Synthesis, characterization, structures and cytotoxic activity of palladium(II) and platinum(II) complexes containing bis(2-pyridylmethyl)amine and saccharinate

Article abstract of DOI:10.1016/j.poly.2010.09.037

New palladium(II) and platinum(II) complexes containing bis(2-pyridylmethyl)amine (bpma) and saccharinate (sac), [Pd(bpma)(sac)](sac) ·2H₂O (1), [Pt(bpma)(sac)](sac)·2H₂O (2), [Pd(bpma)Cl](sac)·2H₂O (3) and [Pt(bpma)(sac)]Cl·1. 5H₂O (4), were synthesized and characterized by elemental analysis, IR, NMR and TG-DTA. A single-crystal X-ray analysis of 3 and 4 proved a distorted square-planar geometry around the metal ions with one tridentate bpma ligand and one Cl or sac monoanion. The [Pd(bpma)Cl]⁺ ions in 3 form dimers by intermolecular N-H?Cl and Pd?Pd interactions. The cations reside in the centers of a hydrogen-bonded honeycomb network formed by the uncoordinated sac ions and the lattice water molecules, while the cations of 4 are connected by N-H?Cl and OW-H?O hydrogen bonds into one-dimensional chains. Cyclic planar tetrameric and trimeric water clusters were observed in 3 and 4, respectively. Cytotoxicity of 1-4 was tested against A549, C6 and CHO cells. Although 2 and 4 have no cytotoxicity, the best results were achieved for 1 and 3. In particular, the cyctotoxic activity of 3 is comparable to cisplatin.

Full text of DOI:10.1016/j.poly.2010.09.037

Polyhedron 30 (2011) 114–122
Contents lists available at ScienceDirect
Polyhedron
journal homepage: www.elsevier.com/locate/poly
Synthesis, characterization, structures and cytotoxic activity of palladium(II)
and platinum(II) complexes containing bis(2-pyridylmethyl)amine and saccharinate
a
a,
⇑
b
c
d
Emel Guney , Veysel T. Yilmaz , Ferda Ari , Orhan Buyukgungor , Engin Ulukaya
a
Department of Chemistry, Faculty of Arts and Sciences, Uludag University, 16059 Bursa, Turkey
Department of Biology, Faculty of Arts and Sciences, Uludag University, 16059 Bursa, Turkey
Department of Physics, Faculty of Arts and Sciences, Ondokuz Mayis University, 55139 Samsun, Turkey
Department of Medical Biochemistry, Faculty of Medicine, Uludag University, 16059 Bursa, Turkey
b
c
d
a r t i c l e i n f o
a b s t r a c t
Article history:
New palladium(II) and platinum(II) complexes containing bis(2-pyridylmethyl)amine (bpma) and sac-
charinate (sac), [Pd(bpma)(sac)](sac)ꢀ2H O (1), [Pt(bpma)(sac)](sac)ꢀ2H O (2), [Pd(bpma)Cl](sac)ꢀ2H
O (4), were synthesized and characterized by elemental analysis, IR,
Received 17 August 2010
Accepted 29 September 2010
Available online 7 October 2010
2
2
2
O
(
3) and [Pt(bpma)(sac)]Clꢀ1.5H
2
NMR and TG-DTA. A single-crystal X-ray analysis of 3 and 4 proved a distorted square–planar geometry
+
around the metal ions with one tridentate bpma ligand and one Cl or sac monoanion. The [Pd(bpma)Cl]
Keywords:
Saccharinate
Bis(2-pyridylmethyl)amine
Palladium(II)
Platinum(II)
ions in 3 form dimers by intermolecular N–Hꢀ ꢀ ꢀCl and Pdꢀ ꢀ ꢀPd interactions. The cations reside in the cen-
ters of a hydrogen-bonded honeycomb network formed by the uncoordinated sac ions and the lattice
water molecules, while the cations of 4 are connected by N–Hꢀ ꢀ ꢀCl and OW–Hꢀ ꢀ ꢀO hydrogen bonds into
one-dimensional chains. Cyclic planar tetrameric and trimeric water clusters were observed in 3 and 4,
respectively. Cytotoxicity of 1–4 was tested against A549, C6 and CHO cells. Although 2 and 4 have no
cytotoxicity, the best results were achieved for 1 and 3. In particular, the cyctotoxic activity of 3 is com-
parable to cisplatin.
Water cluster
Cytotoxic activity
Ó 2010 Elsevier Ltd. All rights reserved.
1
. Introduction
Cisplatin, chemically named as cis-diamminedichloroplati-
The coordination chemistry of saccharin (sacH, also named 1,1-
dioxo-1,2-benzothiazol-3-one or o-benzosulfimide) is interesting.
SacH readily loses the amine hydrogen forming the saccharinate
monoanion (sac) in solutions. Owing to the presence of the imino,
carbonyl and sulfonyl donor sites, sac acts as a mono-, bi- or tri-
dentate polyfunctional ligand and coordinates many transition me-
tal ions, forming complexes from mononuclear species to
coordination polymers [7]. Moreover, these donor sites together
with the aromatic ring make sac as a good acceptor for non-cova-
num(II), is an extensively used cytotoxic anti-cancer drug [1].
Despite its remarkable success, several side effects such as the
dose-dependent nephrotoxicity, neuorotoxicity and emetogensis
are major medical problems associated with this drug [2]. Carbo-
platin, cis-diammine(cyclobutane-1,1-dicarboxylate-O,O )platinum(II),
and oxaliplatin, (1R,2R)-cyclohexane-1,2-diamine](ethanedioato-
0
0
O,O )platinum(II), were approved as the second, and third plati-
lent interactions such as hydrogen bonding and
p p stackings.
ꢀ ꢀ ꢀ
num-based drug generations, respectively [3,4]. Both platinum(II)
complexes met requirements of improving antitumor activity
and reducing disadvantages of cisplatin to some extent [5]. There-
fore, there are demands for the design and synthesis of new metal
complexes with high antitumor activity and less side effects in this
field. On the other hand, palladium(II) complexes show similar
chemical and structural properties with those of platinum(II) com-
plexes and are, therefore, expected to have antitumor activity. Re-
cent studies demonstrate that some palladium(II) complexes
exhibit a noticeable in vitro cytotoxic activity, comparable to stan-
dard platinum-based drugs, cisplatin, carboplatin and oxaliplatin
Our systematic studies have been directed to palladium(II) and
platinum(II) complexes of sac, since palladium and platinum com-
plexes of sac are rare and only a few complexes have been reported
[8–12]. We have recently reported several palladium(II) and plati-
0
0
00
num(II) complexes of sac with 2,2 :6 ,2 -terpyridine (terpy) [13],
0
0
2,2 -bipyridine (bpy) [14], 2,2 -dipyridylamine (dpya) [15], 2-ami-
nomethyl (ampy) and -ethylpyridines (aepy) [16]. The cytotoxic
activity of the palladium(II) and platinum(II) complexes with bpy
and dpya was not tested due to their low solubility in common sol-
vents. However, especially the palladium(II) complexes of terpy
have demonstrated a distinct antitumor activity against a lung can-
cer cell line (A549) compared to cisplatin [17]. To the best of our
knowledge, the structure of palladium(II) and platinum(II)-bis(2-
pyridylmethyl)amine (bpma) complexes with sac and their cycto-
toxic activity have not been reported. Herein, we report the
[
6].
⇑
Corresponding author.
E-mail address: vtyilmaz@uludag.edu.tr (V.T. Yilmaz).
0
277-5387/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.poly.2010.09.037

E. Guney et al. / Polyhedron 30 (2011) 114–122
115
0
,5
0
5
synthesis, characterization, crystal structures of new palladium(II)
and platinum(II) complexes of bpma with sac, namely [Pd(bpma)
7.97–7.85 (m, 2H, H ), 7.85–7.72 (d, 2H, H3,3 ), 7.72–7.43 (m,
sac
13
8H, H ), 5.18–4.98 (m, 2H, CH
2
), 4.86–4.58 (m, 2H, CH
2
).
C
(
(
sac)](sac)ꢀ2H
2
O (1), [Pt(bpma)(sac)](sac)ꢀ2H
2
O (2), [Pd(bpma)Cl]
O (4). In vitro cytotoxic-
NMR (400 MHz, DMSO-d ): d 167.72, 166.93, 166.74, 150.42,
150.12, 142.13, 140.87, 140.30, 136.03, 135.01, 131.58, 131.03,
6
sac)ꢀ2H O (3) and [Pt(bpma)(sac)]Clꢀ1.5H
2
2
ity studies were performed using Chinese hamster ovary cell line
CHO), a human lung carcinoma cell line (A549), and a rat brain tu-
mor (glioma) cell line (C6). The cytotoxic activity of new complexes
–4 was compared to that of the standard chemotherapeutic drug,
cisplatin.
125.30, 125.12, 124.01, 122.88, 122.51, 120.51, 119.13, 58.66. (So-
ꢂ1
(
lid KBr pellet):
m
(cm ) 3530m, 3381mb, 3258sh, 3089m, 3069m,
2862w, 1686vs, 1635vs, 1585m, 1479w, 1455m, 1331m, 1303vs,
1248vs, 1169vs, 1149vs, 1118s, 1056m, 1025w, 952m, 790m,
1
752m, 678m, 598s, 564m, 536m, 449w. UV–Vis (k/nm) (e/
3
ꢂ1
ꢂ1
dm mol cm ): 270 (19 217).
Pd(bpma)Cl](sac)ꢀ2H O (3): Yield 92%. M.p. 235–240 °C. Anal.
Calc. for C19 21ClN PdS: C, 40.8; H, 3.8; N, 10.0. Found: C,
0.6; H, 4.1; N, 9.8%. H NMR (400 MHz, DMSO-d
[
2
2
. Experimental
.1. Materials and measurements
O (M = PdII or Pt ) was prepared as described
H
4 5
O
1
4
6
): d 9.05 (s, 1H,
0
2
6,6
0
4,4
NH), 8.66–8.51 (d, 2H, H ), 8.26–8.08 (td, 2H, H ), 7.81–7.70
0
0
3
,3
5,5
sac
(
d, 2H, H ), 7.69–7.51 (m, 6H, H
and H ), 5.33–4.68 (s, 2H,
II
[
M(bpma)Cl]ClꢀH
2
13
CH
2
), 4.68–4.12 (s, 2H, CH
2
). C NMR (400 MHz, DMSO-d ): d
6
in the literature [18]. Other chemicals were purchased and used as
received. Elemental analyses for C, H, and N were performed using
a Costech elemental analyzer. UV–Vis spectra were measured on a
1
1
3
1
1
4
68.30, 166.61, 150.41, 145.73, 141.62, 135.26, 132.01, 131.43,
ꢂ1
25.33, 123.14, 122.94, 119.56, 58.72. (Solid KBr pellet):
m
(cm
)
396mb, 3136m, 3097m, 2966w, 2934w, 2874w, 1640vs, 1609m,
584m, 1479w, 1442m, 1330w, 1254vs, 1168m, 1136vs, 1054w,
010w, 955m, 775s, 722w, 684m, 604m, 549m, 528m, 489w,
ꢂ5
Shimadzu 1700UV spectrophotometer using 1 ꢁ 10 M EtOH/
water (1:1) solutions in the 200–800 nm range. IR spectra were re-
corded on a Thermo Nicolet 6700 FT-IR spectrophotometer as KBr
3
ꢂ1
ꢂ1
39w. UV–Vis (k/nm) (
Pt(bpma)(sac)]Clꢀ1.5H
comp.). Anal. Calc. for C19
Found: C, 35.8; H, 3.3; N, 8.7%. H NMR (400 MHz, DMSO-d
e
/dm mol cm ): 263 (14 119).
O (4): Yield 90%. M.p. 230–240 °C (de-
20ClN 4.5PtS: C, 35.7; H, 3.2; N, 8.8.
): d
ꢂ1
1
13
pellets in the frequency range 4000–400 cm
NMR spectra were recorded on a Varian Mercuryplus spectrome-
.
H NMR and
C
[
2
H
4
O
ꢂ3
ter. Excitation and emission spectra of 1 ꢁ 10 M EtOH/water
1
6
solutions (1:1) were recorded at room temperature with a Varian
Cary Eclipse spectrophotometer equipped with a Xe pulse lamp
of 75 kW. Thermal analysis curves (TG and DTA) were obtained
from a Seiko Exstar TG/DTA 6200 thermal analyzer in a flowing
6,6
0
0
4,4
8
7
4
.93–8.78 (d, 2H, H ), 8.69 (s, 1H, NH), 8.33–8.16 (td, 2H, H ),
0
0
3,3
5,5
sac
.86–7.72 (d, 2H, H ), 7.72–7.51 (m, 6H, H
and H ), 5.03–
). C NMR (400 MHz,
): d 167.85, 166.95, 148.81, 145.23, 140.88, 134.72,
31.56, 131.00, 125.14, 122.87, 122.48, 120.00, 58.82. (Solid KBr
13
2 2
.86 (q, 2H, CH ), 4.75–4.53 (d, d, 2H, CH
DMSO-d
1
6
ꢂ1
air atmosphere with a heating rate of 10 K min using a sample
size of 5–10 mg and platinum crucibles.
ꢂ1
pellet):
m (cm ) 3373mb, 3130m, 3101m, 2974w, 2934w,
2
874w, 1641vs, 1613m, 1584m, 1482w, 1442m, 1330w, 1254vs,
2.2. Synthesis of the palladium(II) and platinum(II) complexes
1168m, 1138vs, 1054w, 1016w, 955m, 777s, 724w, 685m, 605m,
3
ꢂ1
ꢂ1
5
50m, 528m, 494w, 450w. UV–Vis (k/nm) (e/dm mol cm ):
Complexes 1 and 2 were synthesized by the following method.
273 (23 056).
Solid [M(bpma)Cl]ClꢀH
2 3
O (0.5 mmol) and solid AgNO (1 mmol,
.17 g) were added to water (200 ml) and set to reflux for 6 h.
0
2.3. X-ray crystallography
The precipitate of AgCl was removed by filtering through Celite
paste to obtain a clear solution. The filtrate was concentrated to
The intensity data of the complexes 3 and 4 were collected
using a STOE IPDS 2 diffractometer with graphite-monochromated
2
5 ml and followed by the addition of Na(sac)ꢀ2H
2
O (1 mmol,
0
.24 g) and stirred at 60 °C for 30 min. Yellow polycrystalline solids
of 1 and 2 were obtained after a day.
Table 1
In order to prepare complexes of
3 and 4, the solid
Crystallographic data and structure refinement for 3 and 4.
[
M(bpma)Cl]ClꢀH
then, to this solution, a 5 ml aqueous solution of Na(sac)ꢀ2H
0.5 mmol, 0.12 g) was added and stirred at 60 °C for 2 h. The
2
O (0.5 mmol) was dissolved in 15 ml water and
Complex
3
4
2
O
Formula
M
T (K)
C
19
H
21ClN
4
O
5
PdS
C
19 4
H20ClN O4.5PtS
(
559.31
296(2)
0.71073
638.99
296(2)
0.71073
resulting clear solution was allowed to stand at room temperature
and yellow crystals of 3 and 4 were obtained after two days.
k (Å)
[
Pd(bpma)(sac)](sac)ꢀ2H
comp.). Anal. Calc. for C26
Found: C, 44.3; H, 3.8; N, 9.8%. H NMR (400 MHz, DMSO-d
2
O (1): Yield 85%. M.p. 235–237 °C (de-
PdS : C, 44.2; H, 3.6; N, 9.9.
): d
Crystal system
Space group
a (Å)
b (Å)
c (Å)
monoclinic
P2 /c
7.7947(4)
23.4307(16)
14.1668(8)
123.322(3)
2162.0(2)
4
1.719
1.118
1128
1.93–26.50
monoclinic
C2/c
H
25
N
5
O
8
2
1
1
22.8136(12)
7.4613(3)
26.8694(11)
116.580(3)
4090.3(3)
4
2.075
7.132
2472
1.69–25.64
6
0
0
6,6
4
,4
8
7
8
.70 (s, 1H, NH), 8.28–8.14 (td, 2H, H ), 8.14–8.00 (b, 2H, H ),
.95–7.82 (m, 2H, H ), 7.82–7.69 (d, 2H, H ), 7.69–7.48 (m,
H, H ), 5.45–4.80 (s, 2H, CH
400 MHz, DMSO-d
46.62, 142.51, 142.24, 136.06, 135.09, 132.88, 132.31, 126.40,
26.09, 124.12, 123.91, 123.74, 121.82, 120.34, 59.67. (Solid KBr
pellet):
0
0
5
,5
3,3
b (°)3
sac
13
), 4.80–4.25 (s, 2H, CH
2
). C NMR
V (Å )
2
Z
D
l
(
6
): d 169.43, 168.48, 167.65, 151.36, 150.22,
ꢂ3
calcd (g cm
)
1
1
ꢂ1
(mm
)
F(0 0 0)
h range (°)
Index range
ꢂ1
m
(cm
)
3527m, 3335mb, 3254sh, 3093m, 3069m,
ꢂ9 6 h 6 9, ꢂ29 6 k 6 26,
ꢂ25 6 h 6 27, ꢂ9 6 k 6 9,
2
1
7
865w, 1681s, 1635vs, 1587m, 1479w, 1456w, 1330w, 1299vs,
248vs, 1167vs, 1149vs, 1118s, 1055w, 1021w, 952m, 790m,
72w, 752m, 677m, 598s, 561w, 539m, 439w. UV–Vis (k/nm) (
ꢂ17 6 l 6 17
ꢂ32 6 l 6 32
Reflections
collected
13122
17137
e/
3
ꢂ1
ꢂ1
dm mol cm ): 264 (7585).
Pt(bpma)(sac)](sac)ꢀ2H O (2): Yield 82%. M.p. 245–250 °C (de-
comp.). Anal. Calc. for C26 PtS : C, 39.3; H, 3.2; N, 8.8.
Found: C, 39.3; H, 3.3; N, 8.9%. H NMR (400 MHz, DMSO-d ): d
Data/parameters
Goodness-of-fit
4453/292
1.013
3853/286
1.140
[
2
(
GOF) on F2
H
25
N
5
O
8
2
1
R
1
[I > 2r]
0.0426
0.1138
0.0393
0.0898
6
4,4
0
0
wR
2
8
.90 (s, 1H, NH), 8.56–8.38 (d, 2H, H6,6 ), 8.35–8.15 (td, 2H, H ),

1
16
E. Guney et al. / Polyhedron 30 (2011) 114–122
H
N
H
N
O
N
N
O
M
N
2
Na(sac) 2H O
N
2H O
2
N
N
2
o
H O 60 C
O
S
M
2
O
S
O
H O
2
O
NO3
(
aq)
reflux
2
AgNO3
1
or 2
H
N
N
N
Cl H O (M = PdII or PtII)
2
M
Cl
H O
2
Na(sac) 2H O
H
N
2
0oC
6
H
N
N
N
O
Pt
N
N
N
2H O
or
2
O
Cl 1.5H
O
2
N
O
Pd
Cl
S
S
O
O
O
3
4
Scheme 1. Synthesis of complexes 1–4.
Table 2
a
Selected FT-IR spectral data for 1–4 .
Assignment
1
2
3
4
m
m
m
m
m
m
m
m
(OH)
(NH)
(CH)
(CO)
3527m, 3335mb
3254sh
3093m–2865w
1681s, 1635vs
1330w
1299vs, 1248vs
1167vs, 1149vs
952m
3530m, 3381mb
3258sh
3089m–2862w
1686vs, 1635vs
1331m
1303vs, 1248vs
1169vs, 1149vs
952m
3396mb
3136m
3097m–2874w
1640vs
1330w
1254vs
3373mb
3130m
3101m–2874w
1641vs
1330w
1254vs
s
(CNS)
as(SO
(SO
as(CNS)
2
)
s
2
)
1168m, 1136vs
955m
1168m, 1138vs
955m
a
ꢂ1
Frequencies in cm . b = broad; m = medium; w = weak; vw = very weak; vs = very strong; s = strong; sh = shoulder.
Mo Ka radiation (k = 0.71073 Å). The structures were solved by di-
3
3'
2
rect methods and refined on F with the SHELX-97 program [19]. All
non-hydrogen atoms were found from the difference Fourier map
and refined anisotropically. Hydrogen atoms bonded to C and N
atoms were refined using a riding model, with C–H = 0.93–0.97 Å
and N–H = 0.91 Å. The constraint Uiso(H) = 1.2Ueq(C and N) or
H
N
4
5
4'
5'
N
N
1
.5Ueq(methyl C) was applied. The water hydrogen atoms are re-
fined freely. The details of data collection, refinement and crystal-
lographic data are summarized in Table 1.
6
6'
Scheme 2. Numbering of the protons of bpma.
2.4. In vitro cytotoxicity studies
Cisplatin was obtained from Sigma (St. Louis, MO, USA).
The human lung cell cancer cell line A549, Chinese hamster
ovary cell line CHO, and C6 glioma cell line were cultured in Ham’s
F-12 supplemented with penicillin G (100 U/ml), streptomycin
Stock concentrations of the complexes 1–4 were prepared in
culture medium, while that of cisplatin in DMSO, and the final
concentrations were prepared in culture medium in six different
(100
lg/ml), L-glutamine, and 10% fetal calf serum at 37 °C in a
concentrations ranging from 3.25 to 100
l
M were used.
humidified atmosphere containing 5% CO .
2

E. Guney et al. / Polyhedron 30 (2011) 114–122
117
The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbro-
mide (MTT) cell viability assay was performed as previously de-
trol, cells were incubated with 1 mM H
2
O
2
(positive control for cell
death). Untreated cells grown in culture medium were used for the
maximum viability control (negative control for cell death). MTT
was supplied as a stock solution (5 mg/ml PBS, pH 7.2) and ster-
ile-filtered. At the end of the treatment period, 20
tion was added to each well and then, after another 4 h at 37 °C,
scribed [20]. For the MTT assay, the cells were seeded in 200 ll
3
culture medium in triplicates at a density of 5 ꢁ 10 cells per well
in a 96-well plate. Cells were treated with different concentration
of each complex and cisplatin for 72 h. For minimum viability con-
ll of MTT solu-
Fig. 1. (a) Molecular structure of [Pd(bpma)Cl](sac)ꢀ2H
2
O (3). C–H hydrogen atoms were omitted for clarity. (b) A view of the tetrameric water cluster in 3. (c) Two-
dimensional network of 3, viewed down the a axis, showing [Pd(bpma)Cl] ions in a honeycomb structure formed by the hydrogen bonded sac ions and water molecules.
+

1
18
E. Guney et al. / Polyhedron 30 (2011) 114–122
1
00
l
l of solubilizing buffer (10% SDS dissolved in 0.01 N HCl) was
The signals in the 1H NMR spectra of complexes 1–4 are as-
signed according to the numbering diagram in Scheme 2. The spec-
tra of the metal complexes are similar. The NH proton appear as a
singlet in the range d 9.05–8.69 ppm. The pyridine protons appear
as four signals between 8.93 and 7.51 ppm, while the protons of
added to each well. After overnight incubation, the absorbance was
determined by an ELISA plate reader (FLASH Scan S12, Analytik
Jena, Germany) at 570 nm as a read-out for cell viability. The cyto-
toxicity is mainly determined by the IC50 value of each metal com-
plex. The IC50 values are drug concentrations that inhibit cell
growth for 50% with respect to control.
sac are observed as a multiplet in the range d 7.72–7.43 ppm. In
0
3
,3
the spectra of 3 and 4, the signals of the H
atom of the bpma li-
gand overlap with those of sac. The proton resonances of the CH
2
group of bpma appear as a broad doublet at d 5.00 and 4.50 ppm,
whereas they are observed as a singlet in the spectra of the re-
ported mixed-ligand bpma complexes of platinum(II) [18]. Con-
trary to the palladium(II) and platinum(II) complexes of terpy
with sac [13], the proton resonances of the coordinated and unco-
ordinated sac rings occur in the same frequency range. The signals
3
. Results and discussion
3.1. Synthesis
Complexes 1 and 2 are prepared by the reaction of the
+
II
II
13
[
M(bpma)Cl] ion (M = Pt or Pd ) with the stoichiometric amount
of Na(sac) after removal of the chlorides in [M(bpma)Cl]ClꢀH O by
using AgNO , while 3 and 4 are synthesized by the direct reaction
of [M(bpma)Cl]ClꢀH O with Na(sac) in solution (Scheme 1). Com-
plexes 1 and 2 can also be prepared using the similar method of
and 4, but the purity and yield of these compounds were found
to be low. Complexes 1 and 2 are formulated as [M(bpma)(sac)]-
O, in which the metal ions are coordinated by a sac ligand
of C NMR are consistent with the number of the C atoms in the
structures of the metal complexes.
2
3
2
3.3. Description of crystal structures
3
The molecular structure of complex 3 is shown in Fig. 1a. Se-
lected bond distances and angles are listed in Table 3. Complex 3
(
sac)ꢀ2H
2
+
consists of a [Pd(bpma)Cl] cation, a sac anion and two lattice
and a bpma ligand, while one sac anion remains as a counterion.
ꢂ
water molecules. The palladium(II) ion has a distorted square–pla-
nar coordination arrangement with a tridentate bpma ligand and a
The structures of 3 and 4 differ due to the coordination of Cl
ꢂ
and sac anions. In [Pd(bpma)Cl](sac)ꢀ2H
2
O (3), the Cl anion is in
ꢂ
Cl ligand. The distortion in the coordination geometry is mainly
the coordination sphere and sac is a counterion, whereas in
O (4) vice versa. All complexes were crys-
due to conformation of the bpma ligand, which gives rise to nar-
rowing the angles. The structure of the cation is identical to the
[
Pt(bpma)(sac)]Clꢀ1.5H
2
tallized, but only 3 and 4 yielded single crystals suitable for
X-ray diffraction. All complexes are air-stable, water-soluble and
obtained in high yields (over 80%).
chloride salt, [Pd(bpma)Cl]ClꢀH
2
O [21]. The Pd–N bond distances
are similar ranging from 2.007(4) to 2.014(3) Å, while the Pd–Cl
bond distance is 2.296(1) Å. These bond distances are typical for
the palladium(II) complexes containing bpma or ligands with the
bpma moiety [21–26]. The two py rings are close to planarity with
an angle of 4.20°.
3.2. Spectroscopic characterization
ꢂ5
The electronic spectra were measured using 1 ꢁ 10 M EtOH/
water (1:1) solutions of the ligands and their complexes. The free
bpma and Na(sac) display single absorption bands in the UV region
centered at 260 and 269 nm, respectively. These absorption bands
Table 3
a
Selected bond lengths [Å], angles [°] and hydrogen bonding parameters for 3 and 4 .
are attributed to the
p
–p* transitions. The spectra of 1–4 display
3
4
broad bands in the range of 264–273 nm, including transitions of
both bpma and sac ligands. The absence of shifts between the
absorption bands of the free ligands and the complexes clearly
indicates that the spectra of the metal complexes are dominated
mainly by ligand-based transitions.
M1–N1
M1–N2
M1–N3
M1–N4
2.014(3)
2.007(4)
2.012(4)
–
2.296(1)
82.80(15)
165.70(13)
–
83.84(15)
–
–
96.73(10)
175.42(11)
96.99(9)
2.026(6)
1.995(7)
2.010(6)
2.038(6)
–
82.6(2)
165.7(3)
97.0(2)
83.6(2)
178.9(2)
96.7(2)
–
M1–Cl1
N1–M1–N2
N1–M1–N3
N1–M1–N4
N2–M1–N3
N2–M1–N4
N3–M1–N4
N1–M1–Cl1
N2–M1–Cl1
N3–M1–Cl1
The selected IR bands of the complexes are listed in Table 2. The
IR spectra show one or two broad bands centered over 3340 nm,
due to the
m
(OH) vibrations of the lattice water molecules, while
ꢂ1
the single bands in the frequency range 3090–3140 cm
are
attributed to the NH stretching of the bpma ligand, which signifi-
cantly shifted to the low frequency region compared to that of
–
–
ꢂ1
the free bpma ligand (3293 cm ). The sac moiety is characterized
by the IR bands of the carbonyl and sulfonyl groups. Complexes 1
and
2
exhibit two sharp bands centered at ca. 1685 and
Hydrogen bonds
ꢂ1
1
635 cm due to the absorption of the carbonyl groups of both
D–HꢀꢀꢀA
3
D–H (Å)
Hꢀ ꢀ ꢀA (Å)
Dꢀ ꢀ ꢀA (Å)
D–Hꢀ ꢀ ꢀA (°)
coordinated and uncoordinated sac anions. But in the spectra of
3
and 4, the carbonyl groups appeared as sharp bands at around
i
O1W–H1Wꢀ ꢀ ꢀO2W
0.84(7)
0.83(9)
0.83(15)
0.83(11)
0.91
1.96(5)
2.31(9)
2.25(10)
2.07(11)
2.45
2.753(8)
3.128(5)
2.856(10)
2.885(6)
3.274(4)
157(11)
168(8)
130(11)
170(12)
151
ꢂ1
ii
1
640 cm . The splitting of the carbonyl bands in the spectra of 1
O1W–H11Wꢀ ꢀ ꢀO3
iii
O2W–H2Wꢀ ꢀ ꢀO1W
and 2 indicates the presence of two different sac anions as ob-
served in the IR spectra of the palladium(II) and platinum(II) com-
plexes of terpy with sac [13]. The antisymmetric (
symmetric ( ) stretchings of the SO group are observed as two
ii
O2W–H21Wꢀ ꢀ ꢀN4
iv
N2–H2Aꢀ ꢀ ꢀCl1
mas) and
4
m
s
2
N2–H2Aꢀ ꢀ ꢀCl1
0.91
2.29
3.132(7)
155
strong IR bands, which appeared two bands in 1 and 2 at ca.
O2W–H3Wꢀ ꢀ ꢀCl1
0.83(14)
0.84(14)
0.83(16)
2.54(10)
2.44(10)
2.60(8)
3.363(12)
3.206(16)
3.380(14)
170(15)
152(20)
155(18)
ꢂ1
v
1
300–1248 and 1170–1149 cm , respectively, while in 3 and 4
O1W–H1Wꢀ ꢀ ꢀO3
ꢂ1
vi
appeared as a single band at 1254 and 1138 cm , respectively.
The
gands appear at ca. 1330 and 955 cm , respectively.
O1W–H2Wꢀ ꢀ ꢀCl1
m
s
and
m
as stretching modes of the CNS moiety of the sac li-
a
Symmetry codes: (i) x + 1, y, z; (ii) ꢂx + 1, y + 1/2, ꢂz + 3/2; (iii) ꢂx + 1, ꢂy + 2,
ꢂz + 1; (iv) ꢂx + 2, ꢂy + 1, ꢂz + 1; (v) x + 1/2, y ꢂ 1/2, z; (vi) ꢂx + 3/2, y + 1/2, ꢂz + 3/2.
ꢂ1

E. Guney et al. / Polyhedron 30 (2011) 114–122
119
In the solid state, complex 3 exhibits an interesting hydrogen
bonding scheme as listed in Table 3. The [Pd(bpma)Cl] cations
water molecules are also involved in hydrogen bonds with the
adjacent sac ions to form the honeycomb structure in the crystal-
lographic bc plane as illustrated in Fig 1c. The [Pd(bpma)Cl] cat-
ions occupy the centers of the honeycomb network and form
weak C–Hꢀ ꢀ ꢀO hydrogen bonds with the carbonyl and sulfonyl O
atoms of the uncoordinated sac anions.
+
+
are doubly bridged into dimeric units by N–Hꢀ ꢀ ꢀCl hydrogen bonds,
and orientation is head-to-tail. Moreover, the dimeric units are
reinforced by a Pd–Pd interaction with a distance of 3.475 Å. In
addition, the lattice water molecules O1W and O2W are connected
with two symmetrically related water molecules by O1W–
H1Wꢀ ꢀ ꢀO2W and O2W–H2Wꢀ ꢀ ꢀO1W hydrogen bonding interac-
The molecular structure of 4 is shown in Fig. 2a and selected
bond distances and angles are listed in Table 3. The complex is
+
tions, leading to a D2h-symmetric cyclic (H
O)
2 4
water cluster (Fig
composed of [Pt(bpma)(sac)] cation, a chloride counterion and lat-
1
b). The water tetramer is similar to that observed in
tice water molecules. The platinum(II) ion is coordinated by a tri-
dentate bpma ligand and a sac ligand, forming a distorted
square–planar geometry of PtN . In contrast to 3, the sac anion
4
0
[
Cd
3
(pbtz)
(DMF) (H
3 4 2
2 4 2 4
O) ]ꢀ(DMF) (H O) , where 2H-pbtz is 5,5 -
(
1,4-phenylene)bis(1H-tetrazole) [27]. The four co-crystallized
Fig. 2. (a) Molecular structure of [Pt(bpma)(sac)]Clꢀ1.5H
dimensional hydrogen-bonded chain in 4.
2
O (4). C–H hydrogen atoms were omitted for clarity. (b) A view of the trimeric water cluster in 4. (c) A view of one-

1
20
E. Guney et al. / Polyhedron 30 (2011) 114–122
coordinates the metal and the chloride anion remains outside the
coordination sphere as a counterion. In order to reduce steric hin-
drance, the sac ligand tends to be oriented perpendicularly to the
coordination plane with a dihedral angle of 79.67°. Both py rings
of bpma are almost co-planar as in 3. The Pt–N(bpma) bond
lengths are typical of those found in platinum(II) complexes con-
taining the dpya ligand [18,28], while the Pt–N(sac) bond distance
of 2.038(6) Å is within the expected range of platinum(II)–sac com-
plexes [1.990(15)–2.064(6) Å] [10,11,13–15].
3.4. Photoluminescence
The room temperature emission spectra of complexes 1–4 are
presented in Fig. 3. The ligands and their metal complexes are
weakly fluorescent upon excitation at their absorption wave-
lengths. However, when bpma and sac are excited at 357 and
285 nm, respectively, they moderately fluoresce at ca. 430 nm.
On the other hand, complexes 1–3 have a single emission band,
being emissive at 432 nm when excited at ca. 300 nm. Complex 1
showed maximum emission intensity. The resemblance of the
emission spectra of 1–3 with those of the ligands indicates that
the fluorescence of the complexes is due to the ligand-based
In the crystal lattice of 4, two crystallographically independent
water molecules (O1W and O2W) are observed and they are asso-
ciated by hydrogen bonds to form a water trimer. The water tri-
mers form hydrogen bonds with the neighboring chloride anions
forming an irregular hexagonal ring (Fig 2b). The water molecules
p–p* transitions at the excited state. Since both sac and bpma
ligands are emissive at the similar wavelength (ca. 430 nm), the
transitions in the metal complexes may be originated from both
ligands. Upon excitation at 335 nm, complex 4 exhibits three emis-
sion bands at 374, 432 and 553 nm. The higher energy bands may
+
and chloride anions are further connected to the [Pt(bpma)(sac)]
cations by strong N–Hꢀ ꢀ ꢀCl and OW–Hꢀ ꢀ ꢀCl hydrogen bonds, lead-
ing to one-dimensional chain running along the b axis (Fig. 2c).
The hydrogen-bonded chains are extended into a three-dimen-
be attributed to the p–p* transitions, while the band at 553 nm can
sional network by weak
p
(bpma)ꢀ ꢀ ꢀ
p
(bpma) stacking interactions
tentatively assigned to a metal-to-ligand charge transfer (MLCT) at
the excited state [29,30].
where the shortest Cgꢀ ꢀ ꢀCg contact is 3.795 Å (Cg is the center of
gravity of the ring).
3.5. Thermal behavior
The thermal stability and thermal decomposition behavior of
complexes 1–4 were studied by a simultaneous TG/DTA analysis
in the atmosphere of air. The thermoanalytical data are presented
in Table 4. In general, the palladium complexes (1 and 3) decom-
pose in four stages, while the platinum complexes (2 and 4) in
Table 5
IC50 values of complexes 1–4 and cisplatin.
Complex
IC50 (lM)
A546a
C6b
CHOc
[
[
[
[
Pd(bpma)(sac)](sac)ꢀ2H
Pt(bpma)(sac)](sac)ꢀ2H
Pd(bpma)Cl](sac)ꢀ2H O (3)
Pt(bpma)(sac)]Clꢀ1.5H O (4)
2
O (1)
O (2)
43
>100
23
>100
20
65
>100
43
>100
14
21
>100
12
>100
11
2
2
2
Cisplatin
a
b
c
Human lung cancer cell.
Glioma cell.
Normal cell.
Fig. 3. Emission spectra of 1–4 in EtOH/water solutions (1:1) at room temperature.
Table 4
TG/DTA data for 1–4.
a
Mass loss (%)b
Stage
Temperature range (°C)
DTAmax (°C)
Solid residue
1
1
2
3
4
30–111
68 (+)
5.3 (5.1)
[Pd(bpma)(sac)](sac)
–
PdO
Pd
200–380
380–573
810–878
236 (ꢂ), 253 (ꢂ)
42.5 (77.0)
34.6 (77.0)
1.6 (2.2)
567 (ꢂ)
817 (+)
Total: 84.0 (84.9)
2
3
1
2
3
35–113
221–385
385–505
75 (+)
4.5 (4.5)
[Pt(bpma)(sac)](sac)
247 (ꢂ)
23.2 (25.1)
46.8 (45.9)
Total: 74.5 (75.5)
[Pt(sac)
Pt
2
]
501 (ꢂ)
1
2
3
4
37–127
87 (+)
4.7 (6.4)
[Pd(bpma)Cl](sac)
[PdCl(sac)]
PdO
222–380
380–647
815–849
235(+), 277 (ꢂ)
36.5 (35.6)
33.9 (32.6)
3.4 (2.9)
590 (ꢂ)
834 (+)
Pd
Total: 78.5 (77.5)
4
1
2
3
45–94
233–372
372–514
79 (+)
5.6 (4.2)
[Pt(bpma)(sac)]Cl
–
Pt
252 (ꢂ)
26.0 (65.3)
39.1 (65.3)
Total: 70.7 (69.5)
504 (ꢂ)
a
(
+) and (ꢂ) donate endothermic and exothermic processes.
b
Calculated values are given in parentheses.

E. Guney et al. / Polyhedron 30 (2011) 114–122
121
three stages. All complexes dehydrate in the range of 30–115 °C
and the mass losses are consistent with the water content of the
metal complexes. The anhydrous complexes are stable up to
doses of complexes 1–4 and cisplatin. Viability was assessed and
then the IC50 values were calculated (Table 5). The complexes
yielded interesting results. Based on the IC50 values, complex 3
was found to be the most potent/cytotoxic one. In addition, com-
plexes 2 and 4 resulted in no cytotoxic effect on the cell lines used
(Fig. 4). This may imply that they have either no biologically active
in cells, or not being taken up by cells, or pumped out by cells
through the multidrug resistance proteins. However, palladium
complexes are considered that they might always be promising in
medicine as anti-cancer agents and encourage further studies in
the field [6]. Various cells were treated with a large number of pal-
ladium complexes, but A549 and C6 cells have received less atten-
tion [6]. In this work, we have selected these cells in order to
explore their behavior towards the new complexes. The results of
the present study clearly show that complex 3 was especially potent
in inducing cell death in the cell lines used, especially being compa-
rable with cisplatin in the case of A549 cells. Regarding the palla-
dium complexes in the literature, IC50 values seem to vary in a
2
30 °C and the exothermic elimination of bpma begins over this
temperature. It is followed by the highly exothermic decomposi-
tion of the sac moiety. In case of complexes 1 and 4, the decompo-
sition processes of bpma and sac overlap and it is impossible to
estimate the mass losses associated with the individual ligands.
The end product for the palladium(II) complexes is PdO, which
decomposes to metallic Pd over ca. 800 °C, while the platinum(II)
complexes produce metallic Pt at ca. 510 °C. The overall mass
losses determined by the TG analyses agree well with those calcu-
lated to PdO or Pt as the final product of thermal decomposition
(Table 4).
3.6. Cytotoxic activity
The cytotoxic effects of complexes 1–4 were assessed by the MTT
assay. A549, CHO and C6 cells were treated for 72 h with increasing
broad range from 0.5 [31] to 2500
different cell lines in our study ranged from 12 to 43
are clinically achievable doses. In another study in which two differ-
ent palladium complexes, [Pd(dmnp) Cl ] and [Pd (dmnp) Cl
dmnp = 2,6-dimethyl-4-nitro-pyridine), used in A549 cells [33], it
was reported that the corresponding IC50 values ranged from 8.4
to 21.3 g/ml (estimated as 17.4 to 32.3 M). These values are in
good agreement with our result of complex 3 that was 23 M for
the same cell line. On the other hand, extremely low IC50 values
0.5 and 0.75 M) were reported for C6 cells treated with the
palladium(II) complexes [Pd(C2-dmba)(N )(dppp)] and [Pd(C2-N-
lM [32]. IC50 values for 3 with
l
M, which
2
2
2
2
4
]
(
l
l
l
(
l
3
dmba)(cis-dppet)](N
3
) (dmba = N,N-dimethylbenzylamine, dppp =
ꢂ
1
,3-bis(diphenylphosphino)propane and N
3
= azide) [31].
4
. Conclusions
A series of novel palladium(II) and platinum(II) complexes of
bpma with sac have been synthesized and characterized by elemen-
tal analysis, FT-IR and NMR spectroscopy. Two representative com-
plexes, [Pd(bpma)Cl](sac)ꢀ2H
2
O (3) and [Pt(bpma)(sac)]Clꢀ1.5H
2
O
(
4), were subjected to X-ray crystallographic analysis. The crystal
structures exhibit that the palladium(II) and platinum(II) ions
achieve a typical square planar arrangement. The complexes show
photoluminescence in solution. The cytotoxicity of the complexes
was evaluated in the normal cell line (CHO) and two cancer cell
lines (A549 and C6). Significant differences have been found in
the in vitro studies of the palladium(II) and platinum(II) complexes.
The platinum(II) complexes (2 and 4) were found to be less active
against all cells. However, the palladium(II) complexes (1 and 3)
show significant cytotoxicity on the sensitive cell lines. In particu-
lar, complex 3 exhibits a cytotoxicity, close to cisplatin and deserves
further exploration in vitro and in vivo screening.
Acknowledgements
This work is a part of a research project 106T664. We thank
TUBITAK for the financial support given to the project.
Appendix A. Supplementary data
CCDC 783745 and 783746 contain the supplementary crystallo-
graphic data for complexes 3 and 4. These data can be obtained
free of charge via http://www.ccdc.cam.ac.uk/conts/retriev-
ing.html, or from the Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033;
or e-mail: deposit@ccdc.cam.ac.uk.
Fig. 4. Cytotoxicity of complexes 1–4 and cisplatin against A549, C6 and CHO cells.

1
22
E. Guney et al. / Polyhedron 30 (2011) 114–122
[
18] B. Pitteri, G. Marangoni, L. Cattalini, F. Visentin, V. Bertolasi, P. Gilli, Polyhedron
0 (2001) 869.
References
2
[
[
19] G.M. Sheldrick, Acta Cryst. A64 (2008) 112.
20] E. Ulukaya, F. Ozdikicioglu, A.Y. Oral, M. Demirci, Toxicol. In Vitro 22 (2008)
[
[
1] B. Rosenberg, L. Van Camp, T. Krigas, Nature 205 (1965) 698.
2] L.R. Kelland, N.P. Farrell, Platinum-Based Drugs in Cancer Therapy, Humana,
Totowa, 2000.
232.
[
[
[
[
[
[
21] Z.D. Bugarcic, G. Liehr, R. van Eldik, J. Chem. Soc., Dalton Trans. (2002) 951.
22] M.G.B. Drew, M.J. Riedl, J. Rodgers, J. Chem. Soc., Dalton Trans. 1 (1972) 234.
23] Z.H. Zhang, X.H. Bu, Z.A. Zhu, Y.T. Chen, Polyhedron 15 (1996) 2787.
24] A. Hazell, C.J. McKenzie, L.P. Nielsen, J. Chem. Soc., Dalton Trans. 1 (1998) 1751.
25] Z. Nagy, I. Fabian, A. Benyei, Imre Sovago, J. Inorg. Biochem. 94 (2003) 291.
26] S.I. Kirin, T. Wheyhermuller, K. Merz, N. Metzler-Nolte, Z. Anorg. Allg. Chem.
[
[
[
3] K.R. Harrap, Cancer Treat. Rev. 12 (1985) 21.
4] Y. Kidani, K. Inagaki, J. Med. Chem. 21 (1978) 1315.
5] L.M. Pasetto, R.M. D’Andrea, A.A. Brandes, E. Rossi, S. Monfardini, Crit. Rev.
Oncol. Hematom. 60 (2006) 59.
6] A. Garoufis, S.K. Hadjikakou, N. Hadjiliadis, Coord. Chem. Rev. 253 (2009) 1384.
7] E.J. Baran, V.T. Yilmaz, Coord. Chem. Rev. 250 (2006) 1980.
8] D.M. Roundhill, Inorg. Chem. 9 (1970) 254.
[
[
[
[
633 (2007) 2706.
[
[
27] J. Tao, Z.J. Ma, R.B. Huang, L.S. Zhen, Inorg. Chem. 43 (2004) 6133.
28] B. Pitteri, G. Annibale, G. Marangoni, V. Bertolasi, V. Ferretti, Polyhedron 21
9] W. Henderson, B.K. Nicholson, D.C. Chung, Acta Cryst. E58 (2002) m432.
[
[
10] W. Henderson, B.K. Nicholson, L.J. McCaffrey, Inorg. Chim. Acta 285 (1999) 145.
11] M. Cavicchioli, A.C. Massabni, E.E. Castellano, L.P.B. Sabeh, C.M. Costa-Neto,
Inorg. Chim. Acta 360 (2007) 3055.
12] N.S.C.R. Kumar, I.V.P. Raj, A. Sudalai, J. Mol. Catal. A: Chem. 269 (2007) 218.
13] E. Guney, V.T. Yilmaz, A. Sengul, O. Buyukgungor, Inorg. Chim. Acta 363 (2010)
(
2002) 2283.
[
29] W. Paw, S.D. Cummings, M.A. Mansour, W.B. Connick, D.K. Geiger, R. Eisenberg,
Coord. Chem. Rev. 171 (1998) 125.
30] R.C. Evans, P. Douglas, C.J. Winscom, Coord. Chem. Rev. 250 (2006) 2093.
31] A.C.F. Caires, E.T. Almeida, A.E. Mauro, J.P. Hemerly, S.R. Valentini, Quim. Nova
[
[
[
[
4
38.
22 (1999) 329.
[
[
[
14] E. Guney, V.T. Yilmaz, C. Kazak, Polyhedron 29 (2010) 1285.
15] E. Guney, V.T. Yilmaz, O. Buyukgungor, Inorg. Chim. Acta 363 (2010) 2416.
16] V.T. Yilmaz, A. Ertem, E. Guney, O. Buyukgungor, Z. Anorg. Allg. Chem. 636
[
[
32] F.K. Keter, S. Kanyanda, S.S. Lyantagaye, J. Darkwa, D.J. Rees, M. Meyer, Cancer
Chemother. Pharmacol. 63 (2008) 127.
33] J. Kuduk-Jaworska, A. Puszko, M. Kubiak, M. Pelczynska, J. Inorg. Biochem. 98
(
2010) 610.
(
2004) 1447.
[
17] E. Ulukaya, F. Ari, E. Guney, V.T. Yilmaz, in preparation.