Synthesis, in vitro anticancer activity and in silico study of new disubstituted thiazolidinedione derivatives

Article abstract of DOI:10.1007/s00044-013-0902-z

Thiazolidinediones are known to have antidiabetic activity, but new activities are being discovered every year; among these, their anticancer activity has received the most attention. In this study, we synthesized three new disubstituted thiazolidinedione

Full text of DOI:10.1007/s00044-013-0902-z

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-013-0902-z
ORIGINAL RESEARCH
Synthesis, in vitro anticancer activity and in silico study of new
disubstituted thiazolidinedione derivatives
•
Moacyr Jesus Barreto de Melo Rego Marina Rocha Galdino-Pitta
•
ˆ
Daniel Tarciso Martins Pereira Juliana Cruz da Silva Marcelo Montenegro Rabello
•
•
•
•
Maria do Carmo Alves de Lima Marcelo Zaldini Hernandes
•
•
Ivan da Rocha Pitta Suely Lins Galdino Maira Galdino da Rocha Pitta
•
Received: 31 January 2013 / Accepted: 20 December 2013
Ó Springer Science+Business Media New York 2014
Abstract Thiazolidinediones are known to have antidia-
betic activity, but new activities are being discovered every
year; among these, their anticancer activity has received
the most attention. In this study, we synthesized three new
disubstituted thiazolidinediones and assayed their cyto-
toxicity against six tumor cell lines, as well as against
normal cells. Cytometry studies and molecular modeling
were also performed to elucidate the mechanism of cyto-
toxicity. Of the three new thiazolidinediones synthesized,
(5Z)-5-(3-bromo-benzylidene)-3-(4-nitrobenzyl)-thiazoli-
dine-2,4-dione (LPSF/SF-13) exhibited the most promising
activity; it was selectively cytotoxic against leukemia,
lymphoma, glioblastoma, and hepatocarcinoma cell lines
without being toxic to normal cells. Apoptosis was the
main cell death process induced by this compound,
although it also induced necrosis. Furthermore, molecular
modeling studies showed that LPSF/SF-13 had good
affinity for peroxisome proliferator-activated receptor c;
binding to the receptor involved hydrogen bonds with
Arg288 and Ser342 residues (bond distances of 3.1 and
˚
2.8 A, respectively), as well as a p-bonding interaction
with His449. We concluded that LPSF/SF-13 is a promis-
ing compound for in vivo and combination therapy studies
against cancer.
Keywords Thiazolidinediones Á Cytotoxicity Á
Anticancer Á Molecular modeling
Introduction
Thiazolidine-2,4-diones have been extensively studied
owing to their involvement in the regulation of various
physiological processes such as cell proliferation, angio-
genesis, inflammation, and glucose metabolism (Barros
et al., 2004). These compounds show significant antidia-
betic (Moura˜o et al., 2005), antimicrobial (Gouveia et al.,
2008), antichagasic (Du et al., 2002; Cohen et al., 2004),
This article is dedicated to the memory of Suely Lins Galdino.
Electronic supplementary material The online version of this
article (doi:10.1007/s00044-013-0902-z) contains supplementary
material, which is available to authorized users.
ˆ
anti-HIV (Rawal et al., 2007), anti-inflammatory (Uchoa
ˆ
M. J. B. M. Rego Á J. C. da Silva Á S. L. Galdino Á
M. G. da Rocha Pitta (&)
´
Laboratorio de Imunomodulac¸a˜o e Novas Abordagens
Terapeuticas (LINAT), Nucleo de Pesquisa para Inovac¸a˜o
et al., 2009), and anticancer (Chandrappa et al., 2008)
activities.
ˆ
´
Thiazolidine-2,4-diones have been shown to have a
broad-spectrum antineoplastic activity, including activity
against human leukemia (Liu et al., 2006), melanoma
(Klopper et al., 2009), prostate cancer (Matsuyama and
Yoshimura, 2008), and hepatocarcinoma cells (Wu et al.,
2012). These molecules are agonists of peroxisome pro-
liferator-activated receptor c (PPARc), which is expressed
in many human tumors, including lung, breast, colon,
prostate, and bladder tumors (Han and Roman, 2007).
Thiazolidine-2,4-diones act mainly as tumor suppressors
ˆ
Terapeutica (NUPIT), Universidade Federal de Pernambuco
(UFPE), s/n, Cidade Universitaria, Recife, PE 50670-901, Brazil
e-mail: mgrpitta@gmail.com
´
M. R. Galdino-Pitta Á D. T. M. Pereira Á
M. C. Alves de Lima Á I. da Rocha Pitta
´
Laboratorio de Planejamento e Sıntese de Farmacos (LPSF),
NUPIT, UFPE, Recife, Brazil
´
´
M. M. Rabello Á M. Z. Hernandes
´
Laboratorio de Quimica Teorica e Medicinal (LQTM), UFPE,
Recife, Brazil
´
123

Med Chem Res
by inducing the expression of proapoptotic molecules and
other molecules that regulate the cell cycle (Han et al.,
2004), as well as by disabling critical pathways that pro-
mote cancer survival, such as the Akt pathway, by inhib-
iting K-Ras-induced phosphorylation (Shao et al., 2002).
Furthermore, activation of PPARc by its ligands induces
apoptosis inhibiting nuclear factor kappa B activity, which
upregulates various anti-apoptotic genes, and suppressing
the expression of pro-apoptotic ones (Chen et al., 2002;
Tachibana et al., 2008).
Materials and methods
Synthesis and characterization of LPSF/SF-13, LPSF/
SF-15, and LPSF/SF-17
LPSF/SF-13, LPSF/SF-15, and LPSF/SF-17 were synthe-
sized as shown in Scheme 1. In brief, 3-(4-nitrobenzyl)-
thiazolidine-2,4-dione was synthesized by condensation of
thiazolidine-2,4-dione with 4-nitrobenzyl bromide in the
presence of KOH in ethanol (Silva et al., 2001). Then an
equimolar mixture of 3-(4-nitrobenzyl)-thiazolidine-2,4-
dione and an appropriately substituted ethyl-2-cyano-3-
phenylacrylate in ethanol containing 350 lL of piperidine
was stirred under reflux for 4 h and cooled to room tem-
perature. The solid that precipitated was filtered under
vacuum and washed with water, and absolute ethanol to
afford the expected 3,5-disubstituted thiazolidine-2,4-dione
products in good yields ([76 %). All the compounds were
characterized by infrared (IR) spectroscopy, 1H nuclear
magnetic resonance (NMR) and 13C NMR spectroscopy,
and mass spectrometry. The configurations of the exocyclic
C=C double bond of the final products were assigned by
The thiazolidine-2,4-dione derivatives rosiglitazone,
pioglitazone, and troglitazone, which act via PPARc, have
been used for the treatment of type 2 diabetes. They share a
common thiazolidine-2,4-dione structure that is responsible
for the majority of their pharmacological effects, including
their anti-inflammatory effects (Barros et al., 2010).
Because inflammation is a crucial hallmark of cancer
(Hanahan and Weinberg, 2011), it may also be a good
target for thiazolidine-2,4-dione derivatives.
The chemical reactivity of the thiazolidine ring allows
the introduction of many substituents, which makes the
ring a useful framework for the development of novel
compounds. Among the many reactions involving the thi-
azolidine ring, the most frequently reported reactions in the
literature include N-alkylation at the 3-position (Graciet
et al., 1996) and the reactions of carbonyl compounds with
the methylene carbon at the 5-position (Vicini et al., 2006).
Here, we describe the synthesis and characterization of
three new 3,5-disubstituted thiazolidine-2,4-diones. The
synthesized compounds were screened for in vitro cyto-
toxicity against six tumor cell lines, as well as against
human peripheral blood mononuclear cells. The molecular
mechanism by which the most promising derivative
induced cell death was elucidated by flow cytometry, and
we also performed molecular modeling of the binding of
the derivative to PPARc.
1
means of H NMR spectroscopy; the spectra showed only
one kind of methine proton, which was characteristic of
Z geometrical isomers.
All melting points were measured on a Quimis-340.27
apparatus (Quimis, Diadema, SP, Brazil) and are uncor-
rected. All reactions were monitored by thin-layer chro-
matography on 0.25-mm silica gel plates (60F254, Merck,
Germany). IR spectra were recorded on potassium bromide
pellets with a Bruker IFS-66 IR spectrophotometer (Bru-
1
ker, USA). H NMR spectra were recorded on a Unity
Plus-300 MHz Varian spectrometer (Varian, USA) with
tetramethylsilane as an internal standard and DMSO-d6 as
the solvent. LPSF/SF-15 and LPSF/SF-17 were subjected
to electron-impact mass spectrometry (70 eV; Delsi-
O
O
benzyl halide
N
NH
NaOH ETOH
S
S
NO2
O
O
O
NO2
S
N
CHO
CN
R
CH2(CN)COOEt
piperidine
O
COOEt
LPSF/SF
R
R
LPSF/SF-13 R = 3-Br
LPSF/SF-15 R = 3-Br, 4-OCH3
LPSF/SF-17 R = 3,4,5 OCH3
Scheme 1 Synthesis of new disubstituted thiazolidinedione derivatives
123

Med Chem Res
Selectivity assay
Nermag R1010C, Delsi-Nermag), and LPSF/SF-13 was
subjected to negative-ion-mode electrospray-ionization
mass spectrometry (HCTultra, Bruker Daltonics).
Peripheral blood mononuclear cells were obtained from
heparinized blood from healthy, nonsmoking donors who
had not taken any drugs for at least 15 days prior to sample
collection (n = 6), and the cells were isolated via a stan-
dard method of density-gradient centrifugation over Ficoll-
Hypaque solution (GE Healthcare). Cells were counted in a
Neubauer chamber, and viability was determined by the
trypan blue exclusion method. Cells were used only when
the viability was [98 %. All donors gave informed con-
sent, and the study was approved by the Human Research
Ethics Committee of UFPE in the Health Sciences Center
(CEP/CCS/UFPE N0 145/09). Cells were plated in 96-well
plates (106 cells/well). After 24 h, the test compound was
added (0.1–100 lM), and the cells were incubated for 48 h
and then subjected to the MTT assay as described above.
Biological evaluation
Human tumor cell lines and MTT assay
The cytotoxicities of LPSF/SF-13, LPSF/SF-15, and LPSF/
SF-17 were tested against six human tumor cell lines:
NG97 (glioblastoma), HepG2 (hepatocarcinoma), MIA
PaCa (pancreatic adenocarcinoma), T47D (human breast
cancer), Raji (Burkitt’s lymphoma), and Jukart (T cell
leukemia). All cell lines were obtained from Rio de Janeiro
Tissue Cell Bank except for the NG97 cells, which were
kindly provided by Professor Roger Chammas (Univer-
sidade de Sa˜o Paulo). Cells were cultured in RPMI-1640
medium supplemented with 10 % fetal calf serum, 2 mM
glutamine, 100 mg/mL streptomycin, and 100 U/mL pen-
icillin at 37 °C with 5 % CO2.
Flow cytometry
The mechanism by which the test compounds induced cell
death was evaluated by Brdu/propidium iodide staining
using an APO-Brdu Apoptosis Detection Kit (eBioscienc-
es, San Diego, CA, USA). Tumor cells were seeded at a
density of 1 9 105/mL into 6-well plates, and the test
compound was added. After 24 h of incubation with the
test compound, the cells were washed twice with ice-cold
phosphate buffered saline. Each cell sample was trans-
ferred to a tube and then centrifuged at 2009g for 5 min. In
accordance with the manufacturer’s instructions, cells were
resuspended in washing buffer before incubation with
DNA-labeling solution (containing TdT enzyme and
BrdUTP) for 60 min at 37 °C. After being washed, the
cells were resuspended in 100 lL of the antibody solution
FITC-anti-BrdU mAb and then incubated in a propidium
iodide/RNAse A solution before cytometry acquisition
(FACSAria II, Becton, Dickinson and Company, Franklin
Lakes, NJ, USA) and data analysis by means of FACSDiva
software (Becton, Dickinson and Company).
For the cytotoxicity assay, cells were plated in 96-well
plates (104 cells/well). After 24 h, a dimethyl sulfoxide
solution of the test compound (1–100 lM) was added to
each well, and the cells were incubated for 72 h. Control
groups were treated with the same amount of dimethyl
sulfoxide (0.1 %). Amsacrine was used as a positive con-
trol. The growth of tumor cells was quantified by the ability
of living cells to reduce the yellow dye 3-(4,5-dimethyl-2-
thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) to
a blue formazan product, as follows. At the end of 72 h of
incubation, the medium in each well was replaced with
fresh medium (200 lL) containing MTT (0.5 mg/mL).
After 3 h, the formazan product of MTT reduction was
dissolved in 20 % sodium dodecyl sulfate, and the absor-
bance of the solution at 570 nm was measured with a
multiplate reader (EL808, Biotek, USA). The effect of each
test compound was quantified in terms of the absorbance as
a percentage of the absorbance of the reduced dye in the
0.1 % DMSO treated group.
Statistical analysis
All experiments were performed at least three times. IC50
values and 95 % confidence intervals were obtained by
nonlinear regression with the OriginPro program (ver. 8.0,
OriginLab, Northampton, MA, USA).
Table 1 IC50 values of LPSF/SFs in tumor cells
Compounds Cell lineages IC50 (lM)
T47D MiaPaca HepG2 NG97 Raji Jukart PBMC
Molecular modeling
SF-13
SF-15
SF-17
[100 [100
[100 [100
[100 [100
58.58 73.73 58.8 62.54 [100
[100 [100 [100 80.58 [100
[100 [100 [100 96.51 [100
The structure of PPARc used for molecular modeling was
obtained from the Protein Data Bank (http://www.pdb.org,
PDB code 2HWQ). This protein has been recognized as a
possible target for cancer therapy. The structure of the first
Amsacrine 12.18 13.2
1.51
2.1
4.15 \1
3.73
123

Med Chem Res
monomer of the PPAR-c protein was chosen as a target for
docking calculations, which were carried out by means of
GOLD software (ver. 5.1, Cambridge Crystallographic Data
Centre). The active site of the protein was defined as all
With the target thiazolidinone derivatives in hand, we
initially performed a selectivity assay because compounds
with high toxicity against nontumor cells are not viable for
in vivo transposition assays (Chari, 2008). All three thia-
zolidine derivatives were nontoxic to normal human
peripheral blood mononuclear cells (IC50 [ 100 lm),
whereas the positive control (amsacrine) showed an IC50
of 3.73 lm against the normal cells. Next, we assayed the
cytotoxicity of the thiazolidinone derivatives against vari-
ous tumor cell lines (Table 1). None of the compounds
showed activity against the T47D breast cell line, the line
for which the IC50 of the positive control was the highest.
LPSF/SF-15 and LPSF/SF-17 showed no anticancer
activity against most of the tested cell lines; they showed a
small cytotoxic effect against the leukemia cell line (Juk-
art). In contrast, LPSF/SF-13 showed significant anticancer
activity in four cells lines (HepG2, NG97, Jukart, and
Raji), presenting a typical dose–response curve (Fig. 1).
These results suggest that the bromine substituent on the
benzylidene group of LPSF/SF-13 and LPSF/SF-15 con-
tributed substantially to the cytotoxicity against these four
cell lines. LPSF/SF-13 contains only one substituent on the
benzylidene group (a bromine atom at the 3-position),
whereas LPSF/SF-15 and LPSF/SF-17 both have at least
one relatively bulky methoxy group, which may have
˚
atoms within a radius of 6.0 A from the cocrystallized ligand
[(1-{3-[(6-benzoyl-1-propyl-2-naphthyl)oxy]propyl}-1H-in-
dol-5-yl)oxy]acetic acid (designated as ‘DRY’). The BI-
NANA program (Durrant and Mccammon, 2011) was used
to conduct a detailed inspection of the molecular interactions
obtained from the docking calculations; the default settings
were used, except for the hydrogen bond distance, which
˚
was changed to 3.5 A.
Results and discussion
Thiazolidinone derivatives LPSF/SF-13, LPSF/SF-15, and
LPSF/SF-17 were prepared as shown in Scheme 1. The
presence of the arylidene proton peak in the 1H NMR
spectra of the compounds confirmed that the nucleophilic
addition reaction was successful. The identity of the com-
pounds was confirmed by mass spectrometry data obtained
in positive- or negative-ion mode, and the IR spectra of the
compounds showed peaks characteristic of a carbonyl group
and an arylidene group (HC=).
HepG2
NG97
A
B
100
90
SF13
SF15
SF17
Amsacrine
100
90
80
70
60
50
40
30
20
10
0
SF13
SF15
SF17
Amsacrine
80
70
60
50
40
30
20
10
0
1
10
50
75
100
Compound Concentration
1
10
50
75
100
Compound Concentration
Jukart
Raji
C
D
100
90
80
70
60
50
40
30
20
10
0
100
90
80
70
60
50
40
30
20
10
0
SF13
SF15
SF17
Amsacrine
SF13
SF15
SF17
Amsacrine
1
10
50
75
100
1
10
50
75
100
Compound Concentration
Compound Concentration
Fig. 1 Dose–response curves for the cytotoxicity of the new thiazolidine-2,4-diones against (a) HepG2, (b) NG97, (c) Jurkat, and (d) Raji cancer
cell lines. Against all the analyzed cell lines, LPSF/SF-13 showed the best response among all the three synthesized derivatives
123

Med Chem Res
Control
SF13
Control Vs SF13
***
100
80
60
40
20
0
*
***
24H
e
c
c
l
i
le
b
t
otic
ecr
N
oti
t
op
ab
to
crotic
Ne
Vi
op
13 Via
SF
NT
Ap
Ap
13
NT
SF
13
NT
SF
***
100
80
60
40
20
0
***
48H
**
c
le
le
ic
ot
cr
tic
b
oti
ecr
N
ab
totic
to
op
p
o
Vi
T
p
A
13 Via
SF
N
T
13 Ne
SF
N
SF
13 Ap
NT
Fig. 2 Flow cytometry analysis of the method of cell death induction
by LPSF/SF-13 against Raji cells. The rows show the treatment
period, the columns show the cytometry profiles of the untreated
control and LPSF/SF-13, and the bar graph shows the untreated
control versus the LPSF/SF-13 control
Fig. 3 Calculated solution for
docking of LPSF/SF-13 (gray)
on PPAR-c. The residues that
interact hydrophobically are
highlighted in green, the
residues that form hydrogen
bonds are highlighted in blue,
and the residues that form a p-
bonding (T-shaped) interaction
with LPSF/SF-13 are
highlighted in orange. The
figure was generated with the
PYMOL program (Color figure
online)
reduced their cytotoxicity. The steric effect of a methoxy
group has already been reported in studies of epidermal
growth factor receptor tyrosine kinase inhibitors (Zhou
et al., 2009).
To better understand, how the most promising compound
(LPSF/SF-13) induced the death of cancer cells, we per-
formed a flow cytometry assay with the Raji cell line which
was one of the two cell lines that showed the highest
123

Med Chem Res
(5Z)-5-(3-bromo-4-methoxy-benzylidene)-3-(4-nitrobenzyl)-
thiazolidine-2,4-dione, and (5Z)-5-(3,4,5-trimethoxy-ben-
zylidene)-3-(4-nitrobenzyl)-thiazolidine-2,4-dione were
synthesized and characterized. None of the compounds was
toxic to normal human cells, but (5Z)-5-(3-bromo-benzyli-
dene)-3-(4-nitrobenzyl)-thiazolidine-2,4-dione showed sig-
nificant antitumor activity. This compound induced cell
death primarily by necrosis but also by apoptosis and is a
promising compound for in vivo and combination therapy
studies against cancer.
Acknowledgments We thank the Brazilian National Research
Council, the Research Foundation of Pernambuco State, the National
Institute for Science and Technology in Pharmaceutical Innovation,
and Coordination for the Improvement of Higher Level Personnel
(CAPES) for student scholarships.
Fig. 4 Calculated solutions for docking of LPSF/SF-13 (gray sticks)
and the cocrystallizedligand ‘DRY’(blue lines) on PPAR-c (green). The
figure was generated with the PYMOL program (Color figure online)
Conflict of interest The authors declare that they have no conflicts
of interest.
susceptibility to LPSF/SF-13. Raji cells were incubated with
LPSF/SF-13 at the IC50 dose for 24 and 48 h (Fig. 2). At
both incubation durations, death by necrosis was observed to
a greater extent in relation to the nontreated group
(p \ 0.001). However, there was a small, but significant
increase in the induction of apoptosis after 24 h of treatment
(p \ 0.05) and a large increase after 48 h (p \ 0.001),
revealing a time-dependent relationship. The activation of
both death mechanisms could be useful for cancer treatment
(Amaravadi and Thompson, 2007) because apoptosis
involves self-elimination of cells and necrosis could promote
recruitment and activation of immune cells that could attack
the tumor (Rovere-Querini et al., 2004).
References
Amaravadi RK, Thompson CB (2007) The roles of therapy-induced
autophagy and necrosis in cancer treatment. Clin Cancer Res
13(24):7271–7279
Barros GFJ, Bernalte GA, Higes RFJ, Luna GF, Maldonado RMA,
Vinuelas ZE (2004) Synthesis, crystal structure, spectroscopic
and magnetic properties of copper(II) complexes with 2-(2-
pyridyl)imino-N-(2-thiazolin-2-yl)thiazolidine (PyTT). Inorg
Chim Acta 357:3574–3582. doi:10.1155/S1565363304000184
Barros CD, Amato AA, Oliveira TB, Iannini KBR, Silva AL, Silva
TG, Leite ES, Hernandez MZ, Lima MCA, Galdino SL, Neves
FAR, Pitta IR (2010) Synthesis and anti-inflammatory activity of
new arylidene-thiazolidine-2,4-diones as PPARc ligands. Bioorg
Med Chem 18:3805–3811. doi:10.1016/j.bmc.2010.04.045
Chandrappa S, Benaka Prasad SB, Vinaya K, Kumar ACS, Thim-
megowda NR, Rangappa KS (2008) Synthesis and in vitro
antiproliferative activity against human cancer cell lines of novel
5-(4-methyl benzylidene)-thiazolidine-2,4-diones. Investig New
Drugs 26:437–444. doi:10.1007/s10637-008-9130-7
Chari RV (2008) Targeted cancer therapy: conferring specificity to
cytotoxic drugs. Acc Chem Res 41(1):98–107
Chen GG, Lee JFY, Wang SH, Chan UPF, Ip CP, Lau WY (2002)
Apoptosis induced by activation of peroxisomeproliferator
activated receptor-gamma is associated with Bcl-2 and Nf-jB
in human colon cancer. Life Sci 70(22):2631–2646
Cohen FE, Du X, Guo C, Mckerrow JH (2004) U.S. Patent 6 897 240
Du X, Guo C, Hansell E, Doyle P, Caffrey C, Holler T, Mckerrow J,
Cohen FJ (2002) Synthesis and structure-activity relationship
study of potent trypanocidal thio semicarbazone inhibitors of the
trypanosomal cysteine protease cruzain. Med Chem 45:2695–
2703
Durrant JD, Mccammon JA (2011) Binana: a novel algorithm for
ligand-binding characterization. J Mol Graph Mode 29(6):888–
893. doi:10.1016/j.jmgm.2011.01.004
To clarify the binding interactions between LPSF/SF-13
and PPARc, we performed molecular docking calculations.
The proposed binding mode for LPSF/SF-13 was chosen as
the solution with the highest (most positive) ChemPLP
score among all the possible solutions (Korb et al., 2009).
LPSF/SF-13 showed good affinity for the PPARc receptor,
with a ChemPLP score of 73.26 (Fig. 3). The complex formed
with PPARc exhibited hydrogen bonds involving the Arg288
˚
and Ser342 residues, with bond distances of 3.1 and 2.8 A,
respectively. A p-bonding interaction (T-shaped) with His449
was also observed, and six additional residues interacted
hydrophobically with the ligand. In Fig. 4, superimposition of
the docking solution for LPSF/SF-13 with the solution for the
cocrystallized ligand (‘DRY’) reveals that LPSF/SF-13 binds
to the active site of PPARc in the same orientation as the co-
crystallized ligand.
Gouveia FL, Oliveira RMB, Oliveira TB, Silva IM, Nascimento SC,
Sena KXFR, Albuquerque JFC (2008) Synthesis, antimicrobial
and cytotoxic activities of some 5-arylidene-4-thioxo-thiazoli-
dine-2-ones. Eur J Med Chem 44(5):2038–2043. doi:10.1016/j.
ejmech.2008.10.006
Conclusion
The three novel thiazolidine derivatives (5Z)-5-(3-bromo-
benzylidene)-3-(4-nitrobenzyl)-thiazolidine-2,4-dione,
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Med Chem Res
Graciet JC, Niddam V, Gamberoni M, Trabaud C, Dessolin J, Medou
M, Mourier N, Zoulim F, Borel C, Hantz O, Camplo M,
Chermann JC, Kraus JL (1996) Modelisation, synthesis and
antiviral evaluation of new 2,3-disubstituted thiazolidinone
nucleoside analogues. Bioorg Med Chem Lett 6:1775–1780.
doi:10.1016/0960-894X(96)00316-2
and biological activity of novel acridinylidene and benzylidene
thiazolidinediones. Eur J Med Chem 40:1129–1133
Rawal RK, Tripathi R, Katti SB, Pannecouque C, De Clerq E (2007)
Design, synthesis, and evaluation of 2-aryl-3-heteroaryl-1,3-
thiazolidin-4-ones as anti-hiv agents. Bioorg Med Chem 15:
1725–1731
Han S, Roman J (2007) Peroxisome proliferator-activated receptor
gamma: a novel target for cancer therapeutics? Anticancer Drugs
18(3):237
Han S, Sidell N, Fisher PB, Roman J (2004) Up-regulation of p21
gene expression by peroxisome proliferator-activated receptor
gamma in human lung carcinoma cells. Clin Cancer Res
10(6):1911–1919
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next
generation. Cell 144(5):646–674. doi:10.1016/J.CELL.2011.02.
013
Klopper JP, Sharma V, Berenz A, Hays WR, Loi M, Pugazhenthi U,
Said S, Haugen BR (2009) Retinoid and thiazolidinedione
therapies in melanoma: an analysis of differential response based
on nuclear hormone receptor expression. Mol Cancer 8:16.
doi:10.1186/1476-4598-8-16
Rovere-Querini P, Capobianco A, Scaffidi P, Valentinis B, Catalanotti
F, Giazzon M, Dumitriu IE, Mu¨ller S, Iannacone M, Traversari
C, Bianchi ME, Manfredi AA (2004) HMGB1 is an endogenous
immune adjuvant released by necrotic cells. EMBORep
5:825–830
Shao J, Sheng H, DuBois RN (2002) Peroxisome proliferator-
activated receptors modulate K-Ras-mediated transformation of
intestinal epithelial cells. Cancer Res 62(11):3282–3288
Silva TG, Barbosa FSV, Brandao SSF, Lima MCA, Galdino SL, Pitta
IR, Barbe J (2001) Synthesis and structural elucidation of new
benzylidene imidazolidines and acridinylidene thiazolidines.
Heterocycl Commun 7(6):523–528
Tachibana K, Yamasaki D, Ishimoto K, Doi T (2008) The role of
PPARs in cancer. PPAR Res 2008:102737. doi:10.1155/2008/
102737
ˆ
Korb O, Stu¨tzle T, Exner TE (2009) Empirical scoring functions for
advanced protein-ligand docking with plants. J Chem Inf Model
49(1):84–96. doi:10.1021/ci800298z
Liu H, Zang C, Fenner MH, Liu D, Possinger K, Koeffler HP, Elstner
E (2006) Growth inhibition and apoptosis in human Philadelphia
chromosome-positive lymphoblastic leukemia cell lines by
treatment with the dual PPARalpha/gamma ligand TZD18.
Blood 107(9):3683–3692
Matsuyama M, Yoshimura R (2008) Peroxisome proliferator-acti-
vated receptor-c is a potent target for prevention and treatment in
human prostate and testicular cancer. PPAR Res 2008:249849.
doi:10.1155/2008/249849
Uchoa FT, Silva TG, Lima MCA, Galdino SL, Pitta IR, Costa TD
(2009) Preclinical pharmacokinetic and pharmacodynamic eval-
uation of thiazolidinone PG15: an anti-inflammatory candidate.
J Pharm Pharmacol 61:339–345. doi:10.1211/jpp/61.03.0008
´
Vicini P, Geronikaki A, Anastasia K, Incerti M, Zani F (2006) Synthesis
and antimicrobial activity of novel 2-thiazolylimino-5-arylidene-
4-thiazolidinones. Bioorg Med Chem 14(11):3859–3864
Wu CW, Geoffery CF, Jun Y (2012) Functional role of PPARc in
hepatocellular carcinoma. J Gastroenterol Hepatol 27(11):1665–
1669. doi:10.1111/j.1440-1746.2012.07213.x
Zhou W, Ercan D, Chen L, Yun CH, Li D, Capelletti M, Cortot AB,
Chirieac L, Iacob RE, Padera R, Engen JR, Wong KK, Eck MJ,
¨
Gray NS, Janne PA (2009) Novel mutant-selective EGFR kinase
inhibitors against EGFR T790M. Nature 462(7276):1070–1074
Moura˜o RH, Silva TG, Soares ALM, Vieira ES, Santos JN, Lima
MCA, Lima VLM, Galdino S, Barbe J, Pitta IR (2005) Synthesis
123