Synthesis, Structural Characterization and Anti-Proliferative Activity of (κ1-C)- and (κ2-C,S)-PtII Complexes Bearing Thioether-Functionalized N-Heterocyclic Carbenes

Article abstract of DOI:10.1002/ejic.201701183

A series of platinum(II) complexes bearing thioether-functionalized N-heterocyclic carbene ligands have been synthesized and characterized. The hemilabile and reversible character (i.e., coordination/decoordination) of the sulfur moiety in these platinum complexes has been established by ligand displacement (addition of pyridine) and ligand abstraction (on silica gel). The chemical reactivity of these complexes with glutathione has been investigated by NMR spectroscopy and mass spectrometry. Their biological activity towards various human cancer cells has been studied; these S-functionalized NHC–platinum complexes displayed moderate cytotoxicity.

Full text of DOI:10.1002/ejic.201701183

A Journal of
Accepted Article
Title: Synthesis, structural characterisation and anti-proliferative activity
of (κ1-C)- and (κ2-C,S)-Pt(II) complexes bearing thioether-
functionalized N-heterocyclic carbenes.
Authors: Julien EGLY, Mathilde BOUCHE, Weighang CHEN, Aline
MAISSE-FRANCOIS, Thierry ACHARD, and Stéphane
Bellemin-Laponnaz
This manuscript has been accepted after peer review and appears as an
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To be cited as: Eur. J. Inorg. Chem. 10.1002/ejic.201701183
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10.1002/ejic.201701183
European Journal of Inorganic Chemistry
FULL PAPER
Synthesis, structural characterisation and anti-proliferative
activity of (κ1-C)- and (κ2-C,S)-Pt(II) complexes bearing thioether-
functionalized N-heterocyclic carbenes
Julien Egly, Mathilde Bouché, Weighang Chen, Aline Maisse-François, Thierry Achard,* and Stéphane
Bellemin-Laponnaz*[a]
Abstract: A series of platinum(II) complexes, bearing thioether-
functionalized N-heterocyclic carbene ligands has been synthesized
and characterized. The hemilabile and reversible character (i.e.
coordination/decoordination) of the sulfur moiety on these platinum
complexes has been established by ligand displacement (addition of
pyridine) or ligand abstraction (on silica gel). The chemical reactivity
with glutathione has been investigated by NMR and mass
spectrometry. Biological activities on various human cancer cells
have been studied and these S-functionalized NHC-platinum
complexes displayed moderate cytotoxicity activity.
death.[7b] In this purpose, cytoprotective sulfur-containing
reagents/ligands have been largely investigated to reduce side
effects.[9] For example, Borch and co-workers showed the
chemoprotective effect of diethyldithiocarbamate sodium salt
(NaDEDT) during cisplatin chemotherapeutic treatment.[10] The
particularity of this ligand is to selectively remove platinum from
thiol functionalities of different proteins but not from nucleotides
involved in Pt-DNA adducts. Lately, platinum-drugs that include
in their coordination sphere a S-donor ligand -that may act as
chemoprotectant group- have been successfully investigated in
chemotherapy and some of them showed promising results in
clinical trials.[11] Oxaliplatin-like complexes containing bidentate
hybrid
N,S
ligand,
such
as
dichloro(2-
Introduction
methylthiomethylpyridine)Pt(II), were found to be promising
cytotoxic agents.[12,13]
Despite all these years spent, cisplatin compound still remains
the bestseller drug to fight several types of cancer (i.e. colorectal,
head neck, lung, non-Hodgkin lymphoma, ovarian and testicular
cancer).[1] Indeed, more than 50% of cancer tumours are
currently cured with platinum-based drugs alone or with
complementary treatment.[2,3] This includes few new platinum
drugs (e.g. carboplatin, oxaliplatin) but their number is small
compared to the thousands of Pt compound biologically tested
so far.[4] Moreover, the main disadvantage of their therapeutic
efficacy is the serious side effects and the potential emergence
of cellular resistance.[5] Additionally, the undesired accumulation
of platinum in organs is responsible of high level of
nephrotoxicity, neurotoxicity and ototoxicity.[6] These toxicities
are also amplified by the great affinity of platinum for sulfur
containing molecule (cysteine, methionine, glutathione,
metallothionein and albumin), which are highly abundant in the
human body.[7]
The necessity of discovering new metal-drugs with improved
stability in physiological media is of importance. In this context,
several groups highlighted the interest of N-heterocyclic ligands
(NHCs) as new scaffold for drug design.[14] Various benefits
were observed while using NHC ligands including: (i) the strong
carbene–metal σ-bond enhances the stability of the NHC-metal
complex, essential condition in physiological media, (ii) the
stereoelectronic properties of the NHC may be finely tuned and
(iii) high modularity is possible via simple synthetic pathways
thus allowing the quick development of libraries of metal-NHC
compounds.[15] The presence of the NHC also has a dramatic
impact on the mode of action since several mechanistic studies
suggest concurrent cell death mechanisms involving for example
mitochondria
in
addition
to
classical cisplatin-based
mechanisms.[16] Platinum NHC complexes of general formula
[(NHC)PtX2L] (X = halogen, L = nitrogen-containing ligand) have
been highlighted as valuable candidate to fight cancer by
Marinetti and co-workers in 2010.[17] Since then, numerous
groups including us extended this family of compounds by
introducing new substituents or functions through new synthetic
strategies, with the aim of increasing efficiency, selectivity and
reducing side effects of such Pt-NHC complexes.[18]
Platinum-based drugs exert cytotoxic effects by binding the DNA
through various mechanisms.[8] However, on the long way to first
penetrate the targeted cell and then the nucleus, Pt complexes
will inexorably meet potentially reactive functions including
various sulfur-containing molecules.[7a] Consequently only a
small quantity of Pt will finally reach the goal and induce cell
[a]
J. Egly, M. Bouché, W. Chen, A. Maisse-François, T. Achard, S.
Bellemin-Laponnaz
Institut de Physique et Chimie des Matériaux de Strasbourg
CNRS-Université de Strasbourg UMR7504
R'
S
N
N
R
C
Pt
L
23 rue du Loess BP 43, 67034 Strasbourg, France.
X
X
http://www.ipcms.unistra.fr
E-mail : bellemin@unistra.fr, achard@ipcms.unistra.fr
Chemoprotective effect toward
S-containing biological molecules?
Supporting information for this article is given via a link at the end of
the document.
Scheme 1. General structure of the NHC Pt compounds.
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10.1002/ejic.201701183
European Journal of Inorganic Chemistry
FULL PAPER
Interestingly, sulfur-containing NHC complexes have not been
the subject of study in medicinal chemistry. Nevertheless, sulfur-
functionalized NHC ligands (S-NHC) and their corresponding
transition metal complexes have become a dynamic field of
investigation. These studies are principally focused on their
coordination chemistry and their use in catalysis and nothing is
yet described for their use as a bioactive molecule.[19] In this
paper, we report on the synthesis, characterisation and
preliminary results on the biological effects of Pt complexes that
contain thioether-functionalized NHCs (Scheme 1). These ligand
systems are expected to bind tightly the platinum centre to
stabilize the complex and on the other hand the labile thioether
group is expected to provide a chemoprotective effect toward
sulfur sites in biological media.
The analytical data (IR, HRMS, 1H NMR) advocate for the
coordination of NHC in a monodentate fashion. Indeed in the H
1
NMR spectrum both the methylene protons in α-position to N
and S atom showed two sets of triplet signals in the vicinity of
3.3 and 4.4 ppm respectively, which is similar to those observed
for free imidazolium salts 2a-e in the range of 3.1 and 4.5 ppm.
The structure of the pyridine complex was lately confirmed by X-
ray diffraction studies (vide infra).
However, a meticulous analysis by proton NMR of the crude
product before purification by column chromatography revealed
the presence of a second platinum compound as minor product
which was assigned as the (NHC)PtI2 complex 4 with the
carbene acting as a bidentate ligand. Indeed, 1H NMR spectrum
shows noticeable changes in signals of the thioether chain
bound to the NHC and the complexity of the coupling pattern for
both N-CH2 and S-CH2 protons suggests the coordination of the
sulfur atom which renders those protons diastereotopic (see SI).
The κ2-C,S coordination mode was confirmed by X-ray analysis
on suitable crystal (vide infra). The crude product ratio between
3 and 4 was 90:10 with the smallest thioether group (i.e., Et)
whereas all other crudes contained less than 5 % of the minor
compound 4.
Results and Discussion
Synthesis of proligands 2a-e and the corresponding platinum
complexes
Several new S-functionalized imidazolium salts 2a-d have been
prepared starting from benzyl imidazole as displayed in Scheme
2. Reaction of benzyl imidazole in 1,2-dibromoethane at 85 °C
R
Ph
S
N
N
R
I
S
K2CO3, KI
C
Pt
N
N
N
gave the corresponding imidazolium salt precursor
1 in
C Pt
I
2a-e + PtCl2
I
I
+
quantitative yield, which was next easily and quantitatively
functionalized by reacting with the desired thiolate. The phenyl
thioether imidazolium 2e was synthesized in one step according
to standard procedure. [20]
Pyridine, Δ
Ph
Conv. > 95%
4a-e
3a-e
The NHC-platinum(II) complexes were readily prepared in a
one-step process by reaction of the azolium precursor 2a-e in
the presence of one equivalent of PtCl2 and excess of KI and
K2CO3 in dry pyridine at 100 °C overnight (Scheme 3).[18g]
[(NHC)PtI2(pyridine)] complexes were obtained in moderate to
good yield (47-71%) after purification by chromatography on
silica gel. The formation of the (NHC)Pt-pyridine complexes 3a-e
was easily established by the disappearance of the resonances
Product ratio (crude)
R = Et
90
:
:
10
<5
R = Cy, tBu, Ad, Ph
>95
Isolated yield:[a]
R = Et
Cy
47%
63%
70%
71%
60%
26%
1
20%
<2%
<2%
<2%
assigned to the 2H-imidazolium proton in the H NMR spectrum
tBu
Ad
Ph
and also by the appearance of a signal at δ 135–138 ppm in the
13C NMR spectrum, which was assigned as the carbenic carbon.
Scheme 3. Synthesis of platinum thioether-functionalized NHC complexes 3-4
RSNa
[a] isolated yield after purification by column chromatography on silica gel.
Br(CH2)2Br
N
N
N
N
Bn
Bn
CH3CN, R.T.
(quant.)
Br
85°C, 16 h
(quant.)
SR
Br
Br
2a R = Et
1
Interestingly, during the purification step, we have noticed that
platinum complexes 3 partially decompose into complex 4 over
silica. Indeed, the pyridine molecule is known to interact with
acidic sites on the silica surface which occurs by a proton
transfer from silanol to pyridine to form pyridinium species.[21] In
our case, this protonation process coupled to the chelate effect
might favour the coordination of the sulfur atom, which removes
the pyridine from the metal center. The adsorption of pyridine
through the silica gel makes then its displacement irreversible
preventing any new coordination onto the platinum center. Thus,
it was possible to isolate complexes 4a and 4b in 20-26% yield
2b
2c
2d
Cy
tBu
Ad
N
N
Cl
S
N
N
Bn
S
150°C, 3 h, neat
(quant.)
Cl
2e
Scheme 2. Synthesis of imidazolium precursors 2a-e.
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10.1002/ejic.201701183
European Journal of Inorganic Chemistry
FULL PAPER
as a white solid (Scheme 3). Both compounds were found to be
poorly soluble in either CDCl3 or DMSO-d6 and only moderately
soluble in acetone and dichloromethane. In the 13C NMR spectra
of the complexes, the resonance of the carbenic carbon is
observed between 147 and 148 ppm which are in good
agreement with literature values.[22] Here, the bulkiness of the
thioether group plays a crucial role in the sulfur coordination to a
metal center. In fact, larger groups, most likely because of their
steric hindrance on sulfur atom, are less able to form the chelate
in contrast to more flexible or smaller groups such as Cy or Et.
Curiously, after several hours in CD2Cl2, the solution of pure
complexes 4a (R = Et) evolved into a 1:1 mixture of complex 4a
awaited coordination square-planar geometry where the pyridine
ligand is trans to the N-heterocyclic carbene ligand. Both
carbene-platinum and platinum-pyridine bond lengths are in
accordance with literature reports with 1.985(10) and 2.6041(8)
18f-h, 18k-n, 24]
Å respectively.[18d,
The two iodide ligands adopt a
trans geometry (I-Pt-I angle of 177.30°) and point
perpendicularly toward the NHC ligand plane [Pt(1)-C(1)-N(1)-
C(4), -0.3(14)°] or [Pt(1)-C(1)-N(1)-C(2), -179.8(8)°], a classical
[18d, 18f-h, 18k-n,
feature that has been observed in such complexes.
24]
For complex 4a, the coordination geometry at the platinum
center is distorted square planar. Coordination of the sulfur onto
and a new platinum specie as evidence by its 1H and 13C spectra. the metal generated a boat-shaped (Pt-C-N-C-C-S) chelate ring.
1
The H NMR experiment performed after this time shows clearly
new set of visible signals in several regions of the spectrum for
CHimid (doublet at 6.74 ppm, J = 2 Hz), CH2Benz (singlet at 5.54
ppm) and CH3 (triplet at 1.33 ppm J = 7 Hz) protons. It has been
suggested that platinum thioether-functionalized NHC ligands
exhibit dynamic hemilabile behaviour with multiple species
The Ccarbene–Pt bond length [Pt(1)-C(1) 1.976(12) Å] is within the
range for such NHC–Pt(II) complexes. The Pt-S (Pt(1)-S(1)
2.290(3) Å) bond length is consistent with the average bond
length of 2.27 Å reported by Hyun for various S-NHC platinum
complexes derived from benzimidazole.[22] The strong trans
influence of the NHC ligand is reflected in the lengthening of the
Pt–I distance in trans disposition to the carbene ligand
compared to the Pt–I distance trans to the S donor atom
[2.6534(9) vs. 2.6127(9) Å].
coexisting in solution.[22] This character could involve
a
reversible de- and recoordination of the sulfur donor in a
hemilabile fashion. The decoordination would result in the
formation of a formally unsaturated metal center, which could be
stabilized by dimerization. Additionally, the inversion at the sulfur
atom could flip of the six-membered ring providing access to
other chair- or boat-like conformations. Finally, the situation
could be even more complicated due to the fact that the
thioether function becomes a chiral center upon coordination.
Consequently, it is not surprising to observe the formation of a
new species after a few hours in CD2Cl2 solution for complex 4a.
X-ray diffraction studies of complexes 3c and 4a.
Figure 2. Molecular structure of (κ2-C,S) complex 4a. Selected bond lengths
[Å] and angles [°]: Pt(1)-C(1): 1.976(12); Pt(1)-I(1): 2.6127(9); Pt(1)-I(2):
2.6534(9); Pt(1)-S(1): 2.290(3); C(1)-Pt(1)-S(1): 86.8(4); C(1)-Pt(1)-I(1):
91.5(3); C(1)-Pt(1)-I(2): 176.0(4); S(1)-Pt(1)-I(1): 174.20(10); S(1)-Pt(1)-I(2):
90.39(8); I(1)-Pt(1)-I(2): 91.63(3); N(2)-C(11)-C(12)-S(1): 52.3(13).
Figure 1. Molecular structure of the pyridine complex 3c. Selected bond
lengths [Å] and angles [°]: Pt(1)- C(1): 1.985(10); Pt(1)- I(1): 2.6041(8); Pt(1)-
I(2): 2.6100(8); Pt(1)-N(3): 2.097(8); C(1)-Pt(1)-I(1): 90.0(3); C(1)-Pt(1)-I(2):
89.3(3); I(1)-Pt(1)-I(2): 177.30(2); C(1)-Pt(1)-N(3): 179.1(4); I(2)-Pt(1)-C(1)-
N(1): -71.14; I(2)-Pt(1)-N(3)-C(21): 60.16.
Reactivity of the platinum NHC complexes
The formation of the chelate from the pyridine complex
demonstrates that the thioether moiety is able to displace one
ligand from the coordination sphere. In order to get more insight
into the labile character of the thioether, complex 4b was
dissolved in d5-pyridine at 20 °C. The compound was
quantitatively converted back to 3b in less than 10 min as
deduced from NMR data, (Scheme 4 and Fig S2) and no more
evolution was then observed.[25] Interestingly, the bidentate
complex 4b could be regenerated in presence of SiO2 in a
By slow diffusion of diethyl ether into a chloroform solution of
complex 3c and by slow evaporation of a dichloromethane
solution of 4a, single crystals have been obtained and the
molecular structures have been elucidated by X-ray diffraction
analysis (Figures 1 and 2).[23] Pyridine complex 3c displays the
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10.1002/ejic.201701183
European Journal of Inorganic Chemistry
FULL PAPER
dichloromethane solution stirred for 24h; then, it is quantitatively
recovered after filtration.
from the NHC ring were also shifted downfield. At this stage it is
difficult to conclude about which platinum species are present in
solution since several scenarios could occur.[27a] It is noteworthy
that no more evolution in the crude mixture was observed for the
sample even after 72h of experiment.
Interestingly, in the presence of an excess of glutathione (10
equiv.) the resulting H1 NMR seems cleaner than previously
observed with 1 equivalent (see SI, Fig. S5). Analysis of the
resonance in the region of the cys-α protons suggests the
formation of a new platinum species. A new NH gly-proton signal
appeared as small doublet at 8.31 ppm, slightly deshielded
compared to free GSH in solution (8.21 ppm). As observed
previously, the two benzylic proton signals of the NHC are
transformed in a large multiplet between 5.2 and 5.8 ppm (see
SI, Fig. S6). Again, after 72h of experiment no notable evolution
was observed for the sample.
Cy
Ph
Cy
I
S
N
N
S
pyridine
R.T., 10 min
(quant.)
C
Pt
N
N
N
C
Pt
I
I
I
Ph
4b
3b
SiO2, CH2Cl2
R.T., 24 h
Scheme 4. Experiment on the lability of the Cy-S group in the presence of
pyridine.
MALDI-TOF experiments were conducted on 4b/GSH (1/10
equiv) reaction in DMSO-d6 after 72 hours of reaction, the mass
spectrum display three peaks at m/z 1217.05, 1293.88 and
1473.09 (see SI, Fig. S7-10). Assignment was confirmed by
isotopic distribution analysis (see SI, Fig. S11). The fragment
ions correspond to a single species which is most likely a
dinuclear complex of general formula [{(NHC)PtI}2(GSH)]+, thus
confirming the GSH/Pt interaction (eq 1). Altogether, the
analyses by NMR and mass spectrometry show that, despite the
presence of a labile thioether group onto the NHC ligand,
glutathione still displays a high affinity for the Pt center, most
likely to generate Pt-S thiolate bond.
Glutathione (GSH), proteins and peptides that contain sulfur
residue such as methionine or cysteine are considered as a
major inactivation step for platinum-based drugs.[7a, 26] Numerous
works have been done on its reaction with cisplatin showing in
most cases its coordination to the complex through the thiol
function.[27] The behaviour of the S,C chelate complex 4b in
presence of GSH was investigated by 1H NMR in deuterated
DMSO.[28] The platinum species was first dissolved in DMSO-d6
and then the desired quantity of GSH was added to the solution
and NMR spectra were recorded over the time. Interestingly,
GSH can act as a monodentate ligand binding the platinum
center via the cysteine thiolate but can also act as a bidentate
ligand by binding the platinum through both the thiol and one of
the amide nitrogen.[27d] Its ability allows the formation of a variety
of possible GS-Pt adducts. Moreover, the presence of DMSO
should increase the number of platinum species present in the
mixture, but since DMSO is known to be easily displaced from
the coordination sphere of platinum in the presence of a better
donor ligand,[29] it is envisioned that glutathione will do
(NHC)PtI2 + GSH
[(NHC)PtI]2(GSH)+
(eq 1)
4b
SH
O
β
O
O
H
β
α
γ
N
α
HO
N
OH
α
H
GSH =
NH2
O
The initial reaction with GSH (1 equiv) took place rapidly (<30
min) to form a mixture of several species. The signals for the NH
protons in the cysteine and glycine residues are shielded (8.35
and 8.23 ppm) with respect to free GSH (8.73 and 8.30 ppm,
see SI, Fig. S1),[30] and no residual signals of free GSH are
observed in this region (Fig. S3).
glutamic acid cysteine
(Glu) (Cys)
glycine
(Gly)
Antiproliferative effect
Both the chemical shift and the multiplicity of the cys-β protons
are impacted in presence of the platinum complex (Fig. S4).
Compared to free GSH the multiplet at 2.88 ppm may have
shifted in be obscured by the large residual pick of water; in the
same time the multiplet at 2.65 ppm seems to become a broad
singlet at 2.7 ppm which might indicate a very different magnetic
and chemical environment. In this region we observed as well a
multiplet that would correspond to degraded complex 4b in
presence of dmso
The signal at 4.35 ppm corresponding to cys-α proton in free
GSH was also shifted downfield, as well as the gly-α proton. The
overall shift of GSH protons and more particularly those of
cysteine residue advocate for coordination on the platinum
center through the sulfur atom. The signals of the two protons
The cytotoxicity of complexes 3 and 4 on cancer cells was
investigated on a panel of three human cancer cell lines namely
HCT116 (human colorectal adenocarcinoma), PC3 (human
prostate adenocarcinoma) and MCF7 (breast carcinoma). Half
inhibitory concentrations (IC50) induced by these compounds are
displayed in Table 1. Cisplatin was used as reference for the
studies.
Even though all determined IC50 values are higher than those
measured for cisplatin, complexes 3-4 showed antiproliferative
activities toward the three cell lines. The bulkiness of the
substituent attached to the sulfur atom was found to influence
the potency of the resulting complex. Increasing both the size
and the lipophilicity of the thioether group increased the
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10.1002/ejic.201701183
European Journal of Inorganic Chemistry
FULL PAPER
cytotoxicity effect of the compound. Effectively, phenyl and
adamantyl derivatives 3d and 3e showed the highest cytotoxic
activity (IC50 up to 16 µM, Entry 6) for this series which are
expected to promote greater cell uptake. These results are
consistent with previous studies on platinum bearing bidentate
O,S ligand.[32] The presence of adamantyl group so called
“lipophilic bullet” onto platinum complex is known to be beneficial
for cytotoxic activity.[33] This trend is verified in this platinum
complexes series as S-Ad complex 3d displayed better IC50
values than other alkyl groups.
the thioether moiety has been established by competition
experiments which discarded an excessive protective effect on
the platinum centre that could inhibit cytotoxic activity.
Accordingly, the protective effect of the thioether moiety was not
sufficiently robust to prevent the coordination of the GSH to the
platinum center. These complexes displayed moderate cytotoxic
activity although enhanced cytotoxicities were observed for more
lipophilic compounds, which are expected to be linked to greater
cellular uptake.
Surprisingly, the monodentate complex 3c containing the larger
and more lipophilic group S-tBu exhibited low cytotoxic activities
(IC50 > 100 µM) compared to smaller and less lipophilic S-Et
derivative 3a (Entries 1 and 3).
Experimental Section
The bidentate complex 4a displayed a poor cytotoxic activity
which is comparable to its corresponding monodentate
derivative (with the exception of HCT116; Entries 1 & 2). Its poor
cytotoxic activity does not appear to be related to the strength of
the Pt-S bond as shown by the competition experiment but more
surely might be due to low drug uptake induced by its low
solubility rather than unduly stability of the Pt-S bond. Overall,
the IC50 values do not vary massively, suggesting that the
compounds could induce their cytotoxic effect through similar
mechanisms.
Materials and methods. All manipulations were carried out using
standard Schlenk techniques unless stated otherwise. Reagents were
purchased from commercial chemical suppliers (mainly Acros, Aldrich,
Alfa Aesar, TCI Europe and Strem) and used without further purification.
Solvents were dried according to standard procedures. Pyridine
employed during complexation reactions was distilled over calcium
hydride and carefully stored under argon. Metal complexes were
1
synthesized using distilled solvents. H, 13C nuclear magnetic resonance
(NMR) spectra were recorded on a Bruker Avance 300 spectrometer. 13
C
assignments were confirmed when necessary with the use of DEPT-135
experiments. 1H and 13C-NMR spectra were referenced using the
residual solvent peak (CDCl3: δ H = 7.26 ppm; δ C = 77.16 ppm; CD2Cl: 2
δ H = 5.32 ppm; δ C = 53.84 ppm;DMSO-d6: δ H = 2.50 ppm; δ C =
39.52 ppm) at 295K. Chemical shifts δ are given in ppm whereas
coupling constants J are stated in Hertz (Hz). The following abbreviations
are used to classify the multiplicity of the observed signals: s = singlet, d
= doublet, t = triplet, q = quartet, quint = quintuplet, dd = doublet from
doublet, dt = doublet from triplet, m = complex multiplet or broad signal,
pyr = pyridine proton, imid = NHC alkene proton, Ar = aromatic protons.
Positive mode electrospray ionization mass spectra (ESI-MS) were
recorded on microTOF, Bruker Daltonics. Because of possible platinum
carbide formation during combustion, Pt complexes such as those
reported in this study are not easily amenable to accurate elemental
analysis. X-Ray diffraction studies were carried out by Dr. Corinne Bailly
at Institut de Chimie X-ray Facility of the University of Strasbourg. Crystal
data were collected at 173 K using a MoKα graphite monochromated (λ =
Table 1. Half inhibitory concentrations (IC50 in µM) of the selected compounds
against a range of cell lines.[a]
Entry - Complex - R
HCT116
63.2 ± 0.1
118 ± 6
MCF7
PC3
1
2
3
4
5
6
3a
4a
3b
3c
3d
3e
R = Et
R = Et
R = Cy
R = tBu
R = Ad
R = Ph
130 ± 20
104 ± 1
113 ± 9
161 ± 15
43.5 ± 0.4
110 ± 3
37.3 ± 2.5
100.7 ± 0.1
20 ± 2
58.3 ± 2.0
172 ± 46
52.4 ± 1.4
44.5 ± 3.1
4.2 ± 0.7
33.1 ± 3.7
23.6 ± 0.6
3.1 ± 0.2
0.71073 Å) radiation on
a Nonius KappaCCD diffractometer. The
16.6 ± 1.3
3.7 ± 0.1
structures were solved using direct methods with SHELXS97552 and
refined against F2 using the SHELXL97 software.[34] Non-hydrogen
atoms were refined anisotropically. Hydrogen atoms were generated
cisplatin
[a] After 72h of incubation; stock solutions in DMSO for all complexes; stock
solutions in H2O for cisplatin. MCF7 (breast carcinoma), HCT116 (colon
cancer cells), PC3 (prostate adenocarcinoma).
according to stereochemistry and refined using
a riding model in
SHELXL97. CCDC 1570177 (for 3c) to CCDC 1570178 (for 4a) contain
the supplementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic Data
Centre.
Conclusions
Synthesis of imidazolium salts precursors
A novel class of platinum(II) compounds based on bidentate
thioether-functionalized NHC ligands κ1-C or κ2-C,S coordinated
has been described and fully characterized. They have been
prepared based on a straightforward synthesis that requires only
three steps from the appropriate imidazole ring. Interestingly, the
steric hindrance on the sulfur atom strongly influences its
coordination mode to be monodentate κ1-C when R group is
large or bidentate κ2-C,S when R group is small. The lability of
1-benzyl-3-(2-bromoethyl)-1H-imidazol-3-ium bromide (1):
Precursor 1 was synthesized according to the procedure reported in
literature and all data correspond to previously reported material.[35]
A
mixture of 1-benzylimidazole (3 g, 0.037 mmol) and 1,2-dibromobutane
(40 mL) was heated at 85 °C for 15h. After cooling at room temperature,
two phases were observed. The excess of 1,2-dibromobutane is
removed under vacuum giving a white residue which was extracted with
40 ml of CH2Cl2 and filtered through celite. The solvent was removed to
This article is protected by copyright. All rights reserved.

10.1002/ejic.201701183
European Journal of Inorganic Chemistry
FULL PAPER
give an egg shell solid. Yield: 98%. 1H NMR (300MHz, DMSO-d6): δ 3.96
(t, J = 6 Hz, 2H, CH2Br), 4.64 (t, J = 6 Hz, 2H, NCH2), 5.48 (s, 2H, CH2),
7.4 (m, 5H, CHbenz), 7.87 (m, 2H, CHimid) and 9.4 (s, 1H, CHimid) ppm.
pressure to give an orange/brown oil. Yield: 98%. 1H NMR (300MHz,
CDCl3) : δ 1.28 (s, 9H, CH3), 3.09 (t, J = 6 Hz, 2H, CH2S), 4.57 (t, J = 6
Hz, 2H, NCH2), 5.56 (s, 2H, CH2), 7.2 (s, 1H, CHimid), 7.45-7.39 (m, 6H,
CHimid, CHbenz) and 10.79 (s, 1H, CHimid) ppm. 13C NMR (75MHz, CDCl3) :
δ 29 (CH2S), 26.3 (3xCH3), 43.7 (SC), 50.5 (PhCH2), 53.6 (NCH2), 121.4
(CHimid), 122.9 (CHimid), 129 (2xCHbenz), 129.6 (2xCHbenz), 129.7 (CHbenz),
1-benzyl-3-(2-(ethylthio)ethyl)-1H-imidazol-3-ium bromide (2a):
133 (Cbenz
) and 137.5 (CHimid) ppm. FTIR: ν max(pure, diamond
Precursor 1 (2 g, 5.8 mmol, 1 equiv) was dissolved in distillated
acetonitrile (60 mL). Sodium ethanethiolate (0.5 g, 5.8 mmol, 1 equiv)
was added, and stirring was continued for 15 hours at ambient
temperature under argon. After this time, the volatiles were removed
under reduced pressure. The solid residue was suspended in CH2Cl2 and
filtered through celite. Volatiles were removed under reduced pressure
and the resulting orange/brown oil is passed through a silica plug, first
with dichloromethane (to remove traces of unreacted thiolate) and then
with 90/10 DCM/MeOH mixture. The solvent was removed under
reduced pressure to give an orange/brown oil. Yield: 99%. δ 1H NMR
(300 MHz, CDCl3) 1.24 (t, J = 7.4 Hz, 3H), 2.62 (q, J = 7.4 Hz, 2H, CH2S),
3.06 (t, J = 6.3 Hz, 2H, CH2S), 4.61 (t, J = 6.3 Hz, 1H, NCH2), 5.54 (s, 2H,
NCH2), 7.13 (s, 1H, CHimid), 7.50-7.36 (m, 6H, CHimid + CHbenz) and 10.89
(s, 1H, CHimid) ppm. 13C NMR (75MHz, CDCl3) : δ 14.8 (CH3), 26.3
(SCH2), 32.1 (CH2S), 49.5 (PhCH2), 53.5 (NCH2), 121.6 (CHimid), 123
(CHimid), 129 (2xCHbenz), 129.45 (3xCHbenz), 133.2 (Cbenz) and 137.4
(CHimid) ppm. FTIR: ν max(pure, diamond orbit)/cm−1: 3439br, 3100m,
3000s, 2850m, 1559s, 1493w, 1455s, 1260w, 1146vs, 1080w, 864w,
713vs, 640m. HRMS (positive ESI) m/z, calcd for [C14H19N2S]+ calculated
247.1295, found 247.1263.
orbit)/cm−1: 2900m, 1559s, 1456s, 1364s, 1208m, 1152s, 754w, 714s,
698vs, 643m. HRMS (positive ESI) m/z, calcd for [C16H23N2S]+calculated
275.1600, found 275.1576.
3-(2-(((1R,3s)-adamantan-1-yl)thio)ethyl)-1-benzyl-1H-imidazol-3-ium
bromide (2d):
It was prepared following the same procedure of 2d: Adamantane-1-thiol
(0.73 g, 4.34 mmol, 1.5 equiv) dry acetonitrile (30 mL), Sodium hydroxide
(0.17g, 4.34 mmol, 1.5 equiv) stirring for 48 hours at ambient
temperature under argon. Orange/brown oil was obtained. Yield: 99%. 1H
NMR (300 MHz, CDCl3) δ 1.60 (br, 6H), 1.70 (br, 6H), 1.95 (br, 3H), 2.99
(t, J = 6 Hz, 2H, CH2S), 4.48 (t, J = 6 Hz, 2H, NCH2), 5.55 (s, 2H, PhCH2),
7.32-7.39 (m, 4H, CHbenz, CHimid), 7.45 (m, 2H, CHbenz), 7.57 (s, 1H,
CHimid) and 10.36 (s, 1H, CHimid) ppm. 13C NMR (75MHz, CDCl3) : δ 26.4
(Cad), (3xCad), 29.6, 36 (3xCad), 43.4 (SCad), 46.7 (CH2S), 50.7 (NCH2),
53.42 (PhCH2), 121.4 (CHimid), 123 (CHimid), 129 (2xCHbenz), 129.5
(2xCHbenz), 129.6 (CHbenz), 133 (Cbenz) and 137.5 (CHimid) ppm. FTIR: ν
max(pure, diamond orbit)/cm−1: 3500br, 3000s, 2870s, 1557m, 1498w,
1445m, 1163s, 1105m, 1039s, 815m, 745m, 706vs, 650s, 606m. MS
(ESI): m/z, [M-Br]+ 343.2 (100).
1-benzyl-3-(2-(cyclohexylthio)ethyl)-1H-imidazol-3-ium
bromide
(2b) :
Cyclohexanethiol (0.1 g, 0.86 mmol, 1.5 equiv), was dissolved in dry
acetonitrile (7 mL). Sodium hydroxide (37 mg, 0.9 mmol, 1.5 equiv) in
water (0.5 mL) was added, and the resulting mixture was stirred for 30
minutes at room temperature under argon. Then 1 (0.2 g, 0.58 mmol, 1
equiv) was added, and the solution was stirred for 15 hours at room
temperature. After this time, the solvent was removed under vacuum and
the solid residue was suspended in dichloromethane and filtered through
celite. Volatiles were removed under reduced pressure and the resulting
1-benzyl-3-(2-(phenylthio)ethyl)-1H-imidazol-3-ium chloride (2e):
Pure 1-Benzylimidazole (1.43 g, 9.06 mmol, 1 equiv) and 2-chloroethyl
phenyl sulfide (1.34 ml, 9.06 mmol, 1 equiv) were placed in a Schlenk.
The mixture was heated for 3 hours at 130 °C under argon, during this
time the colorless mixture turned brown. After cooling, the brown oil was
washed two times with 40 ml THF, which provoke its precipitation as a
soft pale flesh solid. The pure product was obtained after
chromatography (silica gel, CH2Cl2/CH3OH 95:5) Yield: 97% 1H NMR
(300MHz, DMSO-d6) : δ 3.5 (t, J =7 Hz, 2H, CH2), 4,39 (t, J =7 Hz, 2H,
CH2), 5.4 (s, 2H, CH2), 7.43-7.23 (m, 10H, CHbenz), 7.77 (m, 1H, Himid),
7.81 (m, 1H, CHimid) and 9.32 (m, 1H, CHimid) ppm. 13C NMR (75MHz,
DMSO-d6) : δ 32.2 (CH2S), 48.4 (PhCH2), 51.9 (NCH2), 122.5 (CHimid),
122.9 (CHimid), 128.2 (CHbenz), 128.6 (2xCHbenz), 128.7 (CHbenz), 128.9
orange/brown oil is passed through
a
silica plug, first with
dichloromethane (to remove traces of unreacted thiolate) and then with
90/10 DCM/MeOH mixture. Compound is obtained as orange oil after
being concentrated. Yield: 99%. 1H NMR (300MHz, DMSO-d6) : δ 1.86-
1.1 (m, 10H, CH2), 2.64 (m, 1H, SCH), 3.00 (t, J = 7 Hz, 2H, CH2S), 4.35
(t, J = 7 Hz, 2H, NCH2), 5.45 (s, 2H, PhCH2), 7.83 (s, 1H, CHimid), 7.84 (s,
1H, CHimid) and 9.34 (s, 1H, CHimid) ppm. 13C NMR (300MHz, CDCl3) : δ
25.6 (CH2), 25.8 (2xCH2), 30.4 (2xCH2), 33.6 (SCH), 44.0 (SCH2), 50.0
(NCH2), 53.6 (PhCH2), 121 (CHimid), 122.6 (CHimid), 128.9 (2xCHbenz),
(4xCHbenz), 129(2xCHbenz), 134 (Cbenz), 134.8 (Cbenz) and 136.7 (CHimid
)
ppm. FTIR: ν max(pure, diamond orbit)/cm−1:3000m, 1559s, 1440m,
1352w, 1156s, 1117m, 1027m, 742vs, 713vs, 691vs, 487s. MS (ESI):
m/z, [M-Cl]+ 295.13(100).
129.43 (3xCHbenz), 132.7 (Cbenz
) and 137.7 (CHimid) ppm. FTIR: ν
max(pure, diamond orbit)/cm−1: 2900m, 1557s, 1447s, 1209m, 1163s,
757s, 713vs, 698vs, 611s, 465m. MS (ESI): m/z, [M-Br]+ 301.17 (100).
General Procedure for the Synthesis of the Pyridine/NHC-S platinum
complexes 3
1-benzyl-3-(2-(tert-butylthio)ethyl)-1H-imidazol-3-ium bromide (2c):
It was prepared following the same procedure of 2a : Precursor 1 (2 g,
5.8 mmol, 1 equiv), was dissolved in distillated acetonitrile (60 mL).
Sodium 2-methylpropane-2-thiolate (0.972 g, 8.66 mmol, 1.5 equiv) was
added, and stirring was continued for 24 hours at ambient temperature
under argon. After this time, the volatiles were removed under reduced
pressure. The solid residue was suspended in CH2Cl2 and filtered
through celite. Volatiles were removed under reduced pressure and the
resulting orange/brown oil is passed through a silica plug, first with
dichloromethane (to remove traces of unreacted thiolate) and then with
90/10 DCM/MeOH mixture. The solvent was removed under reduced
The ligand precursor (Imidazolium halide, 1.1 equiv), PtCl2 (1 equiv), NaI
(10 equiv) and K2CO3 (10 equiv) were suspended under argon in
anhydrous pyridine (10 mL). The mixture was sonicated during 10
minutes, heated overnight at 100 °C, then concentrated under reduced
pressure, dissolved in CH2Cl2 and filtered through a celite plug. The
residue was purified by
a silica gel chromatography (gradient
CH2Cl2/pentane 1/1, CH2Cl2) affording the complex as a yellow solid.
Compound 3a: Starting from 1-benzyl-3-(2-(ethylthio)ethyl)-1H-imidazol-
3-ium bromide 2a (100 mg, 0.305 mmol). Yield 66 mg (47%). 1H NMR
This article is protected by copyright. All rights reserved.

10.1002/ejic.201701183
European Journal of Inorganic Chemistry
FULL PAPER
(400 MHz, CDCl3) δ 1.36 (t, J = 7 Hz, 3H), 2.70 (q, J = 7 Hz, 2H, S-CH2),
3.25-3.28 (m, 2H, S-CH2), 4.67-4.70 (m, 2H, N-CH2), 5.73 (s, 2H), 6.61 (s,
1Himid), 6.95 (s, 1Himid), 7.31-7.39 (m, 6H), 7.50 (d, J = 7 Hz, 2H), 7.73 (t,
J = 8 Hz, 1H) and 9.03 (d, J = 6 Hz, 2HPyr) ppm. 13C NMR (101 MHz,
CDCl3) δ 15.4 (CH3), 26.4 (S-CH2), 30.9 (S-CH2), 51.0 (N-CH2), 55.0 (N-
CH2), 120.2 (CHimid), 121.8 (CHimid), 125.1 (2 x CHpyr), 128.5 (2 x CHpyr),
129.00 (2 x CHAr), 129.37 (2 x CHAr), 135.4 (CAr), 136.5 (C-Pt), 137.6
Pt), 137.6 (CHpyr) and 153.94 (2 x CHpyr) ppm. FTIR: ν max(pure,
diamond orbit)/cm−1: 1604, 1446, 1419, 1227, 1071, 758, 726 and 686
cm-1.HRMS (positive ESI) m/z [M-I]: calculated for C23H23IN3PtS
695.0301, found 695.0309.
General Procedure for the Synthesis of the (κ2-S,C)NHC-platinum
complexes 4
(CHpyr) and 153.90 (2 x CHpyr). FTIR: ν max(pure, diamond orbit)/cm−1
:
1603, 1456, 1445, 1419, 1222, 1069, 796, 721 and 687 cm-1. HRMS
(positive ESI) m/z [M-I]: calculated for C19H23IN3PtS: 647.0301, found
647.0242.
Complex 4 were obtained as byproduct during the synthesis of complex 3
and had been isolated by chromatography on silicagel in a DCM/MeOH
mixture.
Compound 3b: Starting from 1-benzyl-3-(2-(cyclohexylthio)ethyl)-1H-
imidazol-3-ium bromide 2b (100 mg, 0.262 mmol). Yield 136 mg (63 %).
1H NMR (400 MHz, CDCl3) δ 1.46-1.19 (m, 6H), 1.64-1.58 (m, 1H), 1.81-
1.72 (m, 2H), 2.15-2.05 (m, 2H), 2.75-2.80 (m, 1H), 3.29-3.20 (t, J = 7 Hz,
2H, S-CH2), 4.67 (t, J = 7 Hz, 2H, N-CH2), 5.72 (s, 2H, N-CH2), 6.60 (d, J
= 2 Hz, 1Himid), 6.96 (d, J = 2 Hz, 1Himid), 7.43-7.29 (m, 5H), 7.50 (d, J = 7
Hz, 2H), 7.73 (t, J = 8 Hz, 1H) and 9.04 (d, J = 5 Hz, 2Hpyr) ppm. 13C
NMR (101 MHz, CDCl3) δ 25.8 (2 x CH2), 26.3 (2 x CH2), 29.5 (S-CH2),
34.1 (2 x CH2), 44.1 (CH), 51.6 (N-CH2-CH2-S), 55.0 (N-CH2), 120.1
(CHimid), 121.9 (CHimid), 125.1 (2 x CHpyr), 128.52 (CHAr), 128.99 (2 x
CHAr), 129.36 (2 x CHAr), 135.5 (CAr), 136.1 (C-Pt), 137.6 (CHpyr) and
153.9 (2 x CHpyr) ppm. FTIR: ν max(pure, diamond orbit)/cm−1: 1606,
1445, 1421, 1224, 1067, 761, 727 and 689 cm-1. HRMS (positive ESI)
m/z [M-I]: calculated for C23H29IN3PtS 701.0771, found 701.0711.
Compound 4a: Starting from 1-benzyl-3-(2-(ethylthio)ethyl)-1H-imidazol-
3-ium bromide 2a (100 mg, 0.305 mmol). Yield 55 mg (25%). 1H NMR
(300 MHz, CD2Cl2) δ 1.04 (br, 3H, CH3), 2.12 (br, 3H, S-CH2 + S-CH2-
CH3), 3.04 (br, 1H, S-CH2), 4.20 (br, 1H, N-CH2), 4.50 (br, , N-CH2), 5.35
(overlapped with solvent signal, N-CH2), 6.02 (br, 1H, N-CH2), 6.95-7.02
(m, 2H, CHimid), 7.30-7.540 (m, 5H, CHAr) and 7.53-7.42 (m, 2H, CHAr)
ppm. FTIR: ν max(pure, diamond orbit)/cm−1: 1559, 1454, 1419, 1234,
1216, 1051, 724, 727 and 688 cm-1. HRMS (positive ESI) m/z [M-I]:
calculated for C14H18IN2PtS: 567.9879, found 567.9834.
Compound 4b: Starting from 1-benzyl-3-(2-(cyclohexylthio)ethyl)-1H-
imidazol-3-ium bromide 2b (100 mg, 0.262 mmol). Yield 40 mg (20%). 1H
NMR (500 MHz, CD2Cl2) δ 1.48-1.06 (m, 6H) peak overlap with grease,
2.01-1.61 (m, 4H), 2.22 (td, J = 13 and 3 Hz, 1H, S-CH2), 2.38-2.26 (m,
1H, S-CH), 3.08-2.89 (m, 1H, S-CH2), 4.24-4.18 (dt, J = 15 and 3 Hz, 1H,
N-CH2), 4.51 (ddd, J = 15, 13 and 3 Hz, 1H, N-CH2), 5.58 (d, J = 15 Hz,
1H, N-CH2), 5.78 (d, J = 15 Hz, 1H, N-CH2), 6.84 (d, J = 2 Hz, 1H, CHimid),
7.01 (d, J = 2 Hz, 1H, CHimid) and 7.43-7.33 (m, 5H) ppm. 13C NMR (126
MHz, CD2Cl2) δ 25.5 (CH2), 26.2 (CH2), 26.5 (CH2), 30.3 (CH2) 31.0
(CH2), 32.2 (S-CH2), 33.8 (S-CH), 49.9 (N-CH2), 56.5 (N-CH2), 121.0
(CHimid), 121.8 (CHimid), 129.15(CHAr), 129.32(2 x CHAr), 129.53(2 x CHAr),
Compound 3c: Starting from 1-benzyl-3-(2-(tert-butylthio)ethyl)-1H-
imidazol-3-ium bromide 2c (100 mg, 0.281 mmol). Yield 160 mg (71%).
1H NMR (400 MHz, CDCl3) δ 1.44 (s, 9H), 3.31-3.17 (m, 2H, S-CH2),
3.96 (s, 2H, N-CH2), 4.67-4.56 (m, 2H, N-CH2), 6.84 (d, J = 2 Hz, 1Himid),
6.94 (d, J = 2 Hz, 1Himid), 7.38-7.27 (m, 1H), 7.73 (t, J = 8 Hz, 1H) and
9.03 (d, J = 5.0 Hz, 1H) ppm. 13C NMR (101 MHz, CDCl3) δ 28.4 (S-CH2),
31.5 (3 x CH3), 43.6 (C-tBu), 51.6 (N-CH2), 55.0 (N-CH2), 120.2 (CHimid),
121.8 (CHimid), 125.1 (2 x CHpyr), 128.5 (CHpyr), 128.99 (2 x CHAr), 129.36
135.68 (CAr) and 148.27 (C-Pt) ppm. FTIR:
ν max(pure, diamond
orbit)/cm−1: 1458, 1444, 1419, 1261, 1234, 1218, 1077, 1057, 1027, 800,
724, 715 and 688 cm-1. HRMS (positive ESI) m/z [M-I]: calculated for
C18H24IN2PtS: 622.03473, found 622.03776.
(2 x CHAr), 135.4 (CAr), 136.4 (C-Pt), 137.61 (CHAr), 153.90 (2 x CHpyr
)
ppm. FTIR: ν max(pure, diamond orbit)/cm−1: 1606, 1448, 1420, 1224,
1153, 1069, 761, 740, 724 and 689 cm-1;HRMS (positive ESI) m/z [M-I]:
calculated for C21H27IN3PtS: 675.0614, found 675.0656.
In vitro cytotoxic activity. These tests were performed at Institut de
Chimie des Substances Naturelles CNRS – UPR2301, Gif-Sur-Yvette,
France. Samples were prepared by dissolution of the compounds in
DMSO at stock concentration of 10 mM. Cells were plated in 96-well
tissue culture plates in 200 µL complete medium at a density of 1000-
2500 cells per well and treated 24 hours later with 2 µL of compounds
Compound
3d:
Starting
from
3-(2-(((3s,5s,7s)-adamantan-1-
yl)thio)ethyl)-1-benzyl-1H-imidazol-3-ium bromide 2d (50 mg, 0.115
mmol). Yield 71 mg (70%). 1H NMR (400 MHz, CDCl3) δ 1.69 (m, 6H),
2.03 (m, 9H), 3.27-3.17 (m, 2H, S-CH2), 4.66-4.59 (m, 2H, N-CH2), 5.72
(s, 2H, N-CH2), 6.59 (d, J = 2 Hz, 1Himid), 6.92 (d, J = 2 Hz, 1Himid), 7.42-
7.27 (m, 5H), 7.50 (d, J = 7 Hz, 2H), 7.73 (t, J = 8 Hz, 1H) and 9.04 (d, J
= 7 Hz, 2Hpyr) ppm. 13C NMR (101 MHz, CDCl3) δ 25.9 (S-CH2), 30.0 (3 x
CH), 36.3 (3 x CH2), 43.7 (3 x CH2), 45.8 (CH), 52.2 (N-CH2-CH2-S), 54.9
(N-CH2), 120.2 (CHimid), 121.7 (CHimid), 125.0 (2 x CHpyr), 128.5 (CHAr),
128.98 (2 x CHAr), 129.4 (2 x CHAr), 135.4 (CAr), 136.3 (C-Pt), 137.6
using
a Biomek 3000 automation workstation (Beckman-Coulter).
Controls received the same volume of the appropriate vehicle (DMSO,
1% final volume). After 72 hours exposure, MTS reagent (CellTiter 96
Aqueous One, Promega) was added and incubated for 3 hours at 37 °C:
the absorbance was monitored at 490 nm and results expressed as the
inhibition of cell proliferation calculated as the ratio [(1 - (OD490
treated/OD490control)) x 100] in triplicate experiments after subtraction
of the blank without cells. Positive controls (cells incubated with a
reference drug at its IC50 concentration) were routinely added to check
the responsiveness of cells. For IC50 determination [50% inhibition of cell
proliferation], cells were incubated for 72 hours following the same
protocol with compound concentrations ranging 5 nM to 100 µM in
separate duplicate experiments.
(CHpyr), 153.93 (2 x CHpyr) ppm. FTIR: ν max(pure, diamond orbit)/cm−1
1605, 1445, 1420, 1222, 1067, 761, 727 and 689 cm-1. HRMS (positive
ESI) m/z [M-I]: calculated for C27H33IN3PtS: 753.1084, found 753.1068.
:
Compound 3e: Starting from 1-benzyl-3-(2-(phenylthio)ethyl)-1H-
imidazol-3-ium bromide 2e (50 mg, 0.151 mmol). Yield 78 mg (60 %). 1H
NMR (400 MHz, CDCl3): δ 3.68 (t , J = 8 Hz, 2H, S-CH2), 4.70 (t , J = 8
Hz, 2H, N-CH2), 5.71 (s, 2H, N-CH2), 6.58 (d, J = 2 Hz, 1H, CHimid), 6.87
(d, J = 2 Hz, 1H, CHimid), 7.20-7.24 (m, 1H), 7.42-7.27 (m, 7H), 7.50 (d, J
= 7 Hz, 2H), 7.55 (d, J = 7 Hz, 2H) , 7.73 (t, J = 8 Hz, 1H) and 8.94 (d, J
= 5.1 Hz, 2Hpyr) ppm. 13C NMR (101 MHz, CDCl3): δ 32.8 (S-CH2), 50.3
(N-CH2-CH2-S), 55.0 (N-CH2), 120.3 (CHimid), 121.8 (CHimid), 125.0 (2 x
CHpyr), 126.6 (CHAr), 128.55 (CHAr), 129.0 (2 x CHAr), 129.33 (2 x CHAr),
129.39 (2 x CHAr), 130.05 (2 x CHAr), 134.9 (CAr), 135.3 (CAr), 136.8 (C-
Acknowledgements
This article is protected by copyright. All rights reserved.

10.1002/ejic.201701183
European Journal of Inorganic Chemistry
FULL PAPER
N. Gurbuz, Hum. Exp. Toxicol. 2011, 30, 1342; (c) R. W.-Y. Sun, A. L.-
F. Chow, X.-H. Li, J. J. Yan, S. S.-Y. Chui, C.-M. Che, Chem. Sci. 2011,
2, 728; (d) E. Chardon, G. L. Puleo, G. Dahm, G. Guichard, S.
Bellemin-Laponnaz, Chem. Commun. 2011, 47, 5864; (e) O. Ciftci, A.
Beytur, N. Vardi, I. Ozdemir, Drug Dev. Ind. Pharm. 2012, 38, 40; (f) E.
Chardon, G. L. Puleo, G. Dahm, S. Fournel, G. Guichard, S. Bellemin-
Laponnaz, Chempluschem 2012, 77, 1028; (g) E. Chardon, G. Dahm,
G. Guichard, S. Bellemin-Laponnaz, Organometallics 2012, 31, 7618;
(h) E. Chardon, G. Dahm, G. Guichard, S. Bellemin-Laponnaz, Chem-
Asian J. 2013, 8, 1232; (i) J. K. Muenzner, T. Rehm, B. Biersack, A.
Casini, I. A. M. de Graaf, P. Worawutputtapong, A. Noor, R. Kempe, V.
Brabec, J. Kasparkova, R. Schobert, J. Med. Chem. 2015, 58, 6283; (j)
F. Cisnetti, C. Gibard, A. Gautier, J. Organomet. Chem. 2015, 782, 22;
(k) G. Dahm, C. Bailly, L. Karmazin, S. Bellemin-Laponnaz, J.
Organomet. Chem. 2015, 794, 115; (l) G. Dahm, E. Borre, G. Guichard,
S. Bellemin-Laponnaz, Eur. J. Inorg. Chem. 2015, 1665; (m) E. Borre,
G. Dahm, G. Guichard, S. Bellemin-Laponnaz, New J. Chem. 2016, 40,
3164; (n) M. Bouche, G. Dahm, A. Maisse-Francois, T. Achard, S.
Bellemin-Laponnaz, Eur. J. Inorg. Chem. 2016, 2828.
Dr Lydia Brelot and Corinne Bailly are gratefully acknowledged
for X-ray crystallographic analyses. Dr. Jean-Marc STRUB is
thankfully acknowledged for mass analyses. The authors also
thank the Centre National de la Recherche Scientifique (CNRS),
the Ministère de l'Enseignement Supérieur et de la Recherche
for a Ph.D. grant to M. B. and La Ligue contre le Cancer-Région
Grand Est.
Keywords: Platinum, Carbene ligands, S-Functionalization,
Antitumor agents, Cytotoxicity
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This article is protected by copyright. All rights reserved.

10.1002/ejic.201701183
European Journal of Inorganic Chemistry
FULL PAPER
This article is protected by copyright. All rights reserved.

10.1002/ejic.201701183
European Journal of Inorganic Chemistry
FULL PAPER
Entry for the Table of Contents
FULL PAPER
R'
Platinum(II) complexes, bearing
thioether-functionalized N-
heterocyclic carbene ligands,
have been synthesized and
characterized. The effect of
thioether on the biological
activities of the platinum centre
has been investigated on various
cancer cell lines.
NHC complexes
S
N
N
R'
I
R
pyridine
SiO2
S
C
Pt
N
N
N
J. Egly, M. Bouché, W. Chen, A.
Maisse-François, T. Achard,* and S.
Bellemin-Laponnaz*
I
I
C Pt
I
R
Page No. – Page No.
Biological activity?
Synthesis, structural
characterisation and anti-
proliferative activity of (κ1-C)- and
(κ2-S,C)-Pt(II) complexes bearing
thioether-functionalized N-
heterocyclic carbenes
This article is protected by copyright. All rights reserved.