcl-2 (Fig. 5). These
results implied that compound promoted apoptosis in HepG2
cells by regulating the apoptosis-related proteins.
6
decreased the compound
6
in the next assays.
6
Fig. 6 Compound
6 (12 μg/mL) significantly inhibits HUVECs proliferation.
** p< 0.01 versus control.
Endothelial cells migration is one of the essential steps in
the process of angiogenesis. We first investigated the
Fig. 5 Immunoblotting analysis of apoptosis related proteins of HepG2 cells migration of HUVECs in wound healing assay. HUVECs were
treated with compound wounded by sterile tips and incubated with 0, 3, 6 μg/mL of
compound for 24 h. The migration of HUVECs was
6.
6
Angiogenesis plays an important role in solid tumour significantly blocked by compound
growth. It has become a major target in exploiting anticancer were shown in Fig.7.
6
at 3 and 6 μg/mL, which
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Fig. 7 HUVECs were plated at 6-well plate until 90% confluence. And then the HUVECs were scratched and treated with compound
6 as indicated
concentrations for 24 h. (a) Images of the wounded monolayers of the HUVECs (200× magnification); (b) The migrated length of HUVECs. The data shown
in the graphs are the mean ± SD values of at least three individual experiments. *p < 0.05 and **p < 0.01 compared to the control.
Tube formation is another major step of angiogenesis. length of endothelial tubes formed on Matrigel was
Next, a tube formation assay was performed on growth factor significantly reduced by compound
enhanced Matrigel. As showed in Fig.8 (a and b), the total manner.
6 in a dose-dependent
Fig. 8 HUVECs were seeded onto the growth factor enhanced Matrigel-coated 96-well plate with or without compound 6. (a) After 7 h incubation, the tube-
like networks were photographed (200× magnification); (b) The length of the tube networks was quantified. The data shown in the graphs are the mean ± SD
values of at least three individual experiments. ** p< 0.01 versus control.
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The work was supported by the National Natural Science
Foundation of China (No. 41276167, 41206066, 41506169 and
41306157), China Postdoctoral Science Foundation (No.
2015T80755 and 2014M551972), the National science and
technology support project (2013BAB01B02-2), Science and
Technology Development Program of Qingdao Shinan District
(NO. 2013-12-008-SW), Basic Research Projects of Qingdao
Science and Technology Plan (NO. 14-2-4-35-jch).
Author Contributions
Shuai-Yu Wang, Li-Jun Wang, and Da-Yong Shi contributed
to the study concept and design, and the manuscript
preparation. Li-Jun Wang and Shuai-Yu Wang performed the
experimental studies and analyzed the data. Bo Jiang, Ning Wu,
Xiang-Qian Li, Jiao Luo, Bao-Cheng Wang, Ren-Shuai Zhang and
6 for 24 h. Qi Xu contributed in critical reading and discussion on the
Fig. 9 HUVECs were incubated with 3–6µg/ml compound
Nitrite concentration was determined using the NO Kit. *p < 0.05 and **p < manuscript. All the authors approved the final version.
0.01 compared to the control.
Notes and references
Nitric oxide (NO) is a signalling molecule that plays
various roles pathologically and physiologically.22 In endothelial
cells, NO plays a key role in tumour angiogenesis. Finally, we
checked the NO production in HUVECs after treated with
1
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compound
reduced after treating HUVECs for 24 h (Fig.9). Above all,
compound was considered to have an antiangiogenic activity
6. The concentration of NO was significantly
6
2
L. Qi, X. M. Wang, G .H. Lu and Y. H. Yang, RSC Adv., 2014,
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In summary, we synthesized a series of novel fluorinated
anticancer agents containing indolin-2-one moiety and
evaluated for their anticancer activities against A549, Bel7402,
HepG2, HeLa and HCT116 cancer cell lines by using MTT assay
5
5
6
5, 37887.
O. Afzal, S. Kumar, M. R. Haider, M. R. Ali, R. Kumar, M. Jaggi
and S. Bawa, Eur. J. Med. Chem., 2015, 96, 871.
in vitro. Among them, compounds
potent activity against the tested five human cancer cell lines.
Notably, compound showed significant activity against A549,
6, 7, 9, 12 and 13 showed
7
8
K. W. Wellington, RSC Adv., 2015,
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Bel7402, HepG2, HCT116 and HeLa cancer cell lines with IC50
values of 5.10 ± 0.64, 4.40 ± 0.78, 3.30 ± 0.14, 4.40 ± 1.09 and
4.30 ± 0.77 μg/mL, which were comparable to those of
sunitinib. The further study on its mechanism demonstrated
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for inhibiting proliferation and inducing apoptosis of cancer
cells, along with inhibiting angiogenesis of HUVECs. The further
studies on structural modifications and related mechanism of
action of these compounds are currently in progress, which
will be reported in future.
Luo, M. Yang, S. H. Jin and D. Y. Shi, Mar. Drugs, 2015, 13
806.
,
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17 K. Müller, C. Faeh and F. Diederich, Science, 2007, 317, 1881.
18 D. A. Nagib and D. W. MacMillan, Nature, 2011, 480, 224.
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Org / prog / peo /. ( accessed 16-9-2015
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23 Compound
ppm): 10.17(s, 1H), 9.13(s, 1H), 8.38(s, 1H), 8.18(s, 1H),
8.12(s, 1H), 7.74(d, 1H, = 8.0Hz),7.42(d, 2H, = 8.5Hz),
7.20(d, 2H, = 8.5Hz), 7.07(d, 1H,
= 8.0Hz); 13C NMR
(Acetone-d6, 125 MHz, ppm): 166.7, 145.0, 137.7, 136.0,
6
: Yellow solid; 1H NMR (Acetone-d6, 500 MHz,
δ
J
J
J
J
δ
135.0, 132.9, 132.1(2C), 131.9(2C), 131.1(2C), 129.4, 128.7,
124.8, 123.4(2C), 122.6(2C), 122.3, 119.6, 116.7, 110.0;
ESIMS: m/z 588 [M-H]- HRESIMS: calc for
C23H12F6BrN2O3S [M-H]- 588.9648, found 588.9662.
8 | RSC. Adv., 2015, 00, 1-3
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Synthesis and Biological Evaluation of Novel Fluorinated Anticancer Agents Incorporating
Indolin-2-One Moiety
Shuai-Yu Wang†, Li-Jun Wang†, Bo Jiang, Ning Wu, Xiang-Qian Li, Jiao Luo, Bao-Chen Wang, and
Da-Yong Shi*