Evaluation of 3-(4′-(4″-fluorophenyl)-6′-phenylpyrimidin- 2′-yl)-2-phenylthiazolidin-4-one for in vivo modulation of biomarkers of chemoprevention in the 7,12-dimethylbenz[a]anthracene-induced hamster buccal pouch carcinogenesis

Article abstract of DOI:10.3109/14756366.2010.525507

A new bis heterocycle comprising both bioactive 2-aminopyrimidine and thiazolidin-4-one nuclei namely 3-(4′-(4″-fluorophenyl)-6′- phenylpyrimidin-2′-yl)-2-phenylthiazolidin-4-one 3 was synthesized, characterized with the help of melting point, elemental analysis, FT-IR, MS, one-dimensional NMR (¹H, ¹³C) spectra and we evaluated the chemopreventive potential of 3-(4′-(4″-fluorophenyl)-6′- phenylpyrimidin-2′-yl)-2-phenylthiazolidin-4-one based on in vivo inhibitory effects on 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch carcinogenesis. Administration of 3 effectively suppressed oral carcinogenesis initiated with DMBA as revealed by the reduced incidence of neoplasms. Lipid peroxidation, glutathione (GSH) content, and the activities of glutathione peroxidase (GPx), glutathione S-transferase (GST) were used to biomonitor the chemopreventive potential of 3. Lipid peroxidation was found to be significantly decreased, whereas GSH, GPx, GST, and GGT were elevated in the oral mucosa of tumor-bearing animals. Our data suggest that 3 may exert its chemopreventive effects in the oral mucosa by modulation of lipid peroxidation and enhancing the levels of GSH, GPx, and GST.

Full text of DOI:10.3109/14756366.2010.525507

Journal of Enzyme Inhibition and Medicinal Chemistry, 2011; 26(3): 422–429
© 2011 Informa UK, Ltd.
ISSN 1475-6366 print/ISSN 1475-6374 online
DOI: 10.3109/14756366.2010.525507
ORIGINAL ARTICLE
Evaluation of 3-(4′-(4″-fluorophenyl)-6′-phenylpyrimidin-
2′-yl)-2-phenylthiazolidin-4-one for in vivo modulation of
biomarkers of chemoprevention in the 7,12-dimethylbenz[a]
anthracene-induced hamster buccal pouch carcinogenesis
J. anusu1, V. Kanagarajan1, S. Nagini2, and M. Gopalakrishnan1
1Synthetic Organic Chemistry Laboratory, Department of Chemistry, and 2Department of Biochemistry and
Biotechnology, Faculty of Science, Annamalai University, Annamalai Nagar, Tamil Nadu, India
Abstract
A new bis heterocycle comprising both bioactive 2-aminopyrimidine and thiazolidin-4-one nuclei namely 3-(4′-
(4″-fluorophenyl)-6′-phenylpyrimidin-2′-yl)-2-phenylthiazolidin-4-one 3 was synthesized, characterized with the
help of melting point, elemental analysis, FT-IR, MS, one-dimensional NMR (1H, 13C) spectra and we evaluated the
chemopreventive potential of 3-(4′-(4″-fluorophenyl)-6′-phenylpyrimidin-2′-yl)-2-phenylthiazolidin-4-one based on
in vivo inhibitory effects on 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch carcinogenesis.
Administration of 3 effectively suppressed oral carcinogenesis initiated with DMBA as revealed by the reduced
incidence of neoplasms. Lipid peroxidation, glutathione (GSH) content, and the activities of glutathione peroxidase
(GPx), glutathione S-transferase (GST) were used to biomonitor the chemopreventive potential of 3. Lipid peroxidation
was found to be significantly decreased, whereas GSH, GPx, GST, and GGT were elevated in the oral mucosa of tumor-
bearing animals. Our data suggest that 3 may exert its chemopreventive effects in the oral mucosa by modulation of
lipid peroxidation and enhancing the levels of GSH, GPx, and GST.
Keywords: Oral cancer, 3-(4′-(4″-fluorophenyl)-6′-phenylpyrimidin-2′-yl)-2-phenylthiazolidin-4-one, DMBA,
chemoprevention, hamster buccal pouch carcinogenesis, lipid peroxidation
Introduction
In recent years, pyrimidine nucleus has attracted increase
attention owing to their diverse biological activities [1–5].
Substituted pyrimidines, particularly with an amino group
at 2 or 4 positions, are known pharmacophores in several
structure-based drug-design approaches in medicinal
chemistry [6–9]. For example, aryl-2-aminopyrimidines
have been reported for the treatment of diseases modu-
lated by the adenosine receptor. Drugs containing a
pyrimidine with a hydroxy group such as tetrahydrofolate
and 5-methyltetrahydrofolate possess high antioxidant
activity [10]. Biological importance of pyrimidines inspired
us to report the synthesis, antibacterial and antifungal
activity of 2-phenyl-3-(4,6-diarylpyrimidin-2-yl)thiazoli-
din-4-onesand4-(4-morpholinophenyl)-6-arylpyrimidin-
2-amines [11,12]. Various 4-thiazolidinones have attracted
considerable attention as they are endowed with wide
range of pharmacological activities. A wide variety of bio-
logicalpropertiessuchashypolipidemic,antidegenerative,
muscarinicreceptor1agonist, antiproteolytic, anti-inflam-
matory, antiviral, antifungal, antibacterial, antitubercular,
anticonvulsant, respiratory, and hypnotic activities have
been reported for 4-thiazolidinones [13–25].
Squamous cell carcinoma of the oral cavity is the sixth
most common malignant neoplasm worldwide and con-
stitutes 47% of all cancers in the Indian subcontinent [26].
Despite advances in cancer detection and therapy, the
mortality rate of oral cancer remains high and the 5-year
survival rate is among the lowest of the major cancers [27].
Address for Correspondence: M. Gopalakrishnan, Synthetic Organic Chemistry Laboratory, Department of Chemistry, Faculty of Science,
Annamalai University, Annamalai Nagar-608 002, Tamil Nadu, India. Tel: +91-4144-228-233. E-mail: profmgk@yahoo.co.in
(Received 07 April 2010; revised 09 September 2010; accepted 17 September 2010)
422

Evaluation of 3-(4′-(4″-fluorophenyl)-6′-phenylpyrimidin-2′-yl)-2-phenylthiazolidin-4-one 423
S
1
Patients with oral squamous cell carcinoma (OSCC) are
susceptible to multiple primary and secondary tumors
due to the phenomenon of “field cancerization” [28,29].
Furthermore, treatment of these tumors results in severe
disfigurement and functional compromise.
5
4
2
3
O
2'''
N
Chemoprevention offers a novel approach to control
the incidence of oral cancer. e buccal mucosa of the
Syrian hamster is an excellent model for the investiga-
tion of oral cancer development and intervention by
chemopreventive agents. Squamous cell carcinomas
induced by the application of 7,12-dimethylbenz[a]
anthracene (DMBA) to the cheek pouch of the Syrian
hamsters are morphologically and histologically similar
to human tumors [30,31]. In addition, hamster tumors
express many metabolic and molecular markers that are
expressed in human oral cancer [32–34].
N
2'
5'
N
3'
4'
1'
6'
4''
6''
F
3-(4'-(4''-fluorophenyl)-6'-phenylpyrimidin-2'-yl)
-2-phenylthiazolidin-4-one
Scheme 1. Potential biolabile hybrid chemopreventive drug
Several markers have been developed to biomoni-
tor chemoprevention. ese are based on the fact that
chemopreventive agents can exert their anticarcinogenic
effects by one or a combination of the following mecha-
nisms: inhibiting formation of reactive carcinogenic
metabolites, induction of enzymes that detoxify car-
cinogens, scavenging reactive oxygen species, influenc-
ing apoptosis, and inhibiting cell proliferation [35,36].
e tripeptide glutathione, a physiologically important
nucleophile, and the enzymes glutathione peroxidase
(GPx), glutathione S-transferase (GST), and gamma-
glutamyltranspeptidase (GGT), which utilize reduced
glutathione (GSH) as substrate, have assumed signifi-
cance as biomarkers of chemoprevention owing to their
antioxidant and detoxification properties [37–39].
A large number of chemopreventive agents have been
identified in epidemiological and experimental studies,
preclinical systems, and clinical observations [40,41].
However, the toxic side effects produced by some of
these agents have limited their extensive use [42]. ere
is therefore a need to identify synthetic compounds that
have significant chemopreventive potential. In view of
our continued interest in the development of simpler
and more convenient synthetic routes for achieving the
biologically challenging hybrid heterocyclic systems
[43–51] and as part of our ongoing research program,
we planned to design a system, which combines both
bioactive 2-aminopyrimidine and thiazolidin-4-one
nuclei together to give a compact structure like the title
compound 3-(4′-(4″-fluorophenyl)-6′-phenylpyrimidin-
2′-yl)-2-phenylthiazolidin-4-one 3, and we investigate
the effects of 3 in a hamster buccal pouch (HBP) car-
cinogenesis model using lipid peroxidation, superoxide
dismutase (SOD), catalase, GSH, GPx, and GST as bio-
chemical endpoints of chemoprevention (Scheme 1).
melting point was taken in open capillaries and was
uncorrected. IR spectra were recorded in KBr (pellet
forms) on a ermo Nicolet-Avatar-330 FT-IR spectro-
photometer and noteworthy absorption values (per
1
centimeter) alone were listed. One-dimensional H and
13C NMR spectra were recorded at 400 and 100 MHz,
respectively, on Bruker AMX 400 NMR spectrometer
using DMSO-d as solvent. e electron spray impact
(ESI) positive (+ve) mass (MS) spectrum was recorded
on a Bruker Daltonics LC-MS spectrometer. Satisfactory
microanalysis was obtained on Carlo Erba 1106 CHN
analyzer. All the chemicals were purchased from
Fluka, Sigma-Aldrich Corp, St.Louis MO, USA, S.D.Fine
Chemicals Ltd, 248, Worli Road, Mumbai, India and
Spectrochem Pvt. Ltd, 221, Anand Bhuvan, Mumbai,
India.&
By adopting the literature precedent [11] (E)-1-(4-
fluorophenyl)-3-phenylprop-2-en-1-one 1 and 4-(4-
fluorophenyl)-6-phenylpyrimidin-2-amine
2
were
synthesized.
Typical method for the synthesis of 3-(4′-(4″-
fluorophenyl)-6′-phenylpyrimidin-2′-yl)-2-
phenylthiazolidin-4-one 3
To an ice-cold stirred solution of 4-(4-fluorophenyl)-
6-phenylpyrimidin-2-amine (0.01mol) in dry dichlo-
romethane was added benzaldehyde (0.012mol) in drops
followed by dicyclohexylcarbodiimide (DCC). After
5min, thioglycolic acid (0.01mol) was added and stirring
was continued for additional 5h at 0°C. en the reaction
mixture was filtered to remove dicyclohexyl urea followed
by washing with 5% citric acid, 10% sodium bicarbonate,
brine solution, finally with water and dried over anhy-
drous sodium sulfate. After evaporation of the solvent
under reduced pressure, a gummy mass was obtained,
which was solidified on treatment of petroleum ether
(bp40–60). Final purification of 3-(4′-(4″-fluorophenyl)-
6′-phenylpyrimidin-2′-yl)-2-phenylthiazolidin-4-one
was done by column chromatography using silica gel
(100–200 mesh), with ethyl acetate–petroleum ether
Materials and methods
Chemicals
General remarks
We used thin-layer chromatography (TLC) to assess the
reactions and the purity of the products. e reported
© 2011 Informa UK, Ltd.

424 J. Thanusu et al.
(bp40–60) in the ratio (2:8) as eluent (yield=70%, melting
point=104°C).
nitroblue tetrazolium. Catalase was assayed colorimetri-
callybythemethodofSinha[55]. ReducedGSHwasdeter-
mined using the method of Beutler and Kelley [56]. GPx
activity was assayed by following the utilization of hydro-
gen peroxide according to the method of Rotruck et al.
[57]. e activity of GST was assayed using the method
of Habig et al. [58] using 1-chloro-2,4-dinitrobenzene
(CDNB) as substrate. Tissue protein was estimated by the
method of Lowry et al. [59] using bovine serum albumin
as the standard.
Spectral data of 3-(4′-(4″-fluorophenyl)-6′-
phenylpyrimidin-2′-yl)-2-phenylthiazolidin-4-one
IR (KBr) (per centimeter): 3071, 3027, 2928, 2852, 1712,
1626, 1575, 1352, 836, 769, 698; MS: m/z= 428, [M+1]+
Molecular formula C25H18FN3OS; elemental analysis:
carbon 70.27cal (70.23found), hydrogen 4.21cal (4.18found),
1
Nitrogen 9.79cal (9.83found); H NMR (δ ppm): 3.20 (d, 1H,
CH2a at H5a, J= 15.24 Hz), 3.37 (d, 1H, CH2e at H5e, J= 15.28
Hz), 5.26 (s, 1H, CH at H2), 6.64–8.19 (m, 15H, Harom), A
singlet for CH proton at position 5′ of pyrimidine moiety
is merged with aromatic protons. 13C NMR (δ ppm): 34.5
C-5, 62.9 C-2, 108.9 C-5′, 127.3–143.1 Carom, 143.6 C-2′″,
145.1 C-4″, 146.1 C-6″, 166.8 C-4′, 167.0 C-6′, 163.9 C-2′,
171.4 C-4.
Statistical analysis
edataareexpressedasmean standarddeviation(SD).
Statistical analysis on the data for bws and tumor burden
was carried out using Student’s t-test. Tumor incidence
was statistically compared using χ2-test. Statistical analy-
sis on the data for biochemical assays was analyzed using
analysis of variance (ANOVA) and the group means were
compared by the least significant difference test (LSD).
e results were considered statistically significant if the
P< 0.05.
Animals
Male Syrian hamsters aged 6–10 weeks weighing between
90 and 110g obtained from the Central Animal House,
Annamalai University, India were used in this study. e
animals were housed six in a polypropylene cage and pro-
vided with food and water ad libitum. e animals were
maintained in a controlled environment under standard
conditions of temperature and humidity with an alternat-
ing 12h light:dark cycles. All animals were fed standard
pellet diet (Mysore Snack Feed Ltd., Mysore, India).
Results and discussion
Chemistry
Initial classical synthesis for the conversion of 4-(4-
fluorophenyl)-6-phenylpyrimidin-2-amine
2
to
3-(4′-(4″-fluorophenyl)-6′-phenylpyrimidin-2′-yl)-2-
phenylthiazolidin-4-one3iseffectedintheabsenceofDCC.
No yield was achieved. Instead, if DCC was used as a dehy-
drating agent, the yield of the product has been improved
significantly (i.e. about 70%) in stirring mode at about 0°C.
e Claisen-Schmidt condensation of equimolar quanti-
ties of various p-fluoroacetophenone with benzaldehyde
in the presence of sodium hydroxide base as a catalyst
yields (E)-1-(4-fluorophenyl)-3-phenylprop-2-en-1-one.
When (E)-1-(4-fluorophenyl)-3-phenylprop-2-en-1-one
is treated with guanidine nitrate in the presence of potas-
sium hydroxide alkali in refluxing ethanol for 8h gives 4-(4-
fluorophenyl)-6-phenylpyrimidin-2-amine. Novel title
compound, 3-(4′-(4″-fluorophenyl)-6′-phenylpyrimidin-
2′-yl)-2-phenylthiazolidin-4-one 3, is synthesized by the
addition of benzaldehyde, followed by thioglycolic acid
to 4-(4-fluorophenyl)-6-phenylpyrimidin-2-amine in dry
dichloromethane at 0°C catalyzed by DCC. e schematic
synthetic route representation of 3-(4′-(4″-fluorophenyl)-
6′-phenylpyrimidin-2′-yl)-2-phenylthiazolidin-4-one is
given in Scheme 2. e importance of the title compound
is due to their diverse potential, broad-spectrum bio-
logical activity. e structure of the newly synthesized
3-(4′-(4″-fluorophenyl)-6′-phenylpyrimidin-2′-yl)-2-
phenylthiazolidin-4-one is confirmed by melting point,
elemental analysis, MS, FT-IR, one-dimensional NMR (1H
and 13C) spectroscopic data.
Treatment schedule
e animals were randomized into experimental and
control groups and divided into four groups of six ani-
mals each. Animals in group 1 were painted with a 0.5%
solution of DMBA in liquid paraffin on the right buccal
pouches using a number 4 brush three times per week for
14 weeks. Each application leaves ∼0.4 mg DMBA [52].
Group 2 animals were painted with DMBA as in group
1. In addition, the animals were administered title com-
pound,
3-(4′-(4″-fluorophenyl)-6′-phenylpyrimidin-
concentration
2′-yl)-2-phenylthiazolidin-4-one, at
a
of 1 mg/kg body weight (bw) orally three times per
week on days alternate to DMBA application. Animals
in group 3 received only 3-(4′-(4″-fluorophenyl)-6′-
phenylpyrimidin-2′-yl)-2-phenylthiazolidin-4-one
as in group 2. Group 4 (untreated control) animals
received neither DMBA nor 3-(4′-(4″-fluorophenyl)-6′-
phenylpyrimidin-2′-yl)-2-phenylthiazolidin-4-one. e
experiment was terminated at 14 weeks and all animals
were sacrificed by cervical dislocation after an overnight
fast. Fresh tissues were used for estimations.
Estimations
iobarbituric acid reactive substances (TBARS) released
from endogenous lipid peroxides reflecting the lipid per-
oxidation process were assayed in tissues as described
by Ohkawa et al. [53]. e activity of SOD was assayed by
the method of Oberley and Spitz [54] based on the inhibi-
tion of the formation of NADPH phenazine methosulfate,
Biology
e bw, tumor incidence, tumor multiplicity and tumor
burden, and incidence of preneoplastic and neoplastic
Journal of Enzyme Inhibition and Medicinal Chemistry

Evaluation of 3-(4′-(4″-fluorophenyl)-6′-phenylpyrimidin-2′-yl)-2-phenylthiazolidin-4-one 425
H
O
H3C
O
F
HC
CH
NaOH
EtOH
+
O°C
1h
O
(E)-1-(4-fluorophenyl)-3-phenylprop-2-en-1-one (1)
F
NH
NaOH
reflux
8 h
.H Cl
NH2
H2N
NH2
N
N
H
O
O
N
N
HS
OH
0°C, stirring
5 h
F
S
5
1
4-(4-fluorophenyl)-6-phenylpyrimidin-2-amine (2)
4
2
3
N
O
2'''
N
2'
5'
N
O
3'
4'
1'
6'
N
H
N
H
4''
6''
+
1,3-dicyclohexylurea
F
3-(4'-(4''-fluorophenyl)-6'-phenylpyrimidin-2'-yl)
-2-phenylthiazolidin-4-one(3)
Scheme 2. Synthesis of novel biolabile 3-(4′-(4″-fluorophenyl)-6′-phenylpyrimidin-2′-yl)-2-phenylthiazolidin-4-one.
lesions in control and experimental animals are shown in
Table 1. e mean final bws were significantly decreased
in group 1 compared with control (group 4). No signifi-
cant differences in the bws were observed in groups 2 and
3. In DMBA-painted animals (group 1), the incidence of
SCC was 100% with a tumor multiplicity of 1.17 per ham-
ster. ese tumors were large and exophytic with a mean
tumor burden of 208.00 mm3. In group 2, only one animal
developed SCC, whereas others exhibited moderate to
severe dysplasia without infiltration. Although no tumors
were observed in group 3, histopathological examina-
tion of pouches revealed varying degrees of hyperplasia,
hyperkeratosis, and dysplasia. While administration of
3-(4′-(4″-fluorophenyl)-6′-phenylpyrimidin-2′-yl)-2-
phenylthiazolidin-4-one (1 and 10 mg/kg bw) decreased
tumor incidence as well as preneoplastic lesions, the
inhibitory effect was more pronounced at 10 mg/kg bw
of 3-(4′-(4″-fluorophenyl)-6′-phenylpyrimidin-2′-yl)-2-
phenylthiazolidin-4-one. In group 4, the epithelium was
normal, intact, and continuous.
e levels of TBARS and the activities of SOD, catalase,
GPx, and GST in the buccal pouches of control and exper-
imental animals are shown in Table 2. e changes in the
levels of TBARS and GSH and the activities of GPx and
© 2011 Informa UK, Ltd.

426 J. Thanusu et al.
Table 1. Body weight, tumor incidence, tumor multiplicity and tumor burden, and incidence of preneoplastic and neoplastic lesions in
control and experimental animals (mean SD; n=6).
Body weight (g)
Tumor
multiplicity
Tumor
incidence
(no. of tumors/ Tumor Burden
Group Treatment
Initial
Final
hamsters)
1.17 0.41
0.18 0.24b
(mm3)*
Keratosis Hyperplasia Dysplasia
1
2
DMBA
103.0 9.21 115.0 10.0a
6/6
1/6b
208.00 43.68
5.81 12.92b
+++
+++
+++
++
+++
DMBA +title
compound
104.0 10.10 125.0 11.0
+/++
(1mg/kg bw)
3
4
DMBA + title
compound
(10mg/kg bw)
105.0 8.40 128.0 10.0
110.0 11.00 134.0 11.0
−
−
−
++
++
+
Control
−
−
−
++
++
+/++
+ ⇒ mild, ++ ⇒ moderate, +++ ⇒ severe, − ⇒ no change.
*Mean tumor burden was calculated by multiplying the mean tumor volume (4/3πr3) with the mean number of tumors (r=1/2 tumor
diameter in mm).
aSignificantly different from group 4 by Student’s t-test (P<0.01).
bSignificantly different from group 1 by χ2-test (P<0.001).
Table 2. e cellular redox status in the buccal pouches of experimental and control animals (mean SD; n=10).
TBARS (n mol/mg
protein)
SOD (Ua/mg
protein)
2.34 0.21♦
Catalase (Ub/mg GSH (mg/g
GPX (Uc/mg
protein
10.65 0.75♦
GST (Ud/mg
protein)
5.70 0.43♦
Group
Treatment
DMBA
protein)
tissue)
0.18 0.01♦
4.60 0.33♦
1.18 0.10♦
1
2
DMBA + title
compound
5.63 0.39*
2.98 0.19*
1.41 0.14**
0.22 0.02**
12.51 0.88*
6.54 0.59**
(1mg/kg bw)
3
4
DMBA + title
compound
(10mg/kg bw)
5.91 0.58***
4.35 0.35***
1.65 0.17***
0.27 0.01*** 13.13 0.93***
7.23 0.65***
Control
6.0 0.92
5.01 0.43
2.13 0.21
0.13 0.01
7.25 0.51
3.98 0.34
♦Significantly different from group 4 (P<0.001) ANOVA followed by LSD.
*Significantly different from group 1 (P<0.01) ANOVA followed by LSD.
**Significantly different from group 1 (P<0.05) ANOVA followed by LSD.
***Significantly different from group 1 (P<0.001) ANOVA followed by LSD.
ae amount of enzyme required to inhibit 50% NBT reduction.
bMicromoles of H2O2 utilized per minute.
cMicromoles of GSH utilized per minute.
dMicromoles of 1-chloro-2,4-dinitrobenzene-reduced glutathione conjugate formed per minute.
GST were significantly increased with decrease in SOD
and catalase activities in DMBA-painted animals (group
1) compared with control (group 4). Administration of
3-(4′-(4″-fluorophenyl)-6′-phenylpyrimidin-2′-yl)-2-
phenylthiazolidin-4-one significantly enhanced the lipid
peroxidation and the activities of antioxidants in the buc-
cal pouches of groups 2 and 3 animals compared with
group 1. However, the antioxidant-enhancing effects
were more significant in group 3 (10 mg/kg bw) com-
pared with other groups. DMBA, an aryl hydrocarbon, is
a potent carcinogen that induces significant histological
and biochemical changes during HBP carcinogenesis.
In the present study, topical application of DMBA to the
cheek pouch for 14 weeks resulted in well-differentiated
SCCs with very high tumor burden.
studies have documented decreased lipid peroxidation in
rapidly proliferating tumors compared with their normal
counterparts [60,61]. e thiol antioxidant GSH, which
provides cellular protection against ROS in conjunction
with GPx, γ-glutamyl tranferase (GGT), and glutathione
reductase (GR), is recognized to play a key role in regu-
lating cell proliferation [62]. Overexpression of GSH- and
GSH-dependent enzymes has been reported in a wide
range of tumors including OSCC [63]. e elevated GSH
redox cycle antioxidants may serve to maintain a reduced
environment providing a selective growth advantage
to HBP tumors. Our results are in agreement with the
hypothesis of Slater et al. [64] that an increase in antioxi-
dant capacity is associated with a decrease in lipid perox-
idation. In contrast to GSH-dependent antioxidants, the
activities of the antioxidant enzymes SOD and CAT were
decreased in the HBP tumors. An increase in the activities
of GPx with decreased SOD and CAT has been reported
in various tumors, including the hamster cheek pouch
carcinoma cell line HCPC-1 [65–67]. Reduced activities
of SOD and CAT reported in fast-growing tumor tissues
In DMBA-induced HBP tumors, low lipid was associ-
ated with enhanced activities of GSH redox cycle antioxi-
dants. Lipid peroxidation, which prolongs the G1 phase of
the cell cycle, has been suggested to control cell division.
Das have demonstrated that tumor cells are more resis-
tant to lipid peroxidation than normal cells [60]. Several
Journal of Enzyme Inhibition and Medicinal Chemistry

Evaluation of 3-(4′-(4″-fluorophenyl)-6′-phenylpyrimidin-2′-yl)-2-phenylthiazolidin-4-one 427
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Administration
of
3-(4′-(4″-fluorophenyl)-6′-
phenylpyrimidin-2′-yl)-2-phenylthiazolidin-4-one at two
different doses (1 and 10mg/kg bw) significantly sup-
pressed tumor incidence, multiplicity, and tumor burden
in the HBP by modulating oxidant–antioxidant status.
e results of the present study substantiate the anticar-
cinogenic effects of bioactive 2-aminopyrimidines and
thiazolidinones derivatives reported in literature [4,25,69].
Administration of synthetic compounds reversed the
susceptibility to lipid peroxidation while simultaneously
increasing the antioxidant status in the buccal pouch.
ese findings support reports by us and other work-
ers that chemopreventive agents exert an “electrophilic
counterattack response” characterized by the elevation
of antioxidant enzymes [70]. Among these two differ-
ent doses used in the present study, the maximum dose
10mg/kg bw was more effective in chemoprevention.
We have demonstrated that 3-(4′-(4″-fluorophenyl)-
6′-phenylpyrimidin-2′-yl)-2-phenylthiazolidin-4-one
suppresses DMBA-induced oral neoplasms as revealed
by the reduced incidence of carcinomas. e present
preliminary study suggests that 3-(4′-(4″-fluorophenyl)-
6′-phenylpyrimidin-2′-yl)-2-phenylthiazolidin-4-one has
potential anticarcinogenic properties in experimental ani-
mals and are promising candidates for chemoprevention.
Further development of this group of pyrimidino thiazoli-
dine hybrid heterocycles, which may lead to compounds
with better pharmacological profiles, is under progress.
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Acknowledgements
Authors are thankful to NMR Research Centre, Indian
Institute of Science, Bangalore for recording spectra.
One of the authors namely V. Kanagarajan is grateful to
Council of Scientific and Industrial Research (CSIR), New
Delhi, Republic of India for providing financial support
in the form of CSIR-Senior Research Fellowship (SRF) in
Organic Chemistry.
Declaration of interest
e authors report no conflicts of Interest.
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