Platinum (II) N-heterocyclic carbene complexes: Synthesis, characterization and cytotoxic properties

Article abstract of DOI:10.1002/aoc.4851

Platinum (II) complexes bearing N-heterocyclic carbene (NHC) ligands have been widely used in catalytic chemistry, but there are very few reports of biological properties of this type of complexes. A series of [PtCl₂(NHC)(PEt₃)] comp

Full text of DOI:10.1002/aoc.4851

Received: 17 October 2018
DOI: 10.1002/aoc.4851
Revised: 9 January 2019
Accepted: 13 January 2019
F U L L P A P E R
Platinum (II) N‐heterocyclic carbene complexes: Synthesis,
characterization and cytotoxic properties
Emine Özge Karaca1
Muhittin Aygün5
| Osman Çiftçi2
| Nevin Gürbüz1,3
| İlknur Özdemir3
| İsmail Özdemir1,3
| Gül Yakali4
|
1 Catalysis Research and Application
Center, İnönü University, 44280 Malatya,
Turkey
2 Department of Pharmacology,
Pamukkale University Faculty of
Medicine, 20070 Denizli, Turkey
3 Faculty of Science and Arts, Department
of Chemistry, İnönü University, 4280
Malatya, Turkey
4 Serik Gülsün‐Süleyman Süral Vocational
School of Higher Education, Department
of Opticianry Program, Akdeniz
Platinum (II) complexes bearing N‐heterocyclic carbene (NHC) ligands have
been widely used in catalytic chemistry, but there are very few reports of bio-
logical properties of this type of complexes. A series of [PtCl2(NHC)(PEt3)]
complexes were synthesized. The structures of all compounds were character-
ized by H‐NMR, 13C‐NMR, IR and elemental analysis techniques, which sup-
1
ported the proposed structures. The single crystal structures of complexes 1a
and 1e were determined. The title complexes show slightly distorted square‐
planar coordination around the platinum (II) metal center. The cytotoxic prop-
erties of the platinum (II)–NHC complexes have been assessed in various
human cancer lines, including cisplatin‐sensitive and resistant cells. IC50
values of these four complexes were determined by the MTS‐based assay on
three human cell lines—brain (SHSY5Y), colon (HTC116) and liver (HEP3B).
These complexes have been highlighted cancer therapeutic agent with unique
structures and functions.
University, 07070‐Serik, Antalya, Turkey
5 Faculty of Sciences, Department of
Physics, Dokuz Eylül University, 35160‐
Buca, İzmir, Turkey
Correspondence
İsmail Özdemir, İnönü University,
Catalysis Research and Application
Center, 44280 Malatya, Turkey, İnönü
University, Faculty of Science and Arts,
Department of Chemistry, 4280 Malatya,
Turkey.
KEYWORDS
antitumor activity, Imidazolidine‐2‐ylidene, N‐heterocyclic carbene, platinum complexes
Email: ismail.ozdemir@inonu.edu.tr
Funding information
TÜBİTAK, Grant/Award Number:
114Z624
1 | INTRODUCTION
acquired or intrinsic drug resistance. These severe side
effects are important factors motivating scientists to
In recent years, medicinal inorganic chemistry has
become a rapidly growing field with a broad range of
medicinal applications for inorganic and metal‐based
compounds, including mineral supplements (Fe, Cu,
Zn) and antimicrobial (Ag), anticancer (Pt), diagnostic
(Ba, Mn, Gd, I), antiulcer (Bi) and antiarthritic (Au)
agents, among others.[1,2] Cisplatin and other platinum
(II) derivatives such as oxaliplatin play a key role as anti-
cancer agents despite their dose‐dependent toxicity and
design new drugs that can overcome the limitations of
the clinically used platinum compounds.[3] It is generally
accepted that the mecanism of action of cisplatin
involves adduct formation with DNA, which causes
DNA damage and subsequently induces cell death.[4,5]
Undoubtedly, these platinum (II) complexes can also
interact with other cellular macromelecules and induce
a parallel mode of action that is different from DNA
damage.[4,6]
Appl Organometal Chem. 2019;e4851.
wileyonlinelibrary.com/journal/aoc
© 2019 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.4851

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KARACA ET AL.
As potential anticancer drugs, metal‐N‐heterocyclic
structures is easily accessible by some relatively simple
synthetic pathways; and (c) the steric and electronic
effects can contribute to the bonding formation between
the metal centers and the NHC ligands. Moreover, the
volume of the attached side chains can also influence
the stabilty and reactivity of the complexes.[27] The cyto-
toxic activity of a variety of NHC‐containing metal com-
plexes (metal: Ag, Au, Cu, Pd and Pt) has been
successfully studied on cancer cell lines.[18–22] Since the
first report of platinum–NHC complexes as potential drug
candidated by Marinetti and co‐workers[26,28], several
groups have confirmed in vitro the cytotoxic effect of such
platinum complexes.[29–35]
In a recent study we have reported the synthesis of sil-
ver (I), gold and ruthenium complexes, which were tested
as potential antimicrobial agents.[36–40] We report herein
the synthesis and characterization of five imidazolidine‐
2‐ylidene platinum (II) complexes of the general formula
[PtCl2(NHC)(PEt3)] 1a–e (Figure 1). The anticancer activ-
ities of these new compounds were evaluated over several
cancer cell lines—brain (SHSY5Y), colon (HTC116) and
liver (HEP3B)—and these data confirmed the high level
of cytotoxicity of Pt–NHC complexes.
carbenes (NHCs) constitute a recent and very rapidly
growing field of research. Metal complexes with N‐het-
erocyclic carbene ligands were first reported by the group
of Wanzlick[7] and Öfele[8] followed by Lappert and co‐
workers.[9,10] However, it was not until the isolation of a
crystalline carbene by Arduengo et al. in 1991 that NHCs
turned from mere curiosities into applicable chemical
reagents.[11] Metal–NHC complexes have played a signif-
icant role in catalytic processes.[12–15] In recent years, a
number of research groups have highlighted the potential
of NHCs as new chemical structures for the development
of metal‐based drugs.[16–24] These highly σ‐donating
ligands form stable transition metal complexes, which
might be a key requirement for biological applications.[25]
Indeed, the lack of in vivo efficacy and the side effects
of some metal‐based anticancer drugs are strongly
correlated with their instability under physiological
conditions.[26] The benefits of the using NHC–metal
complexes as anticancer agents lie in several aspects: (a)
the NHC ligand can form strong bonds with different
metal centers and the resulting complexes are more stable
toward moisture, air and heat; (b) the large diversity of
FIGURE 1 Platinum complexes 1a–e synthesized and assessed in the present study

KARACA ET AL.
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for 1 h (Scheme 1). The toluene was removed in vacuum,
and the product was used in the synthesis of the complex,
which was very sensitive to air humidity and oxygen. The
electron‐rich olefin (0.1 mol) was dissolved in toluene
and then [PtCl2(PEt3)2]2 (0.9 mol) was added and heated
at 100 °C for 5 h. The solution was removed in vacuo to
give a yellow solid. After washing with hexane, the
product was crystallized in a dichloromethane–diethyl
ether mixture (1:2).
2 | EXPERIMENTAL SECTION
2.1 | General methods
All reactions for the preparation imidazolidine‐2‐ylidene
and their complexes were carried out under argon in
flame‐dried glassware using standard Schlenk techniques.
Chemicals and solvents were purchased from Sigma‐
Aldrich and Merck. Dichloromethane, dimethylfor-
mamide, toluene and diethyl ether were of anhydrous
quality and were used as received. The solvents used were
purified by distillation over the drying agents indicated
and were transferred under argon. All reagents were
purchased from commercial sources and used without
further purification. Microanalyses were performed by
İnönü University Scientific and Technological Research
Center (Malatya, Turkey). IR spectra were recorded on
an ATR unit in the range of 400–4000 cm−1 with a Perkin
Elmer Spectrum 100 Spectrofotometer. Melting points
were measured in open capillary tubes with a Stuart
2.3 | trans‐Dichloro‐[1,3‐bis(4‐
dimethylaminobenzyl)imidazolidine‐2‐
ylidine]triethylphosphineplatinum (II), 1a
Yield: 0.25 g, 68%; m.p., 222.4 °C. IR: ν(CN), 1510 cm−1. 1H
NMR (400 MHz, CDCl3, 25 °C): δ = 1.16 and 1.20
(t, J = 8.0 Hz, 9H, PCH2CH3), 1.86 (p, J = 8.0 Hz, 6H,
PCH2CH3), 2.90 [s, 12H, CH2C6H4N(CH3)2 – 4], 3.33
(s, 4H, NCH2CH2N), 5.15 [s, 4H, CH2C6H4N(CH3)2 – 4],
6.70 and 7.42 [d, J = 8.0 Hz, 8H, CH2C6H4N(CH2CH3)2
– 4] ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 7.75
(PCH2CH3), 12.4 (d, J = 120 Hz, PCH2CH3), 44.3
1
automatic point apparatus (SMP‐40). Routine H NMR
and 13C NMR spectra were recorded using a Bruker
1
Avance AMX spectrometer operating at 400 MHz for H
[CH2C6H4N(CH3)2
[CH2C6H4N(CH3)2
–
–
4], 47.6 (NCH2CH2N), 52.9
4], 112.6, 123.7, 129.9, 150.3
NMR, and at 100 MHz for 13C NMR in CDCl3 with
tetramethylsilane as an internal reference. The NMR
studies were carried out in high‐quality 5 mm NMR
tubes. Chemical shifts (δ) and coupling constants (J) are
reported in ppm and in Hz, respectively. 1H NMR spectra
are referenced to residual protiated solvents
(δ = 7.26 ppm for CDCl3), and 13C chemical shifts are
reported relative to deuteriated solvents (δ = 77.16 ppm
for CDCl3).
[CH2C6H4N(CH3)2 – 4], 193.4 (d, J = 300 Hz, Pt‐Ckarb
)
ppm. Elemental analysis for C27H43Cl2N4PPt: calcd, C
45.00, H 6.01, N 7.77; found, C 45.02, H 6.00, N 7.75.
2.4 | cis‐Dichloro‐[1,3‐bis(4‐
dibutylaminobenzyl)imidazolidine‐2‐
ylidene] triethylphosphineplatinum (II), 1b
Yield, 0.34 g, 76%; m.p., 110.9 °C. IR: ν(CN), 1519 cm−1. 1H
NMR (400 MHz, CDCl3, 25 °C): δ = 0.95 [t, J = 8.0 Hz,
2.2 | General procedure for the
preparation of the platinum–(NHC)
complexes (1a–e)
12H, CH2C6H4N(CH2CH2CH2CH3)2
– 4], 1.20 [p,
J = 8.0 Hz, 8H, CH2C6H4N(CH2CH2CH2CH3)2 – 4], 1.34
[p, J = 8.0 Hz, 8H, CH2C6H4N(CH2CH2CH2CH3)2 – 4],
1.54 (t, J = 8.0 Hz, 9H, PCH2CH3), 1.95 (p, J = 8.0 Hz,
The aromatic aldehyde (20 mmol) and the
ethylenediamine (10 mmol) were stirred overnight in
methanol. The diimine was collected as a white solid,
filtrated and recrystallized in an alcohol–ether mixture.
The diimine (10 mmol) was subsequently reduced by
NaBH4 (30 mmol) in CH3OH (30 mL). The solution was
then treated with 1 M HCl, and the organic phase was
extracted with CH2Cl2 (3 × 30 mL). After drying over
MgSO4 and evaporation, the 1,2‐bis(benzylamino)ethane
was isolated as a solid. 1,2‐Bis(benzylamino)ethane
(0.10 mol) was dissolved in toluene (15 mL) and N,N‐
dimethylformamide dimethylacetal (0.12 mol) was added.
The solution was submitted to a water bath for 3 h in an
inert atmosphere. At the end of this period, the mixture
temperature was raised to 100 °C and allowed to stand
6H, PCH2CH3), 3.23 [t,
J
=
8.0 Hz, 8H,
CH2C6H4N(CH2CH2CH2CH3)2 – 4], 3.30 (t, J = 4.0 Hz,
4H, NCH2CH2N), 4.48 and 5.63 [d, J = 8.0 Hz, 4H,
CH2C6H4N(CH2CH2CH2CH3)2 – 4], 6.58 and 7.31 [d,
J = 8.0 Hz, 8H, CH2C6H4N(CH2CH2CH2CH3)2 – 4]. 13C
NMR (100 MHz, CDCl3, 25 °C):
[CH2C6H4N(CH2CH2CH2CH3)2 – 4], 14.0 [CH2C6H4N
(CH2CH2CH2CH3)2 4], 20.3 [CH2C6H4N
(CH2CH2CH2CH3)2 – 4], 29.4 (PCH2CH3), 15.9 (d,
152 Hz, 6H, PCH2CH3), 50.7 [CH2C6H4N
(CH2CH2CH2CH3)2 4], 50.8 (NCH2CH2N), 54.7
δ
=
8.9
–
J
=
–
[CH2C6H4N(CH2CH2CH2CH3)2 – 4], 111.8, 120.6, 130.1,
147.9 [CH2C6H4N(CH2CH2CH2CH3)2 – 4], 176.7 (d,
J = 14 Hz, Pt‐Ckarb). Elemental analysis for C39H67

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KARACA ET AL.
SCHEME 1 Synthesis of platinum complexes 1a–e
Cl2N4PPt: calcd, C 52.69, H 7.60, N 6.30; found, C 52.68,
H 7.59, N, 6.32.
CH2C6H4(NC5H10O)‐4], 3.29 (s, 4H, NCH2CH2N), 4.55
and 5.65 [d, J = 8.0 Hz, 4H, CH2C6H4(NC5H10) − 4],
6.89 and 7.36 [d, J = 4.0 Hz, 8H, CH2C6H4(NC5H10) –
4]. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 7.7
(PCH2CH3), 8.3 (d, J = 152 Hz, PCH2CH3), 25.7, 47.4
2.5 | cis‐Dichloro‐[1,3‐bis(4‐
diethylaminopropoxybenzyl)imidazolidine‐
2‐ylidine]triethylphosphineplatinum
(II), 1c
and 50.5 [CH2C6H4(NC5H10O)
– 4], 47.4 (s, 4H,
NCH2CH2N), 54.7 [CH2C6H4(NC5H10) – 4], 116.3, 129.7,
137.9 and 151.9 [d, J = 4.0 Hz, 8H, CH2C6H4(NC5H10) –
4], 177.5 (d, J = 12 Pt‐Ckarb). Elemental analysis for
C33H51Cl2N4PPt: calcd, C 49.50, H 6.42, N 7.00; found,
C 49.53, H 6.40, N 7.02.
Yield: 0.29 g, 69%; m.p., 172.3 °C. IR: ν(CN), 1510 cm−1. 1H
NMR (400 MHz, CDCl3, 25 °C): δ = 1.19 (t, J = 8.0 Hz, 9H,
PCH2CH3), 1.91–1.96 [m, 10H, PCH2CH3 and
CH2C6H4OCH2CH2CH2N(CH3)2 – 4)], 2.23 [s, 12H,
CH2C6H4OCH2CH2CH2N(CH3)2 – 4], 2.44 [t, J = 8.0 Hz,
2.7 | cis‐Dichloro‐[1,3‐bis(4‐
morpholinylbenzyl)imidazolidine‐2‐
ylidine] triethylphosphineplatinum (II), 1e
4H, CH2C6H4OCH2CH2CH2N(CH3)2
– 4], 3.28–3.34
[m, 4H, CH2C6H4OCH2CH2CH2N(CH3)2 – 4], 3.99
(t, J = 8.0 Hz, 4H, NCH2CH2N), 4.51 and 5.77 [d,
J = 12.0 Hz, 4H, CH2C6H4OCH2CH2CH2N(CH3)2 – 4],
6.87 and 7.43 [d, J = 4.0 Hz, 8H, CH2C6H4OCH2
CH2CH2N(CH3)2 – 4]. 13C NMR (100 MHz, CDCl3,
25 °C): δ = 8.22 (PCH2CH3), 27.6 and 15.9 [d,
Yield: 0.26 g, 65%; m.p., 192.9 °C. IR: ν(CN), 1515 cm−1. 1H
NMR (400 MHz, CDCl3, 25 °C): δ = 1.20 (h, J = 8.0 Hz,
9H, PCH2CH3), 1.95 (p, J = 8.0 Hz, 6H, PCH2CH3), 3.13
and 3.84 [t, J = 4.0 Hz, 16H, CH2C6H4(NC4H8O) – 4],
3.25–3.40 (m, 4H, NCH2CH2N), 4.48 and 5.77 [d,
J = 8.0 Hz, 4H, CH2C6H4(NC4H8O) – 4], 6.87 and 7.43
[d, J = 4.0 Hz, 8H, CH2C6H4(NC4H8O) – 4]. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 8.2 (PCH2CH3), 15.7 (d,
J
=
156 Hz, PCH2CH3 and CH2C6H4OCH2CH2
CH2N(CH3)2 – 4], 45.6 [CH2C6H4OCH2CH2CH2N(CH3)2
– 4], 47.3 [CH2C6H4OCH2CH2CH2N(CH3)2 – 4], 54.5
[CH2C6H4OCH2CH2CH2N(CH3)2 – 4], 56.4 (NCH2CH2N),
66.3 [CH2C6H4OCH2CH2CH2N(CH3)2 – 4], 114.7, 126.4,
130.2, 159.0 [CH2C6H4OCH2CH2CH2N(CH3)2 – 4], 177.8
(d, J = 12 Hz, Pt‐Ckarb). Elemental analysis for
C33H55Cl2N4O2PPt: calcd, C 47.37, H 6.63, N 6.70; found,
C 47.35, H 6.61, N 6.72.
J
= 152 Hz, PCH2CH3), 47.4, 48.8, 49.0, 51.7
[CH2C6H4(NC4H8O) – 4], 53.4 and 54.5 (NCH2CH2N),
66.8 [CH2C6H4(NC4H8O) – 4], 115.6, 123.4, 125.6,
129.9, 151.1, 158.1 [CH2C6H4(NC4H8O) – 4], 177.2 (d,
J = 12 Hz, Pt‐Ckarb). Elemental analysis for C31H47Cl2
N4O2PPt: calcd, C 46.27, H 5.89, N 6.96; found, C 46.25,
H 5.88, N, 6.94.
2.6 | cis‐Dichloro‐[1,3‐bis(4‐
piperidinylbenzyl)imidazolidine‐2‐ylidine]
triethylphosphineplatinum (II), 1d
2.8 | X‐ray crystallographic data
Yield: 0.30 g, 75%; m.p., 151.2 °C. IR: ν(CN), 1515 cm−1. 1H
NMR (400 MHz, CDCl3, 25 °C): δ = 1.19 (t, J = 8.0 Hz,
9H, PCH2CH3), 1.93 (p, J = 8.0 Hz, 6H, PCH2CH3),
Single crystals of complexes 1a and 1e suitable for X‐ray
analysis were obtained by slow diffusion of diethyl ether
into a dichloromethane solution of the complexes. Sin-
gle crystal X‐ray diffraction data of trans‐dichloro‐[1,3‐
1.57, 1.71 and 3.16 [p,
J
=
8.0 Hz, 20H,

KARACA ET AL.
5 of 11
bis(4‐dimethyllaminobenzyl)imidazolidine‐2‐ylidene]trie-
thylphosphineplatinum (II) 1a and cis‐dichloro‐[1,3‐
bis(4‐morpholinilbenzyl)imidazolidine‐2‐ylidene]triethyl-
phosphineplatinum (II) 1e were collected at room
temperature on an Rigaku‐Oxford Xcalibur diffractome-
ter with an Eos‐CCD detector, operated at 50 kV and
40 mA using graphite monochromated Mo–Kα
(λ = 0.71073 Å) radiation. Data collections and reduc-
tions along with absorption corrections were performed
using CrysAlisPro software package.[41] Structure
solutions were performed using SHELXT[42] embedded
in the Olex2.[43] Refinement of coordinates and aniso-
tropic thermal parameters of non‐hydrogen atoms were
carried out by the full‐matrix least‐squares method in
SHELXL.[44]
3 | RESULTS AND DISCUSSION
3.1 | Preparation of platinum (II)
complexes
4,5‐Dihydroimidazol‐2‐ylidenes containing an unhin-
dered R group[46,47] readily dimerize to give tetraami-
R
noethene derivativea (L2 ), which behave as carbene
precursors under relatively mild conditions. The synthesis
of the tetraaminoethene was accomplished in a three‐step
procedure as described in Scheme 1. The Schiff base was
synthesized using a method similar to that reported by
Billman et al.[48] The 1,2‐disubstituted ethylendiamine
was prepared successfully and subsequently reduced by
R
NaBH4 in CH3OH. The tetraaminoethene (L2 ) was
synthesized by formylation of the NH bonds in an excess
of Me2NCH(OMe)2 according to the literatüre.[49] The
functional tetraaminoethenes readily reacted with the
[PtCl2(PEt3)]2 to afford [PtCl2(NHC)(PEt3)] (1a–e) via a
cleavage C=C bond. Each of the complexes (1a–e) was
obtained in high yield as air‐stable crystals, which where
2.9 | Cytotoxic activity
2.9.1 | Cell culture and incubation
Neuroblastoma (SHSY5Y), adenocarcinoma (HEP3B),
colon carcinoma (HTC116) and human fibroblast (HF)
cells were obtained from the American Type culture
collection and maintained at 37 °C in a humidified incu-
bator under 5% CO2 conditions.[45] Cells were cultured in
DMEM containing 10% fetal bovine serum and 1%
antibiotics (100 μg/mL streptomycin and 10000 U/mL
penicillin). Media were changed twice a week until cells
reached 70–80% confluency.
1
characterized by elemental anaysis, IR, H and 13C‐NMR
spectra. Their 13C NMR spectra compare well with those
of analogous complexes described in the literature. The
characteristic peak of the platinum (II)–carbene reso-
nance for compounds 1a–e displays as a singlet at 193.4
176.7, 177.8, 177.5 and 177.2 ppm, respectively, in the
13C NMR spectra. The chemical shift is consistent with
those of the known platinum (II)–NHC complexes in
the range of 173–195 ppm.[50] Platinum (II)–NHC
complexes (1a–e) exhibit a characteristic ν(CN) band typi-
cally at 1510, 1519, 1510, 1515 and 1515 cm−1, respec-
tively. Additional elemental analyses of these complexes
are in agreement with the molecular formula proposed
(Table 1).
2.9.2 | Cell viability assay
The MTS [3‐(4,5‐dimethylthiazol‐2‐yl)‐5‐(3‐carboxyme-
thoxyphenyl)‐2‐(4sulfophenyl)‐2H‐tetrazolium]
assay
was performed to identify the viable cell ratio according
to the manufacturer's instructions (Promega). Briefly cells
were seeded in 96‐well flat‐bottomed tissue culture plates
at a concentration of 5 × 103 cells/well. After 24 h, the
cells were treated with DMEM medium containing differ-
ent concentrations (15, 25, 50 and 100 μM) of the test
compounds for different incubation periods of 24, 48
and 72 h). At the end of each time point, fresh complete
medium containing 10 μL of MTS solution was added
and further incubated for 2 h in the incubator. Cell prolif-
eration was assessed by measuring the absorbance with
an ELISA microplate reader (Weida). Each experiment
was performed in quadruplicate and results are expressed
as the percentage growth inhibition with respect to the
untreated cells. Statistical deviations for the viability were
calculated automatically using Excel 2007 (SE ≤ 5%) and
for the IC50 using “Origin Pro 7.5” and “Origin 6.1” (for
7Crf) PC.
3.2 | Single crystal X‐ray diffraction and
structure analysis of platinum complexes
(1a, 1e)
All non‐hydrogen atoms were refined anisotropically.
The positions of the hydrogen atoms of the title com-
pounds on their respective parent carbon atoms were
generated geometrically: C–H = 0.96 Å for methyl
groups, C–H = 0.93 Å for methylene groups and
C–H = 0.93 Å for aromatic groups. In 1e, the H atoms
bounded to C4 atom appeared in two positions with equal
s.o.f. values because of the symmetrical disorder. Equal
Uij constraints (EADP) were used for the C atoms of
phenyl and morpholinylbenzyl rings in 1e, but for the C
atoms of only one phenyl ring in 1a. A summary of crys-
tallographic data, experimental details and refinement

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KARACA ET AL.
TABLE 1 Physical and spectroscopic properties of new compounds
Compound
Formula
Isolated yield (%)
m.p. (°C)
v(CN) (cm−1
)
C(2) 13C NMR (ppm)
J (Hz)
1a
1b
1c
1d
1e
C27H43Cl2N4PPt
C39H67Cl2N4PPt
C33H55Cl2N4O2PPt
C33H51Cl2N4PPt
C31H47Cl2N4O2PPt
68
76
69
75
65
222.4
110.9
172.3
151.2
192.9
1510
1519
1510
1515
1515
193.4
176.7
177.8
177.5
177.2
300
14
12
12
12
results for the compounds is given in the Supporting
Information. Further details concerning data collection
and refinements are given in the Supporting Information.
A coordination of the N‐heterocyclic carbene group
(trans for 1a and cis for 1e) and phosphine group to Pt
(II) atom is observed in the single crystal X‐ray analysis
of the complexes. The Pt (II) atom in 1e lies on a twofold
reflection plane. The asymmetric unit of the 1a contains
one molecule whereas the asymmetric unit of the 1e
contains half of a molecule (Figure 2). The other half of
the molecule is generated with an x, 1/2 − y, z symmetry
operator. The dihedral angle between the two
morpholinylbenzyl ring is 70.2(4)° in 1a. The Pt1/Cl1/
Cl2/P1/C1 coordination plane of the complexes is formed
FIGURE 2 The molecular structure of
1a and 1e with atom numbering scheme
and 75% probability displacement
ellipsoids

KARACA ET AL.
7 of 11
by the slightly distorted square‐planar coordination of the
platinum (II) metal as reported for similar N‐heterocyclic
carbene complexes.[51] This coordination plane of 1a and
1e is nearly perpendicular to the plane of the
imidazolidine ring, making a dihedral angle of 78.2 (3)°
and 85.7 (6)°, respectively. The Pt–C bond lengths
[1.977(10), 2.047 (6) Å] are compatible with those of
many other Pt (II) complexes.[52] However, the value in
1e is shorter than that in 1a. These results show that
the N‐heterocyclic carbene ligands are more weakly
bound to the Pt center in the trans form.[53] The Pt–P
bond distances [2.231(4), 2.295(18) Å] are similar to those
reported previously.[54–56] The bond angles at the Pt atom
involving trans pairs of substituents deviating from the
expexted values of 180° and 90° are Cl2–Pt1–P1
[91.78(6)° in 1a; 177.99° (12) in 1e] and Cl1–Pt1–C1
[89.40(8)° in 1a; 180.00°(3) in 1e]. The small difference
between these angles confirms the distorted square pla-
nar geometry. These can be taken as a larger proportion
of the σ‐donor character in the Pt–P bonds, which results
in a greater strict effect.[57] All of the bond lengths and
bond angles (Table 2) are approximately within the
normal range compared with other similar complexes
(Figure 3).[58,59]
1, and N1–C1 = 1.309(7) Å and N2–C1 = 1.334(4) Å are
shorter than the N1–C3 = 1.466(8) Å and N2–
C2 = 1.466(8) Å in 1a in accordance with a previous
study.[58] This is possibly indicative of a greater partial
double bond character owing to partial electron donation
by nitrogen to the carbene C‐atom donor.[60]
Molecular packing in the crystal structure of the
compound 1e is stabilized by the intermolecular
C–H···O interactions with the following dimensions
C13–H13
=
0.929(15) Å, H13···O1
=
2.438 Å,
C13···O1 = 3.336(13) Å, C13–H13···O1 = 162.6(12) Å
along the c‐axis (Figure 4) whereas molecular packing
in the crystal structure of the compound 1a is stabilized
by the intermolecular C–H···Cl interactions which are
formed with an R22 (12) ringmotif[61] with the following
dimensions: C2–H2A = 0.97(10) Å, H2A···Cl1 = 2.783(7)
Å, C2···Cl1 = 3.677(7) Å, C2–H2A···Cl1 = 153.6(7) Å
along the abc plane (Figure 3).
3.3 | Antitumor activities of platinum–
NHC complexes
The IC50 values of all complexes against three human
cancer cell lines (SHSY5Y, HTC116, HEP3B) and healthy
cell line (HF) were measured and are listed in Table 3. It
was determined that the complexes 1a–e have lower
The bonding within the NHC ring demonstrates a
pattern of delocalization in which the N1–C1 = 1.325(8)
Å is significantly shorter than N1–C2 = 1.477(10) Å in
TABLE 2 Selected experimental parameters of the compounds
Compound 1a
Compound 1e
Bond lengths (Å)
Bond lengths (Å)
Pt1–Cl1
Pt1–Cl2
Pt1–P1
2.2979(19)
2.2926(18)
2.2950(18)
2.047(6)
Pt1–Cl1
Pt1–Cl2
Pt1–P1
Pt1–C1
P1–C3
2.351(3)
2.355(4)
2.231(4)
Pt1–C1
Pt1–C23
1.977(10)
1.777(8)
1.817(12)
Bond angles (deg)
Bond angles (deg)
Cl1–Pt1–Cl2
Cl1–Pt1–P1
Cl1–Pt1–C1
Cl2–Pt1–P1
Cl2–Pt1–C1
P1–Pt1–C1
Pt1–P1–C23
Pt1–P1–C25
Pt1–P1–C27
Pt1–C1–N1
Pt1–C1–N2
176.78(6)
91.18(7)
89.40(18)
91.97(6)
87.47(18)
178.7(2)
115.4(3)
111.8(3)
113.8(4)
125.9(5)
124.0(4)
Cl1–Pt1–Cl2
Cl1–Pt1–P1
Cl1–Pt1–C1
Cl2–Pt1–P1
Cl2–Pt1–C1
P1–Pt1–C1
Pt1–P1–C3
Pt1–P1–C5
Pt1–C1–N1
89.93(12)
88.06(12)
180.0(3)
177.99(12)
90.1(3)
91.9(3)
116.1(4)
113.1(5)
124.4(5)

8 of 11
KARACA ET AL.
FIGURE 3 The packing diagram of the
compound 1a by C–H···Cl hydrogen bonds
along the (abc) plane
FIGURE 4 The packing diagram of the
compound 1e by C–H···O hydrogen bonds
along the c‐axis
cytotoxic activity against both cancer cell lines and
healthy cell line compared with the cispaltin group. On
the other hand, compound 1b showed significant cytotox-
icity in three cancer cell lines, but did not cause a cyto-
toxic effect in HF cells. Cisplatin caused more severe
cytotoxic effects in HF compared with 1b. In this context
we determined that 1b is safer compared to cisplatin.
In addition, the IC50 values of 1b (1.629 ) were lower
than those for cisplatin (11.28) in SHSY5Y cell lines.
Therefore we claimed that 1b was more effective and
more cytotoxic for the SHSY5Y cell line compared with
cispaltin. Furthermore, 1b exhibits cytotoxic activity in
all cancer cell lines in which IC50 values below 50 μM
are observed (Table 3). In addition, cytotoxic activities
of 1a–e were weaker as they had higher IC50 values when
compared with cisplatin. Therefore, cisplatin has been

KARACA ET AL.
9 of 11
TABLE 3 IC50 values for NHC complexes (μM), (mean SEM)
IC50
Complex
Hep3B
SHSY5Y
HTC116
HF
Cisplatin
13.29 1.16
453.8 44.65
49.60 6.75
867.8 74.5
546.3 48.7
837.5 78.1
11.28 0.98
66.23 6.13
1.629 0.098
118.1 9.65
95.34 8.64
78.21 8.01
14.32 1.67
170.9 16.5
31,62 2.96
2190 198
354.1 29.6
1464 154
0.012 0.0001
1298 117
1a
1b
1c
1d
1e
114.6 10.87
2945 280
459.6 39.3
1478 125
shown to have more effective cytotoxic activity. All of
these data show that the most potent cytotoxic compound
is 1b, and that some cell lines (SHSY5Y) may be more
effective and safe than cisplatin in terms of IC50 values.
The cell viability of complexes and cisplatin against
cancer cell lines and healthy cell line is given in Figures
S5–S9 (see Supporting Information). The compound
1a partially affected the SHSY5Y cells on 100 μM
concetration in third day, but no effect was observed at
the other cancer cells on determined concentrations.
Similarly, compound 1d affected only SHSY5Y cells on
50 μM concentration but it did not effect other cell lines
(Figure S9). In terms of 1c and 1e, no cytotoxic activity
was seen at 15–100 μM concentration on the first, second
and third days in all cancer and healthy cell lines.
The NHC complexes have been important for selective
and effective cancer therapy in recent years. The interest
in the development of gold‐based anticancer drugs is
generally related to the treatment of rheumatoid arthritis,
whereas the use of platinum‐based anticancer drugs
suggests that NHC platinum derivatives may have the
same effect.[62] Until now, many reports on NHC com-
plexes have shown that many derivatives, such as gold,
silver and platinium in micromolar or submicromolar
concentrations, have cytotoxicity.[63,64]
After the discovery of cisplatin, platinum complexes
have begun to play an important role in anticancer
therapy and are now the strongest metal‐based drug type.
We determined that the 1b complexes have greater anti-
proliferative activity than cisplatin in three cancer cell
lines (SHSY5Y, HTC116, HEP3B). In addition, they were
safer than cisplatin in HF cells, with low IC50 values. On
the other hand 1a, c–e complexes did not have significant
antiproliferative activity compared with cispaltin. These
results agree well with a general feature reported in the
literature. Similar to this paper, many biological studies
on platinum NHC complexes have shown that different
kinds of NHC ligands (e.g. xanthine, benzimidazole or
imidazole derivatives) have antiproliferative activity in
cancer cell lines.[65] Chtchigrovsky determined that new
mono‐ and bimetallic (NHC)PtX2(amine) complexes
induce cell death by cellular pathways in various cancer
cell lines such as nasopharyngeal epidermis carcinoma,
ovarian carcinoma and myelomonocytic leukemia.[66]
Additionally, Bippus et al. reported that some cationic
platinum phosphine complexes containing thiocarbamate
ligands show in vitro cytotoxicity in three human cancer
cell lines (A549, CH1, SW480), particularly in the ovarian
carcinoma cell line (CH1).[67] Also Marzano et al
determined that a series of new platinum (II) amidine
derivatives were active against a panel of human tumor
cell lines containing examples of cervix (HeLa), breast
(MCF7), lung (A549) and colon (HCT‐15) cancer.[68a, b]
A genereal feature of structure–activity correlations for
such complexes is unfolding, allowing a predection of
the influence of the central metal, the NHC substituents,
the charge, the lipophilicity and the sterical encum-
brance around the metal center on their biological
properties.[68a,b,69] The reason for the high cytotoxic activ-
ity of 1b complex would be the well governed steric bulk
and the chemical environment around the platinium cen-
ter by the NHC ligand. In the case of other complexes,
which are sterically less bulky than 1b, weak governed
steric and electronic properties by NHC ligands may lead
to lesser cyctotoxic activity. These observations point out
that the steric and electronic properties of NHCs have a
major influence on the cyctotoxic activity of the platinium
center and complexes can show different activities against
various cancer cell lines. Amongst the generally bigger
and more lipophilic monophosphine complexes, the N‐4‐
dibutylaminobenzyl substituted 1b was more active than
other complexes. The complex cis‐[Pt (PEt3)(NHC)Cl2],
which bear an accesible chlorido leaving group ligand,
although to a lesser extent, bound coordinatively to DNA
but also initiated some DNA aggregation.[69]
4 | CONCLUSIONS
In summary, in this study, a series of functionalized
imidazolidine‐2‐ylidine platinum (II) complexes (1a–e)
are accessible from appropriately N‐substituted

10 of 11
KARACA ET AL.
R
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tetraaminoalkene, L2 . All of these compounds were
characterized by spectroscopic and analytic techniques.
A preliminary anticancer study of these compounds was
evaluated against the three human cell lines brain
(SHSY5Y), colon (HTC116), and liver (HEP3B). The
platinum complexes were found to be active against the
tested cell lines, showing comparable activity with exam-
ples in the literature. An important effort is currently
being made in our laboratories to develop the potential
of these complexes for biological or catalytic applications.
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and Scientific Research Council of Turkey (TÜBİTAK–
MHESR 114Z624).
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ORCID
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Bendirdjian, J. Poupon, S. Bombard, T. Cresteil, P. Retailleau,
A. Marinetti, J. Med. Chem. 2013, 56, 2074.
Emine Özge Karaca
4438
https://orcid.org/0000-0002-3190-
Osman Çiftçi https://orcid.org/0000-0001-5755-3560
İlknur Özdemir https://orcid.org/0000-0002-8566-8979
Gül Yakali https://orcid.org/0000-0002-0015-5948
Muhittin Aygün http://orcid.org/0000-0001-9670-9062
Nevin Gürbüz https://orcid.org/0000-0003-3201-3597
İsmail Özdemir https://orcid.org/0000-0001-6325-0216
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How to cite this article: Karaca EÖ, Çiftçi O,
Özdemir İ, et al. Platinum (II) N‐heterocyclic
carbene complexes: Synthesis, characterization and
cytotoxic properties. Appl Organometal Chem. 2019;
e4851. https://doi.org/10.1002/aoc.4851
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