Synthesis and anticancer activity of indolin-2-one derivatives bearing the 4-thiazolidinone moiety

Article abstract of DOI:10.1002/ardp.201100082

A novel series of indolin-2-one derivatives containing the 4-thiazolidinone moiety (5a-5p) was synthesized and the cytotoxicity of these derivatives was evaluated in vitro against three human cancer cell lines (HT-29, H460 and MDA-MB-231) by standard MTT assay. Some prepared compounds exhibited significant cytotoxicity against different human cancer cell lines. Several potent compounds were further evaluated against one normal cell line (WI-38). In particular, the promising compound 5h showed remarkable cytotoxicity and selectivity against the HT-29 and H460 cancer cell lines (IC₅₀ = 0.016 μmol/L, 0.0037 μmol/L, respectively). A novel series of indolin-2-one derivatives containing the 4-thiazolidinone moiety (5a-5p) was synthesized and evaluated in vitro against three human cancer cell lines (HT-29, H460 and MDA-MB-231). The promising compound 5h showed remarkable cytotoxicity and selectivity against HT-29 and H460 cancer cell lines (IC₅₀ = 0.016 μmol/L, 0.0037 μmol/L, respectively) Copyright

Full text of DOI:10.1002/ardp.201100082

Arch. Pharm. Chem. Life Sci. 2012, 345, 73–80
73
Full Paper
Synthesis and Anticancer Activity of Indolin-2-one
Derivatives Bearing the 4-Thiazolidinone Moiety
Shuobing Wang, Yanfang Zhao, Wufu Zhu, Ying Liu, Kaixing Guo, and Ping Gong
Key Laboratory of Original New Drugs Design and Discovery of Ministry of Education,
Shenyang Pharmaceutical University, Shenhe District, Shenyang, P. R. China
A novel series of indolin-2-one derivatives containing the 4-thiazolidinone moiety (5a–5p) was
synthesized and the cytotoxicity of these derivatives was evaluated in vitro against three human
cancer cell lines (HT-29, H460 and MDA-MB-231) by standard MTT assay. Some prepared compounds
exhibited significant cytotoxicity against different human cancer cell lines. Several potent
compounds were further evaluated against one normal cell line (WI-38). In particular, the
promising compound 5h showed remarkable cytotoxicity and selectivity against HT-29 and H460
cancer cell lines (IC50 ¼ 0.016 mmol/L, 0.0037 mmol/L, respectively).
Keywords: Anticancer activity / Indolin-2-one / 4-Thiazolidinone
Received: March 3, 2011; Revised: May 14, 2011; Accepted: May 18, 2011
DOI 10.1002/ardp.201100082
Introduction
Wan) that was used for the treatment of chronic myelogen-
ous leukemia (CML) (Fig. 1) [9].
Cancer is the worldwide health problem and the most fright-
ening disease of human. Recently, considerable attention has
been devoted to the construction of new derivatives of indo-
lin-2-one or 4-thiazolidinone moieties on the account of their
reported anticancer activities.
Thiazolidinone derivatives are known for their broad spec-
trum of biological activities [10], including anticancer effect
[11–16]. Among them, 4-thiazolidinone-3-carboxylic acid
derivatives are promising anticancer agents. Recently, a
series of 5-benzylidene-2-thioxo-4-thiazolidinone-3-carboxylic
acids (Fig. 1) have been reported as inhibitors for anti-apop-
totic Bcl-2 proteins [17, 18]. Their analogues are highly active
inhibitors of JNK-stimulating phosphatase-1 (JSP-1) [19].
Moreover, novel 4-thiazolidinone-3-carboxylic acid amides
having furan moiety exhibited significant cytotoxicity and
induction of apoptosis in human leukemia cell (Fig. 1) [20].
Based on aforementioned compounds, indolin-2-one and 5-
benzylidene-4-thiazolidinone moieties are promising scaf-
folds for design of anticancer drugs. In addition, different
anticancer biotargets and mechanism of indolin-2-one or 4-
thiazolidinone derivatives encourage us to design hybrids
containing these two moieties within their structures.
They may display improved anticancer activity and be less
susceptible to the development of multi-drug resistance
(MDR). To our knowledge, there were hardly any studies
about combination of indolin-2-one and 4-thiazolidinone
moieties at the 2 position of the 4-thiazolidinone ring so
far. Thus, a series of novel indolin-2-one derivatives with 5-
benzylidene-4-thiazolidinone moieties (5a–5p) were designed
(Fig. 1). The acidic group at the 3 position of the 4-thiazoli-
dinone ring may prevent entry of the compounds into the
A variety of 3-substituted indolin-2-ones have been utilized
as anticancer drugs or drug candidates [1–5]. A representative
member of this class is sunitinib (SU11248, SutentTM; Pfizer,
Inc.) which is currently used in the clinics as a multi-targeting
tyrosine kinase inhibitor with antiangiogenic activity (Fig. 1)
[6, 7]. 6-Methoxycarbonyl group substituted indolin-2-ones
(BIBF1000, BIBF1120) are potent inhibitors of VEGFR-1/2/3,
PDGFRa, and FGFR-1, with low cross-reactivity against a panel
of other kinases (Fig. 1) [8]. Notably, BIBF1120 is currently
being evaluated in phase III clinical trials in the treatment
of non small cell lung cancer and is in clinical development
for other tumor types. Indirubin was identified as the active
ingredient of a traditional Chinese recipe (Danggui Longhui
Correspondence: Ping Gong, Key Laboratory of Original New Drugs
Design and Discovery of Ministry of Education, Shenyang Pharmaceutical
University, 103 Wenhua Road, Shenhe District, 110016 Shenyang,
Liaoning, P. R. China.
E-mail: gongpinggp@126.com
Fax: þ86 24 2398-6429
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S. Wang et al.
Arch. Pharm. Chem. Life Sci. 2012, 345, 73–80
Figure 1. Structures of indolin-2-ones, 4-
thiazolidinone and target compounds.
cancer cell. In order to increase cancer cell membrane per-
meability of these structures, the ester group was retained at
the 3 position of the 4-thiazolidinone ring.
synthesized via reaction of the glycine and carbon disulfide
under basic conditions followed by ring closure with chloro-
acetic acid. Knoevenagel condensation of 1 with appropriate
benzaldehydes in the refluxing acetic acid afforded the 2-(5-
benzylidene-2-thioxo-4-thiazolidin-3-yl)acetic acids 2a–2f.
The presence of only one signal for the methyne proton at
Results and discussion
1
Chemistry
more downfield 7.83–7.95 ppm in H-NMR spectra of 2a–2f
The synthetic route of the target compounds 5a–5p is illus-
trated in Scheme 1. The indolin-2-ones 4a–4e were
synthesized from corresponding anilines according to the
reported procedures [1, 2]. Rhodanine-3-acetic acid 1 was
suggested that a single Z-configuration isomer was present.
The exclusive formation of the thermodynamically stable
Z-isomers of 2a–2f is in agreement with the literature reports
for similar compounds [21, 22]. S-Ethylation of 2a–2f with
Scheme 1. Synthesis of target compounds.
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Arch. Pharm. Chem. Life Sci. 2012, 345, 73–80
Indolin-2-one Derivatives Bearing 4-thiazolidinone Moiety
75
boron trifluoride diethyl etherate and triethyl orthoformate
produced thiazolinium salts 3a–3f, which reacted with indo-
lin-2-ones 4a–4e in the presence of triethylamine to yield
compounds 5a–5p.
nearly as active as sunitinib against H460 and MDA-MB-231
cancer cell lines. All tested precursors 4a–4e were inactive. As
shown in Table 1, compounds 5a–5p were more potent
against H460 cancer cell line than against HT-29 and MDA-
MB-231 cancer cell lines. These results suggested this series of
compounds possessed selectivity for H460 cancer cell line.
As shown in Table 1, the indolin-2-one and 5-benzylidene-4-
thiazolidinone hybrid derivatives 5a–5p were more active
than the corresponding precursors 4a–4e in most cases. It
suggested that the substituted 5-benzylidene-4-thiazolidi-
none ring is a necessary moiety for these compounds to
possess potent cytotoxicity. Compounds 5a–5d showed mod-
erate cytotoxicity against one or more cancer cell lines.
Introduction of smaller electron-withdrawing fluoro-atom
at 5-position of the indolin-2-one ring was more favorable
for increasing cytotoxicity against all three cancer cell lines
(5c vs. 5f, 5d vs. 5h). In contrast, introduction of a methyl
group (electron-donating group) reduced their cytotoxicity
against both HT-29 and H460 cancer cell lines (5a vs. 5i, 5b vs.
5k, 5d vs. 5l). However, compound 5i exhibited better activity
and selectivity against MDA-MB-231 cancer cell line than
compound 5a. Compound 5p possessing bulky electron-with-
drawing bromo-atom only showed marginal activity against
MDA-MB-231 cancer cell line. These results suggested that
small electron-withdrawing fluoro-substitution at the 5-pos-
ition of indolin-2-one ring is more favorable than electron-
donating methyl group and bulky bromo-atom. In addition,
the position of substituents appears to play an important role
in activity, since the change of fluoro from 5- to 6-position of
indolin-2-one ring led to a clear loss of activity against HT-29
and MDA-MB-231 cancer cell lines (5e vs. 5n). These results are
not surprising, as substitution at the 5 position of indolin-2-
one ring has previously been associated with increased bio-
logical activity for a range of indole-based compounds.
Compounds (5d, 5h, 5l) with three electron-donating
groups (such as methoxy in this study) in the phenyl ring,
exhibited moderate to excellent cytotoxicity against both HT-
29 and H460 cancer cell lines. Replacement of the electron-
donating group with electron-withdrawing group (such as
fluoro, trifluoromethyl, chloro) or hydrogen atom resulted in
compounds (5a–5c, 5e–5g, 5i–5k) possessing less cytotoxicity
against HT-29 and H460 cancer cell lines. However, in the case
of MDA-MB-231 cancer cell line, compounds (except 5b) with-
out electron-donating group in the phenyl ring were more
active against MDA-MB-231 cancer cell line (5e–5g vs. 5h; 5i–
5k vs. 5l; 5a, 5c vs. 5d). Interestingly, compound 5i, possessing
5-methylindolin-2-one ring and phenyl ring without substi-
tutions, exhibited the most potent cytotoxicity against MDA-
MB-231 cancer cell line. Therefore, we tentatively concluded
that the electronic influences of the substituent in the phenyl
ring appear to play an important role in activity, and this
behavior depends on the cancer cell lines to which they are
Because of the exocyclic double bond at 2-position of 4-
thiazolidinone ring, compounds 5a–5p existed as either
exclusively (2E, 5Z) isomer or a mixture of the (2E, 5Z) and
(2Z, 5Z) isomers with the (2E, 5Z) isomer being the predom-
inant one (>90%) and the single (2E, 5Z) isomer was obtained
by recrystallization. The two isomers were assigned on the
basis of different chemical shift of a-methylene proton. In 1H-
NMR spectra the a-methylene proton of the (2E, 5Z) isomer
was more downfield (5.25–5.36 ppm) than that of the (2Z, 5Z)
isomer (4.95–5.01 ppm) due to the deshielding effect of
the carbonyl group at the 2-position of the indolin-2-one
ring (Fig. 2). In 1H-NMR spectra of compounds 5a–5p the
NH proton of indolin-2-one appeared as one singlet at
10.56–10.84 ppm. The IR spectra of compounds 5a–5p
showed three strong absorption bands (1761.1–
1736.3 cmꢀ1, 1719.0–1708.3 cmꢀ1, 1683.0–1656.8 cmꢀ1) cor-
responding to two lactam and one ester carbonyl groups.
Biological results and discussion
The cytotoxicity of compounds 5a–5p and precursors 4a–4e
were evaluated against three cancer cell lines, i.e. human
colon cancer cell line (HT-29), human lung cancer cell line
(H460) and human breast cancer cell line (MDA-MB-231). In
order to investigate the cytotoxicity of these compounds
against a normal cell line, several potent compounds
(5a, 5d, 5f, 5h, 5l) were further evaluated against human
fetal lung fibroblasts (WI-38). For comparison purposes, the
cytotoxicity of sunitinib, a standard anticancer drug, was
evaluated under the same conditions. The cytotoxicity was
determined by standard MTT assay and the results expressed
as IC50 were summarized in Table 1. The IC50 values are the
average of two independent experiments.
According to the cytotoxicity data in Table 1, some of the
new compounds exhibited potential anticancer activities.
Compound 5h showed the highest potency against HT-29
and H460 cancer cell lines while compounds 5e–5g were
Figure 2. Deshielding effect of carbonyl group in (2E, 5Z) isomers.
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Arch. Pharm. Chem. Life Sci. 2012, 345, 73–80
Table 1. The cytotoxicity of compounds 5a-5p and precursors 4a-4e against HT-29, H460, MDA-MB-231 and WI-38 cell lines in vitro a
Y
O
S
N
COOEt
X
O
N
H
5a-5p (2E,5Z)
Compd.
X
Y
IC50 (mmol/L)b ꢂ SD
HT-29c
H460c
MDA-MB-231c
WI-38c
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
4a
4b
4c
4d
4e
Sunitinibf
H
H
H
H
5-F
5-F
5-F
H
4-F
3.45 ꢂ 0.14
NAd
1.9 ꢂ 0.07
5.2 ꢂ 0.14
12.8 ꢂ 1.13
0.8 ꢂ 0.07
2.28 ꢂ 0.11
2.74 ꢂ 0.19
2.13 ꢂ 0.10
0.0037 ꢂ 0.0004
56.5 ꢂ 3.53
NAd
7.25 ꢂ 0.21
NAd
13.5 ꢂ 0.30
NDe
4-CF3
3,4,5-trimethoxy
2-F
4-CF3
2,4-dichloro
3,4,5-trimethoxy
NAd
18.6 ꢂ 0.85
27.1 ꢂ 1.84
3.47 ꢂ 0.18
3.79 ꢂ 0.12
3.49 ꢂ 0.12
10.5 ꢂ 0.42
2.3 ꢂ 0.28
20 ꢂ 2.83
37.8 ꢂ 1.13
52 ꢂ 2.83
NAd
NDe
1.78 ꢂ 0.10
19.1 ꢂ 1.56
46.3 ꢂ 1.84
NAd
1.23 ꢂ 0.35
NDe
13.4 ꢂ 0.41
NDe
5-F
0.016 ꢂ 0.006
7.60 ꢂ 0.22
5-CH3
5-CH3
5-CH3
5-CH3
6-F
6-F
6-F
5-Br
H
5-F
6-F
5-CH3
5-Br
–
H
2-F
NAd
NDe
NAd
NDe
4-F
3,4,5-trimethoxy
NAd
NAd
NDe
7.8 ꢂ 0.85
2.1 ꢂ 0.28
3.6 ꢂ 0.28
H
2-F
4-F
4-F
–
–
–
–
–
NAd
NAd
NDe
NAd
3.51 ꢂ 0.15
NAd
NAd
NAd
NDe
NAd
NDe
NAd
NAd
56 ꢂ 4.24
NDe
NAd
NAd
NAd
NDe
NAd
NAd
NAd
NDe
NAd
NAd
NAd
NDe
NAd
NAd
NAd
NDe
NAd
NAd
NAd
NDe
–
1.83 ꢂ 0.16
2.59 ꢂ 0.13
3.46 ꢂ 0.06
6.20 ꢂ 0.25
a
b
Several potent compounds (5a, 5d, 5f, 5h, 5l) were evaluated against a normal cell line (WI-38). IC50: Concentration of the
compound (mmol/L) producing 50% cell growth inhibition after 72 h of drug exposure, as determined by the MTT assay. Each
experiment was run at least twice, and the results are presented as average values ꢂ standard deviation. c HT-29, human colon cancer
cell line; H460, human lung cancer cell line; MDA-MB-231, human breast cancer cell line; WI-38, human fetal lung fibroblasts.
d
e
f
NA: Compound showing IC50 value >200 mmol/L. ND: Not determined. Used as a positive control.
faced to. Compounds 5h exerted markedly weaker cytotox-
icity against WI-38 normal cell line than against HT-29 and
H460 cancer cell lines. The selective index (IC50 normal cell/
IC50 cancer cell) for HT-29 and H460 cancer cell lines was 475
and 2.05 ꢁ 103, respectively.
which has already been partially confirmed by anticancer
activity of the rhodacyanine dyes [25].
Experimental
Chemistry
In the present study, the coupling between indolin-2-one
and 5-benzylidene-4-thiazolidinone systems led to several
compounds with better anticancer activity than the pre-
viously reported analogues [15, 23, 24]. Two neutral conju-
gate systems integrated at the 4-thiazolidinone moiety may
contribute to the anticancer activity of these compounds,
All melting points were obtained on a Bu¨chi Melting Point B-540
apparatus (Bu¨chi Labortechnik, Flawil, Switzerland) and were
uncorrected. The IR spectra were recorded by means of the KBr
pellet technique on a Bruker FTS 135 spectrometer. 1H-NMR
spectra were performed using Bruker 300-MHz spectrometers
(Bruker Bioscience, Billerica, MA, USA) with TMS as an internal
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Arch. Pharm. Chem. Life Sci. 2012, 345, 73–80
Indolin-2-one Derivatives Bearing 4-thiazolidinone Moiety
77
standard. Mass spectra (MS) were taken in ESI mode on Agilent
1100 LC–MS (Agilent, Palo Alto, CA, USA). Elemental analysis was
determined on a Carlo-Erba 1106 Elemental analysis instrument
(Carlo Erba, Milan, Italy). All chemicals were obtained from
commercial suppliers and used without purification. TLC analysis
was carried out on silica gel plates GF254 (Qindao Haiyang
Chemical, China). The indolin-2-ones 4a–4e were synthesized
from corresponding anilines according to the reported pro-
cedures [1, 2].
(Z)-2-(5-(2,4-Dichlorobenzylidene)-4-oxo-2-
thioxothiazolidin-3-yl)acetic acid 2e
Yield: 56.5%. M.p.: 263–2668C; 1H-NMR (DMSO-d6, ppm): d 4.76
(s, 2H), 7.67 (dd, 1H, J ¼ 8.7, 2.1 Hz), 7.88 (d, 1H, J ¼ 2.1 Hz), 7.92
(d, 1H, J ¼ 8.7 Hz), 7.95 (s, 1H); MS (ESI): m/z 346.0 (MꢀH)ꢀ.
(Z)-2-(5-(3,4,5-Trimethoxybenzylidene)-4-oxo-2-
thioxothiazolidin-3-yl)acetic acid 2f
Yield: 32.5%. M.p.: 217–2198C; 1H-NMR (DMSO-d6, ppm): d 3.76
(s, 3H), 3.86 (s, 6H), 4.71 (s, 2H), 6.98 (s, 2H), 7.83 (s, 1H); MS (ESI):
m/z 368.0 (MꢀH)ꢀ.
2-(4-Oxo-2-thioxothiazolidin-3-yl)acetic acid 1
Glycine (24.0 g, 320 mmol) was dissolved with 25%
NH4OH (70 mL) in water (10 mL). Then, carbon disulfide (24.3 g,
320 mmol) was added to the reaction mixture, which was stirred
vigorously for 1 h. An aqueous solution of sodium chloroacetate
(37.1 g, 320 mmol) was added and stirring was continued at 238C
for 3 h. Then the reaction mixture was acidified with dilute HCl
until pH 1.0 and refluxed for 1 h. The reaction mixture was
neutralized with saturated NaHCO3 solution. The resultant
solution was acidified again with dilute HCl. The cyclized product
was extracted in ethyl acetate, dried over anhydrous sodium
sulfate and evaporated under vacuum and the residue was puri-
fied by recrystallization with water to obtain intermediate 1. Yield:
86.0%. M.p.: 145–1488C; 1H-NMR (DMSO-d6, ppm): d 4.41 (s, 2H),
4.56 (s, 2H); MS (ESI): m/z 190.2 (MꢀH)ꢀ.
General procedure for the synthesis of ethyl 2-(5-
benzylidene-2-(2-oxo-indolin-3-ylidene)-4-oxothiazolidin-
3-yl)acetate derivatives 5a–5p
To a solution of (Z)-2-(5-benzylidene-4-oxo-2-thioxothiazolidin-3-
yl)acetic acid (2a–2f) (3 mmol) in 1,4-dioxane (15 mL) was added
HC(OEt)3 (2 mL) and BF3 ꢃ Et2O (2 mL). The reaction mixture was
heated to 808C and stirring was continued at the same tempera-
ture for 4 h. The resulting thiazolium fluoroborate (3a–3f) was
precipitated, filtered off, dried, without any additional purifi-
cation, as starting material for the following reactions. To a
mixture of thiazolium fluoroborate (3a–3f) (3 mmol) and indo-
lin-2-one (4a–4e) (3 mmol) in acetonitrile (15 mL) was added
triethylamine (0.91 g, 9 mmol) dropwise at 258C, and the mix-
ture was stirred for 3 h at 608C. The orange precipitate was
collected and washed with ethyl acetate (8 mL). The crude prod-
uct thus obtained was recrystallized from methanol or acetone
to give compound (5a–5p).
General procedure for the synthesis of (Z)-2-(5-
benzylidene-4-oxo-2-thioxothiazolidin-3-yl)acetic acid
derivatives 2a–2f
A mixture of rhodanine-3-acetic acid 1 (30 mmol), appropriate
benzaldehyde (33 mmol) and anhydrous sodium acetate
(30 mmol) was refluxed for 3–4 h in glacial acetic acid (60 mL)
and the reaction was monitored by TLC. After cooling, the pre-
cipitated product was filtered off, washed with water and recrys-
tallized with ethanol.
(2E,5Z) Ethyl 2-(5-benzylidene-2-(2-oxo-indolin-3-
ylidene)-4-oxothiazolidin-3-yl)acetate 5a
Yield: 42.5%. M.p.: 168–1718C; IR (KBr, cmꢀ1): 3428.9, 3191.7,
1761.1, 1710.1, 1657.6, 1563.9, 1203.7, 1154.7; MS (ESI)
m/z: 407.1 (MþH)þ; 1H-NMR (300 MHz, DMSO-d6) d: 1.20 (t, 3H,
J ¼ 7.2 Hz), 4.12 (q, 2H, J ¼ 7.2 Hz), 5.33 (s, 2H), 6.87 (d, 1H,
J ¼ 7.5 Hz), 7.06–7.22 (m, 2H), 7.52–7.64 (m, 3H), 7.80–7.83
(m, 3H), 7.89 (s, 1H), 10.69 (s, 1H); anal. calcd. for
C22H18N2O4S (%): C, 65.01; H, 4.46; N, 6.89. Found (%): C, 65.07;
H, 4.51; N, 6.93.
(Z)-2-(5-Benzylidene-4-oxo-2-thioxothiazolidin-3-yl)acetic
acid 2a
Yield: 66.0%. M.p.: 249–2508C; 1H-NMR (DMSO-d6, ppm): d 4.75
(s, 2H), 7.21–7.52 (m, 3H), 7.67–7.70 (m, 2H), 7.91 (s, 1H), 13.45
(br s, 1H); MS (ESI): m/z 278.1 (MꢀH)ꢀ.
(Z)-2-(5-(2-Fluorobenzylidene)-4-oxo-2-thioxothiazolidin-
(2E,5Z) Ethyl 2-(5-(4-fluorobenzylidene)-2-(2-oxo-indolin-
3-yl)acetic acid 2b
3-ylidene)-4-oxothiazolidin-3-yl)acetate 5b
Yield: 62.0%. M.p.: 201–2048C; 1H-NMR (DMSO-d6, ppm): d 4.76
(s, 2H), 7.40–7.46 (m, 2H), 7.59–7.66 (m, 2H), 7.85 (s, 1H); MS (ESI):
m/z 296.3 (MꢀH)ꢀ.
Yield: 43.0%. M.p.: 156–1588C; IR (KBr, cmꢀ1): 3448.2, 3119.9,
1739.5, 1719.0, 1674.5, 1524.4, 1509.3, 1214.5, 1198.7, 1160.3,
1144.2; MS (ESI) m/z: 425.1 (MþH)þ ; 1H-NMR (300 MHz, DMSO-d6)
d: 1.20 (t, 3H, J ¼ 7.2 Hz), 4.11 (q, 2H, J ¼ 7.2 Hz), 5.33 (s, 2H),
6.87–7.91 (m, 9H), 10.69 (s, 1H); anal. calcd. for C22H17FN2O4S (%):
C, 62.25; H, 4.04; N, 6.60. Found (%): C, 62.30; H, 4.08; N, 6.67.
(Z)-2-(5-(4-Fluorobenzylidene)-4-oxo-2-thioxothiazolidin-
3-yl)acetic acid 2c
Yield: 70.3%. M.p.: 256–2598C; 1H-NMR (DMSO-d6, ppm): d 4.75
(s, 2H), 7.40–7.45 (m, 2H), 7.74–7.79 (m, 2H), 7.93 (s, 1H), 13.47
(br s, 1H); MS (ESI): m/z 296.3 (MꢀH)ꢀ.
(2E,5Z) Ethyl 2-(5-(4-trifluoromethylbenzylidene)-2-(2-
oxo-indolin-3-ylidene)-4-oxothiazolidin-3-yl)acetate 5c
Yield: 42.6%. M.p.: 185–1878C; IR (KBr, cmꢀ1): 3428.1, 3161.2,
1741.4, 1711.6, 1676.3, 1532.5, 1326.1, 1216.0, 1165.2; MS (ESI)
m/z: 475.3 (MþH)þ; 1H-NMR (300 MHz, DMSO-d6) d: 1.21 (t, 3H,
J ¼ 7.2 Hz), 4.12 (q, 2H, J ¼ 7.2 Hz), 5.32 (s, 2H), 6.87–8.03 (m, 9H),
10.72 (s, 1H); anal. calcd. for C23H17F3N2O4S (%): C, 58.22; H, 3.61;
N, 5.90; Found (%): C, 58.12; H, 3.60; N, 5.85.
(Z)-2-(5-(4-Trifluoromethylbenzylidene)-4-oxo-2-
thioxothiazolidin-3-yl)acetic acid 2d
Yield: 45.2%. M.p.: 240–2438C; 1H-NMR (DMSO-d6, ppm): d 4.75
(s, 2H), 7.41 (d, 2H, J ¼ 8.8 Hz), 7.75 (d, 2H, J ¼ 8.8 Hz), 7.93
(s, 1H), 13.50 (br s, 1H); MS (ESI): m/z 345.9 (MꢀH)ꢀ.
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m/z: 421.5 (MþH)þ; 1H-NMR (300 MHz, DMSO-d6) d: 1.20 (t, 3H,
J ¼ 7.2 Hz), 2.39 (s, 3H), 4.11 (q, 2H, J ¼ 7.2 Hz), 5.31 (s, 2H, CH2),
6.76 (d, 1H, J ¼ 10.8 Hz), 6.99 (d, 1H, J ¼ 10.8 Hz), 7.52–7.65 (m,
4H), 7.79–7.82 (m, 2H), 7.88 (s, 1H), 10.57 (s, 1H); anal. calcd.
for C23H20N2O4S (%): C, 65.70; H, 4.79; N, 6.66. Found (%): C, 65.76;
H, 4.87; N, 6.70.
(2E,5Z) Ethyl 2-(5-(3,4,5-trimethoxybenzylidene)-2-
(2-oxo-indolin-3-ylidene)-4-oxothiazolidin-3-yl)acetate 5d
Yield: 43.8%. M.p.: 140–1428C; IR (KBr, cmꢀ1): 3435.8, 3095.5,
1744.5, 1709.2, 1674.0, 1529.0, 1504.4, 1322.2, 1221.0, 1140.8;
MS (ESI) m/z: 497.5 (MþH)þ; 1H-NMR (300 MHz, DMSO-d6) d: 1.20 (t,
3H, J ¼ 7.2 Hz), 3.77 (s, 3H), 3.90 (s, 6H), 4.11 (q, 2H, J ¼ 7.2 Hz),
5.33 (s, 2H), 6.86–7.73 (m, 6H), 7.83 (s, 1H), 10.68 (s, 1H); anal.
calcd. for C25H24N2O7S (%): C, 60.47; H, 4.87; N, 5.64. Found (%):
C, 60.52; H, 4.92; N, 5.73.
(2E,5Z) Ethyl 2-(5-(2-fluorobenzylidene)-2-(2-oxo-5-
methylindolin-3-ylidene)-4-oxothiazolidin-3-yl)acetate 5j
Yield: 38.2%. M.p.: 135–1378C; IR (KBr, cmꢀ1): 3429.4, 3149.1,
1751.9, 1710.2, 1673.2, 1531.8, 1506.2, 1198.7, 1159.3, 1142.7;
MS (ESI) m/z: 439.1 (MþH)þ; 1H-NMR (300 MHz, DMSO-d6) d: 1.20 (t,
3H, J ¼ 6.9 Hz), 2.39 (s, 3H), 4.14 (q, 2H, J ¼ 6.9 Hz), 5.31 (s, 2H),
6.76 (d, 1H, J ¼ 7.8 Hz), 6.99 (d, 1H, J ¼ 7.8 Hz), 7.43–7.49 (m, 2H),
7.57 (s, 1H), 7.86–7.90 (m, 3H), 10.57 (s, 1H); anal. calcd.
for C23H19FN2O4S (%): C, 63.00; H, 4.37; N, 6.39. Found (%):
C, 63.08; H, 4.40; N, 6.42.
(2E,5Z) Ethyl 2-(5-(2-fluorobenzylidene)-2-(2-oxo-5-
fluoroindolin-3-ylidene)-4-oxothiazolidin-3-yl)acetate 5e
Yield: 46.5%. M.p.: 172–1748C; IR (KBr, cmꢀ1): 3432.7, 3160.1,
1749.2, 1710.7, 1668.8, 1540.0, 1507.9, 1211.8, 1162.0, 1141.9;
1
MS (ESI) m/z: 443.2 (MþH)þ; H-NMR (300 MHz, DMSO-d6) d: 1.20
(t, 3H, J ¼ 7.2 Hz), 4.11 (q, 2H, J ¼ 7.2 Hz), 5.30 (s, 2H), 6.83
(dd, 1H, J ¼ 8.4, 4.8 Hz), 6.99–7.06 (m, 1H), 7.42–7.48 (m, 2H),
7.60 (dd, 1H, J ¼ 9.9, 2.4 Hz), 7.89–7.94 (m, 3H), 10.69 (s, 1H); anal.
calcd. for C22H16F2N2O4S (%): C, 59.72; H, 3.65; N, 6.33. Found (%):
C, 59.76; H, 3.77; N, 6.40.
(2E,5Z) Ethyl 2-(5-(4-fluorobenzylidene)-2-(2-oxo-5-
methylindolin-3-ylidene)-4-oxothiazolidin-3-yl)acetate 5k
Yield: 42.2%. M.p.: 147–1498C; IR (KBr, cmꢀ1): 3430.7, 3156.7,
1751.9, 1710.0, 1673.5, 1532.5, 1506.4, 1198.8, 1159.2; MS (ESI)
m/z: 439.5 (MþH)þ; 1H-NMR (300 MHz, DMSO-d6) d: 1.20 (t, 3H,
J ¼ 7.2 Hz), 2.39 (s, 3H), 4.11 (q, 2H, J ¼ 7.2 Hz), 5.31 (s, 2H), 6.76–
7.90 (m, 8H), 10.57 (s, 1H); anal. calcd. for C23H19FN2O4S (%):
C, 63.00; H, 4.37; N, 6.39. Found (%): C, 63.10; H, 4.45; N, 6.45.
(2E,5Z) Ethyl 2-(5-(4-trifluoromethylbenzylidene)-2-
(2-oxo-5-fluoroindolin-3-ylidene)-4-oxothiazolidin-3-yl)-
acetate 5f
Yield: 52.5%. M.p.: 162–1648C; IR (KBr, cmꢀ1): 3428.7, 3173.0,
1757.8, 1709.5, 1656.8, 1541.2, 1325.3, 1214.3, 1170.4; MS (ESI)
m/z: 493.1 (MþH)þ; 1H-NMR (300 MHz, DMSO-d6) d: 1.21 (t, 3H,
J ¼ 7.2 Hz), 4.12 (q, 2H, J ¼ 7.2 Hz), 5.29 (s, 2H), 6.83 (d, 1H,
J ¼ 8.4, 4.8 Hz), 7.00–7.07 (m, 1H), 7.59 (dd, 1H, J ¼ 9.6,
2.1 Hz), 7.93 (d, 2H, J ¼ 8.4 Hz), 7.98 (s, 1H), 8.02 (d, 2H,
J ¼ 8.4 Hz), 10.72 (s, 1H); anal. calcd. for C23H16F4N2O4S (%):
C, 56.10; H, 3.27; N, 5.69. Found (%): C, 56.12; H, 3.30; N, 5.72.
(2E,5Z) Ethyl 2-(5-(3,4,5-trimethoxybenzylidene)-2-
(2-oxo-5-methylindolin-3-ylidene)-4-oxothiazolidin-3-yl)-
acetate 5l
Yield: 56.5%. M.p.: 157–1598C; IR (KBr, cmꢀ1): 3432.9, 2939.7,
1736.3, 1713.0, 1671.9, 1531.3, 1502.8, 1325.9, 1213.9, 1156.4,
1136.3; MS (ESI) m/z: 511.2 (MþH)þ; 1H-NMR (300 MHz, DMSO-d6)
d: 1.20 (t, 3H, J ¼ 7.2 Hz), 2.30 (s, 3H), 3.76 (s, 3H), 3.92 (s, 6H), 4.18
(q, 2H, J ¼ 7.2 Hz), 5.36 (s, 2H), 6.58–7.56 (m, 5H), 7.81 (s, 1H),
10.56 (s, 1H); anal. calcd. for C26H26N2O7S (%): C, 61.16; H, 5.13;
N, 5.49. Found (%): C, 61.22; H, 5.20; N, 5.56.
(2E,5Z) Ethyl 2-(5-(2,4-dichlorobenzylidene)-2-(2-oxo-5-
fluoroindolin-3-ylidene)-4-oxothiazolidin-3-yl)acetate 5g
Yield: 45.7%. M.p.: 153–1558C; IR (KBr, cmꢀ1): 3425.9, 3160.5, 1744.2,
1715.9, 1669.2, 1555.1, 1478.8, 1372.6, 1218.9, 1171.7, 1137.6; MS
(ESI) m/z: 493.0 (MþH)þ; 1H-NMR (300 MHz, DMSO-d6) d:1.21 (t, 3H,
J ¼ 6.9 Hz), 4.12 (q, 2H, J ¼ 6.9 Hz), 5.28 (s, 2H), 6.83 (dd, 1H, J ¼ 8.7,
4.8 Hz), 6.99–7.06 (m, 1H), 7.54 (dd, 1H, J ¼ 9.9, 2.4 Hz), 7.67 (dd, 1H,
J ¼ 8.7, 2.1 Hz), 7.88 (d, 1H, J ¼ 2.1 Hz), 7.92 (d, 1H, J ¼ 8.7 Hz), 7.95
(s, 1H), 10.72 (s, 1H); anal. calcd. for C22H15Cl2FN2O4S (%): C, 53.56;
H, 3.06; N, 5.68. Found (%): C, 53.62; H, 3.17; N, 5.80.
(2E,5Z) Ethyl 2-(5-benzylidene-2-(2-oxo-6-fluoroindolin-3-
ylidene)-4-oxothiazolidin-3-yl)acetate 5m
Yield: 46.2%. M.p.: 183–1858C; IR (KBr, cmꢀ1): 3427.8, 3165.5,
1757.9, 1709.6, 1661.9, 1566.6, 1205.5, 1142.9; MS (ESI)
m/z: 425.1 (MþH)þ; 1H-NMR (300 MHz, DMSO-d6) d: 1.20 (t, 3H,
J ¼ 7.2 Hz), 4.12 (q, 2H, J ¼ 7.2 Hz), 5.28 (s, 2H), 6.68 (dd, 1H,
J ¼ 9.0, 2.4 Hz), 6.84–6.91 (m, 1H), 7.51–7.63 (m, 3H), 7.79–7.83
(m, 3H), 7.88 (s, 1H), 10.83 (s, 1H); anal. calcd.
for C22H17FN2O4S (%): C, 62.25; H, 4.04; N, 6.60. Found (%): C,
62.14; H, 4.11; N, 6.69.
(2E,5Z) Ethyl 2-(5-(3,4,5-trimethoxybenzylidene)-2-
(2-oxo-5-fluoroindolin-3-ylidene)-4-oxothiazolidin-3-yl)-
acetate 5h
Yield: 52.5%. M.p.: 176–1788C; IR (KBr, cmꢀ1): 3311.2, 1746.4,
1708.3, 1677.8, 1524.4, 1504.9, 1332.1, 1295.1, 1132.9; MS (ESI)
m/z: 515.5 (MþH)þ; 1H-NMR (300 MHz, DMSO-d6) d: 1.20 (t, 3H,
J ¼ 7.2 Hz), 3.77 (s, 3H), 3.91 (s, 6H), 4.12 (q, 2H, J ¼ 7.2 Hz), 5.34
(s, 2H), 6.82–7.04 (m, 2H), 7.11 (s, 2H), 7.50 (dd, 1H, J ¼ 10.2, 2.4 Hz),
7.87 (s, 1H), 10.69 (s, 1H); anal. calcd. for C25H23FN2O7S (%): C, 58.36;
H, 4.51; N, 5.44. Found (%): C, 58.43; H, 4.56; N, 5.50.
(2E,5Z) Ethyl 2-(5-(2-fluorobenzylidene)-2-(2-oxo-6-
fluoroindolin-3-ylidene)-4-oxothiazolidin-3-yl)acetate 5n
Yield: 43.0%. M.p.: 188–1908C; IR (KBr, cmꢀ1): 3434.7, 3131.0,
1740.6, 1712.3, 1683.0, 1540.7, 1507.7, 1236.2, 1146.5; MS (ESI)
m/z: 443.2 (MþH)þ; 1H-NMR (300 MHz, DMSO-d6) d: 1.20
(t, 3H, J ¼ 7.2 Hz), 4.12 (q, 2H, J ¼ 7.2 Hz), 5.28 (s, 2H),
6.67 (dd, 1H, J ¼ 9.0, 2.4 Hz), 6.83-6.90 (m, 1H), 7.41–7.46
(m, 2H), 7.78–7.89 (m, 4H), 10.83 (s, 1H); anal. calcd.
for C22H16F2N2O4S (%): C, 59.72; H, 3.65; N, 6.33. Found (%):
C, 59.79; H, 3.70; N, 6.39.
(2E,5Z) Ethyl 2-(5-benzylidene-2-(2-oxo-5-methylindolin-
3-ylidene)-4-oxothiazolidin-3-yl)acetate 5i
Yield: 54.3%. M.p.: 145–1478C; IR (KBr, cmꢀ1): 3430.7, 3156.7,
1742.5, 1714.2, 1674.2, 1531.0, 1212.9, 1162.4; MS (ESI)
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2012, 345, 73–80
Indolin-2-one Derivatives Bearing 4-thiazolidinone Moiety
79
(2E,5Z) Ethyl 2-(5-(4-fluorobenzylidene)-2-(2-oxo-6-
of the 4-thiazolidinone ring could enhance anticancer activi-
ties, and 5-fluoroindolin-2-one core was more favorable. As for
5-benzylidene moiety, introduction of electron-donating
group at the phenyl ring is beneficial for the cytotoxicity
and selectivity against HT-29 and H460 cancer cell lines.
Further studies are in progress in our laboratories and will
be reported upon in the future.
fluoroindolin-3-ylidene)-4-oxothiazolidin-3-yl)acetate 5o
Yield: 46.3%. M.p.: 134–1368C; IR (KBr, cmꢀ1): 3438.5, 3135.7,
1738.9, 1711.1, 1680.7, 1540.0, 1506.9, 1232.8, 1191.3, 1144.9;
MS (ESI) m/z: 443.1 (MþH)þ; 1H-NMR (300 MHz, DMSO-d6) d: 1.20 (t,
3H, J ¼ 7.2 Hz), 4.11 (q, 2H, J ¼ 7.2 Hz), 5.28 (s, 2H), 6.68–7.90 (m,
8H), 10.84 (s, 1H); anal. calcd. for C22H16F2N2O4S (%): C, 59.72; H,
3.65; N, 6.33. Found (%): C, 59.80; H, 3.70; N, 6.42.
We like to thank Department of Analytical and Testing Center, Shenyang
Pharmaceutical University, Shenhe District, Shenyang, China, for NMR
measurements.
(2E,5Z) Ethyl 2-(5-(4-fluorobenzylidene)-2-(2-oxo-5-
bromoindolin-3-ylidene)-4-oxothiazolidin-3-yl)acetate 5p
Yield: 56.3%. M.p.: 162–1648C; IR (KBr, cmꢀ1): 3430.7, 3154.5,
1759.0, 1708.3, 1659.8, 1560.1, 1508.5, 1207.3, 1156.4; MS (ESI)
m/z: 503.3 (MþH)þ; 1H-NMR (300 MHz, DMSO-d6) d: 1.20 (t, 3H,
J ¼ 7.2 Hz), 4.11 (q, 2H, J ¼ 7.2 Hz), 5.25 (s, 2H), 6.83–7.89 (m, 7H),
7.96 (m, 1H), 10.82 (s, 1H); anal. calcd. for C22H16BrFN2O4S (%):
C, 52.50; H, 3.20; N, 5.57. Found (%): C, 52.53; H, 3.26; N, 5.65.
The authors have declared no conflict of interest.
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