Tetrakis(thione)platinum(II) complexes: Synthesis, spectroscopic characterization, crystal structures, and in vitro cytotoxicity

Article abstract of DOI:10.1080/00958972.2015.1072175

A new series of platinum(II) complexes based on thione ligands with general formula [Pt(thione)₄]X₂ (X^- = Cl^-, NO₃^-) has been synthesized and characterized using CHNS elemental analysis, infrared, ¹H and ¹³C solution-state NMR as well as ¹³C and ¹⁵N solid-state NMR spectroscopy, and X-ray crystallography. The spectroscopic methods confirm the coordination of Pt(II) with thiocarbonyl groups via sulfur of the thione ligands. The X-ray structures showed a distorted square planar geometry for 1, [Pt(MeImt)₄]Cl₂ (MeImt = N-Methylimidazolidine-2-thione) while the hydrogen bonding interactions in 7, [Pt(iPrImt)₄](NO₃)₂·0.6(H₂O) induce a bent see-saw distortion relative to the ideal square planar geometry. The in vitro cytotoxicity studies showed that 2, [Pt(EtImt)₄]Cl₂ is generally the most effective, a two-fold better cytotoxic agent than cisplatin and carboplatin against MCF7 (human breast cancer).

Full text of DOI:10.1080/00958972.2015.1072175

Journal of Coordination Chemistry
ISSN: 0095-8972 (Print) 1029-0389 (Online) Journal homepage: http://www.tandfonline.com/loi/gcoo20
Tetrakis(thione)platinum(II) complexes: synthesis,
spectroscopic characterization, crystal structures,
and in vitro cytotoxicity
A. Zainelabdeen A. Mustafa, M. Monim-ul-Mehboob, M. Y. Jomaa, M. Altaf, M.
Fettouhi, A. A. Isab, M. I. M. Wazeer, H. Stoeckli-Evans, G. Bhatia & V. Dhuna
To cite this article: A. Zainelabdeen A. Mustafa, M. Monim-ul-Mehboob, M. Y. Jomaa, M.
Altaf, M. Fettouhi, A. A. Isab, M. I. M. Wazeer, H. Stoeckli-Evans, G. Bhatia & V. Dhuna (2015)
Tetrakis(thione)platinum(II) complexes: synthesis, spectroscopic characterization, crystal
structures, and in vitro cytotoxicity, Journal of Coordination Chemistry, 68:19, 3511-3524, DOI:
10.1080/00958972.2015.1072175
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Date: 24 September 2015, At: 02:22

Journal of Coordination Chemistry, 2015
Vol. 68, No. 19, 3511–3524, http://dx.doi.org/10.1080/00958972.2015.1072175
Tetrakis(thione)platinum(II) complexes: synthesis,
spectroscopic characterization, crystal structures, and in vitro
cytotoxicity
A. ZAINELABDEEN A. MUSTAFA†, M. MONIM-UL-MEHBOOB†, M. Y. JOMAA†,
M. ALTAF†,1, M. FETTOUHI†, A. A. ISAB*†, M. I. M. WAZEER†,
H. STOECKLI-EVANS‡, G. BHATIA§ and V. DHUNA*¶
†Department of Chemistry, King Fahd University of Petroleum and Minerals, Dhahran, Saudi Arabia
‡Institute of Physics, University of Neuchâtel, Neuchâtel, Switzerland
§Department of Molecular Biology and Biochemistry, Guru Nanak Dev University, Amritsar, India
¶Department of Biotechnology, DAV College, Amritsar, India
(Received 6 February 2015; accepted 22 June 2015)
A new series of platinum(II) complexes based on thione ligands with general formula [Pt(thione)4]X2
(X− = Cl−, NO3−) has been synthesized and characterized using CHNS elemental analysis, infrared, 1H
and 13C solution-state NMR as well as 13C and 15N solid-state NMR spectroscopy, and X-ray crystal-
lography. The spectroscopic methods confirm the coordination of Pt(II) with thiocarbonyl groups via sul-
fur of the thione ligands. The X-ray structures showed a distorted square planar geometry for 1,
[Pt(MeImt)4]Cl2 (MeImt = N-Methylimidazolidine-2-thione) while the hydrogen bonding interactions in
7, [Pt(iPrImt)4](NO3)2·0.6(H2O) induce a bent see-saw distortion relative to the ideal square planar
geometry. The in vitro cytotoxicity studies showed that 2, [Pt(EtImt)4]Cl2 is generally the most effective,
a two-fold better cytotoxic agent than cisplatin and carboplatin against MCF7 (human breast cancer).
Keywords: Pt(II) thione complexes; N-Alkylimidazolidine-2-thione; N-Ethyl-1,3-diazinane-2-thione;
1,3-Diazipane-2-thione; NMR; In vitro cytotoxicity
*Corresponding authors. Email: aisab@kfupm.edu.sa (A.A. Isab); vikramdhuna@gmail.com (V. Dhuna)
1Present address: Center of Excellence in Nanotechnology, King Fahd University of Petroleum and Minerals,
Dhahran, Saudi Arabia.
© 2015 Taylor & Francis

3512
A. Zainelabdeen A. Mustafa et al.
1. Introduction
Since the discovery of the platinum(II)-based drug cisplatin [1], its clinical use has been
reduced by its severe side effects such as nephrotoxicity [2] and gastrointestinal effects [3],
and also by the resistance of cancer cells to the drug. As a result, several alternative
platinum complexes have been synthesized to overcome these side effects. Platinum(II)
complexes that have the classical structure cis-[PtX2(NHR2)2], in which X = leaving group
and R = organic fragment, bind to DNA through 1,2-intrastrand cross-links, between N7 of
two adjacent guanines (G) with platinum(II) [4–6].
The search for a new generation of platinum(II) complexes, which are able to broaden
the biological activity spectrum and eliminate the multifactorial drug resistance, resulted in
the synthesis of platinum(II) complexes containing biologically active ligands. These com-
plexes are supposed to interact with DNA through a mechanism different from that of cis-
platin. Studies found that cisplatin-like drugs could introduce nephrotoxicity due to their
reaction with sulfur-containing amino acids of the proteins: cysteine and methionine [6].
Platinum(II) complexes with sulfur-containing ligands, like dimethyl sulfoxide (DMSO),
dimethyl sulfide, xanthate, and thiosemicarbazones [7–9], have shown high efficacy against
some human cancer cell lines.
Thiourea and its derivatives as sulfur-containing ligands are expected to give better
results if they coordinate with platinum(II) center. They have been used as antifungal agents
[10], rescue agents against nephritic side effects during cisplatin administration, and as inhi-
bitors of HIV-1 and HIV-2 reverse transcriptases [11]. Platinum(II) complexes with thiourea
ligands demonstrated that they can bind to DNA in a different mechanism to that of
cisplatin and showed an excellent cytotoxicity against ovarian and leukemia cancer cell
lines [12, 13].
Such success of thiourea and its derivatives in cancer treatment encouraged us to
synthesize new platinum(II) complexes with thiourea derivatives and characterize those
using different analytical and spectroscopic techniques. Along this line, tetrakis(1–3-diazi-
nane-2-thione)platinum(II) chloride monohydrate was recently synthesized and evaluated
in vitro for cytotoxic activity against a panel of cancer cell lines [14]. In continuation of this
research, we report herein the synthesis, spectroscopic, and X-ray structural characterization
and in vitro cytotoxicity of a new series of platinum(II) complexes (1–7) based on the
structurally different thione ligands, shown in scheme 1.
5
6
5
2
4
5
6
7
4
3
4
3
1
N
1
N
1
3
N
N
N
N
2
R
H
2
H
R
H
H
S
S
S
a-d
e
f
Scheme 1. Structures of different thione ligands. (a) R = CH3; N-methylimidazolidine-2-thione (MeImt),
(b) R = C2H5; N-ethylimidazolidine-2-thione (EtImt), (c) R = C3H7; N-propylimidazolidine-2-thione (PrImt),
(d) R = i-C3H7; N-(i-propyl)imidazolidine-2-thione (i-PrImt), (e) R = C2H5; N-ethyl-1,3-diazinane-2-thione
(EtDiaz) and (f) 1,3-Diazipane-2-thione (Diap).

Tetrakis(thione)platinum(II)
3513
2. Experimental
2.1. Chemicals and reagents
Potassium tetrachloridoplatinate(II), K2PtCl4, was purchased from Strem Chemicals, Inc.
Carbon disulfide (CS2) and diamines i.e. N-methyl-1,2-diaminoethane, N-ethyl-1,2-di-
aminoethane, N-propyl-1,2-diaminoethane, and N-isopropyl-1,2-diaminoethane, N-ethyl-
1,3-diaminopropane, 1,4-diaminobutane, were obtained from Sigma Aldrich. Dulbecco’s
modified eagle medium (DMEM), (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide) (MTT), DMSO and deuterated solvents were also obtained from Sigma Aldrich
Chemical Co. All other solvents were obtained from Fluka Chemical Co., and used without
purification.
2.2. Synthesis of the compounds
2.2.1. Thione ligands. The thione ligands were synthesized using a procedure given in the
literature [15, 16] by the reaction of carbon disulfide (CS2) with diamines in diethyl ether.
The resultant mixture was then refluxed at 100–110 °C for 2–3 h. The clear yellow product
was recrystallized from methanol.
2.2.2. General procedure for the synthesis of [Pt(thione)4]Cl2 complexes 1–6. K2PtCl4
(0.500 mmol) in 3.0 mL of water and thione (2.00 mmol) in 25.0 mL hot water were mixed
and refluxed for 4 h. A yellow solution was finally obtained. It was filtered while hot. The
solvent was evaporated. Quality yellow-orange crystals of 1 suitable for X-ray diffraction
were obtained by slow evaporation of the solvent. The CHNS data, melting/decomposition
points, and % yield of the synthesized complexes are presented below:
Complex 1: [Pt(MeImt)4]Cl2·2H2O: C 24.91 (25.06), H 4.61 (4.73), N 14.51 (14.62), S
16.36 (16.73) decomposition point 262 °C, and yield 58.9%; Complex 2: [Pt(EtImt)4]Cl2: C
30.56 (30.53), H 5.01 (5.12), N 14.46 (14.24), S 16.47 (16.30); decomposition point
225 °C and yield 64.3%; Complex 3: [Pt(PrImt)4]Cl2: C 33.98 (34.20), H 5.40 (5.47), N
13.35 (13.30), S 12.34 (12.22); decomposition point 106 °C and yield 89.3%; Complex 4:
[Pt(i-PrImt)4]Cl2: C 34.22 (34.20), H 5.33 (5.47), N 13.21 (13.30), S 12.27 (12.22); melting
point 145 °C and yield 92.5%; Complex 5: [Pt(EtDiaz)4]Cl2: C 33.80 (34.19), H 5.82
(5.74), N 13.10 (13.29), S 12.24 (12.22); melting point 113 °C and yield 52.5%; Complex
6: [Pt(Diap)4]Cl2: C 30.27 (30.53), H 5.22 (5.12), N 14.13 (14.24), S 16.12 (16.30);
decomposition 285 °C and yield 35.3%.
2.2.3. Synthesis of [Pt(iPrImt)4](NO3)2∙0.6(H2O) (7). 168.8 mg (1.000 mmol) of AgNO3
was added to solution containing 150.06 mg (0.500 mmol) of K2PtCl4 in 10.0 mL water
and stirred for 24 h in the dark at room temperature, then filtered. 288.2 mg (2.000 mmol)
of N-iPropyl-Imt dissolved in 10.0 mL methanol was added to the filtrate. The brown solu-
tion was filtered after stirring for 3 h and the filtrate was kept at room temperature for evap-
oration to afford X-ray quality crystals. Complex 7: [Pt(iPrImt)4](NO3)2·0.6(H2O): C 31.04
(31.78), H 5.18 (5.48), N 15.57 (15.44), S 13.99 (14.14); melting point 119 °C and yield
42.9%.

3514
A. Zainelabdeen A. Mustafa et al.
2.3. Stability and solubility of 1–7
1
Complexes 1, 5, and 6 were dissolved in DMSO-d6 and their H NMR spectra were mea-
sured. The extent of decomposition over time was determined by comparing the NMR spec-
tra collected after 1, 6, 12, 24, 48, and 72 h. No significant change in the chemical shifts
1
and the splitting patterns of 1 and 2 was observed in their time dependent H NMR spectra.
Complex 1 was moderately soluble in CDCl3 but completely soluble in DMSO and DMF.
Complexes 2–7 were completely soluble in polar organic solvents i.e. CDCl3, DMSO, and
DMF.
2.4. Spectroscopic and other characterization methods
The solid-state FT-IR spectra of thione ligands and their corresponding tetrakis(thione)
platinum(II) chloride or nitrate complexes (1–7) were recorded on a Nicolet 6700 FTIR
1
spectrometer using KBr pellets from 4000 to 400 cm−1. H NMR spectra were obtained
on a Jeol JNM-LA 500 NMR spectrometer operating at a frequency of 500.00 MHz.
13C NMR spectra were obtained at the frequency of 125.65 MHz with 1H broadband
decoupling at 298 K. The spectral conditions were: 32 k data points, 0.967 s acquisi-
tion time, 1.00 or 30.00 s pulse delay, and 45° pulse angle. Elemental analyses for the
platinum(II) thione complexes were performed on a Perkin Elmer 2400 Series II
CHNS/O Analyzer.
2.5. X-ray diffraction analysis
For 1, the X-ray diffraction data were recorded on a Bruker-Axs Smart Apex system
equipped with graphite monochromated MoKα radiation (λ = 0.71073 Å). The data were
collected using SMART [17]. The data integration was performed using SAINT [18]. An
empirical absorption correction was carried out using SADABS [19]. The structure was
solved with direct methods and refined by full-matrix least-squares based on F2 using the
structure determination package SHELXTL [20] based on SHELX 97 [21]. Graphics were
generated using ORTEP-3 [22] and Mercury [23]. With the help of a riding model, H-atoms
other than those of the water molecules were included at calculated positions. Nitrogens
belonging to NH groups were assumed to have sp2 hybridization. The hydrogens of the
water molecules could not be located.
For 7, the intensity data were collected at 173 K (−100 °C) on a Stoe Mark II-Image
Plate Diffraction System [24] equipped with a two-circle goniometer and using MoKα gra-
phite monochromated radiation (λ = 0.71073 Å). The structure was solved by direct methods
with SHELXS-2014 [21]. The refinement and all further calculations were carried out with
SHELXL-2014 [21]. The hydrogens were either located from Fourier difference maps and
freely refined or included in calculated positions and treated as riding using SHELXL
default parameters. The non-H atoms were refined anisotropically using weighted full-ma-
trix least-squares on F2. Empirical or multiscan absorption corrections were applied using
the MULSCANABS routines in PLATON [25]. A summary of crystal data and refinement
details for 1 and 7 are given in table 1.

Tetrakis(thione)platinum(II)
Table 1. Crystal and structure refinement data for 1 and 7.
3515
Parameter
1
7
CCDC deposit no.
Empirical formula
Formula weight
Temperature (K)
Wavelength (Å)
Crystal system
Space group
Unit cell dimensions
a (Å)
902,467
C16H36Cl2N8O2PtS4
766.76
1,008,031
C24H49.20N10O6.60PtS4
906.86
173(2)
0.71073
296(2)
0.71073
Triclinic
P-1
Tetragonal
P43212
9.011(2)
9.424(2)
9.627(2)
92.275(4)
11.608(3)
11.608(3)
27.182(1)
90
b (Å)
c (Å)
α (°)
β (°)
99.333(4)
90
γ (°)
116.185(3)
718.2(3)
1
1.773
5.39
90
3662.7(2)
4
1.645
4.11
Volume (Å3)
Z
Calcd density (g cm−3
)
Absorp. coefficient (mm−1
F(0 0 0)
)
380
1832
Crystal size (mm)
θ range (°)
Limiting indices
0.27 × 0.22 × 0.15
2.16–28.37
−12 ≤ h ≤ 11
−12 ≤ k ≤ 12
−12 ≤ l ≤ 12
Tmin = 0.3239, Tmax = 0.4986
3552/0/153
1.041
0.45 × 0.35 × 0.20
1.9–26.1
−14 ≤ h ≤ 14
−14 ≤ k ≤ 13
−32 ≤ l ≤ 33
Tmin = 0.7681, Tmax = 1.0000
3457/5/230
0.875
Max and min transmission
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2σ(I)]
R indices (all data)
R1 = 0.0255, wR2 = 0.0543
R1 = 0.0193, wR2 = 0.0545
1.310 and −0.842
R1 = 0.0153, wR2 = 0.0265
R1 = 0.0259, wR2 = 0.0269
0.34 and −0.75
Largest diff. peak and hole (eÅ−3
)
2.6. MMT assay for in vitro cytotoxic studies of [Pt(thione)4]Cl2 compounds against a
panel of cancer cell lines
In the present study, [Pt(thione)4]Cl2 complexes 1–7 were tested for their in vitro cyto-
toxicity against MCF7 (human breast cancer), HCT15 (human colon adenocarcinoma),
HeLa (human cervical cancer), and A549 (human lung carcinoma) cell lines as reported
[26]. The cells were seeded at 3 × 103 cells/well in 100 μL DMEM containing 10% fetal
bovine serum (FBS) in a 96-well tissue culture plate and incubated for 72 h at 37 °C, 5%
CO2 in air, and 90% relative humidity in a CO2 incubator. After incubation, 100 μL of 50,
25, 12.5, and 6.25 μM solutions of platinum(II) complexes, prepared in DMEM, were
added to the cells and the cultures were incubated for 24 h. The medium of wells was dis-
carded and 100 μL DMEM containing MTT (0.5 mg mL−1) was added to the wells and
incubated in a CO2 incubator at 37 °C in the dark for 4 h. After incubation, a purple for-
mazan produced in the cells appeared as dark crystals in the bottom of the wells. The cul-
ture medium was discarded from each well carefully to prevent disruption of the monolayer
and 100 μL of DMSO was added in each well. The solution in the wells was thoroughly
mixed to dissolve the formazan crystals which produce a purple solution. The absorbance
of the 96 well-plates was taken at 570 nm with a Labsystems Multiskan EX ELISA reader
against a reagent blank. The experimental results are presented as micro-mole concentration
of 50% cell growth inhibition (IC50) of each drug. The MTT assay was performed in three
independent experiments, each in triplicate.

3516
A. Zainelabdeen A. Mustafa et al.
3. Results and discussion
3.1. FT-IR spectroscopic characterization
The most important selected FT-IR frequencies are quoted in table 2. As mentioned by many
authors, the assignment of the thioamide absorptions of free thiones and their related com-
pounds is not straight forward, due to strong coupling between thiocarbonyl absorption and
various bond absorptions in the fingerprint region of the FTIR spectrum [27–30]. Neverthe-
less, a strong and broad band at 1400–1600 cm−1 appears for all the thione ligands and their
related complexes. Based on the data of previous literature, this band must be due to (N–H)
deformation and (N–C–N) antisymmetric stretching. This band is often split and significantly
shifted to higher frequency upon complexation; this is an indication of increase in the double
bond character of the C–N bond due to coordination with sulfur [29–31]. The band observed
at 3220–3300 cm−1 for most of the thione ligands and their related complexes is directly
assigned for N–H stretching vibrations [27–30, 32]. This band shifts to higher frequencies
for most of the platinum(II) complexes due to increase in double bond character, which also
supports the idea of coordination with the sulfur of thiocarbonyl in the thione form. The
assignment of thiocarbonyl frequencies is the most difficult part in the FTIR spectra because
it strongly couples with other bonds within the molecule and gives many bands in the finger-
print region. Many absorption bands in the FTIR spectrum of the free thiones, for instance
MeImt: 1236, 1111, 957, 670, 637, 612, and 516 cm−1, have shifted to lower wave number
with not more than 21 cm−1 in its related corresponding complex, and could be assigned to
thiocarbonyl frequencies [28]. The same pattern of this shift has been noticed for most of the
platinum(II) complexes which indicate the presence of the Pt-S bond. Finally, it seems
appropriate to obtain more definitive evidence of the coordination site through NMR
spectroscopy and X-ray crystallography, discussed in the forthcoming parts.
3.2. Solution and solid-state NMR characterization
1
The H NMR chemical shifts of the free thione ligands and their corresponding complexes
were studied in 50 : 50 v/v ratio of a mixture of CDCl3 and DMSO solvents, except 5 which
1
was studied in CDCl3. The H NMR solution-state data are given in table 3.
Table 2. Selected mid-FTIR frequencies, υ(cm−1) for tetra-
kis(thione)Pt(II) complexes (1–7).
Compound
υ(N–H) (cm−1
)
υ(C=S) (cm−1
)
MeImt
1
EtImt
2
PrImt
3
i-PrImt
4
EtDiaz
5
Diap
6
7
3200 m
3172 m
3188.2
3426 s
3205 m
3202 s
3208.2
3202 s
3220 m
3249 b
3214 s
3186 b
3209 s
515 s
503 s
514
497
514 s
507 sh
494, 526
507 sh
453 s, 509 sh
443 m, 512 sh
526
514 sh
489, 520 sh
Note: m = medium, b = broad, s = strong, sh = shoulder.

Tetrakis(thione)platinum(II)
3517
3
Table 3. 1H chemical shifts (ppm) and couplings JH–H (Hz) of the thiones and their tetrakis(thione)Pt(II) com-
plexes (1–7) in CDCl3.
Species
MeImta
N–H
H–4 or H–5
H–6
N–C1–H
N–C2–H
7.95
s
9.41
s
5.67
s
9.67
s
5.88
s
9.58
s
5.63
s
9.65
s
6.31
s
9.39
s
6.69
s
9.09
s
3.58
t(8.85)
3.78
t(8.90)
3.70
m
3.36
t(8.85)
3.58
t(9.30)
3.58
t(8.70)
3.56
m
2.93
s
3.00
s
3.67
m
3.67
m
3.56
m
3.46
t(7.48)
4.82
m
4.45
m
3.91
m(6.82)
3.76
br s
1a
EtImtb
1.20
t(7.00)
1.19
t(6.10)
2
3.71
m
PrImtb
3.71
t(8.70)
3.73
t(8.93)
3.61
t(7.05)
3.82
br s
3.34
t(5.35)
3.47
br s
3.58
m
1.64, 0.96d
m(7.31), t(7.18)
1.63, 0.95d
m(7.42), t(7.48)
1.19
3
3.58
t(9.40)
3.57
t(7.30)
3.73
t(8.25)
2.01
m(5.15)
2.00
br s
i-PrImtb
d(6.70)
1.20
d(6.10)
1.23
t(7.03)
1.24
4
EtDiazb
3.28
br s
3.43
br s
1.75
br s
1.71
br s
5
br s
Diapb
6c
3.26
br s
3.30
br s
1.75
br s
1.71
br s
7a
8.77
3.68
3.57
4.30
1.06
Note: s = singlet, d = doublet, t = triplet, m = multiplet, br = broad signal.
a1H resonances in DMSO.
b1H resonances of these thiones in DMSO are reported in literature [15, 16, 42].
c1H resonances of these complexes in 50 : 50 (v/v) mixture of CDCl3 and DMSO.
dN–C3–H.
The N–H protons of the coordinated thiones shift to higher frequency with respect to the
free thiones. This de-shielding of the N–H protons is an indication of relatively more double
bond character of the C–N bond upon coordination with Pt(II) center, consistent with the
coordination of thiourea or its derivatives [30, 33–35]. The appearance of an N–H signal is
a sign of coordinating with Pt(II) via the thione group.
H-4 of coordinated thiones is slightly downfield shifted in comparison to the free thiones
due to double-bond character of the C–N bond upon coordination with Pt(II) through sulfur
of the thiocarbonyl in thione ligands. There is no general trend observed in chemical shifts
of H-5 and H-6, owing to different alkyl (methyl, ethyl, n-propyl and iso-propyl) groups
attached to nitrogen of Imt containing ligands and different ring strains in R-Imt, EtDiaz,
and Diap.
The 13C NMR solution-state data are given in table 4. 13C NMR signal for the thiocar-
bonyl carbon in all the complexes shifted upfield by 8–11 ppm with respect to the free
ligands. This shift in thiocarbonyl carbon and NH proton signals is attributed to decrease in
C=S bond order and increase in C–N bond order upon complexation [30, 34].
The solid-state 13C NMR, data shown in table 5, indicate that complexation of Pt(II) with
the thiones resulted in shielding of thiocarbonyl carbons in the synthesized complexes by
8–10 ppm in comparison with their free thiones [36]. This also confirms that the ring form
of thione is retained in the complexes. The diap ligand and the corresponding complex (6)

3518
A. Zainelabdeen A. Mustafa et al.
Table 4. 13C chemical shifts (ppm) of the thiones and their tetrakis(thione)Pt(II) complexes (1–7) in CDCl3.
Species
C–2
C–4
C–5
C–6
N–C1
N–C2
MeImta
182.90
173.55
183.02
174.41
183.72
174.90
182.51
173.89
176.88
168.55
189.42
178.27
174.17
40.60
42.27
41.56
42.78
41.38
42.80
41.48
42.73
45.41
46.90
46.28
46.25
42.71
50.18
51.68
47.85
49.11
48.63
49.66
42.85
44.00
21.00
20.56
27.33
26.43
44.65
33.39
33.60
41.23
41.78
48.63
48.48
46.90
47.59
48.92
49.08
1a
EtImtb
12.02
12.44
2
PrImtb
20.44, 11.18d
20.60, 11.09d
19.32
3
i-PrImtb
4
19.68
11.99
12.76
EtDiazb
40.73
40.38
27.33
26.43
5
Diapb
6c
7
48.78
19.20
a13C resonances in DMSO.
b13C resonances of these thiones in DMSO are reported in literature [15, 16, 42].
c13C resonances of these complexes in 50 : 50 (v/v) mixture of CDCl3 and DMSO.
dN–C3.
Table 5. Solid-state 15N and 13C NMR chemical shifts (ppm) for free thione ligands and their tetrakis(thione)Pt
(II) complexes (1, 5, and 6).
Species
N–1
C–2
C–4
C–5
C–6
N–C1
N–C2
MeImt
1
EtDiaz
5
−275.29 − 277.41a
−269.03 − 279.95a
−271.38 − 74.85a
−258.24 − 270.75a
180.97
173.03
175.76
168.82
166.60
188.22
186.17
183.08
181.70
180.16
174.79
40.68
43.32
41.62
41.58
50.85
52.50
21.58
20.69
34.19
35.07 32.90b
12.77
46.68
48.40
46.68
48.40
12.73
Diap
−265.55
48.62
45.75
44.50
48.47
45.81
43.35
27.80
27.80
6
−259.12 − 263.62a
28.38
23.97
28.38
23.97
aResonance due to non-equivalent amino (–NH2) groups.
bResonance due to non-equivalent methyl (-CH3) groups.
showed three peaks in the thiocarbonyl region, attributed to different conformations of the
seven-membered ring. According to the solid-state 15N spectra (table 5), the nitrogens in
the synthesized complexes are 5–8 ppm de-shielded in comparison with their free ligands,
confirming the increase in C–N bond order upon complexation.
3.3. Crystal structure determination of 1 and 7
The X-ray structure of 1 is shown in figure 1 and the molecular packing in figure 1S (Sup-
plementary material). The platinum(II) is located on an inversion center and bound to sul-
furs of four N-methylimidazolidine-2-thione (MeImt) ligands in a distorted square planar
geometry. The Pt–S bond distances are 2.3243(9) and 2.3263(9) Å and the S–Pt–S bond
angle is 92.11(3)°. These values are in agreement with those reported for the complexes tet-
rakis(imidazolidine-2-thione)platinum(II) iodide [37] and tetrakis(thiourea-S)platinum(II)
chloride [38]. The SCN2 moieties of the two ligand molecules are essentially planar with
the bond lengths (d(S1–C1) = 1.705(4) Å, d(C1–N1) = 1.321(5) Å, d(C1–N2) = 1.468(5) Å),

Tetrakis(thione)platinum(II)
3519
Figure 1. ORTEP diagram of 1 showing the atomic labeling scheme. Displacement ellipsoids are drawn at the
30% probability level. The hydration water was omitted for clarity. (Pt1–S1, 2.3243(9) Å; Pt1–S2, 2.3263(9) Å;
S1–Pt1–S2, 92.11(3)°; S1–Pt1–S2i, 87.89(3)°). Symmetry codes: (i) −x, −y, −z; (ii) −1 − x, −1 − y, −z; (iii) 1 + x,
1 + y, z.
and (d(S2–C5) = 1.709(3) Å, d(C5–N3) = 1.313(5) Å, d(C5–N4) = 1.333(4) Å). The N–H
groups (N1-H1 and N3–H3) of two cis thione ligands are engaged in hydrogen bonding
with a common chloride giving a hydrogen bonding bridge [N–H⋯Cl⋯H–N] as shown in
figure 1.
The X-ray structure of 7 is shown in figure 2 and the molecular packing in figure 2S
(Supplementary material). Similar to 1, Pt(II) is bonded to four sulfurs, each belonging to
an N-isopropylimidazolidine-2-thione (iPrImt) ligand. The Pt–S bond lengths are 2.3035
(8)–2.3222(8) Å while the S–Pt–S bond angles are 89.34(4)°–92.17(4)°. The bond distances
are similar to those found for 1 and the related compound tetrakis(1-methyl-4-imidazoline-
2-thione)platinum(II) chloride dihydrate [39]. Similar to 1, the SCN2 moieties of the four
ligand molecules are also essentially planar with the S–C and C–N bond lengths of 1.706
(4)–1.709(4) Å and 1.321(4)–1.350(4) Å, respectively. However, the geometry around plat-
inum exhibits interesting features. The structure presents a deviation from the ideal square
planar geometry reminiscent of a bent see-saw distortion where the trans-sulfurs S1 and S1i
are displaced above the [PtS4] mean plane by 0.2603(9) Å whereas S2 and S2ii are dis-
placed below the mean plane by 0.2723(8) Å. For 7, the Pt coordination geometry can be
more precisely described by the τ4 (Tor4) parameter [40], as distorted square planar with a
τ4 value of 0.19 (the two largest angles in this four-coordinate species are 168.15(6)° and
165.38(5)°). In 1, the Pt coordination geometry, which is located on an inversion center, has
a perfect square planar geometry with τ4 = 0 (the two largest angles in this four-coordinate
species are both 180°). A closer look to hydrogen bonding interactions reveals that the
thione ligands of each of the two trans pairs are engaged in hydrogen bonding interactions
with one oxygen of the nitrate counter ion playing the role of a bridge between
them: [N–H⋯ONO2⋯H–N]. This H-bonding scheme gives two decametallacycles

3520
A. Zainelabdeen A. Mustafa et al.
Figure 2. ORTEP diagram of 7 showing the atomic labeling scheme. Displacement ellipsoids are drawn at the
30% probability level. The hydration water and hydrogens other than N–H were omitted for clarity. (Pt1–S1,
2.3035(8) Å; Pt1–S2, 2.3222(8) Å; S1–Pt1–S2, 92.17(4)°; S1–Pt1–S2i, 89.34(4)°). Symmetry codes: (i) y, x, −z;
(ii) −y + 1/2, x − 1/2, z − 1/4; (iii) x − 1/2, −y + 1/2, −z + 1/4.
[PtSCNH⋯O⋯HNCS] in which the trans-sulfurs are pushed out of the [PtS4] mean plane
(figure 3) and hence resulting in the minor see-saw distortion. Hydrogen-bond geometry (Å, °)
values of 7 are given in table 2S (Supplementary material).
1
2
A549 Cells
120
3
4
5
6
7
100
80
60
40
20
0
Cisplatin
Carboplatin
Concentration of compound in µM
Figure 3. Effect of concentration of 1–7, cisplatin and carboplatin in μM on the percentage viability of A549
cancer cells.

Tetrakis(thione)platinum(II)
3521
3.4. In vitro cytotoxicity of [Pt(thione)4]Cl2 compounds against a panel of human cancer
cell lines
The cytotoxicity of 1–7, cisplatin and carboplatin were evaluated in vitro against four
human cancers, A549 (human lung carcinoma), MCF7 (human breast cancer), HCT15 (hu-
man colon adenocarcinoma), and HeLa (human cervical cancer) cell lines. The exposure of
the cells to increasing concentrations of the complexes resulted in a dose-dependent cyto-
toxic effect. This cytotoxic effect was obtained by the stipulated increase in the concentra-
tions of the complexes and cisplatin against a fixed number of human cancer cells. The
IC50 concentration of the complexes, cisplatin and caboplatin for different human cell lines
was obtained from curves between the complex concentration and percentage viability of
the cells. Moreover, the effect of concentration of 1–7 in μM on the percentage viability of
A549, MCF7, HCT15, and HeLa cells has been shown graphically in figures 3–6, respec-
tively. The standard anticancer agents cisplatin and carboplatin were also included in the
bar graphs (figures 3–6) for comparison with 1–7.
The IC50 values of the complexes ranged between 36.93 and 137.16 μM for A549 cell
line as given in table 6. Complex 2 has in vitro cytotoxicity comparable to that of cisplatin
and almost two times better than that of carboplatin. Complexes 1 and 3 have in vitro
cytotoxicity between cisplatin and carboplatin. Complexes 4 and 7 have almost equal
cytotoxicity. The IC50 values of the complexes ranged between 11.40 and 120.86 μM for
MCF7 cell line as given in table 6. Complex 2 was two-fold better cytotoxic agent against
the MCF7 cell line than cisplatin with IC50 values 11.40 and 21.33 μM, respectively.
Complexes 1, 4, and 7 have almost the same cytotoxicities. The IC50 values of the com-
plexes ranged from 26.63 to 158.88 μM for HCT15 cell line as given in table 6. Complex 2
has in vitro cytotoxicity between cisplatin and carboplatin. The IC50 values of the
1
2
MCF7 Cells
120
3
4
5
6
7
100
80
60
40
20
0
Cisplatin
Carboplatin
Concentration of compound in µM
Figure 4. Effect of concentration of 1–7, cisplatin and carboplatin in μM on the percentage viability of MCF7
cancer cells.

3522
A. Zainelabdeen A. Mustafa et al.
1
2
HCT15 Cells
120
100
80
60
40
20
0
3
4
5
6
7
Cisplatin
Carboplatin
Concentration of compound in µM
Figure 5. Effect of concentration of 1–7, cisplatin and carboplatin in μM on the percentage viability of HCT15
cancer cells.
1
2
HeLa Cells
120
3
4
5
6
7
100
80
60
40
20
0
Cisplatin
Carboplatin
Concentration of compound in µM
Figure 6. Effect of concentration of 1–7, cisplatin and carboplatin in μM on the percentage viability of HeLa
cells.

Tetrakis(thione)platinum(II)
3523
Table 6. In vitro cytotoxic data of 1–7, cisplatin and carboplatin against A549,
MCF7, HCT15, and HeLa cancer cell lines.
IC50 SEMa
Compound
A549
MCF7
HCT15
HeLa
1
2
3
4
5
6
7
55
37
59
1
75
11
63
78
95
121
74
21
2
147
42
96
122
159
108
116
27
2
2
2
2
3
2
2
1
2
142
79
133
95
166
92
100.
18
2
2
2
1
2
2
2
1
1
1
3
1
2
2
1
2
2
1
2
1
2
3
1
2
2
86
137
119
84
37
70
Cisplatin
Carboplatin
53
63
55
aLimit of errors is given in SEM as standard deviations determined from at least three indepen-
dent experiments.
complexes 1–7 were 18.07–166.41 μM for HeLa cell line as given in table 6. Complexes
1–7 were not better than cisplatin and carboplatin.
The in vitro cytotoxicity of our complexes against HCT15 and HeLa cell lines was less
than the parent drug cisplatin. These results are consistent with a significant selective cyto-
toxicity of 2 against particular cancer cell lines and its tendency to undergo ligand exchange
with biomolecules like proteins and DNA [41–43].
4. Conclusion
A series of complexes, [Pt(thione)4]X2 (X− = Cl−, NO3À), were synthesized and fully
characterized using analytical techniques and spectroscopic methods. NMR as well as X-ray
crystallography data confirmed that Pt(II) center is bonded to the thione ligands through sul-
fur. Hydrogen bonding interactions in 7 induce a bent see-saw distortion relative to ideal
square planar geometry. In vitro cytotoxicity studies showed that [Pt(EtImt)4]Cl2 (2) is the
most effective and two-fold better cytotoxic agent than cisplatin against MCF7 (human
breast cancer) cell.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This work was financially supported by the King Fahd University of Petroleum & Minerals (KFUPM) for the work
through project No. [IN131018].
Supplemental data
Supplemental data for this article can be accessed here http://dx.doi.10.1080/00958972.2015.1072175.

3524
A. Zainelabdeen A. Mustafa et al.
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