Design, Synthesis and Antitumor Activities of 1,2,3-triazole-diethylene Glycol Tethered Isatin Dimers

Article abstract of DOI:10.1002/jhet.3330

A series of novel 1,2,3-triazole-diethylene glycol tethered isatin dimers were designed, synthesized, and screened for their in vitro antitumor activities in this paper. All dimers showed promising activities against the tested HepG2, Hela, A549, DU145, S

Full text of DOI:10.1002/jhet.3330

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Design, Synthesis and Antitumor Activities of 1,2,3-triazole-diethylene
Glycol Tethered Isatin Dimers
a
Yi-Lei Fan,
Zhong-Ping Huang,b and Min Liuc
*
aKey Laboratory of Drug Prevention and Control Technology of Zhejiang Province, Zhejiang Police College, Hangzhou,
People’s Republic of China
bCollege of Chemical Engineering, Zhejiang University of Technology, Hangzhou, People’s Republic of China
cCollege of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, People’s Republic of China
*E-mail: fanyilei@zjjcxy.cn
Received July 22, 2018
DOI 10.1002/jhet.3330
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
A series of novel 1,2,3-triazole-diethylene glycol tethered isatin dimers were designed, synthesized, and
screened for their in vitro antitumor activities in this paper. All dimers showed promising activities against
the tested HepG2, Hela, A549, DU145, SKOV3, MCF-7, and doxorubicin-resistant MCF-7 human cancer
cell lines. The most active dimer 7g was >1.55 folds more potent than etoposide against all tested cell lines,
warrant further investigation.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
resistance to cancer therapy creating an urgent need to
develop new drugs for efficient treatment of cancers [5].
Isatin and triazole derivatives possess diverse biological
and pharmacological properties such as antitubercular
[6,7], antibacterial [8,9], antiviral [10,11], antimalarial
[12,13], and anticancer [14,15] activities, occupying an
important position in the drug discovery. Several isatin-
or triazole-based compounds such as sunitinib,
nintedanib, semaxanib, and carboxyamidotriazole (Fig. 1)
are under clinical trials or have already been used in
clinical practice for the treatment of various cancers
[16,17]. Moreover, isatin dimers were found to have
Cancer is the second leading deadliest diseases
throughout the world, accounting for more than 8 million
deaths annually [1]. Cancer, comprising both
heterogeneous
cellular
compositions
and
microenvironmental cues, is the rapid creation of
abnormal cells which can invade adjoining parts of the
body and spread to other organs [2]. Chemotherapy is a
mainstay modality for cancer, but the traditional cancer
chemotherapy is limited by systemic toxicity and side
effects [3,4]. Moreover, the rapid development of
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Y.-L. Fan, Z.-P. Huang, and M. Liu
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Figure 1. Chemical structures of sunitinib, nintedanib, semaxanib, and carboxyamidotriazole. [Color figure can be viewed at wileyonlinelibrary.com]
promising anticancer potential recently [18–21], and the
structure–activity relationship revealed that the linker
between the two isatin motifs influenced their biological
activities significantly [19,22–24].
RESULTS AND DISCUSSION
We first designed and synthesized the desired 1,2,3-
triazole-diethylene glycol tethered isatin dimers 7a–l
following the synthetic routes shown in Scheme 1.
Treatment of diethylene glycol 1 with tosyl chloride in
presence of triethylamine generated intermediate 2, and
then alkylation of isatins 3 with intermediate 2 yielded the
intermediate 4. Substitution of tosyl in intermediate 4 with
azido provided the key intermediate 5. Alkylation of
isatins 3 with propargyl bromide gave intermediates 6
which were consequently utilized for the synthesis of the
desired isatin dimers 7a–c via click chemistry with copper
acetate as catalyst. Finally, condensations of targets 7a–c
with the requested amine hydrochlorides in the presence
of sodium bicarbonate produced isatin dimers 7d–l [22].
All 1,2,3-triazole-diethylene glycol tethered isatin
dimers 7a–l were evaluated for their in vitro anticancer
activities against HepG2 (liver carcinoma), Hela (cervical
cancer), A549 (lung adenocarcinoma), DU145 (prostatic
cancer), SKOV3 (ovarian carcinoma), MCF-7 (breast
cancer), and drug-resistant MCF-7/DOX (doxorubicin-
resistant MCF-7) by SRB assay [25]. IC50 values were
presented as the concentration of drug inhibition 50% cell
growth and determined by at least three separate tests and
reported. The IC50 values of the synthesized isatin dimers
along with etoposide were measured, and the results were
presented in Table 1.
Based on the earlier research results and as a
continuous research program to develop new anticancer
candidates, a series of novel isatin dimers tethered
through 1,2,3-triazole-diethylene glycol were designed,
synthesized, and evaluated for their in vitro anticancer
activity against HepG2 (liver carcinoma), Hela (cervical
cancer), A549 (lung adenocarcinoma), DU145 (prostatic
cancer), SKOV3 (ovarian carcinoma), MCF-7 (breast
cancer), and drug-resistant MCF-7/DOX (doxorubicin-
resistant MCF-7) human cancer cell lines in this study.
Our major goal is to optimize the linker between the
two isatin moieties and facilitate the further development
of these dimers. The illustration of the design strategy is
depicted in Figure 2.
It can be concluded from Table 1 that all of the
synthesized 1,2,3-triazole-diethylene glycol tethered isatin
dimers with IC50 ranging from 0.18 to 49.26 μM have a
broad-spectrum activity against the tested seven cell lines,
and all of them were more potent than the reference
etoposide against Hela, A549, and doxorubicin-resistant
MCF-7 cell lines. Notably, the resistance index (RI:
IC50(MCF-7/DOX)/IC50(MCF-7)) of all dimers were less than
1, suggesting that these dimers may have novel
mechanism of action.
Figure 2. Schematic of design strategy on 1,2,3-triazole-diethylene gly-
col tethered isatin dimers. [Color figure can be viewed at
wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Design, Synthesis and Antitumor Activities of 1,2,3-triazole-diethylene Glycol
Tethered Isatin Dimers
Scheme 1. Synthesis of 1,2,3-triazole-diethylene glycol tethered isatin dimers 7a–l.
Preliminary structure–activity relationship study
indicated that substituents on both C-3 and C-5 positions
of isatin motif significantly influenced the anticancer
activity. For C-5 position, the unsubstituted dimers were
more potent than the corresponding electron-withdrawing
-F and electron-donating -Me substituted analogs. For C-
3 position, the relative contributions of substituents was -
NOMe > -O > -NOH > -NOEt generally.
cell lines, which could act as a lead for further
optimization.
CONCLUSIONS
In conclusion, the synthesized novel 1,2,3-triazole-
diethylene glycol tethered isatin dimers possess
promising in vitro anticancer activities against a panel of
cancer cell lines. In particular, the most active dimer 7g
was >1.55 folds more potent than etoposide against all
Especially, the most active isatin dimer 7g (IC50: 0.18–
9.92 μM) with RI of 0.32 was >1.55 folds more potent
than etoposide (IC50: 6.94-≥50 μM) against all tested
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Table 1
Structures and anticancer activities of isatin dimers 7a–l.
Structure
R1
IC50 (μM)
Compd.
R2
HepG2
Hela
6.25
12.67
12.11
19.89
36.38
42.15
5.16
10.08
6.62
27.66
44.49
31.70
A549
DU145
SKOV3
MCF-7
MCF-7/DOX
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
H
Me
F
H
Me
F
H
Me
F
H
Me
F
O
O
O
0.42
5.49
4.28
0.98
8.36
6.74
0.18
1.32
3.86
8.98
12.31
10.77
6.94
5.34
13.20
8.47
22.80
28.29
39.40
2.98
9.19
2.91
29.90
43.21
44.79
>50
8.86
5.43
19.67
27.15
16.54
44.24
29.62
22.96
8.30
21.12
14.56
41.36
42.08
33.87
31.79
12.21
23.28
17.72
18.67
31.02
28.49
9.22
16.78
15.62
26.56
35.93
48.30
14.38
3.57
11.54
8.99
11.35
22.24
19.80
2.98
13.49
20.22
29.59
24.56
4.04
8.64
5.52
32.73
49.26
42.24
18.66
NOH
NOH
NOH
NOMe
NOMe
NOMe
NOEt
NOEt
NOEt
-
6.68
12.21
17.51
31.46
24.89
etoposide
-
>50
>50
tested seven cell lines, which could act as a starting point
for further investigation.
The mixture of intermediates 5 (1 mmol), 6 (1 mmol), and
Cu (OAc)2 (0.05 mmol) in dimethylformamide (10 mL) was
stirred at room temperature for 12 h, and then removal of the
solvent under reduced pressure. The residue was purified by
silica gel chromatography eluted with PE:EA = 1:1 to give
the desired isatin dimers 7a–c. To a mixture of isatin
dimers 7a–c (1 mmol) and NaHCO3 (4 mmol) in water
(2 mL) and MeOH (10 mL), the requested amine
hydrochlorides (3 mmol) was added. The mixture was
stirred at 50°C for 12 h. After cooling to room temperature,
the mixture was extracted with EA (10 mL × 3). The
combined organic layers were washed with water
(20 mL × 2) and brine (20 mL) in sequence and were dried
over anhydrous Na2SO4. After filtration, the filtrate was
concentrated under reduced pressure to give a residue
which was purified by silica gel chromatography eluted
with PE:EA = 1:1 to give the desired satin dimers 7d–l.
EXPERIMENTAL SECTION
The general procedure for preparing targets 7a–l.
A
solution of diethylene glycol 1 (1 mmol), tosyl chloride
(2.5 mmol), and triethylamine (3 mmol) in
dichloromethane (30 mL) was stirred at room temperature
overnight. The mixture was concentrated under reduced
pressure to give crude product which was purified by
silica gel chromatography eluted with petroleum ether
(PE):ethyl acetate (EA) = 1:1 yielded the desired
intermediate 2.
A mixture of intermediate 2 (5 mmol), potassium
carbonate (3 mmol), and isatins 3 (2 mmol) in N,N-
dimethylformamide (10 mL) was stirred at room
temperature overnight. After filtration, the filtrate was
concentrated under reduced pressure. The residue was
purified by silica gel chromatography eluted with PE:
EA = 1:1 to give the intermediates 4.
The suspension of intermediates 4 (1 mmol) and sodium
azide (2 mmol) in N,N-dimethylformamide (10 mL) was
stirred at 80°C for 8 h. After cooling to room
temperature, the mixture was filtered. The filtrate was
concentrated under reduced pressure, and the residue was
purified by silica gel chromatography eluted with PE:
EA = 1:1 to give the intermediates 5.
A mixture of isatins 3 (1 mmol), potassium carbonate
(3 mmol), and propargyl bromide (1.5 mmol) in N,N-
dimethylformamide (10 mL) was stirred at room
temperature overnight. After filtration, the filtrate was
concentrated under reduced pressure. The residue was
purified by silica gel chromatography eluted with PE:
EA = 3:1 to give the intermediates 6.
1-((1-(2-(2-(2,3-Dioxoindolin-1-yl)ethoxy)ethyl)-1H-1,2,3-
triazol-4-yl)methyl)indoline-2,3-dione (7a).
Yellow solid,
1
yield: 27%. H NMR (400 MHz, DMSO-d6) 3.42 (2H, t,
-CH2-), 3.49 (2H, t, -CH2-), 3.86 (2H, t, -CH2-), 4.34
(2H, t, -CH2-), 4.98 (2H, s, -CH2-), 7.10 (2H, t, Ar-H),
7.22 (2H, d, Ar-H), 7.50 (2H, d, Ar-H), 7.62 (2H, t, Ar-
H), 8.11 (1H, s, triazole-H). ESI-MS m/z: 468 [M + Na]+.
Elemental Anal. Calcd (%) for C23H19N5O5: C, 62.02; H,
4.30; N, 15.72; Found: C, 61.88; H, 4.12; N, 15.46.
5-Methyl-1-((1-(2-(2-(5-methyl-2,3-dioxoindolin-1-yl)ethoxy)
ethyl)-1H-1,2,3-triazol-4-yl)methyl)indoline-2,3-dione (7b).
Yellow solid, yield: 35%. 1H NMR (400 MHz,
DMSO-d6) 2.28 (6H, s, 2 × CH3), 3.41 (2H, t, -CH2-),
3.46 (2H, t, -CH2-), 3.85 (2H, t, -CH2-), 4.33 (2H, t,
-CH2-), 4.96 (2H, s, -CH2-), 7.12 (2H, d, Ar-H), 7.35
(2H, s, Ar-H), 7.42 (2H, d, Ar-H), 8.10 (1H, s, triazole-
H). ESI-MS m/z: 496 [M + Na]+. Elemental Anal. Calcd
(%) for C25H23N5O5: C, 63.42; H, 4.90; N, 14.79;
Found: C, 63.19; H, 4.73; N, 14.52.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet