Isatin–Coumarin Hybrids Tethered via Diethylene Glycol: Design, Synthesis, and Their In Vitro Antitumor Activities

Article abstract of DOI:10.1002/jhet.3329

A series of novel isatin–coumarin hybrids was designed, synthesized, and assessed for their in vitro antitumor activities against drug-sensitive HepG2, Hela, A549, DU145 (prostatic cancer), SKOV3, and MCF-7 as well as drug-resistant MCF-7/DOX (doxorubicin

Full text of DOI:10.1002/jhet.3329

Month 2018
Isatin–Coumarin Hybrids Tethered via Diethylene Glycol: Design,
Synthesis, and Their In Vitro Antitumor Activities
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 24, 2018
DOI 10.1002/jhet.3329
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
A series of novel isatin–coumarin hybrids was designed, synthesized, and assessed for their in vitro anti-
tumor activities against drug-sensitive HepG2, Hela, A549, DU145 (prostatic cancer), SKOV3, and MCF-7
as well as drug-resistant MCF-7/DOX (doxorubicin-resistant MCF-7) human cancer cell lines. Results re-
vealed that the synthesized hybrids displayed considerable activities against the tested seven cancer cell
lines.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
What is worse, cancer cases will rise to 22 million with
13 million deaths annually within the next two decades
[4]. The traditional cancer chemotherapy is limited by
systemic toxicity, side effects as well as the rapid
development of resistance [5–7]. Therefore, there is an
urgent need to develop newer, safer, and higher effective
anticancer drugs.
Cancer, the second leading cause of death globally, puts
a heavy burden on the health care systems all over the
world [1,2]. The World Health Organization has
estimated that roughly 10.4 million incident cases of
cancer in the year 2015 led to 8.8 million deaths [3].
© 2018 Wiley Periodicals, Inc.

Y.-L. Fan, Z.-P. Huang, and M. Liu
Vol 000
Isatin and coumarin which act as structural subunits of
more complex natural products and drugs are ubiquitous
in nature. Their derivatives exhibit diverse
pharmacological properties such as antitubercular [8–10],
antibacterial [11,12], antiviral [13,14], antimalarial
[15,16], and anticancer [17,18] activities, occupying an
important position in drug discovery. In addition to this,
isatin or coumarin pharmacophore unit containing
derivatives which are exemplified by sunitinb, nintedanib,
semaxanib, and STX64 (Fig. 1) is under clinical trials or
has already been used in clinical practice for the
treatment of various cancers, suggesting that isatin and
coumarin moieties are useful pharmacophores for
searching new anticancer agents. [19,20]. Moreover,
some isatin–coumarin hybrids demonstrated considerable
in vitro activity against cancer cell lines, and the
structure–activity relationship (SAR) revealed that the
linker between isatin and coumarin influenced the activity
greatly [21–23].
Figure 2. Schematic of design strategy on diethylene glycol tethered
isatin–coumarin hybrids. [Color figure can be viewed at
wileyonlinelibrary.com]
To optimize the linker between isatin and coumarin
moieties and facilitate the further development of isatin–
coumarin hybrids, a series of novel isatin–coumarin
hybrids tethered via diethylene glycol were designed,
synthesized, and screened for their in vitro anticancer
activity against drug-sensitive HepG2, Hela, A549,
DU145 (prostatic cancer), SKOV3, and MCF-7 as well as
drug-resistant MCF-7/DOX (doxorubicin-resistant MCF-
7) human cancer cell lines in this study. The illustration
of the design strategy is depicted in Figure 2.
2-one 6 was obtained by treatment of resorcinol 5 with
ethyl acetoacetate in the presence of conc. H2SO4. The
precursors 4 and 6 were utilized for the synthesis of
desired diethylene glycol tethered isatin–coumarin
hybrids 7a–d by substituted reaction in the presence of
K2CO3 in DMF. Finally, condensations of targets 7a–d
with the requested amine hydrochlorides in the presence
of sodium bicarbonate produced isatin–coumarin hybrids
7e–l [23].
The diethylene glycol tethered isatin–coumarin hybrids
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 [24]. 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-1,2,3-triazole-
coumarin hybrids along with etoposide were measured,
and the results were presented in Table 1.
RESULTS AND DISCUSSION
We first designed and synthesized the desired diethylene
glycol tethered isatin–coumarin hybrids 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, which was
subsequently reacted with isatins
3
yielded the
intermediates 4. The 7-hydroxy-4-methyl-7-2H-chromen-
Figure 1. Chemical structures of sunitinb, nintedanib, semaxanib, and STX64. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Isatin–Coumarin Hybrids Tethered via Diethylene Glycol: Design, Synthesis, and
Their In Vitro Antitumor Activities
Scheme 1. Synthesis of diethylene glycol tethered isatin–coumarin hybrids 7a–l.
Table 1
Structures and anticancer activities of isatin–coumarin hybrids 7a–l.
Structure
R2
IC50 (μM)
DU145
Compd.
R1
HepG2
Hela
A549
SKOV3
MCF-7
MCF-7/DOX
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
H
O
O
O
O
NOH
NOH
NOH
NOH
NOMe
NOMe
NOMe
NOMe
-
17.35
28.74
15.40
12.37
15.66
39.71
13.33
10.28
33.54
19.27
27.53
20.37
6.94
26.22
32.21
29.17
11.54
29.38
23.64
19.86
17.39
29.97
49.22
38.41
19.01
>50
19.67
29.90
14.28
14.25
14.52
20.09
11.71
10.92
36.18
41.90
26.92
22.76
>50
39.86
48.99
33.16
21.66
24.39
33.97
36.58
20.80
27.15
36.64
40.34
30.07
18.66
33.54
47.35
36.53
29.15
18.63
48.32
32.19
27.36
39.62
42.13
32.55
29.98
31.79
39.27
44.28
29.31
14.46
26.72
34.78
19.44
11.29
44.19
>50
44.38
46.93
19.42
17.10
15.59
22.16
18.73
14.45
48.76
49.97
>50
Me
Cl
F
H
Me
Cl
F
H
Me
Cl
F
36.53
33.17
14.38
41.19
>50
etoposide
-
Obviously, all of the synthesized diethylene glycol
tethered isatin–coumarin hybrids 7a–l (IC50: 10.28 to
>50 μM) only showed weak to moderate activities against
all tested seven cancer cell lines, which were less potent
than the reference etoposide against most of the tested cell
lines. The SAR revealed that substituents on both C-3 and
C-5 positions of isatin motif affected the anticancer
activity greatly: for C-5 position, electron-withdrawing -Cl
and -F preferred, while electron-donating -Me disfavored;
For C-3 position, hydrogen-bond donor -NOH could boost
up the activity, and the relative contributions of
substituents was -NOH > -O > -NOMe generally.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Y.-L. Fan, Z.-P. Huang, and M. Liu
Vol 000
CONCLUSIONS
5-Chloro-1-(2-(2-((4-methyl-2-oxo-2H-chromen-7-yl)oxy)
ethoxy)ethyl)indoline-2,3-dione (7c). Yield: 84%. 1H NMR
(400 MHz, DMSO-d6) δ 2.41 (3H, s, -CH3), 3.64 (2H, t,
-CH2-), 3.71 (2H, t, -CH2-), 3.90 (2H, t, -CH2-), 4.39
(2H, t, -CH2-), 6.26 (1H, s, Ar-H), 6.81 (1H, d, Ar-H),
6.99 (1H, d, Ar-H), 7.09 (1H, s, Ar-H), 7.35 (1H, d,
Ar-H), 7.59 (1H, d, Ar-H), 7.82 (1H, s, Ar-H). ESI-MS
m/z: 450 [M + H]+, 452 [M + 2 + H]+. Elemental Anal.
Calcd (%) for C22H18ClNO6: C, 61.76; H, 4.24; N, 3.27;
In conclusion, all of the synthesized novel diethylene
glycol tethered isatin–coumarin hybrids displayed weak
to moderate 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). In
spite of that, the SAR was enriched, and the enriched
SAR may pave the way for further rationale design of
this kind of hybrids.
Found: C, 61.58; H, 4.12; N, 3.11.
5-Fluoro-1-(2-(2-((4-methyl-2-oxo-2H-chromen-7-yl)oxy)
ethoxy)ethyl)indoline-2,3-dione (7d). Yield: 67%. 1H NMR
(400 MHz, DMSO-d6) δ 2.42 (3H, s, -CH3), 3.44 (2H, t,
-CH2-), 3.48 (2H, t, -CH2-), 3.87 (2H, t, -CH2-), 4.39
(2H, t, -CH2-), 5.21 (2H, s, -CH2O-), 6.26 (1H, s, Ar-H),
6.88 (1H, d, Ar-H), 7.01 (1H, d, Ar-H), 7.07 (1H, s, Ar-
H), 7.16 (1H, d, Ar-H), 7.66 (1H, d, Ar-H), 7.72 (1H, s,
Ar-H), 8.33 (1H, s, triazole-H). ESI-MS m/z: 434
[M + H]+. Elemental Anal. Calcd (%) for C22H18FNO6: C,
64.23; H, 4.41; N, 3.40; Found: C, 64.08; H, 4.19; N, 3.26.
3-(Hydroxyimino)-1-(2-(2-((4-methyl-2-oxo-2H-chromen-7-
EXPERIMENTAL SECTION
The general procedure for preparing targets 7a–l. The
precursors 4 and 6 were prepared via literature methods
[25–28]. A mixture of isatins 4 (1.0 mmol), coumarin 6
(1.0 mmol), and K2CO3 (3.0 mmol) in DMF (20 mL)
was stirred at room temperature overnight. After
filtration, the filtrate was concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography eluted with petroleum ether (PE) to v
(PE):v (ethyl acetate/EA) = 1:1 to give the targets 7a–d.
A mixture of amine hydrochlorides (1.5 mmol), sodium
bicarbonate (2 mmol), and 7a–d (1 mmol) in a mixture of
in methanol (10 mL) and water (2 mL) was stirred at
60°C for 12 h. After cooling to room temperature, the
mixture was extracted with EA (10 mL × 3). The
combined organic layers were concentrated under
reduced pressure, and the residue was purified by column
chromatography (silica gel) eluted with PE to v (PE):v
(EA) = 1:1 to give the title hybrids 7e–l.
yl)oxy)ethoxy)ethyl)indolin-2-one (7e).
Yield: 72%. 1H
NMR (400 MHz, DMSO-d6) δ 2.40 (3H, s, -CH3), 3.64
(2H, t, -CH2-), 3.69 (2H, t, -CH2-), 3.87 (2H, t, -CH2-),
4.36 (2H, t, -CH2-), 6.25 (1H, s, Ar-H), 6.86 (1H, d, Ar-
H), 6.99 (1H, d, Ar-H), 7.06–7.10 (2H, m, Ar-H), 7.54–
7.59 (2H, m, Ar-H), 7.73 (1H, d, Ar-H), 13.28 (1H, brs,
NOH). ESI-MS m/z: 431 [M + Na]+. Elemental Anal.
Calcd (%) for C22H20N2O6: C, 64.70; H, 4.94; N, 6.86;
Found: C, 64.49; H, 4.73; N, 6.80.
3-(Hydroxyimino)-5-methyl-1-(2-(2-((4-methyl-2-oxo-2H-
chromen-7-yl)oxy)ethoxy)ethyl)indolin-2-one (7f).
Yield:
55%. 1H NMR (400 MHz, DMSO-d6) δ 2.28 (3H, s,
-CH3), 2.41 (3H, s, -CH3), 3.65 (2H, t, -CH2-), 3.68 (2H, t,
-CH2-), 3.88 (2H, t, -CH2-), 4.35 (2H, t, -CH2-), 6.26 (1H,
s, Ar-H), 6.83 (1H, d, Ar-H), 7.04 (1H, d, Ar-H), 7.12 (1H,
s, Ar-H), 7.32–7.35 (2H, m, Ar-H), 7.71 (1H, d, Ar-H),
13.10 (1H, brs, NOH). ESI-MS m/z: 445 [M + Na]+.
Elemental Anal. Calcd (%) for C23H22N2O6: C, 65.39; H,
5.25; N, 6.63; Found: C, 65.17; H, 5.04; N, 6.38.
1-(2-(2-((4-Methyl-2-oxo-2H-chromen-7-yl)oxy)ethoxy)ethyl)
indoline-2,3-dione (7a).
Yield: 61%. 1H NMR
(400 MHz, DMSO-d6) δ 2.40 (3H, s, -CH3), 3.64 (2H,
t, -CH2-), 3.69 (2H, t, -CH2-), 3.87 (2H, t, -CH2-), 4.36
(2H, t, -CH2-), 6.25 (1H, s, Ar-H), 6.86 (1H, d, Ar-H),
6.99 (1H, d, Ar-H), 7.05 (1H, dt, Ar-H), 7.12 (1H, dt,
Ar-H), 7.47–7.51 (2H, m, Ar-H), 7.69 (1H, d, Ar-H).
ESI-MS m/z: 416 [M + Na]+. Elemental Anal. Calcd
(%) for C22H19NO6: C, 67.17; H, 4.87; N, 3.56;
5-Chloro-3-(hydroxyimino)-1-(2-(2-((4-methyl-2-oxo-2H-
chromen-7-yl)oxy)ethoxy)ethyl)indolin-2-one (7g).
Yield:
83%. 1H NMR (400 MHz, DMSO-d6) δ 2.41 (3H, s,
-CH3), 3.63 (2H, t, -CH2-), 3.68 (2H, t, -CH2-), 3.89 (2H,
t, -CH2-), 4.34 (2H, t, -CH2-), 6.26 (1H, s, Ar-H), 6.88
(1H, d, Ar-H), 6.99 (1H, d, Ar-H), 7.06 (1H, s, Ar-H),
7.32 (1H, d, Ar-H), 7.69 (1H, d, Ar-H), 7.88 (1H, s, Ar-
H), 13.44 (1H, brs, NOH). ESI-MS m/z: 465 [M + H]+,
467 [M + 2 + H]+. Elemental Anal. Calcd (%) for
C22H19ClN2O6: C, 59.67; H, 4.32; N, 6.33; Found: C,
59.55; H, 4.03; N, 6.21.
Found: C, 66.89; H, 4.63; N, 3.28.
5-Methyl-1-(2-(2-((4-methyl-2-oxo-2H-chromen-7-yl)oxy)
ethoxy)ethyl)indoline-2,3-dione (7b). Yield: 58%. 1H NMR
(400 MHz, DMSO-d6) δ 2.28 (3H, s, -CH3), 2.40 (3H, s,
-CH3), 3.65 (2H, t, -CH2-), 3.68 (2H, t, -CH2-), 3.88 (2H,
t, -CH2-), 4.39 (2H, t, -CH2-), 6.25 (1H, s, Ar-H), 6.80
(1H, d, Ar-H), 7.05 (1H, d, Ar-H), 7.17 (1H, s, Ar-H),
7.42–7.46 (2H, m, Ar-H), 7.73 (1H, d, Ar-H). ESI-MS
m/z: 430 [M + H]+. Elemental Anal. Calcd (%) for
C23H21NO6: C, 67.80; H, 5.20; N, 3.44; Found: C, 67.64;
H, 4.99; N, 3.27.
5-Fluoro-3-(hydroxyimino)-1-(2-(2-((4-methyl-2-oxo-2H-
chromen-7-yl)oxy)ethoxy)ethyl)indolin-2-one (7h).
Yield:
54%. 1H NMR (400 MHz, DMSO-d6) δ 2.42 (3H, s,
-CH3), 3.64 (2H, t, -CH2-), 3.69 (2H, t, -CH2-), 3.92 (2H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Isatin–Coumarin Hybrids Tethered via Diethylene Glycol: Design, Synthesis, and
Their In Vitro Antitumor Activities
t, -CH2-), 4.38 (2H, t, -CH2-), 6.28 (1H, s, Ar-H), 6.99 (1H,
d, Ar-H), 7.06 (1H, d, Ar-H), 7.12(1H, s, Ar-H), 7.23 (1H,
d, Ar-H), 7.65 (1H, d, Ar-H), 7.74 (1H, s, Ar-H), 13.38
(1H, brs, NOH). ESI-MS m/z: 449 [M + H]+. Elemental
Anal. Calcd (%) for C22H19FN2O6: C, 61.97; H, 4.49; N,
(ovarian carcinoma), MCF-7 (breast cancer), and drug-
resistant MCF-7/DOX (doxorubicin-resistant MCF-7) by
SRB assay [24]. IC50 values were presented as the
concentration of drug inhibition 50% cell growth and
determined by at least three separate tests and reported.
6.57; Found: C, 61.69; H, 4.28; N, 6.31.
3-(Methoxyimino)-1-(2-(2-((4-methyl-2-oxo-2H-chromen-7-
yl)oxy)ethoxy)ethyl)indolin-2-one (7i).
Yield: 56%. 1H
REFERENCES AND NOTES
NMR (400 MHz, DMSO-d6) δ 2.46 (3H, s, -CH3), 3.62
(2H, t, -CH2-), 3.68 (2H, t, -CH2-), 3.88 (2H, t, -CH2-),
4.19 (3H, s, NOCH3), 4.34 (2H, t, -CH2-), 6.27 (1H, s,
Ar-H), 6.94 (1H, d, Ar-H), 7.06 (1H, d, Ar-H), 7.12–7.16
(2H, m, Ar-H), 7.34 (1H, t, Ar-H), 7.72 (1H, d, Ar-H),
7.83 (1H, d, Ar-H). ESI-MS m/z: 445 [M + Na]+.
Elemental Anal. Calcd (%) for C23H22N2O6: C, 65.39; H,
5.25; N, 6.63; Found: C, 65.23; H, 5.14; N, 6.43.
3-(Methoxyimino)-5-methyl-1-(2-(2-(4-(((4-methyl-2-oxo-
2H-chromen-7-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)
ethyl)indolin-2-one (7j). Yield: 48%. 1H NMR (400 MHz,
DMSO-d6) δ 2.25 (3H, s, -CH3), 2.40 (3H, s, -CH3), 3.64
(2H, t, -CH2-), 3.68 (2H, t, -CH2-), 3.89 (2H, t, -CH2-),
4.18 (3H, s, NOCH3), 4.38 (2H, t, -CH2-), 6.24 (1H, s,
Ar-H), 6.77 (1H, d, Ar-H), 7.01 (1H, d, Ar-H), 7.14–7.16
(2H, m, Ar-H), 7.62–7.65 (2H, m, Ar-H). ESI-MS m/z:
459 [M + Na]+. Elemental Anal. Calcd (%) for
C22H24N2O6: C, 66.04; H, 5.54; N, 6.42; Found: C,
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77%. 1H NMR (400 MHz, DMSO-d6) δ 2.40 (3H, s,
-CH3), 3.66 (2H, t, -CH2-), 3.71 (2H, t, -CH2-), 3.89 (2H,
t, -CH2-), 4.24 (3H, s, NOCH3), 4.40 (2H, t, -CH2-), 6.27
(1H, s, Ar-H), 6.81 (1H, d, Ar-H), 6.98 (1H, d, Ar-H),
7.05 (1H, s, Ar-H), 7.32 (1H, d, Ar-H), 7.64 (1H, d, Ar-
H), 7.81 (1H, s, Ar-H). ESI-MS m/z: 479 [M + Na]+, 481
[M + 2 + Na]+. Elemental Anal. Calcd (%) for C23H21
ClN2O6: C, 60.46; H, 4.63; N, 6.13; Found: C, 60.25; H,
4.44; N, 5.87.
5-Fluoro-3-(methoxyimino)-1-(2-(2-((4-methyl-2-oxo-2H-
chromen-7-yl)oxy)ethoxy)ethyl)indolin-2-one (7l).
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58%. 1H NMR (400 MHz, DMSO-d6) δ 2.42 (3H, s,
-CH3), 33.66 (2H, t, -CH2-), 3.71 (2H, t, -CH2-), 3.89
(2H, t, -CH2-), 4.24 (3H, s, NOCH3), 6.28(1H, s, Ar-H),
6.89 (1H, d, Ar-H), 6.99 (1H, d, Ar-H), 7.07 (1H, s, Ar-
H), 7.21 (1H, d, Ar-H), 7.69 (1H, d, Ar-H), 7.74 (1H, s,
Ar-H). ESI-MS m/z: 463 [M + Na]+. Elemental Anal.
Calcd (%) for C23H21FN2O6: C, 62.72; H, 4.81; N, 6.36;
Found: C, 62.67; H, 4.72; N, 6.14.
Antitumor activities.
All the synthesized diethylene
glycol tethered isatin–coumarin hybrids were investigated
for their in vitro activity against HepG2 (liver
carcinoma), Hela (cervical cancer), A549 (lung
adenocarcinoma), DU145 (prostatic cancer), SKOV3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet