Synthesis and bioevaluation of new 5-benzylidenethiazolidine-2,4-diones bearing benzenesulfonamide moiety

Article abstract of DOI:10.1007/s00044-015-1422-9

Two series of new 5-benzylidenethiazolidine-2,4-diones bearing benzenesulfonamide moiety were designed and synthesized. The synthesized compounds were evaluated for several biological activities, including cytotoxicity, histone deacetylation, and protein

Full text of DOI:10.1007/s00044-015-1422-9

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-015-1422-9
ORIGINAL RESEARCH
Synthesis and bioevaluation of new 5-benzylidenethiazolidine-
2,4-diones bearing benzenesulfonamide moiety
Nguyen Thi Thuan1 Do Thi Mai Dung1 Do Nguyet Que1 Phan Thi Phuong Dung1
•
•
•
•
Tran Khac Vu2 Hyunggu Hahn3 Byung Woo Han3 Youngsoo Kim4
Sang-Bae Han4 Nguyen-Hai Nam1
•
•
•
•
•
Received: 6 January 2015 / Accepted: 20 July 2015
Ó Springer Science+Business Media New York 2015
Abstract Two series of new 5-benzylidenethiazolidine-
2,4-diones bearing benzenesulfonamide moiety were
designed and synthesized. The synthesized compounds
were evaluated for several biological activities, including
cytotoxicity, histone deacetylation, and protein phos-
phatase 1B (PTP1B) inhibitory effects. It was found that
those 5-benzylidenethiazolidine-2,4-diones with a chlorine
substituent on the benzenesulfonamide moiety exhibited
significant cytotoxicity, comparable to that of SAHA,
which was used as a positive control. Several cytotoxic
compounds also exhibited inhibitory effects against histone
deacetylation, suggesting that these compounds might
possess histone deacetylase inhibitory property. On the
activity of PTP1B, however, these compounds displayed
insignificant inhibitory effects.
Keywords Thiazolidine-2,4-dione Á
Benzenesulfonamide Á Synthesis Á Cytotoxicity
Introduction
Thiazolidine-2,4-dione is an important scaffold incorpo-
rated in many classes of chemical compounds with
interesting biological properties, including antibacterial,
antifungal (Aneja et al., 2011; Mentese et al., 2009;
Bozdag-Du¨ndar et al., 2007; Desai et al., 2014), antidia-
betic (Jain et al., 2013), cytotoxic (Romagnoli et al.,
˘
2013; Barros et al., 2012), and anti-inflammatory (Nastasa
et al., 2013) activities, to name a few. Several drugs
bearing thiazolidine-2,4-dione moiety have been approved
for clinical applications, for example pioglitazone and
rosiglitazone (Baba, 2001; Cheng-Lai and Levine, 2000),
which were approved for the treatment of type II diabetes
mellitus. The two drugs rosiglitazone and pioglitazone
(Fig. 1) act as potent ligands of PPAR-c and show effi-
cient insulin sensitization in type 2 diabetes patients
(Bhattarai et al., 2010; Patel et al., 1999). Recently, a
number of thiazolidine-2,4-dione incorporating com-
pounds were also reported to be potent protein tyrosine
phosphatase 1B (PTP1B) inhibitors (Bhattarai et al.,
2010; Maccari et al., 2007), and in particular, some thi-
azolidinediones were also demonstrated to have histone
deacetylase inhibitory effects (Mohan et al., 2012)
(Fig. 1).
& Sang-Bae Han
shan@chungbuk.ac.kr
& Nguyen-Hai Nam
namnh@hup.edu.vn
1
Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hanoi,
Vietnam
2
In our continuing research to find new thiazolidine-2,4-
dione derivatives with potential biological activities, we
have designed and synthesized two series of new 5-ben-
zylidenethiazolidine-2,4-diones bearing benzenesulfon-
amide moiety. The present paper describes the recent
results we obtained from this investigation.
School of Chemical Engineering, Hanoi University of
Science and Technology, 1 Dai Co Viet, Hanoi, Vietnam
3
Research Institute of Pharmaceutical Sciences, College of
Pharmacy, Seoul National University, Seoul 151-742, Korea
4
College of Pharmacy, Chungbuk National University,
Cheongju, Chungbuk 361-763, Korea
123

Med Chem Res
O
O
CH3
N
H3C
NH
NH
S
N
S
O
N
O
O
O
Rosiglitazone
CF3
Pioglitazone
O
O
O
O
S
NH
O
S
N
S
N
H
H3C
O
O
O
Br
O
B
A
Fig. 1 Structures of thiazolidine-2,4-dione antidiabetic agents (pioglitazone, rosiglitazone), PTP1B inhibitor (a) and HDAC inhibitor (b)
chemical shifts of the olefinic protons (–CH=group), which
appeared downfield as a singlet at 7.72–7.74 ppm.
According to the literature (Bruno et al., 2002), these
chemical shifts of the olefinic proton should correspond to
Z-configuration. For E-configuration, the chemical shifts of
these olefinic protons should be around 6.52 ppm. The
exclusive formation of Z-isomer in this condensation
reaction has also been clearly demonstrated by X-ray
analysis (Bruno et al., 2002) and reported in many other
similar studies (Alegaon and Alagawadi, 2012; da Rocha
Junior et al., 2013).
Results and discussions
Chemistry
A series of new benzenesulfonamide-incorporated thiazo-
lidine-2,4-diones (4a–f) was synthesized according to the
pathway depicted in Scheme 1. Reaction of different ben-
zenesulfonyl chlorides (1) with 2-chloroethylamine.HCl
gave the intermediates 2a–f. Nucleophilic substitution
between 2a–f and 4-hydroxybenzaldehyde under alkaline
conditions resulted in 4-substituted benzaldehydes 3a–f
which were then condensed with thiazolidine-2,4-dione
catalyzed by piperidine to afford the expected products 4a–
f in moderate-to-good overall yields.
Bioactivity
The SRB (sulforhodamine B) cell proliferation assay was
used to evaluate the antiproliferative activity of the syn-
thesized compounds. The compounds were first screened at
100 lg/mL for cell growth inhibition against SW620
Five other compounds (7a, 7b, 7d–f) were synthesized
by similar procedures. The structures of synthesized com-
pounds were straightforwardly confirmed by analysis of IR,
MS, and NMR spectral data. All compounds showed
CHO
R
b
R
H
N
a
R
H
N
Cl
S
Cl
S
O
S
n
O
n
O
O
1
O
O
O
2 (n = 1)
5 (n = 2)
3 (n = 1)
6 (n = 2)
O
a) R = H
b) R = 2-Cl
c) R = 3-Cl
d) R = 4-Cl
e) R = 4-OCH3
f) R = 4-CH3
c
NH
R
H
N
S
S
O
n
O
O
O
4 (n = 1)
7 (n = 2)
Scheme 1 Synthesis
5-ylidene)methyl)phenoxy)ethyl/propyl)benzenesulfonamide and deriva-
tives. Reagents and conditions: a DMF, TEA, 2-chloroethylamine.HCl
of
(Z)-N-(2-(4-((2,4-dioxothiazolidine-
(for compounds 3)/3-chloropropylamine.HCl (for compound 6); b 4-
hydroxybenzaldehyde, K2CO3, DMF, 45 °C; c ethanol, piperidine,
thiazolidine-2,4-dione
123

Med Chem Res
(human colon cancer) cell line. It was found that all
compounds synthesized (4a–f, 7a, 7b, 7d–f) completely
inhibited the growth of SW620 cells at this concentration.
Therefore, the compounds were subjected to further eval-
uation at five concentrations (30, 10, 3, 1, 0.3 lg/mL) in
SW620 and two human cancer cell lines more, including
PC-3 (prostate cancer) and NCI-H460 (lung cancer) cell
lines. The IC50 (the concentration that causes 50 % of cell
proliferation inhibition) values of each compound were
determined and are summarized in Table 1. SAHA and
ADR (adriamycin) were used as positive controls. Data
from Table 1 clearly indicated that in overall, the com-
pounds synthesized were more sensitive toward a lung
cancer cell line NCI-H460 and less active against the colon
cancer cells SW620. Introduction of substituents at position
4 on the benzenesulfonamide moiety was found to signif-
icantly influence cytotoxicity, but among substituents
investigated, only chlorine group enhanced cytotoxic
effects. Substituents at position 2 seemed more favorable
than at position 3, which was in turn more favorable than at
position 4 for cytotoxicity. Generally, lengthening the alkyl
bridge connecting a benzenesulfonamide and 5-(4-hy-
droxybenzylidene)thiazolidine-2,4-dione moiety seemed to
decrease cytotoxicity in cell lines tested (7a, 7b, 7d vs. 4a,
4b, 4d). From these results, it is reasonable to postulate that
although the synthesized compounds still retain acceptable
lipophilicity and hydrophilicity balance, as manifested by
logP values (Table 1), the increase in lipophilicity might
not be favorable for cytotoxicity of these compounds
series.
Among the two series synthesized, it was encouraging to
note that several compounds (e.g., 4b, 4c) displayed
comparable cytotoxicity to SAHA in some cell lines
assayed (PC-3, NCI-H460) (Table 1). Although the cyto-
toxicity of these compounds was still lower than that of
adriamycin (Table 1), the present results should warrant
further interest and effort in these compounds’ types to find
more potent anticancer agents.
Table 1 Cytotoxicity of the compounds synthesized against several cancer cell lines
O
7"
3
3"
3
2
2
4
5
4
5
2"
1"
NH
O
R
R
O
H
N
H
N
2"
2'
2'
S
O
5"
1
3"
1
S
S
S
O
6
6
6"
3'
1'
1'
O
O
NH
O
O
4
6"
7
5"
7"
O
Cpd code
R
H
Molecular formula
C18H16N2O5S2
Molecular
weight
LogP
Cytotoxicity (IC50,a lg/mL)/cell linesb
SW 620
PC-3
NCI-H460
4a
404.46
438.91
438.91
438.91
418.49
434.49
418.49
452.93
452.93
432.51
448.51
264.32
2.32
2.97
2.97
2.97
2.87
2.40
2.81
3.46
3.46
3.36
2.89
1.44
[30
7.45
9.23
12.36
[30
[30
[30
8.35
10.89
[30
[30
6.42
0.48
21.32
4.26
18.22
2.57
4b
2-Cl
C18H15ClN2O5S2
C18H15ClN2O5S2
C18H15ClN2O5S2
4c
3-Cl
3.45
4.26
4d
4-Cl
6.15
5.41
4e
4-CH3
C19H18ClN2O5S2
C19H18ClN2O6S2
[30
17.26
19.11
6.52
16.53
16.51
21.36
5.14
4f
4-OCH3
H
7a
C
C
C
19H18N2O5S2
7b
2-Cl
19H17ClN2O5S2
19H17ClN2O5S2
7d
4-Cl
5.42
4.24
7e
4-CH3
4-OCH3
C20H20N2O5S2
C20H20N2O6S2
[30
15.23
4.31
24.58
15.47
2.77
7f
SAHAc
ADRd
a
0.30
0.11
The concentration (lg/mL) of compounds that produces a 50 % reduction in cell growth; the numbers represent the averaged results from
triplicate experiments with deviation of less than 10 %
b
Cell lines: SW620, colon cancer; PC3, prostate cancer; NCI-H460, lung cancer
c
SAHA, suberoylanilide acid, a positive control
d
ADR, adriamycin, a positive control
123

Med Chem Res
These compounds possess a 5-benzylidenethiazolidine-
2,4-dione scaffold, which contains an a,b-unsaturated
carbonyl moiety. Therefore, one possible mechanism of
cytotoxicity could be nucleophilic alkylation at the b
position. Recently Mohan et al. (2012) demonstrated that
several thiazolidine-2,4-dione compounds also exhibited
histone deacetylase inhibition effects. Encouraged by this
finding, we evaluated the effects of six compounds
including 4a–f on histone deacetylation using a Western
blot analysis. It was found that compounds 4b, 4c, and 4d
at 10 lg/mL slightly inhibited deacetylation of histone H3
and histone H4 (Fig. 2). Meanwhile, the effects of com-
pounds 4a, 4e, and 4f on histone H3 and histone H4
deacetylation were not observed at this concentration.
Though the inhibition effects of these compounds on his-
tone deacetylation were still very weak, there seemed to
exist a relative correlation between cytotoxicity and the
ability of these compounds to inhibit histone deacetylation.
To gain possible mode of binding of this type of com-
pounds with histone deacetylase, we performed docking
study with one compound 4b using HDAC2 and HDAC8.
We executed control docking experiments with SAHA to
the crystal structures of HDAC2 and HDAC8 using
AutoDock Vina program (Trott and Olson, 2010) after
SAHA was removed from the complex structures, as
described previously (Nam et al., 2013; Tung et al., 2013;
Oanh et al., 2011). It was found from docking experiments
that compound 4b was predicted to sit at the top and block
the SAHA binding pocket (Fig. 3) with stabilization energy
of -5.9 and -6.5 kcal/mol with HDAC2 and HDAC8,
respectively. Meanwhile, the binding energy of SAHA with
HDAC2 and HDAC8 was -7.4 and -7.0 kcal/mol, lower
than that of compound 4b. This docking study indicated
that compound 4b did bind to HDAC2 and HDAC8,
though the binding affinities were lower than that of
SAHA. Thus, collectively, it could be expected that the
thiazolidine-2,4-dione scaffold might be interesting for
further manipulation to obtain more potent histone
deacetylase inhibitors.
In addition to cytotoxicity and the effects on histone
deacetylation, we also screened the synthesized compounds
against the enzyme PTP1B. It was found, however, that
these compounds exerted no significant inhibitory effects
on the activity of PTP1B (Table 2), even when tested at the
concentrations of 30 lM. Meanwhile, suramin, a positive
control, inhibited the enzyme activity by approximately
55 % when tested at a concentration of 10 lM. Thus, the
introduction of a bulky benzenesulfonamide moiety might
not be favorable for binding to this enzyme. Nevertheless,
these results should not discourage further effort in
development of this type of compounds to obtain potent
PTP1B inhibitors.
Conclusions
In conclusion, we have reported two new series of 5-ben-
zylidenethiazolidine-2,4-diones bearing benzenesulfon-
amide moiety and evaluated their cytotoxicity, histone
deacetylation, and PTP1B inhibitory effects. It was found
that compounds with chlorine substituents on the benzene
ring of the benzenesulfonamide moiety exhibited signifi-
cant cytotoxicity against three human cancer cell lines
tested, including SW620 (colon cancer), PC-3 (prostate
cancer), and NCI-H460 (lung cancer). Several compounds
(4b–d) exhibited cytotoxicity against PC-3 and NCI-H460
cell lines comparable to that of SAHA. In particular, these
compounds also exhibited noted inhibition on histone
deacetylation, suggesting that the compounds might pos-
sess histone deacetylase inhibitory property and are
potential to serve as novel leads for design of histone
deacetylase inhibitors. On the activity of PTP1B, however,
these compounds displayed insignificant inhibitory effects.
Experimental protocols
Chemistry
All products were homogenous, as examined by thin-layer
chromatography (TLC), performed on WhatmanÒ 250 lm
Silica Gel GF Uniplates, and visualized under UV light at
254 and 365 nm. Melting points were determined with a
Gallenkamp Melting Point Apparatus (LabMerchant,
London, UK) and are uncorrected. Chromatographic
purification was done by the open flash silica gel column
chromatography using Merck silica gel 60 (240–400
meshes). Nuclear magnetic resonance spectra (1H NMR)
were recorded using tetramethylsilane as an internal stan-
dard on a Bruker 500 MHz spectrometer with DMSO-d6 as
Fig. 2 Effect of compounds 4a–f on histone acetylation in SW620
cells. Cells were treated with compounds (10 lg/mL) or SAHA (1 lg/
mL, a positive control) for 24 h. Levels of acetylated histone H3 and
H4 in total cell lysates were determined by Western immunoblot
analysis
123

Med Chem Res
Fig. 3 Binding poses of the highest affinity binding modes from each
docking experiment between compound 4b and HDAC2 (a) or
HDAC8 (b). Compound 4b shown as green and SAHA as gray color
frames. Compound 4b is represented as a stick model with carbon,
nitrogen, and oxygen atoms in yellow, blue, and red, respectively.
Residues that seem to interact with compound 4b are presented as
cyan (Color figure online)
Table 2 Effects of the compounds 4a–f on the activity of PTP1B
O
NH
S
R
H
N
S
O
O
O
O
4
Cpd code
R
Molecular formula
C18H16N2O5S2
Molecular
weight
Assay
concentration
(lM)
OD
PTP1B inhibition
percentage (EIP, %)
4a
H
404.46
438.91
438.91
438.91
418.49
434.49
30
30
30
30
30
30
–
1.081 0.020
1.061 0.024
1.057 0.038
1.024 0.340
1.013 0.053
1.014 0.031
1.057 0.034
0.473 0.042
-2.270
-0.363
0.047
4b
2-Cl
C
C
C
18H15ClN2O5S2
18H15ClN2O5S2
18H15ClN2O5S2
4c
3-Cl
4d
4-Cl
3.137
4e
4-CH3
4-OCH3
C19H18ClN2O5S2
C19H18ClN2O6S2
4.209
4f
4.131
Blank
Suramin
10
55.258
solvent unless otherwise indicated. Chemical shifts are
reported in parts per million (ppm) downfield from
tetramethylsilane as internal standard. Electron ionization
(EI), electrospray ionization (ESI) and high-resolution
mass spectra were obtained using PE Biosystems API 200
(Perkin Elmer, Palo Alto, CA, USA) and MarinerÒ (Azco
Biotech, Inc. Oceanside, CA, USA) mass spectrometers,
respectively. Reagents and solvents were purchased from
Aldrich or Fluka Chemical Corp. (Milwaukee, WI, USA)
or Merck unless noted otherwise. Solvents were distilled
and dried before use.
The synthesis of two series of (Z)-N-(2-(4-((2,
4-dioxothiazolidine-5-ylidene)methyl)phenoxy)ethyl)ben-
zenesulfonamides (4a–f) and (Z)-N-(3-(4-((2,4-dioxothia-
zolidine-5-ylidene)methyl)phenoxy)propyl)benzenesulfon-
amides (7a, 7b, 7d–f) was carried out as illustrated in
123

Med Chem Res
AcOH = 90:5:1). IR (KBr, cm-1): 3393, 3205 (NH), 3090
(C-H, aren), 2932 (CH, CH2), 1741, 1696 (C=O), 1598,
1511, 1453 (C=C), 1326, 1160 (S=O), 1260 (C-O), 762 (C–
Cl). ESI–MS (m/z): 437.6 [M-H]-. 1H-NMR (500 MHz,
DMSO-d6, ppm): d 8.17 (1H, t, J = 5.5 Hz, sulfonamide),
7.99 (1H, d, J = 8.0 Hz, H-6), 7.72 (1H, s, H-700, olefinic
proton), 7.65 (1H, t, J = 8.0 Hz, H-4), 7.59 (2H, d,
J = 8.0 Hz, H-3), 7.52 (1H, t, J = 8.0 Hz, H-5), 7.49 (2H,
d, J = 9.0 Hz, H-300, H-500), 6.91 (2H, d, J = 9.0 Hz, H-200,
H-600), 4.00 (2H, t, J = 5.5 Hz, H-20), 3.31 (2H, td,
J = 5.5 Hz, J’ = 5.5 Hz, H-10). 13C NMR (125 MHz,
DMSO-d6, ppm): d 167.9 (C-1000), 167.5 (C-900), 159.7 (C-
100), 138.2 (C-1), 133.8 (C-700), 132.0 (C-4), 131.9 (C-300,
C-500), 131.7 (C-2), 130.7 (C-3), 130.1 (C-6), 127.5 (C-5),
125.6 (C-400), 120.5 (C-800), 115.1 (C-200, C-600), 66.5 (C-20),
41.8 (C-10). Anal. Calcd. For C18H15ClN2O5S2 (438.91): C,
49.26; H, 3.44; N, 6.38. Found: C, 49.29; H, 3.55; N, 6.37.
Scheme 1. For numbering, please refer to Table 1. Details
are described as follows:
(Z)-N-(2-(4-((2,4-dioxothiazolidine-5-ylidene)methyl)phenoxy)
ethyl)benzenesulfonamide (4a) Benzenesulfonyl chloride
(525 mg, * 380 lL, 3 mmoL) was gradually added to a
50-mL round-bottom flask containing 2-chloroethy-
lamine.HCl (116 mg, 3 mmol) in dimethyl formamide
(5 mL) and triethylamine (TEA, 500 lL). The reaction
mixture was stirred at room temperature for 3 h and then
poured into a cold solution of HCl 5 % (50 mL). The
precipitate was collected and dried under vacuum at 40 °C
to give compound 2a, which was used for the next step
without further purification. Compound 2a was then dis-
solved in DMF (6 mL). 4-Hydroxybenzaldehyde (366 mg,
3 mmoL) and K2CO3 (207 mg, 1.5 mmoL) were then
added. The resulting mixture was warmed to 45 °C and
stirred at this temperature for 12 h. The reaction mixture
was poured into a cold solution of HCl 5 % (50 mL) to
give white precipitates, which was dried to give 3a
(820 mg). IR (KBr, cm-1): 3125 (NH), 3050 (C-H, aren),
2925, 2855 (CH, CH2), 1745 (C = O), 1602, 1585
(C = C), 1350, 1180 (S=O), 1280 (C-O). ESI–MS (m/z):
304.4 [M-H]-. Compound 3a was dissolved in dry ethanol
(25 mL), to which thiazolidine-2,4-dione (348 mg,
3 mmoL) and piperidine (300 lL) were added. The mix-
ture was refluxed for 12 h, and then ethanol was evapo-
rated. A cold solution of HCl 5 % (50 mL) was added and
gently stirred to give precipitate, which was recrystallized
from ethanol to afford white solids (4a, 900 mg). Yield:
74 %. mp: 212–215 °C. Rf = 0.40 (DCM/MeOH/AcOH =
90:5:1). IR (KBr, cm-1): 3415, 3193 (NH), 3069 (C-H,
aren), 2924, 2853 (CH, CH2), 1736, 1693 (C = O), 1602,
1567 (C = C), 1323, 1160 (S = O), 1267 (C-O). ESI–MS
(m/z): 402.9 [M-H]-. 1H-NMR (500 MHz, DMSO-d6,
ppm): d 7.98 (1H, t, J = 6.0 Hz, sulfonamide), 7.83 (2H,
dd, J = 7.0 Hz, J’ = 1.5 Hz, H-2, H-6), 7.72 (1H, s, H-700,
olefinic proton), 7.63 (1H, tt, J = 7.0 Hz, J’ = 1.5 Hz,
H-4), 7.58 (2H, td, J = 7.0 Hz, J’ = 1.5 Hz, H-3, H-5),
7.52 (2H, d, J = 8.75 Hz, H-300, H-500), 7.00 (2H, d,
J = 8.75 Hz, H-200, H-600), 4.02 (2H, t, J = 5.25 Hz, H-20),
3.16 (2H, td, J = 5.25 Hz, J’ = 6.0 Hz, H-10). 13C NMR
(125 MHz, DMSO-d6, ppm): d 168.1 (C-1000), 167.8 (C-900),
159.8 (C-100), 140.5 (C-1), 132.3 (C-700), 131.9 (C-300,
C-500), 131.4 (C-4), 129.6 (C-2, C-6), 126.4 (C-3, C-5),
125.7 (C-400), 120.8 (C-800), 115.3 (C-200, C-600), 66.7 (C-20),
41.8 (C-10). Anal. Calcd. For C18H16N2O5S2 (404.46): C,
53.45; H, 3.99; N, 6.93. Found: C, 53.29; H, 3.95; N, 6.97.
Other compounds (3b–f, 7a, 7b, 7d–f) were synthesized
by a similar procedure as described for compound 4a.
(Z)-3-Chloro-N-(2-(4-((2,4-dioxothiazolidine-5-ylidene)methyl)
phenoxy)ethyl)benzenesulfonamide (4c) Yield: 79 %. mp:
216–218 °C. Rf = 0.41 (DCM/MeOH/AcOH = 90:5:1).
IR (KBr, cm-1): 3449, 3185 (NH), 3067 (C-H, aren), 1737,
1693 (C=O), 1602, 1514, 1446 (C=C), 1327, 1159 (S=O),
1265 (C-O), 789 (C–Cl). ESI–MS (m/z): 437.1 [M-H]-.
1H-NMR (500 MHz, DMSO-d6, ppm): d 12.50 (1H, s, NH,
thiazolidine-2,4-dione), 8.14 (1H, t, J = 5.5 Hz, sulfon-
amide), 7.82 (1H, t, J = 1.0 Hz, H-2), 7.78 (1H, dt,
J = 7.75 Hz, J’ = 1.0 Hz, H-6), 7.73 (1H, s, H-700, olefinic
proton), 7.69 (1H, dt, J = 7.75 Hz, J’ = 1.0 Hz, H-4), 7.60
(1H, t, J = 8.0 Hz, H-5), 7.52 (2H, d, J = 8.85 Hz, H-300,
H-500), 6.98 (2H, d, J = 8.85 Hz, H-200, H-500), 4.03 (2H, t,
J = 5.5 Hz, H-20), 3.22 (2H, td, J = 5.5 Hz, J’ = 5.5 Hz,
H-10). 13C NMR (125 MHz, DMSO-d6, ppm): d 167.9 (C-
1000), 167.4 (C-900), 159.7 (C-100), 142.6 (C-1), 133.8 (C-700),
132.3 (C-3), 132.0 (C-300, C-500), 131.7 (C-4), 131.2 (C-5),
126.0 (C-6), 125.7 (C-400), 125.1 (C-2), 120.4 (C-800), 115.2
(C-200, C-600), 66.6 (C-20), 41.9 (C-10). Anal. Calcd. For
C18H15ClN2O5S2 (438.91): C, 49.26; H, 3.44; N, 6.38.
Found: C, 49.23; H, 3.54; N, 6.44.
(Z)-4-Chloro-N-(2-(4-((2,4-dioxothiazolidine-5-ylidene)methyl)
phenoxy)ethyl)benzenesulfonamide (4d) Yield: 77 %. mp:
215–217 °C. Rf = 0.41 (DCM/MeOH/AcOH = 90:5:1).
IR (KBr, cm-1): 3412, 3118 (NH), 3066 (C-H, aren) 2940,
2875 (CH, CH2), 1735, 1691 (C=O), 1602, 1541, 1440
(C=C), 1327, 1162 (S=O), 1267 (C-O), 824 (C–Cl). ESI–
1
MS (m/z): 437.4 [M-H]-. H-NMR (500 MHz, DMSO-d6,
ppm): d 12.52 (1H, s, NH, thiazolidine-2,4-dione), 8.10
(1H, t, J = 5.5 Hz, sulfonamide), 7.81 (2H, d, J = 8.5 Hz,
H-3, H-5), 7.74 (1H, s, H-700, olefinic proton), 7.63 (2H, d,
J = 8.5 Hz, H-2, H-6), 7.52 (2H, d, J = 8.5 Hz, H-300,
H-500), 6.98 (2H, d, J = 8.5 Hz, H-200, H-600), 4.02 (2H, t,
J = 5.0 Hz, H-20), 3.19 (2H, td, J = 5.0 Hz, J’ = 5.5 Hz,
H-10). 13C NMR (125 MHz, DMSO-d6, ppm): d 167.8 (C-
(Z)-2-Chloro-N-(2-(4-((2,4-dioxothiazolidine-5-ylidene)
methyl)phenoxy)ethyl)benzenesulfonamide (4b) Yield:
72 %. mp: 215–217 °C. Rf = 0.41 (DCM/MeOH/
123

Med Chem Res
1
1000), 167.4 (C-900), 159.7 (C-100), 139.5 (C-1), 137.2 (C-700),
131.9 (C-300, C-500), 131.7 (C-4), 129.3 (C-2, C-6), 128.3
(C-3, C-5), 125.7 (C-400), 120.4 (C-800), 115.2 (C-200, C-600),
66.6 (C-20), 41.8 (C-10). Anal. Calcd. For C18H15ClN2O5S2
(438.91): C, 49.26; H, 3.44; N, 6.38. Found: C, 49.34; H,
3.55; N, 6.49.
(C-O). ESI–MS (m/z): 417.2 [M-H]-. H-NMR (500 MHz,
DMSO-d6, ppm): d 12.50 (1H, s, NH, thiazolidine-2,4-
dione), 7.80 (2H, d, J = 7.5 Hz, H-2 H-6), 7.73 (1H, s,
H-700, olefinic proton), 7.71 (1H, t, J = 6.25 Hz, NH, sul-
fonamide), 7.61 (1H, t, J = 7.0 Hz, H-4), 7.57 (2H, t,
J = 7,5 Hz, H-3, H-5), 7.52 (2H, d, J = 8.75 Hz, H-300,
H-500), 7.01 (2H, d, J = 8.75 Hz, H-200, H-600), 4.01 (2H, t,
J = 6.5 Hz, H-30), 2.92 (2H, td, J = 6.5 Hz, J’ = 6.25 Hz,
H-10), 1.83 (2H, quintet, J = 6.5 Hz, H-20) 13C NMR
(125 MHz, DMSO-d6, ppm): d 167.90 (C-1000), 167.38 (C-
900), 160.15 (C-100), 140.37 (C-1), 132.33 (C-700), 132.00 (C-
2. C-6), 131.81 (C-4), 129.18 (C-300. C-500), 126.41 (C-3,
C-5), 125.46 (C-400), 120.27 (C-800), 115.29 (C-200, C-600),
64.95 (C-30), 28.70 (C-20). Anal. Calcd. For C19H18N2O5S2
(418.49): C, 54.53; H, 4.34; N, 6.69. Found: C, 54.45; H,
4.44; N, 6.71.
(Z)-N-(2-(4-((2,4-dioxothiazolidine-5-ylidene)methyl)phenoxy)
ethyl)-4-methylbenzenesulfonamide (4e) Yield: 81 %. mp:
224–225 °C. Rf = 0.40 (DCM/MeOH/AcOH = 90:5:1).
IR (KBr, cm-1): 3416, 3201 (NH), 3068 (C-H, aren) 2939,
2875 (CH, CH2), 1736, 1693 (C=O), 1602, 1514, 1440
(C=C), 1322, 1160 (S=O), 1266 (C-O). ESI–MS (m/z):
417.2 [M-H]-. 1H-NMR (500 MHz, DMSO-d6, ppm): d
12.52 (1H, s, NH, thiazolidine-2,4-dione), 7.88 (1H, t,
J = 5.5 Hz, sulfonamide), 7.74 (1H, s, H-700, olefinic pro-
ton), 7.70 (2H, d, J = 8.25 Hz, H-2, H-6), 7.52 (2H, d,
J = 8.75 Hz, H-300, H-500), 7.36 (2H, d, J = 8.25 Hz, H-3,
H-5), 6.99 (2H, d, J = 8.75 Hz, H-200, H-600), 4.02 (2H, t,
J = 5.5 Hz, H-20), 3.13 (2H, td, J = 5.5 Hz, J’ = 5.5 Hz,
H-10), 2.36 (3H, s, -CH3). 13C NMR (125 MHz, DMSO-d6,
ppm): d 167.9 (C-1000), 167.3 (C-900), 159.8 (C-100), 142.6
(C-1), 137.7 (C-700), 131.9 (C-300, C-500), 131.7 (C-4), 129.5
(C-2, C-6), 126.4 (C-3, C-5), 125.6 (C-400), 120.4 (C-800),
115.3 (C-200, C-600), 66.6 (C-20), 41.8 (C-10), 20.9 (CH3).
Anal. Calcd. For C19H18ClN2O5S2 (418.49): C, 54.53; H,
4.34; N, 6.69. Found: C, 54.29; H, 4.49; N, 6.74.
(Z)-2-Chloro-N-(3-(4-((2,4-dioxothiazolidine-5-ylidene)methyl)
phenoxy)propyl)benzenesulfonamide (7b) Yield: 77 %. mp:
210–211.5 °C. Rf = 0.38 (DCM/MeOH/AcOH = 90:5:1).
IR (KBr, cm-1): 3441, 3248 (NH), 2928, 2847 (CH, CH2),
1736, 1693 (C=O), 1600, 1570 (C=C), 1318, 1157 (S=O),
1262 (C-O). ESI–MS (m/z): 451.7 [M-H]-. 1H-NMR
(500 MHz, DMSO-d6, ppm): d 7.97 (1H, t, J = 6.0 Hz,
NH, sulfonamide), 7.96 (1H, dd, J = 8.0 Hz,
J’ = 1,75 Hz, H-6), 7.73 (1H, s, H-700, olefinic proton),
7.60 (1H, td, J = 8.0 Hz, J’ = 2.0 Hz, H-4), 7.58 (1H, td,
J = 8.0 Hz, J’ = 2.0 Hz, H-5), 7.51 (2H, d, J = 8.5 Hz,
H-300, H-500), 7.49 (1H, dd, J = 8.0 Hz, J’ = 2.0 Hz, H-3),
6.98 (2H, d, J = 8.5 Hz, H-200, H-600), 4.01 (2H, t,
J = 6.0 Hz, H-30), 3.02 (2H, td, J = 6.5 Hz, J’ = 6.0 Hz,
H-10), 1.84 (2H, quintet, J = 6.5 Hz, H-20). 13C NMR
(125 MHz, DMSO-d6, ppm): d 168.00 (C-1000), 167.52 (C-
900), 160.12 (C-100), 137.77 (C-700), 133.92 (C-1), 132.00 (C-
300. C-500), 131.79 (C-4), 131.74 (C-2), 130.56 (C-3), 130.46
(C-6), 127.64 (C-5), 125.48 (C-400), 120.36 (C-800), 115.27
(C-200, C-600), 64.83 (C-30), 39.34 (C-10), 28.76 (C-20). Anal.
Calcd. For C19H17ClN2O5S2 (452.93): C, 50.38; H, 3.78;
N, 6.18. Found: C, 50.31; H, 3.75; N, 6.27.
(Z)-N-(2-(4-((2,4-dioxothiazolidine-5-ylidene)methyl)phenoxy)
ethyl)-4-methoxybenzenesulfonamide (4f) Yield: 78 %. mp:
220–222 °C. Rf = 0.39 (DCM/MeOH/AcOH = 90:5:1).
IR (KBr, cm-1): 3418, 3207 (NH), 3067 (C-H, aren), 2932,
2848 (CH, CH2), 1736, 1693 (C=O), 1602, 1575 (C=C),
1324, 1153 (S=O), 1265 (C-O). ESI–MS (m/z): 433.3 [M-
H]-. 1H-NMR (500 MHz, DMSO-d6, ppm): d 12.50 (1H, s,
NH, thiazolidine-2,4-dione), 7.81 (1H, t, J = 5.5 Hz, sul-
fonamide), 7.76–7.74 (3H, overlap, H-700, olefinic proton,
H-3, H-5), 7.53 (2H, d, J = 8.85 Hz, H-300, H-500), 7.08
(2H, dt, J = 7.0 Hz, J’ = 2.0 Hz, H-2, H-6), 7.01 (2H, d,
J = 8.85 Hz, H-200, H-600), 4.02 (1H, t, J = 5.5 Hz, H-20),
3.81 (3H, s, -OCH3), 3.12 (2H, td, J = 5.5 Hz,
J’ = 5.5 Hz, H-10). 13C NMR (125 MHz, DMSO-d6, ppm):
d 167.9 (C-1000), 167.4 (C-900), 162.1 (C-4), 159.8 (C-100),
132.1 (C-1), 132.0 (C-300, C-500), 131.7 (C-700), 128.6 (C-2,
C-6), 125.6 (C-400), 120.4 (C-800), 115.3 (C-3, C-5), 114.3
(C-200, C-600), 66.6 (C-20), 55.6 (C-OCH3), 41.8 (C-10).
Anal. Calcd. For C19H18ClN2O6S2 (434.49): C, 52.52; H,
4.18; N, 6.45. Found: C, 52.50; H, 4.29; N, 6.54.
(Z)-4-Chloro-N-(3-(4-((2,4-dioxothiazolidine-5-ylidene)methyl)
phenoxy)propyl)benzenesulfonamide (7d) Yield: 79 %. mp:
212–213 °C. Rf = 0.37 (DCM/MeOH/AcOH = 90:5:1).
IR (KBr, cm-1): 3446, 3274 (NH), 3036 (C-H, aren), 2929
(CH, CH2), 1741, 1695 (C=O), 1596, 1571 (C=C), 1328,
1156 (S=O). ESI–MS (m/z): 450.5 [M-2H]-. 1H-NMR
(500 MHz, DMSO-d6, ppm): d 7.82 (1H, t, J = 6,0 Hz,
NH, sulfonamide), 7.79 (2H, d, J = 8,5 Hz, H-2, H-6),
7.72 (1H, s, H-700, olefinic proton), 7.62 (2H, d,
J = 8.25 Hz, H-3, H-5), 7.51 (2H, d, J = 8.5 Hz, H-300,
H-500), 7.99 (2H, d, J = 8.5 Hz, H-200, H-600), 3.99 (2H, t,
J = 6.0 Hz, H-30), 2.94 (2H, td, J = 6.0 Hz, J’ = 6.0 Hz,
H-10), 1.83 (2H, quintet, J = 6.0 Hz, H-20). 13C NMR
(125 MHz, DMSO-d6, ppm): d 167.98 (C-1000), 167.56 (C-
(Z)-N-(3-(4-((2,4-dioxothiazolidine-5-ylidene)methyl)phenoxy)
propyl)benzenesulfonamide (7a) Yield: 76 %. mp:
213–214 °C. Rf = 0.42 (DCM/MeOH/AcOH = 90:5:1).
IR (KBr, cm-1): 3519, 3243 (NH), 2937 (CH, CH2), 1742,
1694 (C=O), 1604, 1569 (C=C), 1321, 1157 (S=O), 1264
123

Med Chem Res
900), 160.07 (C-100), 139.26 (C-700), 137.22 (C-1), 131.97 (C-
300, C-500), 131.69 (C-4), 129.30 (C-3, C-5), 128.37 (C-2,
C-6), 125.50 (C-400), 120.41 (C-800), 115.23 (C-200, C-600),
64.79 (C-30), 39.24 (C-10), 28.62 (C-20). Anal. Calcd. For
C19H17ClN2O5S2 (452.93): C, 50.38; H, 3.78; N, 6.18.
Found: C, 50.29; H, 3.65; N, 6.27.
cancer) were obtained from a cancer cell bank at the Korea
Research Institute of Bioscience and Biotechnology
(KRIBB). All media, sera, and other reagents used for cell
culture were obtained from GIBCO Co., Ltd. (Grand
Island, New York, USA). Compounds were initially dis-
solved in dimethyl sulfoxide (DMSO) to make stock
solutions at concentrations of 1000-fold higher than the
testing concentration. Right before assays, the stock solu-
tions were serially diluted by 100-fold using cell culture
medium. One hundred and eighty microliters of cell sus-
pension (9 9 103 cells) was plated in each well in 96-well
plates. The plates were incubated for 24 h, and then the
cells in each well were treated with 20 lL of samples or
positive controls (SAHA or adriamycin) at different con-
centrations as prepared above. To blank wells was added
20 lL of cell culture medium containing no sample.
Cytotoxicity was measured by the method as described in
the literature (Skehan et al., 1990) with slight modifications
(You et al., 2004; Kim et al., 2002). The IC50 values were
calculated according to the probit method (Wu et al.,
1992). The values reported for these compounds are aver-
ages of three separate determinations.
(Z)-N-(3-(4-((2,4-Dioxothiazolidine-5-ylidene)methyl)phenoxy)
propyl)-4-methylbenzenesulfonamide (7e) Yield: 75 %. mp:
210–211 °C. Rf = 0.42 (DCM/MeOH/AcOH = 90:5:1).
IR (KBr, cm-1): 3445, 3291 (NH), 3121 (C-H, aren), 2970,
2875 (CH, CH2), 1735, 1691 (C=O), 1594, 1568 (C=C),
1332, 1156 (S=O), 1266 (C-O). ESI–MS (m/z): 430.5 [M-
2H]-. 1H-NMR (500 MHz, DMSO-d6, ppm): d 7.73 (1H, s,
H-700, olefinic proton), 7.67 (2H, d, J = 8.0 Hz, H-2, H-6),
7.61 (1H, s, J = 5.5 Hz, NH, sulfonamide), 7.51 (2H, d,
J = 9.0 Hz, H-300, H-500), 7.35 (2H, d, J = 9.0 Hz, H-3,
H-5), 7.00 (2H, d, J = 9.0 Hz, H-200, H-600), 3.99 (2H, t,
J = 6.25 Hz, H-30), 2.90 (2H, td, J = 6.25 Hz,
J’ = 6.25 Hz, H-10), 1.82 (2H, quintet, J = 6.25 Hz, H-20).
d 13C NMR (125 MHz, DMSO-d6, ppm): d 167.94 (C-1000),
167.45 (C-900), 160.15 (C-100), 142.55 (C-700), 137.51 (C-1),
131.99 (C-300. C-500), 131.78 (C-4), 129.59 (C-3, C-5),
126.48 (C-2, C-6), 125.46 (C-400), 120.30 (C-800), 115.28
(C-200, C-600), 64.92 (C-30), 39.26 (C-10), 28.65 (C-20),
20.92 (-CH3). Anal. Calcd. For C20H20N2O5S2 (432.51): C,
55.54; H, 4.66; N, 6.48. Found: C, 55.42; H, 4.55; N, 6.57.
Western blot assay
Total protein extracts were prepared by lysing cells in
RIPA buffer (50 mM Tris–Cl [pH 8.0], 5 mM EDTA,
150 mM NaCl, 1 % NP-40, 0.1 % SDS, and 1 mM
phenylmethylsulfonyl fluoride). Protein concentrations in
the lysates were determined using a Bio-Rad protein assay
kit (Bio-Rad Laboratories Inc., Hercules, CA, USA)
according to the manufacturer’s instructions. Samples were
separated on SDS–polyacrylamide gels and transferred to
nitrocellulose membranes. The membranes were incubated
with blocking buffer (Tris-buffered saline containing 0.2 %
Tween-20 and 3 % nonfat dried milk) and probed with the
primary antibodies against acetyl histone H3, H4, and
GAPDH). After washing, membranes were probed with
horseradish peroxidase-conjugated secondary antibodies.
Detection was performed using an enhanced chemilumi-
nescent protein (ECL) detection system (Amersham Bio-
sciences, Little Chalfont, UK).
(Z)-N-(3-(4-((2,4-Dioxothiazolidine-5-ylidene)methyl)phe
noxy)propyl)-4-methoxybenzenesulfonamide (7f) Yield:
74 %. mp: 213–214 °C. Rf = 0.39 (DCM/MeOH/
AcOH = 90:5:1). IR (KBr, cm-1): 3293, 3121 (NH), 2970,
2839 (CH, CH2), 1736, 1690 (C=O), 1596, 1588, 1566
(C=C), 1154 (S=O), 1269 (C-O). ESI–MS (m/z): 446.6 [M-
2H]-. 1H-NMR (500 MHz, DMSO-d6, ppm): d 7.73 (1H, s,
H-700, olefinic proton), 7.71 (2H, d, J = 9.0 Hz, H-2, H-6),
7.53 (1H, t, J = 5.5 Hz, NH, sulfonamide), 7.51 (2H, d,
J = 8.75 Hz, H-300, H-500), 7.07 (2H, d, J = 9.0 Hz, H-3,
H-5), 7.00 (2H, d, J = 8.75 Hz, H-200, H-600), 3.99 (2H, t,
J = 6.0 Hz, H-30), 3.80 (3H, s, OCH3), 2.89 (2H, td,
J = 6.5 Hz, J’ = 6.0 Hz, H-10), 1.82 (2H, quintet,
J = 6.5 Hz, H-20). 13C NMR (125 MHz, DMSO-d6, ppm): d
167.92 (C-1000), 167.42 (C-900), 162.05 (C-4), 160.16 (C-
100), 131.99 (C-300, C-500), 131.78 (C-700), 128.60 (C-2, C-6),
125.45 (C-1), 120.27 (C-400), 115.27 (C-3, C-5), 114.83 (C-
800), 114.27 (C-200, C-600), 64.94 (C-30), 55.54 (-OCH-3),
39.23 (C-10), 28.62 (C-20). Anal. Calcd. For C20H20N2O6S2
(448.51): C, 55.54; H, 4.66; N, 6.48. Found: C, 55.63; H,
4.50; N, 6.53.
PTP1B inhibition assay
The effect of the synthesized compounds on PTP1B was
measured using a colorimetric assay kit purchased from
Biomol International L.P., USA, consisting of recombinant
enzyme, PTP1B substrate (IR5), Biomol Red reagent, and
buffer. Before the assay, enzyme, substrate, and buffer
were thawed on ice. A diluted solution of PTP1B enzyme
(BML-SE332-9092) in cold 1X Assay Buffer, such that
each 5 lL contains the desired amount (2.5 ng) of enzyme
Cytotoxicity assays
Three human cancer cell lines including SW620 (colon
cancer), PC-3 (prostate cancer), and NCI-H460 (lung
123

Med Chem Res
Aneja DK, Lohan P, Arora S, Sharma C, Aneja KR, Prakash O (2011)
Synthesis of new pyrazolyl-2, 4-thiazolidinediones as antibacte-
rial and antifungal agents. Org Med Chem Lett 1:15–19
Baba S (2001) Pioglitazone: a review of Japanese clinical studies.
Curr Med Res Opin 17:166–189
Barros FW, Silva TG, da Rocha Pitta MG, Bezerra DP, Costa-Lotufo
LV, de Moraes MO, Pessoa C, de Moura MA, de Abreu FC, de
Lima Mdo C, Galdino SL, Pitta Ida R, Goulart MO (2012)
Synthesis and cytotoxic activity of new acridine-thiazolidine
derivatives. Bioorg Med Chem 20:3533–3539
per reaction well, was prepared. Following, a diluted
solution of the 1.5 mM IR5 substrate stock at two times the
desired assay concentration was prepared and warmed to
assay temperature. To each reaction well was added 35 lL
of 1X Assay Buffer and warmed to assay temperature, e.g.,
30 °C. Following, 10 lL of a test sample 10X stocks was
appropriately added to each well. For blank wells, 10 lL of
1X Assay Buffer was added instead and for positive control
wells, 10 lL of a suramin solution (100 lM). Then, to each
well, 5 lL of the cold PTP1B dilution was added to the
45 lL of warmed Assay Buffer. The reaction was initiated
by mixing in 50 lL of the warmed 2X substrate. After
incubation for 30 min, reactions were terminated by addi-
tion of 25 lL BIOMOL REDTM Reagent (BML-KI468).
The reaction mixtures were mixed by pipetting (care
should be taken to avoid producing bubbles). Color was
allowed to develop for 20–30 min. ODs were read at
620 nm on a microplate reader. The enzyme inhibition
percentage (EIP) was calculated by an equation:
EIP = (ODblk – ODs)/ODblk 9 100 (%), where ODblk was
the OD of the blank well and ODs was the OD of the
sample’s well. All OD values were calibrated against the
OD value at time zero.
Bhattarai BR, Kafle B, Hwang JS, Ham SW, Lee KH, Park H, Han
IO, Cho H (2010) Novel thiazolidinedione derivatives with anti-
obesity effects: dual action as PTP1B inhibitors and PPAR-c
activators. Bioorg Med Chem Lett 20:6758–6763
˘
Bozdag-Du¨ndar O, Ozgen O, Mentes¸e A, Altanlar N, Atli O, Kendi E,
Ertan R (2007) Synthesis and antimicrobial activity of some new
thiazolyl thiazolidine-2,4-dione derivatives. Bioorg Med Chem
15:6012–6017
´
Bruno G, Costantino L, Curinga C, Maccari R, Monforte F, Nicolo F,
Ottana R, Vigorita MG (2002) Synthesis and aldose reductase
`
inhibitory activity of 5-aryliden-2, 4-thiazolidinediones. Bioorg
Med Chem 10:1077–1084
Cheng-Lai A, Levine A (2000) Rosiglitazone: an agent from the
thiazolidinedione class for the treatment of type 2 diabetes. Heart
Dis 2:326–333
ˆ
da Rocha Junior LF, Rego MJ, Cavalcanti MB, Pereira MC, Pitta MG,
de Oliveira PS, Gonc¸alves SM, Duarte AL, de Lima Mdo C,
Pitta Ida R, Pitta MG (2013) Synthesis of novel thiazolidine-
dione and evaluation of its modulatory effect on IFN-c, IL-6, IL-
17A, and IL-22 production in PBMCs from rheumatoid arthritis
patients. Biomed Res Int 2013:926060
Docking studies
Desai NC, Satodiya HM, Kotadiya GM, Vaghani HV (2014)
Synthesis and antibacterial and cytotoxic activities of new N-3
substituted thiazolidine-2,4-dione derivatives bearing the pyra-
zole moiety. Arch Pharm (Weinheim). doi:10.1002/ardp.
201300466
Jain VS, Vora DK, Ramaa CS (2013) Thiazolidine-2,4-diones:
progress towards multifarious applications. Bioorg Med Chem
21:1599–1620
Kim Y, You YJ, Nam NH, Ahn BZ (2002) Prodrugs of 40-demethyl-
4-deoxypodophyllotoxin: synthesis and evaluation of the antitu-
mor activity. Bioorg Med Chem Lett 12:3435–3438
Lauffer BE, Mintzer R, Fong R, Mukund S, Tam C, Zilberleyb I,
Flicke B, Ritscher A, Fedorowicz G, Vallero R, Ortwine DF,
Gunzner J, Modrusan Z, Neumann L, Koth CM, Lupardus PJ,
Kaminker JS, Heise CE, Steiner P (2013) Histone deacetylase
(HDAC) inhibitor kinetic rate constants correlate with cellular
histone acetylation but not transcription and cell viability. J Biol
Chem 288:26926–26943
AutoDock Vina program (The Scripps Research Institute,
CA, USA) (Trott and Olson, 2010) was used in the docking
studies. Initial structures of HDAC8 (Somoza et al., 2004)
and HDAC2 (Lauffer et al., 2013) (complexed with
SAHA) were obtained from the Protein Data Bank (PDB)
(PDB ID: 1T69 and PDB ID: 4LXZ, respectively), and
coordinates for the compounds were generated using the
GlycoBioChem PRODRG2 Server (http://davapc1.bioch.
dundee.ac.uk/prodrg/) (Schuttelkopf and van Aalten,
2004). The grid maps for docking studies were centered on
the SAHA binding site and comprised 26 9 26 9 22 points
˚
with 1.0 A spacing after SAHA was removed from the
complex structure, as described previously. AutoDock
Vina program was run with eight-way multithreading, and
the other parameters were default settings in AutoDock
Vina program.
`
Maccari R, Paoli P, Ottana R, Jacomelli M, Ciurleo R, Manao G,
Steindl T, Langer T, Vigorita MG, Camici G (2007) 5-Aryli-
dene-2,4-thiazolidinediones as inhibitors of protein tyrosine
phosphatases. Bioorg Med Chem 15:5137–5149
˘
Mentes¸e A, Ceylan-Unlu¨soy M, Bozdag-Du¨ndar O, Altanlar N, Ertan
R (2009) Synthesis and antimicrobial activity of some novel
Acknowledgments We acknowledge the principal financial sup-
ports from the National Foundation for Science and Technology of
Vietnam (NAFOSTED, Grant number 104.01-2014.11). The biolog-
ical study was supported by the Medical Research Center program
(MRC, Grant number 2010-0029480).
thiazolidine-2,4-dione
59:659–665
derivatives.
Arzneimittelforschung
Mohan R, Sharma AK, Gupta S, Ramaa CS (2012) Design, synthesis,
and biological evaluation of novel 2,4-thiazolidinedione deriva-
tives as histone deacetylase inhibitors targeting liver cancer cell
line. Med Chem Res 21:1156–1165
References
Nam NH, Huong TL, do Dung TM, Dung PT, Oanh DT, Quyen D, le
Thao T, Park SH, Kim KR, Han BW, Yun J, Kang JS, Kim Y,
Han SB (2013) Novel isatin-based hydroxamic acids as histone
deacetylase inhibitors and antitumor agents. Eur J Med Chem
70:477–486
Alegaon SG, Alagawadi KR (2012) New thiazolidine-2, 4-diones as
antimicrobial and cytotoxic agent. Med Chem Res
21:3214–3223
123

Med Chem Res
˘
ˆ
Nastasa C, Tiperciuc B, Parvu A, Duma M, Ionu¸t I, Oniga O (2013)
Synthesis of new N-substituted 5-arylidene-2,4-thiazolidine-
diones as anti-inflammatory and antimicrobial agents. Arch
Pharm (Weinheim) 346:481–490
Somoza JR, Skene RJ, Katz BA, Mol C, Ho JD, Jennings AJ, Luong
C, Arvai A, Buggy JJ, Chi E, Tang J, Sang BC, Verner E,
Wynands R, Leahy EM, Dougan DR, Snell S, Navre M, Knuth
MW, Swanson RV, McRee DE, Tari LW (2004) Structural
snapshots of human HDAC8 provide insights into the class I
histone deacetylases. Structure 12:1325–1334
Trott O, Olson AJ (2010) AutoDock Vina: improving the speed and
accuracy of docking with a new scoring function, efficient
optimization, and multithreading. J Comput Chem 31:455–461
Tung TT, Oanh DT, Dung PT, Hue VT, Park SH, Han BW, Kim Y,
Hong JT, Han SB, Nam NH (2013) New benzothiazole/thiazole-
containing hydroxamic acids as potent histone deacetylase
inhibitors and antitumor agents. Med Chem 9:1051–1057
Wu L, Smythe AM, Stinson SF, Mullendore LA, Monks A, Scudiero
DA, Paull KD, Koutsoukos AD, Rubinstein LV, Boyd MR,
Shoemaker RH (1992) Multidrug-resistant phenotype of disease-
oriented panels of human tumor cell lines used for anticancer
drug screening. Cancer Res 52:3029–3034
Oanh DT, Hai HV, Park SH, Kim HJ, Han BW, Kim HS, Hong JT,
Han SB, Hue VT, Nam NH (2011) Benzothiazole-containing
hydroxamic acids as histone deacetylase inhibitors and antitumor
agents. Bioorg Med Chem Lett 21:7509–7512
Patel J, Anderson RJ, Rappaport EB (1999) Rosiglitazone monother-
apy improves glycaemic control in patients with type 2 diabetes:
a twelve-week, randomized, placebo-controlled study. Diabetes
Obes Metab 1:165–172
Romagnoli R, Baraldi PG, Salvador MK, Camacho ME, Balzarini J,
´
Bermejo J, Estevez F (2013) Anticancer activity of novel hybrid
molecules containing 5-benzylidene thiazolidine-2,4-dione. Eur
J Med Chem 63:44–57
Schuttelkopf AW, van Aalten DM (2004) PRODRG: a tool for high-
throughput crystallography of protein-ligand complexes. Acta
crystallogr Sect D Biol Crystallogr 60:1355–1363
Skehan P, Storeng R, Scudiero D, Monk A, MacMahon J, Vistica D,
Warren JT, Bokesch H, Kenney S, Boyd MR (1990) New
colorimetric cytotoxicity assay for anticancer drug screening.
J Natl Cancer Inst 82:1107–1112
You YJ, Kim Y, Nam NH, Bang SC, Ahn BZ (2004) Alkyl and
carboxylalkyl esters of 40-demethyl-4-deoxypodophyllotoxin:
synthesis, cytotoxic, and antitumor activity. Eur J Med Chem
39:189–193
123