Synthesis, characterization and cytotoxicity of a palladium(II) complex of 3-[(2-hydroxybenzylidene)amino]-2-thioxoimidazolidin-4-one

Article abstract of DOI:10.2298/JSC120725154S

The polydentate ligand 3-[(2-hydroxybenzylidene)amino]-2- thioxoimidazolidin-4-one was synthesized in the intermolecular cyclocondensation reaction of 2-hydroxybenzaldehyde thiosemicarbazone and ethyl chloroacetate. A novel palladium(II) complex was obtained from cis-[Pd(DMSO)₂Cl ₂] by nucleophilic substitution of both DMSO ligands with the iminic nitrogen and the thiolactamic sulfur from the ligand. The structures of the compounds were characterized based on their spectral data. The cytotoxic activities of the ligand and the palladium(II) complex were studied on the tumor cell lines: human colon carcinoma HCT-116 and SW-480 cells using the MTT viability test. The results showed that the investigated palladium(II) complex had a significantly greater cytotoxic effect compared to that of the ligand.

Full text of DOI:10.2298/JSC120725154S

J. Serb. Chem. Soc. 78 (2) 217–227 (2013)
JSCS–4410
UDC 546.982+547.857.6+547.496.3+
542.913:576+615.9
Original scientific paper
Synthesis, characterization and cytotoxicity of a palladium(II)
complex of 3-[(2-hydroxybenzylidene)amino]-2-thioxo-
imidazolidin-4-one
1
#
1
*
BILJANA ŠMIT , RADOSLAV Z. PAVLOVIĆ , ANA RADOSAVLJEVIĆ-
-MIHAILOVIĆ2, ANJA DOŠEN2, MILENA G. ĆURČIĆ1, DRAGANA S. ŠEKLIĆ1
and MARKO N. ŽIVANOVIĆ1
1Faculty of Science, University of Kragujevac, Radoja Domanovića 12, P. O. Box 60,
34000 Kragujevac, Serbia and 2Vinča Institute of Nuclear Sciences,
P. O. Box 522, 11001 Belgrade, Serbia
(Received 25 May, revised 21 December 2012)
Abstract: The polydentate ligand 3-[(2-hydroxybenzylidene)amino]-2-thioxo-
imidazolidin-4-one was synthesized in the intermolecular cyclocondensation
reaction of 2-hydroxybenzaldehyde thiosemicarbazone and ethyl chloroacetate.
A novel palladium(II) complex was obtained from cis-[Pd(DMSO)2Cl2] by
nucleophilic substitution of both DMSO ligands with the iminic nitrogen and
the thiolactamic sulfur from the ligand. The structures of the compounds were
characterized based on their spectral data. The cytotoxic activities of the ligand
and the palladium(II) complex were studied on the tumor cell lines: human co-
lon carcinoma HCT-116 and SW-480 cells using the MTT viability test. The
results showed that the investigated palladium(II) complex had a significantly
greater cytotoxic effect compared to that of the ligand.
Keywords: thiohydantoins; palladium(II) complexes; cytotoxic activity.
INTRODUCTION
Thiohydantoins are sulfur analogs of hydantoins with one or both carbonyl
1–5
group(s) replaced by a thiocarbonyl group.
Among the known thiohydantoins,
2-thiohydantoins (2-thioxoimidazolidin-4-ones) are the most well known due to
their wide applications as intermediates and reagents as well as therapeutics, her-
bicides and fungicides. They are traditionally considered as useful intermediates
6
in peptide synthesis and structure determination. 2-Thiohydantoins are also used
7
8
for other purposes, including textile printing, as catalysts for polymerizations,
9
in the production of resins and plastics and as qualitative reagents for the detec-
*Corresponding author. E-mail: biljam@kg.ac.rs
# Serbian Chemical Society member.
doi: 10.2298/JSC120725154S
217
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218
ŠMIT et al.
10
tion of some metal ions upon complexation. Thiohydantoins and their deriva-
11–13
tives exist in many natural products.
In the past decades, great efforts have
been devoted to introducing thiohydantoins and their derivatives into desirable
14–17
substrates, such as pharmacophores and synthetic intermediates.
Com-
pounds containing the thiohydantoin structural motif have been identified to dis-
play a wide range of biological activities. For example, many of them exhibit
18
19
20
21
22
anticonvulsant, anti-epileptic, antimicrobial, antiviral, antineoplastic,
23
24
25,26
hypolipidemic, antithrombotic, and potential antitumor activities,
etc.
2
Several derivatives are employed either as established drugs in clinical practice
27
or as fungicides and herbicides in agriculture.
28
It is known that coordination of these compounds with transition metal
ions sometimes enhances their antiviral and antitumor activities. 2-Thiohydantoin
molecules contain a thioamide fragment and can undergo thione–thiol tautome-
29
rism, due to which they can be coordinated to metal ions through the lone elec-
tron pairs of the nitrogen or sulfur atoms, or both. Coordination with some tran-
30–35
sition metals was previously studied.
. The resulting complexes can contain
2-thiohydantoins as either neutral ligands or monoanions, which are formed upon
36–40
deprotonation of the N–H group.
four-membered metalla-cycles.
Most of the resulting complexes contain
Thiohydantoin molecules containing substituents with an additional donor
40–43
44
atom can form chelate
or supramolecular complexes in which the metal
atom is coordinated by one or two thiohydantoin ligands in the neutral or depro-
tonated form.
The synthesis of coordination compounds that incorporate the thiohydantoin
nucleus could have significant impact in the field of drug design and drug deli-
very.
In this paper, the synthesis and spectroscopic characterization of a palla-
dium(II) complex of 3-[(2-hydroxybenzylidene)amino]-2-thioxoimidazolidin-4-
-one is described. The cytotoxic activities of the ligand and its palladium(II)
complex were studied on two tumor cell lines of human colon carcinoma using
the MTT viability test.
EXPERIMENTAL
Starting materials
All chemicals were purchased from commercial sources (Sigma-Aldrich, Fluka or Cen-
trohem) and were used without further purification. Solvents were purified and dried by
standard methods. Dimethyl sulfoxide (DMSO) and 3-[4,5-dimethylthiazol-2-yl]-2,5-diphe-
nyltetrazolium bromide (MTT) were obtained from Serva, Germany. Dublecco’s modified
Eagle medium (DMEM) was obtained from Gibco Invitrogen. Fetal bovine serum (FBS) and
trypsin–EDTA were obtained from PAA-The cell culture company, Austria.
Cis-[Pd(DMSO)2Cl2]45 and 2-hydroxybenzaldehyde thiosemicarbazone46 1 were synthe-
sized according to literature methods.
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PALLADIUM(II) COMPLEX WITH 2-THIOHYDANTOIN
219
Instrumentations
The elemental analyses were performed by standard micro-methods using an Elemental
Vario ELIII CHNSO analyzer.
The IR spectra were recorded on a Perkin-Elmer FTIR spectrometer, model Spectrum
One.
1
The H- and 13C-NMR spectra were recorded on a Varian Gemini 2000 spectrometer at
200 and 50 MHz, respectively, in DMSO-d6 solution using TMS as internal standard. D2O
exchange was applied to confirm the assignment of the nitrogen- and oxygen-bound protons.
The UV–Vis spectra were recorded on a Perkin-Elmer Lambda 35 double beam spectro-
photometer in 1.00 cm quartz Suprasil cells.
The X-ray powder diffraction (XRPD) patterns were obtained on a Philips PW 1710
automated X-ray powder diffractometer using a Cu tube operated at 40 kV and 35 mA. The
instrument was equipped with a diffracted beam curved graphite monochromator and a Xe-
filled proportional counter. The diffractometer was calibrated with a silicon standard sample.
For the Rietveld profile fitting method, the diffraction data were collected using the step-
scanning mode in the 2θ range between 4 and 130° with 0.02° steps. The counting time was
fixed to 5 s per step. The collected data were refined using FullProff software.
Ligand synthesis
The procedure for preparation of 3-[(2-hydroxybenzylidene)amino]-2-thioxoimidazo-
lidin-4-one 2 was analogous to that described previously.46 A mixture of 5.100 g 1 (26.15
mmol) and 3.204 g ethyl chloroacetate (26.15 mmol) in absolute methanol (150 cm3) in the
presence of 6.433 g fused sodium acetate (78.45 mmol) was heated under reflux for 6 h. The
reaction mixture was cooled and poured into water. The precipitate was separated by filtra-
tion, washed with cold water and dried. The crude product was recrystallized from hot me-
thanol. Yield: 4.548 g.
Complex synthesis
The synthesis of palladium(II) complex with 3-[(2-hydroxybenzylidene)amino]-2-thio-
xoimidazolidin-4-one 3 was achieved by dissolving 0.178 g 2 (0.76 mmol) in 10 cm3 of ab-
solute methanol under reflux until dissolution and then adding 10 cm3 of a methanolic solu-
tion of Pd(DMSO)2Cl2 (0.252 g, 0.76 mmol) in three portions. Reaction mixture was heated
under reflux for 12 h, cooled to 0 °C and the resulting orange–red precipitate was separated by
filtration, washed with hot water, small amount of hot methanol and dried. The complex was
recrystallized from hot methanol. Yield: 0.180 g.
Antiproliferative assay
Tumor cell lines were obtained from the American Type Culture Collection. The cells
were maintained in DMEM supplemented with 10 % FBS, with 100 units mL-1 penicillin and
100 µg mL-1 streptomycin. The cells were cultured in a humidified atmosphere with 5 % CO2
at 37 °C. The cells were grown in 75 cm2 culture bottles supplied with 15 mL DMEM, and
after a few passages, the cells were plated in a 96-multiwell plate (104 cells well-1). All studies
were realized with cells at 70 to 80 % confluence. After 24 h of incubation of the cells, the
medium was replaced with 100 μL medium containing various doses of 2 and 3 (0.1, 1, 10,
50, 100 and 500 μM) for 24 and 72 h. Untreated cells served as the control. After 24 and 72 h
of treatment, the cell viability was determined by the MTT assay.47 The proliferation test is
based on the color reaction of mitochondrial dehydrogenase in living cells with MTT. At the
end of the treatment period, MTT (final concentration 5 mg mL-1 PBS) was added to each
well, which was then incubated at 37 °C in 5 % CO2 atmosphere for 2–4 h. The colored crys-
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ŠMIT et al.
tals of the produced formazan were dissolved in 150 μL DMSO. The absorbance was mea-
sured at 570 nm on Microplate Reader (Elisa 2100C). Cell proliferation was calculated as the
ratio of the absorbance of the treated group divided by the absorbance of the control group,
multiplied by 100 to give the percentage proliferation.
Biological activity was the result of one individual experiment, performed in triplicate
for each dose. The magnitude of correlation between the variables was determined using an
SPSS (Chicago, IL) statistical software package (SPSS for Windows, ver. 17, 2008). The
effect of each extract are expressed by IC50 (inhibitory dose which inhibits 50 % of cell
growth) and by the magnitude of maximal effect in exposed cells. The IC50 values were
calculated from the dose curves using the CalcuSyn computer program.
RESULTS AND DISCUSSION
The polydentate ligand, 3-[(2-hydroxybenzylidene)amino]-2-thioxoimidazo-
lidin-4-one 2, was obtained by intermolecular cyclocondesation reaction of 2-
46
hydroxybenzaldehyde thiosemicarbazone and ethyl chloroacetate (Scheme 1).
Yield: 74.0 %. Anal. Calcd. for C H N O S: C, 51.05; H, 3.86; N, 17.86
10
9 3 2
–1
%. Found: C, 51.08; H, 3.88; N, 17.89 %; IR (KBr, cm ): 3443 (O–H), 3318
(NH), 3173, 3031 (CH Ar), 2987, 2808 (CH ), 1721 (C=O), 1616 (C=N), 1604,
2
1538, 1490 (C=C Ar), 1464, 1368, 1282, 1266 (C=S), 1202 (C–O), 1112, 1062,
1
949, 830, 753 (δ CH Ar), 627; H-NMR (DMSO-d , δ / ppm): 3.97 (2H, s, CH ),
6
2
6.94 (2H, m, H1–, H2–Ar), 7.30 (1H, dt, J = 7.8 and 1.8 Hz, H3–Ar), 7.75 (1H,
dd, J = 8.0 and 1.9 Hz, H4–Ar), 8.64 (1H, s CH=N), 10.88 (1H, s OH), 12.06
13
(1H, bs NH); C-NMR (50 MHz, DMSO-d , δ / ppm = 33.53 (CH ), 116.51,
6
2
118.63, 119.69, 130.76, 132.34, 156.60 (Ar), 158.19 (C=N), 174.04 (C=O),
177.94 (C=S); UV–Vis (DMSO, λ / nm): 305.91, 338.97, 351.14.
max
The novel palladium(II) complex 3 was obtained by nucleophilic substitution
of both DMSO ligands from cis-[Pd(DMSO) Cl ] with the iminic nitrogen and
2
2
thiolactamic sulfur from ligand 2 (Scheme 2). A non-charged complex was iso-
lated as an orange–red amorphous precipitate. The metal complex was non-hyg-
roscopic, soluble in DMSO, sparingly soluble in methanol and ethanol and inso-
luble in water. The analytical data revealed 1:1 (metal:ligand) stoichiometry. The
structures of the ligand and complex were established by its elemental compo-
sition and IR, NMR and electronic spectra.
Yield: 57.7 %. Anal. Calcd. for C H Cl N O PdS: C, 29.11; H, 2.22; N,
10
9
2 3 2
–1
10.18 %. Found: C, 29.08; H, 2.18; N, 10.16 %; IR (KBr, cm ) 3436 (O–H),
3153 (NH), 2925 (CH ), 2853, 1719 (C=O), 1602 (C=N), 1533, 1400, 1385, 1332
2
1
(C=S), 1254, 1201 (C–O), 1154, 755 (δ CH Ar); H-NMR (DMSO-d , δ / ppm):
6
3.16 (2H, s CH ), 6.64 (1H, t, J = 7.0 Hz, H2–Ar), 6.93 (1H, d, J = 8.0 Hz, H1–
2
Ar), 7.29 (1H, dt, J = 8.6 and 1.9 Hz, H3–Ar), 7.48 (1H, dd, J = 7.6 and 1.9 Hz,
13
H4–Ar), 8.10 (1H, s CH=N), 9.78 (1H, s OH), 10.89 (1H, bs NH). C-
-NMR (50 MHz, DMSO-d , δ / ppm) 48.77 (CH ), 115.32, 118.12, 119.67,
6
2
133.47, 134.26, 148.71 (Ar), 161.31 (C=N), 169.91 (C=O), 193.26 (C=S). UV–
–Vis (DMSO, λ
/ nm): 259.25, 304.72, 340.39, 403.33.
max
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ŠMIT et al.
Spectroscopic characterization
In order to confirm complex formation and gain insight into the structure of
obtained compounds, the IR spectra of the free ligand and its complex were re-
–1
corded. The absence of the strong band at ≈2500 cm , assignable to the ν(S–H)
mode, indicate that both compounds exist in the thiono (C=S) form in the solid
state. Comparison of vibrational frequencies of the free ligand with those of the
–1
complex showed a shift in the C=S band to a higher frequency by 66 cm . This
32,48
is evidence that the thionic sulfur atom was involved in the coordination.
In
–1
addition, the C=N absorption band was shifted to a lower frequency by 14 cm .
Consequently, the iminic nitrogen atom is also presumably involved in the co-
ordination. The non-coordination of O is shown by the C=O band shifting only
49
–1
very slightly upon complexation. The broad band observed in region 3153 cm
due to N–H stretch was shifted in complex, probably because of an adjustment in
the current arising due to coordination of the thionic sulfur.
Further evidence for the coordinating mode of the thiohydantoin 2 was ob-
1
tained from the NMR spectra in DMSO-d . In the H-NMR spectrum of the li-
6
gand, there is no resonance at ca. 4.0 ppm, attributed to the resonance of the –SH
proton, while the appearance of a broad peak at 12.06 ppm due to the –NH pro-
ton indicates that even in a polar solvent such as DMSO, it remains in the thione
form. Such a large chemical shift for an –NH proton was already reported for si-
50
milar systems. Various types of primary and secondary hydrogen bond interact-
tions are possible in the studied system. The phenolic H-atom could form an in-
tramolecular hydrogen bond with the iminic nitrogen and additionally, as donat-
ing bifurcated, with the carbonyl group (Fig. 1). This proposal was confirmed ex-
1
perimentally by recording the H-NMR spectrum of ligand 2 in the presence of
NaOH. Upon transformation of the ligand into the phenolate form, the OH proton
at 10.88 ppm disappeared while the other protons shift upfield (the –NH proton
shifted from 12.06 to 10.98 ppm, Fig. 2.) This fact also could explain the upfield
shifts of the corresponding signals in complex 3. It seems that coordination pre-
vented the formation of an intramolecular hydrogen bond because after complex-
ation, iminic nitrogen has no lone electron pair. The –NH proton signal of the
thiohydantoin shifted upfield and appeared at 10.89 ppm in complex 3. The up-
Fig. 1. Intramolecular hydrogen bond inter-
action in ligand 2.
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PALLADIUM(II) COMPLEX WITH 2-THIOHYDANTOIN
223
field shift of the iminic proton signal by 0.54 ppm is clear evidence for coordi-
nation by the iminic nitrogen.
Fig. 2. 1H-NMR spectra of ligand 2 (a) and ligand 2 after the addition of a small amount of
solid NaOH (b).
13
The C-NMR chemical shifts of the C=S and C=N resonances reflected the
involvement of the sulfur from the thiohydantoin ring and the iminic nitrogen in
an intermolecular interaction.
Based on foregoing discussion, the ligand behaves as a neutral NS-bidentate
coordinative agent towards the palladium(II) ion.
In the electronic spectra, two intense absorption bands were exhibited at 305.91
and 351.14 nm for the ligand and at 304.72 and 403.33 nm for the complex.
Three d–d spin allowed singlet–singlet and three spin forbidden singlet–triplet
transitions are predicted for square-planar complexes of palladium(II). However,
strong charge-transfer transitions may interfere and prevent the observation of
some of the expected bands, especially for complexes containing sulfur donor
51
atoms. The prominent strong band at 403.33 nm was assigned to a combination
of intraligand and ligand to metal charge transfer absorptions and d–d bands,
which supports the idea of a square-planar environment for the metal ion.
In the XRPD pattern of the ligand 2, low intensity and fairly broad peaks
showed the poor crystallinity of the substance. The low intensities, poorly de-
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ŠMIT et al.
fined peaks on the XRPD pattern of complex 3 demonstrated its low degree of
crystallinity. The broad hump around 10° 2θ indicates the existence of an amor-
phous phase and might represent extremely poor or partial crystallinity of com-
plex 3. The existence of an amorphous hump between 6 and 15° 2θ in the pattern
of complex 3 is obvious in comparison with the ligand 2. In addition, there is no
clear phase transition, but the metal–ligand complex disrupted the structure,
causing the poor crystallinity demonstrated in the diffraction pattern.
Due to the poor solubility of the isolated complex in suitable solvents, no
single crystal of sufficient quality could be obtained. Therefore, attention was fo-
cused on spectroscopic methods for the structural characterization of complex 3,
which suggested coordination of the ligand to palladium via the iminic nitrogen
and the thionic sulfur (Scheme 2).
Antiproliferative activity
After seeding in standard DMEM medium, the cells were exposed to diffe-
rent concentrations of ligand 2 and complex 3 for 24 and 72 h at 37 °C. The re-
sults obtained with the antiproliferative assays are represented through IC va-
50
lues (Table I).
Comparing the cytotoxic effect of the complex and ligand, a significant dif-
ference was observed. Namely, while the complex exerted extreme cytotoxicity
with IC values for 72-h treatment of 6.51 and 8.89 µM for HCT-116 and SW-
50
480 cell lines respectively (Table I), the ligand did not show a considerable cyto-
toxic effect, even though decreased cell viability was generated with increasing
ligand concentration.
TABLE I. Growth inhibitory effects – IC50 values (μM) of the Pd(II) complex and its ligand
on HCT-116 and SW-480 cell lines after 24 and 72 h of treatment
HCT-116
SW-480
Compound
24 h
72 h
24 h
15.73±0.25
>500
72 h
Pd(II) complex
Ligand
Cisplatin
16.98±0.21
336.75±2.20
293.52±2.36
6.51±0.02
>500
58.55±1.23
8.89±0.36
366.00±2.55
49.58±1.54
325.19±2.35
Complex 3 exerted very high cytotoxic activity, i.e., with increasing com-
plex concentration, the cytotoxicity increased. A statistically significant diffe-
rence in cytotoxicity after 24 h of treatment was noticed compared to that after 72
h of treatment. Interestingly, studying the complex activity it was shown that
sensitivity of investigated cell lines are of similar extent.
Considering the cytotoxicity of the ligand, it was noticed from the IC va-
50
lues (Table I) and from the measured absorbances that the cytotoxicity increased
with increasing applied concentration of the ligand. It was shown that the SW-
-480 cells exhibited greater sensitivity to the ligand 72 h after treatment (IC
=
50
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PALLADIUM(II) COMPLEX WITH 2-THIOHYDANTOIN
225
366 µM) compared to after 24 h (> 500 µM). Interestingly, the HCT-116 cells
show exactly the opposite trend, i.e., a greater cytotoxic effect was observed 24 h
(IC = 337 µM) after treatment compared to after 72 h (> 500 µM). This was
50
probably due to the acute effect of the investigated ligand on the SW-480 cells.
Although the cytotoxicity of the ligand was quantified and statistically processed,
it is important to notice that this cytotoxic effect was certainly not significant,
especially in comparison with the activity of the complex.
The results show that the investigated complex had a significantly greater
cytotoxicity compared to that of cisplatin and further opened up the possibility
for the synthesis of similar complexes of palladium(II).
CONCLUSIONS
A novel palladium(II) complex was synthesized by substitution reaction of
cis-[Pd(DMSO) Cl ] with a 2-thiohydantoin type ligand. Based on spectral data,
2
2
it is proposed that 3-[(2-hydroxybenzylidene)amino]-2-thioxoimidazolidin-4-one
acts as a bidentate ligand, making use of the thiolactamic sulfur and iminic nitro-
gen for coordination to the central metal ion. The cytotoxicity of this complex was
investigated on two independent colon cancer cell lines (HCT-116 and SW-480)
using the MTT viability test. The complex exhibited very high cytotoxic activity
and showed a cytotoxic effect that was much better than that of the ligand. The
observed cytotoxicity could be pursued to obtain a potential chemotherapeutic
drug.
Acknowledgements. The authors are grateful to the Ministry of Education, Science and
Technological Development of the Republic of Serbia for financial support (Project Nos.
172011 and III41010).
И З В О Д
СИНТЕЗА, КАРАКТЕРИЗАЦИЈА И ЦИТОТОКСИЧНОСТ ПАЛАДИЈУМ(II) КОМПЛЕКСА
СА 3-[(2-ХИДРОКСИБЕНЗИЛИДЕН)АМИНО]-2-ТИОКСОИМИДАЗОЛИДИН-4-ОНОМ
БИЉАНА ШМИТ1, РАДОСЛАВ З. ПАВЛОВИЋ1, АНА РАДОСАВЉЕВИЋ-МИХАИЛОВИЋ2, АЊА ДОШЕН2,
МИЛЕНА Г. ЋУРЧИЋ1, ДРАГАНА С. ШЕКЛИЋ1 и МАРКО Н. ЖИВАНОВИЋ1
1
Природно–математички факултет, Универзитет у Крагујевцу, Радоја Домановића 12, п. пр. 60,
2
34000 Крагујевац и Институт за нуклеарне науке Винча, п. пр. 522, 11001 Београд
Полидентатни лиганд, 3-[(2-хидроксибензилиден)амино]-2-тиоксоимидазолидин-4-
он синтетисан је интермолекулском циклокондензацијом 2-хидроксибензалдехидтио-
семикарбазона и етил-хлороацетата. Нов паладијум(II) комплекс добијен је нуклео-
филном супституцијом оба DMSO лиганда из cis-[Pd(DMSO)2Cl2] иминским азотом и
тиолактамским сумпором из лиганда. Структуре једињења су окарактерисане на основу
њихових спектралних података. Цитотоксична активност лиганда и паладијум(II) ком-
плекса испитивана је на туморским ћелијским линијама: хуманог карцинома колона
HCT-116 и SW-480 помоћу МТТ теста вијабилности. Испитивани паладиjум(II) ком-
плекс испољава веома висок цитотоксични ефекат, много бољи од лиганда.
(Примљено 25. маја, ревидирано 21. децембра 2012)
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