Synthesis, DFT calculations and cytotoxic investigation of platinum complexes with 3-thiolanespiro-5′-hydantoin and 4-thio-1H-tetrahydropyranespiro-5′-hydantoin

Article abstract of DOI:10.1016/j.molstruc.2015.02.055

Two organic compounds - 3-thiolanespiro-5′-hydantoin, 4-thio-1H-tetrahydropyranespiro-5′-hydantoin and four new Pt(II) and Pt(IV) complexes with general formulas cis-[Pt(L)₂Cl₂] and cis-[Pt(L)₂Cl₄] were synthesi

Full text of DOI:10.1016/j.molstruc.2015.02.055

Journal of Molecular Structure 1091 (2015) 118–124
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Synthesis, DFT calculations and cytotoxic investigation
of platinum complexes with 3-thiolanespiro-50-hydantoin
and 4-thio-1H-tetrahydropyranespiro-50-hydantoin
a
b
Adriana Bakalova a, , Rossen Buyukliev , Georgi Momekov
⇑
a Department of Chemistry, Faculty of Pharmacy, Medical University-Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria
b Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University-Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria
h i g h l i g h t s
g r a p h i c a l a b s t r a c t
Two organic compounds and four new Pt(II) and Pt(IV) complexes with the same compounds as ligands
were synthesized and investigated. They were characterized by elemental analysis, IR, 1H and 13C NMR
spectroscopy. The coordination mode of the 3-thiolanespiro-50-hydantoin and its Pt(II) complex (1) is
confirmed by DFT calculations. All data showed that the carrier ligands coordinate to the platinum ion
in a monodentate manner through the sulfur atom from the cyclic ring.
The complexes were tested for antiproliferative activity in vitro on panel of human tumor cell lines. The
tested compounds exerted concentration-dependent cytotoxic effects against some of the tumor cell
lines.
ꢀ
ꢀ
ꢀ
Pt(II) complexes with heterocyclic
spiro hydantoins were synthesized
and characterized.
Pt(IV) complexes with heterocyclic
spiro hydantoins were synthesized
and characterized.
New synthesized complexes were
investigated by elemental analysis, IR,
NMR spectra.
ꢀ
ꢀ
DFT calculations of one organic ligand
and its Pt(II) complex were made.
Complexes were studied for
cytotoxicity in vitro on panel of
human tumor cell lines.
a r t i c l e i n f o
a b s t r a c t
Two organic compounds – 3-thiolanespiro-50-hydantoin, 4-thio-1H-tetrahydropyranespiro-50-hydantoin
and four new Pt(II) and Pt(IV) complexes with general formulas cis-[Pt(L)2Cl2] and cis-[Pt(L)2Cl4] were
synthesized. The obtained compounds were characterized by elemental analysis, IR, 1H, 13C NMR spec-
troscopy. The hybrid DFT calculations were used for optimization of the structure geometries of the
ligand (L1) and its Pt(II) complex (1). The calculated structural parameters such as bond lengths and
angles are in good agreement with the experimental data for similar hydantoins and their platinum com-
plexes. The obtained results showed that the geometry of the complex (1) is plane square and the bound-
ing of the L1 with platinum ion is realized by sulfur atom from thiolane ring. The complexes were tested
for cytotoxicity in vitro on four human tumor cell lines. The tested compounds exerted concentration-
dependent cytotoxic effects against some of the tumor cell lines.
Article history:
Received 28 October 2014
Received in revised form 6 January 2015
Accepted 16 February 2015
Available online 24 February 2015
Keywords:
Pt complexes
S-containing saturated rings
DFT calculations
Cytotoxicity
Ó 2015 Elsevier B.V. All rights reserved.
⇑
Corresponding author. Tel.: +359 2 9236578; fax: +359 2 9879874.
E-mail address: adrigebk@abv.bg (A. Bakalova).
http://dx.doi.org/10.1016/j.molstruc.2015.02.055
0022-2860/Ó 2015 Elsevier B.V. All rights reserved.

A. Bakalova et al. / Journal of Molecular Structure 1091 (2015) 118–124
119
The carbon, nitrogen and hydrogen contents of the compounds
were determined by elemental analysis, carried out on a ‘‘EuroEA
3000 – Single, EuroVector SpA’’.
Introduction
All metal containing drugs used in clinics are Pt(II) compounds
such as cisplatin, carboplatin, oxaliplatin, nedaplatin, lobaplatin
and heptaplatin [1]. In the search for new platinum anticancer
drugs, great efforts were devoted to the design of complexes more
efficient and less toxic than drugs already in clinical use. Moreover
in some cases, after the initial treatment, tumors become resistant
[2,3] so an important objective, which is involving great research
efforts is the development of new drugs without acquired resis-
tance [4].
Over the last few decades, there has been considerable interest
in the synthesis and characterization of hydantoin derivatives as an
important class of heterocyclic compounds. Many of the hydan-
toins containing natural and synthetic products exhibit diverse
biological activities, such as antitumor [5], antiarrhythmic [6],
anticonvulsant [7], herbicidal [8], and others [9–11]. Although
hydantoin compounds are studied extensively, there are not many
studies about their anticancer properties. Recently, the cytotoxic
activity of spirohydantoin derivatives was tested in ovarian and
breast cancer cells [12]. It has been shown that a spirohydantoin
derivative induces growth inhibition and apoptosis in leukemic
cells [13].
The diversity associated with the biological activities of cur-
rently available hydantoin derivatives and further scope of devel-
opment of new analogues of hydantoins prompted researchers to
pay attention to the synthesis of new derivatives of hydantoin
and screen its biological activities [12].
However it was shown that Pt(IV) complexes also exhibit
strong cytotoxic activity and can have some advantages in com-
parison to their Pt(II) analogues [14,15]. Significances of the higher
oxidation state are the introduction of two additional ligands and
the change from square planar to octahedral geometry. These
characteristics together with their higher kinetic inertness com-
pared to their Pt(II) counterparts opens up new possibilities in
the design of new platinum-based drugs. The mechanism of action
of the octahedral Pt(IV) complexes was similar with those of
square planar Pt(II) complexes. They can act as prodrugs for
Pt(II) agents (reduction in vivo to the corresponding Pt(II)
counterparts).
The IR spectra were recorded on Thermo Scientific Nicolet iS10
spectrophotometer in the range of 4000–400 as ATR and on IFS 113
v Bruker FTIR spectrophotometer in the range of 400–150 cmꢁ1 in
polyethylene. Intensities of reported IR bands are defined as
br = broad, s = strong, m = medium, and w = weak. The 1H and 13C
NMR spectra were registered on a Bruker WM 250 (250 MHz) spec-
trometer in DMSO-d6 solutions. The splitting of proton resonances
in the 1H NMR spectra is defined as s = singlet, d = doublet,
dd = doublet from doublets and m = multiplet (see Figs. 5 and 6
for NMR numbering scheme). Corrected melting points were deter-
mined, using a Buchi 535 apparatus.
Thermal analysis were performed on a C.MOM thermal analyzer
(Budapest, Hungary) with a simultaneous DTA–TG module using
the following conditions: sample mass 10 mg, heating range 20–
900 °C (293–1173 K), heating rate 5 °C minꢁ1, air atmosphere.
Synthesis of the ligands (L1 and L2)
To 5 mL (0.0490 mol) of thiolane-3-one in 50 mL water/ethanol
or 5 g (0.043 mol) tetrahydro-1H-thiopyran-4-one dissolved in
60 mL water–ethanol (1:1) respectively, were added 2.94 g
(0.0600 mol) NaCN or 9.6 g (0.1000 mol) (NH4)2CO3. The resulting
mixtures were stirred with magnetic stirrer and heated at 65 °C
for 30 h. The obtained reaction mixtures were acidified in a strong
ventilation hood with conc. HCl to pH = 5. The solid products were
filtered off and recrystallized from 50% ethanol (Yields 53% and
75%, respectively) (see Fig. 1).
Synthesis of the complexes (1), (2), (3) and (4)
Water/ethanol solutions of the ligand (L1) (0.0829 g,
0.4819 mmol) and (0.1021 g, 0.5936 mmol) were added dropwise
to the water solutions of K2[PtCl4] (0.1000 g, 0.2409 mmol) and
PtCl4 (0.1007 g, 0.2989 mmol) for the obtaining of the complexes
(1) and (2) resp. To the ethanol solutions of the ligand (L2)
(0.0913 g, 0.4909 mmol) and (0.1124 g, 0.6043 mmol) were
added K2[PtCl4] (0.1025 g, 0.2469 mmol) and PtCl4 (0.1015 g,
0.3014 mmol) for the preparing of the complexes (3) and (4) resp.
The obtained homogenous solutions were stirred for 4–8 h at room
temperature. The solutions were concentrated and cooled to 4 °C.
Yellow products were obtained and filtered off, washed several
times with ethyl ether and dried in a vacuum desiccator. The com-
pounds are soluble in DMSO, water and ethanol. The purity is
checked up by thin layer chromatography with the eluent
CH3COOC2H5/C2H5OH – 2:1 and elemental analysis (Yields 54–
69%). The scheme of the synthesis of the new Pt(II) and Pt(IV) com-
plexes was given in the Fig. 2. The analytical and physical data of
the ligands and of their platinum complexes are given in Table 1.
Over the last few years we have been synthesized and studied
for cytotoxicity in vitro some Pt(II) and Pt(IV) complexes with dif-
ferent hydantoin and spirohydantoin derivatives [16–18]. Some of
them have similar cytotoxic activity to referent antitumor agent
cisplatin.
The present study represents the synthesis, physicochemical
evaluation and pharmacological investigation of new Pt(II) and
Pt(IV) complexes with organic compounds 3-thiolanespiro-50-hy-
dantoin (L1) and 4-thio-1H-tetrahydropyranespiro-50-hydantoin
(L2) as carrier ligands.
Experimental
Computational study
Materials and methods
All calculations were performed with Gaussian 09 program
using the hybrid DFT method B3LYP [20]. 6-31++G(d) basis set
Tetrahydrothiophene-3-one and tetrahydro-1H-thiopyran-4-
one used for preparation of two new organic compounds were
purchased from Aldrich – USA. Potassium tetrachloroplatinate(II)
utilized for the synthetic procedures was purchased from Merck
– Germany, platinum(IV) chloride was purchased from Heraeus
GmbH. All other chemicals were of analytical grade.
O
NH
O
50% C2H5OH
NH
+ NaCN + (NH4)2CO3
S
(CH2)n
S
(CH2)n
O
The synthesized 3-thiolanespiro-50-hydantoin, 4-thio-1H-te-
trahydropyranespiro-50-hydantoin and their Pt(II) and Pt(IV) com-
plexes were characterized by elemental analysis, IR, 1H, 13C NMR
spectra and mass spectrum.
n = 1, 2
Fig. 1. Scheme of the synthesis of the organic compounds (L1 and L2).

120
A. Bakalova et al. / Journal of Molecular Structure 1091 (2015) 118–124
O
NH
NH
O
S
(CH2)n
O
Cl
NH
+ 2 KCl
Pt
NH
+ K2PtCl4
2
Cl
S
S
(CH2)n
n=1,2
O
(CH2)n
NH
O
O
N
H
O
NH
NH
Cl
O
S
(CH2)n
O
Cl
NH
Pt
Cl
NH
+ PtCl4
2
Cl
S
S
(CH2)n
O
(CH2)n
NH
n=1,2
O
O
N
H
Fig. 2. Scheme of the synthesis of new Pt(II) (1,3) and Pt(IV) (2,4) complexes with organic ligands (L1) and (L2).
Table 1
Analytical and physical data of organic ligands and their platinum complexes.
No.
Compound (empirical formula)
Color
m.p. (°C)
%Yield
M. Wt.
Elemental analysis found (calc.)
%C
%H
%N
L1
1
2
L2
3
4
C6H8N2O2S
Pale-yellow
Light-yellow
Lemon-yellow
White
Light-yellow
Light-yellow
236–237
238(Dec.)
209(Dec.)
261–262
222(Dec.)
210(Dec.)
53
56
54
75
66
69
172
610
681
186
674
727
[Pt(C6H8N2O2S)2Cl2]
[Pt(C6H8N2O2S)2Cl4]
[C7H10N2O2S]
23.18 (23.61)
21.37 (21.15)
3.42 (2.62)
2.62 (2.35)
10.13 (9.18)
8.05 (8.23)
[Pt(C7H10N2O2S)2Cl2]ꢂ2H2O
24.39 (24.93)
22.93 (23.11)
3.51 (3.56)
2.93 (3.03)
8.24 (8.31)
7.58 (7.71)
[Pt(C7H10N2O2S)2Cl4]ꢂH2O
was used for optimization the geometry of the L1, while for the
Pt(II) complex (1) LANL2DZ basis set was utilized. We have to men-
tion B3LYP [21–23] as a functional, which is used in the present
investigation. It gives realistic results for molecules up to 60–70
atoms. The basis set involved are 6-31++G(d) for optimization,
because its basic functions are applicable to the lighter elements,
which are in composition in organic molecules. For the metal com-
plexes we have to use heavier LANL2DZ basis set, which is relevant
to heavier elements like platinum. This basis set was chosen in
order to include the pseudo potential of the core electrons in atoms
of heavy elements like platinum and it is compatible with all other
organic elements (C, N, H, O, Cl, S).
chronic myeloid leukemia, established from peripheral blood of a
29-year-old woman with chronic myeloid leukemia). EJ cells (also
designated MGH-U1) were originally isolated from
a high
grade (G3) invasive bladder carcinoma. These cell lines have been
well validated in our laboratory as a proper test system for
platinum agents. The EJ cell line has been obtained from the
unit of Toxicology and Chemotherapy at the Deutsches
Krebsforschungszentrum. The other cell lines were obtained from
DSMZ German Collection of Microorganisms and Cell Cultures.
Their DSMZ catalogue numbers are as follows: HL-60 (ACC 3),
SKW-3 (ACC 53) and LAMA-84 (ACC 168).
The cell culture flasks and the 96-well microplates were
obtained from NUNCLON (Denmark). MTT, FCS and cisplatin were
purchased from Sigma Co. The stock solutions of tested compounds
(10 mM) were freshly prepared in DMSO. The serial dilutions of the
tested compounds were prepared immediately before use. At the
final dilutions obtained the concentrations of DMSO never
exceeded 1%.
Pharmacology
The following cell lines were used for the experiments: (i) SKW-
3 or a KE-37 derivative (human T-cell leukemia, established from
peripheral blood of a 61-year-old man with T-cell lymphocytic leu-
kemia); (ii) HL-60 (acute myeloid leukemia, established from the
peripheral blood of a patient with acute promyelocyte leukemia);
(iii) EJ (human urinary bladder carcinoma), (iv) LAMA-84 (human
Cytotoxicity of the compounds was assessed using the MTT [3-
(4.5-dimethylthiazol-2-yl)-2.5-diphenyltetrazolium bromide] dye
reduction assay as described by Mossman [24] with some

A. Bakalova et al. / Journal of Molecular Structure 1091 (2015) 118–124
121
Table 2
IR spectral bands of the ligands and their platinum complexes.
Compound
m
(NAH)
m
as(C@O)
m
s(C@O)
m
(CAS)
m
(PtAS)
m(PtACl)
L1
3172
3077
3242
3143
3310
3167
3189
3068
3257
3136
3172
3060
1780
1773
1773
1772
1769
1769
1738
1729
1713
1735
1724
1728
1021
1043
1052
1013
1064
1066
(1)
(2)
L2
424
422
314
305
311
302
(3)
(4)
421
418
315
308
312
306
modifications [25]. Exponentially growing cells were seeded in
96-well microplates (100
l
L/well at a density of 3.5 ꢃ 105 cells/
mL for the adherent and 1 ꢃ 105 cells/mL for the suspension cell
lines) and allowed to grow for 24 h prior the exposure to the
studied compounds. Cells were exposed to the tested agents for 72 h,
whereby for each concentration a set of 8 separate wells was used.
Every test was run in triplicate. After incubation with the tested
compounds MTT solution (10 mg/mL in PBS) aliquots were added
to each well. The plates were further incubated for 4 h at 37 °C
and the formazan crystals formed were dissolved by adding
110 lL of 5% HCOOH in 2-propanol. The MTT-formazan absorption
was measured using a multimode microplate reader (Beckman
Coulter DTX880) and the results were normalized as percentage
of the untreated control (set as 100% viable). The data were fitted
to sigmoidal dose-response curves and the IC50 values were calcu-
lated using non-linear regression analysis (Curve-fir; GraphPad
Prism software for PC).
Results and discussion
Chemistry
The ligands 3-thiolanespiro-50-hydantoin (L1) and 4-thio-1H-
tetrahydropyranespiro-50-hydantoin (L2) were prepared by the
Bucherer–Berg method. Their Pt(II) and Pt(IV) complexes were syn-
thesized using reported procedure with minor revisions [19].
The elemental analysis for the new Pt(II) and Pt(IV)
complexes were in good agreement with the following chemical
formulas: [Pt(C6H8N2O2S)2Cl2] (1), [Pt(C6H8N2O2S)2Cl4] (2),
[Pt(C7H10N2O2S)2Cl2]ꢂ2H2O (3) and [Pt(C7H10N2O2S)2Cl4]ꢂH2O (4).
The determination of crystal water content in the complexes (3)
and (4) was defined by DTA analysis. In order to evaluate the mode
of coordination of the ligand to the metal ion, IR, 1H and 13C NMR
spectra of the metal free ligands as well as of their Pt(II) and Pt(IV)
complexes were recorded.
IR spectral studies
In the IR spectra of the platinum compounds shifting of the sig-
nals corresponding to CAS bond is observed: m(CAS) in a metal free
ligand (L1) is at 1030 cmꢁ1, while in the complexes (1) and (2) fre-
quency arises at 1050 and 1052 cmꢁ1, respectively. In the case of
L2 this values are as follows: 1013 cmꢁ1 for L2 and 1040 and
1066 cmꢁ1 for the complexes (3) and (4), respectively. In the IR
spectra of the complexes (1–4) the new bands at 424, 422, 421
and 418 cmꢁ1 are appeared. These stretching vibrations can be
attached to the
302 cmꢁ1 were assigned to the
Two bands for (PtACl) stretching vibrations were observed,
m(PtAS) coordinative bonds. New bands at 315–
m
(PtACl) stretching vibrations.
m

122
A. Bakalova et al. / Journal of Molecular Structure 1091 (2015) 118–124
Table 4
13C spectral data of the ligands and their platinum complexes.
Compound
13C NMR spectra (ppm)
d(CO-40)
d(CO-20)
d(C-50)
d(C-2)
d(C-5)
d(C-4)
d(C-2 + C-6)
d(C-3 + C-5)
L1
176.5
176.0
177.0
177.7
177.4
175.8
156.7
156.2
156.5
156.2
156.1
154.7
71.6
70.6
71.1
60.9
60.1
59.0
41.2
39.8
40.8
40.3
39.5
40.3
30.0
29.5
30.3
(1)
(2)
L2
(3)
(4)
34.1
33.6
32.2
22.7
21.5
20.9
implying cis-location of chloride ligands according to Nakamoto
[26].
The bands related to the stretching vibrations of the two car-
bonyl groups in the metal-free ligands did not shift upon coordina-
tion of L1 and L2 to Pt(II) and Pt(IV) ions, indicating that the C@O
groups were not involved in binding to the metals (Table 2).
S-containing ring is fixed and sulfur atom is bonding with platinum
ions; axial and equatorial hydrogens are easily discernment.
In the 1H NMR spectra of the Pt(II) and Pt(IV) complexes with 4-
thio-1H-tetrahydropyranespiro-50-hydantoin (3,4) the signals of
the protons for CH2(2) and CH2(6) are not in such wide range in
comparison with previous compounds – 2.88 and 2.56 ppm. This
is due to the symmetry of the studied compounds with tetrahy-
dropyran ring. In this case the ring is fixed because sulfur is bonded
with platinum ions; axial and equatorial hydrogens are easily dis-
cernment (Table 3).
1H and 13C NMR spectra of the complexes
In the 1H NMR spectra of freshly prepared DMSO-d6 solutions of
the Pt(II) and Pt(IV) complexes with 3-thiolanespiro-50-hydantoin
(1,2), the signals of the protons for CH2(2) and CH2(5) are in rela-
tively wide range – 3.25 and 2.85 ppm. This is due to the fact that
In the 13C NMR spectra of the Pt(II) and Pt(IV) complexes with
3-thiolanespiro-50-hydantoin (1,2) the signals of the carbon atoms
C(2) and C(4), directly connected to the sulfur are weakly
Fig. 3. 1H NMR spectra of the ligand L2 and its Pt(IV) complex (4).
Fig. 4. 13C NMR spectra of the ligand L2 and its Pt(IV) complex (4).

A. Bakalova et al. / Journal of Molecular Structure 1091 (2015) 118–124
123
Table 5
Selected calculated parameters of L1 and its Pt(II) complex (1).
Parameters
(D)
Ligand(L1)
cis-[Pt(L1)2Cl2] (1)
l
2.06
10.20
Bond lengths (Å)
PtAS1
PtAS2
PtACl1
PtACl2
–
–
–
–
2.43
2.46
2.39
2.41
Angles (°)
CASAC
93.35
113.32
105.22
100.75
–
–
–
–
–
C1AN2AC3
N1AC2AN3
N1AC2AC3
ClAPtACl
SAPtAS
99.22
96.41
180.00
–
SAPtACl
Fig. 5. Chemical formulas of the Pt(II) and Pt(IV) complexes with 3-thiolanespiro-
50-hydantoin.
Fig. 7. Optimized geometry for 3-thiolanespiro-50-hydantoin (L1).
Fig. 6. Chemical formulas of the Pt(II) and Pt(IV) complexes with 4-thio-1H-
tetrahydropyranespiro-50-hydantoin.
influenced from the bonding with platinum ions – 39.2–40.8 ppm.
In the case of the Pt(II) and Pt(IV) complexes with 4-thio-1H-te-
trahydropyranespiro-50-hydantoin (3,4), carbon atoms directly
connected to the sulfur are C(2) and C(6). They give only one signal
due to the symmetry of the cyclic ring. This signal is at 33.6 ppm
for complex (3) and 32.2 ppm for complex (4) (Table 4).
1H and 13C NMR spectra of the complexes show little differences
between metal free ligands and newly synthesized Pt(II) and Pt(IV)
complexes. These results show that sulfur atom has relatively low
polarization when is included in the complex. Pt(IV) complexes
with the N-, S-, O-containing heterocyclic organic ligands are dia-
magnetic and NMR spectra would be recorded [27]. Exemplary
the 1H and 13C NMR spectra of the ligand (L2) and its Pt(IV) com-
plex (4) were presented in Figs. 3 and 4.
Fig. 8. Optimized geometry for cis-[Pt(L1)2Cl2] (1).
disconnection of two molecules of crystal water. This fact is con-
firmed by the endothermic effect at Tmax = 190 °C in the DTA curve.
Geometry optimization
The calculated structural parameters for L1 and its Pt(II) com-
plex (1) are in good agreement with experimental data for similar
hydantoins and their platinum complexes [15,28]. The obtained
results confirm the square-planar geometry of complex (1) with
valent angles S–Pt–Cl close to 90° or 180°, depending on their posi-
tion. Selected calculated parameters (i.e. bond lengths, angles,
dipole moments) are shown in Table 5.
General schemes of the investigated compounds are shown in
Figs. 5 and 6.
Thermogravimetric study
In the temperature range 150–280 °C (in complex (3)) the TG
changes its course after 170 °C. At 190 °C a mass loss
D
m = 5.
Based on the data, obtained from the spectroscopic analysis and
the DFT calculations for (L1) and complex (1), it can be concluded,
68%. ( mcalc. = 5.34%) is registered, which corresponds to the
D

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A. Bakalova et al. / Journal of Molecular Structure 1091 (2015) 118–124
Table 6
Pt(IV) complexes. The molecular formulae of the platinum com-
plexes were determined by elemental analysis, IR, 1H and 13C
NMR spectra. The coordination mode of the 3-thiolanespiro-50-hy-
dantoin and its Pt(II) complex (1) is confirmed by DFT calculations.
Because the very close chemical structures of the L1 and L2 the
mode of coordination of the ligands to the metal ions in all four
complexes is realized through the sulfur atom from the cyclic ring.
The complexes were tested for antiproliferative activity in vitro on
panel of human tumor cell lines. The tested compounds exerted
concentration-dependent cytotoxic effects against some of the
tumor cell lines.
Cytotoxicity of the Pt(II) and Pt(IV) complexes with 3-thiolanespiro-50-hydantoin and
4-thio-1H-tetrahydropyranespiro-50-hydantoin(1–4) in comparison to cisplatin in
four human tumor cell lines.
Cell line compound
IC50 values (
SKW-3a
l
M)
HL-60b
EJc
LAMA-84d
L1
1
2
L2
3
4
114.0
142.3
147.1
92.6
109.4
154.5
11.4
202.8
147.2
195.0
180.9
127.7
167.7
8.7
115.2
>200
112.8
143.5
144.6
165.8
10.2
174.5
197.5
194.2
101.1
129.8
186.4
16.9
Cisplatin
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a
b
c
T-cell leukemia.
Acute myeloid leukemia.
Urinary bladder carcinoma.
Human chronic myeloid.
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The present study describes a comparative evaluation of the
cytotoxic effects of four newly synthesized Pt(II) and Pt(IV) com-
plexes with 3-thiolanespiro-50-hydantoin and 4-thio-1H-tetrahy-
dropyranespiro-50-hydantoin vs. the referent antineoplastic agent
cisplatin on a panel of human tumor cell lines, using the standard
MTT-dye reduction assay for cell viability. The complexes exerted
cytotoxic effects after 72 h continuous exposure, whereby the
individual chemosensitivity varied among the different cell lines,
as evidenced by the IC50 values, summarized in Table 6. The com-
plex (1) proved to be more active as compared to the ligand L1 on
HL-60 cell line. This is due to the fact that maybe complex (1) has
the similar action mechanism to the referent cisplatin. The
cytotoxicity of the complex (2) was comparable to that of the
ligand L1 on EJ cell line. The cytotoxicity of the ligand L2 was com-
parable to these complexes (3) and (4) on EJ cell line. The cytotoxic
effects of the ligands L1 and L2 were similar to the effects of the
complexes (1), (2), (3) and (4), respectively. The tested platinum
compounds displayed cytotoxic effects in a concentration depen-
dent manner. As a result the ligands and the new synthesized plat-
inum complexes are less active than the referent cisplatin.
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Conclusion
Two organic compounds 3-thiolanespiro-50-hydantoin and 4-
thio-1H-tetrahydropyranespiro-50-hydantoin were synthesized
and used as carrier ligands for preparation of four Pt(II) and
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