Dinuclear bridged biphosphinic and mononuclear cyclopalladated complexes of benzylamines: Synthesis, structural characterization and antitumor activity

Article abstract of DOI:10.1016/j.poly.2012.11.002

Reaction of chloro-bridged dinuclear palladacycles, [Pd₂{(C,N)- C₆H₄CH₂NH(R)}₂(μ-Cl) ₂] (R = Et (1a); R = t-Bu (1b)) with pyridine and PPh₃ in the 1:2 M ratio at room temperature was used to prepare the mononuclear complexes, [Pd(C,N)-C₆H₄CH₂NH(R)Cl(L)] (R = Et and L = Py (2a); R = t-Bu and L = PPh₃ (2b)). Bridged biphosphinic palladacycle, [Pd₂(C,N-dmba)₂(μ-dppe)(Cl)₂] (2c), (where dmba = N,N-dimethylbenzylamine and dppe = 1,2- bis(diphenylphosphino)ethane) has been also synthesized. The complexes were fully characterized by elemental analysis, IR and NMR spectroscopies. In addition, the solid structures of palladacycles 2a and 2c were studied by single-crystal X-ray crystallography. In vitro cytotoxicity assays of the cyclopalladated complexes, (2a-2c) and cisplatin were evaluated against the Hela (human cervix carcinoma), HT-29 (colon cancer cell line), K562 (leukemia cancer cell line) and MDA-MB-468 (human breast carcinoma). The complexes 2a-2c display IC₅₀ values in a μM range better than that of the antitumor drug cisplatin.

Full text of DOI:10.1016/j.poly.2012.11.002

Polyhedron 50 (2012) 187–192
Contents lists available at SciVerse ScienceDirect
Polyhedron
journal homepage: www.elsevier.com/locate/poly
Dinuclear bridged biphosphinic and mononuclear cyclopalladated complexes of
benzylamines: Synthesis, structural characterization and antitumor activity
a
b
c
Kazem Karami a, , Mahboubeh Hosseini kharat , Hojjat Sadeghi-Aliabadi , Janusz Lipkowski ,
⇑
Mina Mirian b
a Department of Chemistry, Isfahan University of Technology, Isfahan 84156/83111, Iran
b Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
c Institute of Physical Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Reaction of chloro-bridged dinuclear palladacycles, [Pd2{(C,N)-C6H4CH2NH(R)}2(l-Cl)2] (R = Et (1a); R = t-
Bu (1b)) with pyridine and PPh3 in the 1:2 M ratio at room temperature was used to prepare the mono-
nuclear complexes, [Pd(C,N)-C6H4CH2NH(R)Cl(L)] (R = Et and L = Py (2a); R = t-Bu and L = PPh3 (2b)).
Bridged biphosphinic palladacycle, [Pd2(C,N-dmba)2(l-dppe)(Cl)2] (2c), (where dmba = N,N-dimethylb-
Received 30 September 2012
Accepted 2 November 2012
Available online 12 November 2012
enzylamine and dppe = 1,2-bis(diphenylphosphino)ethane) has been also synthesized. The complexes
were fully characterized by elemental analysis, IR and NMR spectroscopies. In addition, the solid struc-
tures of palladacycles 2a and 2c were studied by single-crystal X-ray crystallography. In vitro cytotoxicity
assays of the cyclopalladated complexes, (2aÀ2c) and cisplatin were evaluated against the Hela (human
cervix carcinoma), HT-29 (colon cancer cell line), K562 (leukemia cancer cell line) and MDA-MB-468
Keywords:
Benzylamine
Cyclopalladated complexes
Bridged biphosphinic
Crystal structure
Antitumor activity
(human breast carcinoma). The complexes 2aÀ2c display IC50 values in a
lM range better than that of
the antitumor drug cisplatin.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
namically stable and kinetically inert Pd(II) complexes [12–17]. In
particular, palladacycles are nowadays attracting attention as po-
tential anticancer agents [18,19] because it is known that their
intercalative mode of cytotoxic action is strictly related to the pres-
ence of a planar and highly stable aromatic metallacycle [20]. It has
been found that some cyclopalladated complexes containing pla-
nar structures such as aromatic and aliphatic amines may bind to
DNA by means of intercalative or coordinate covalent interactions
[21]. Within this context, tertiary amine N,N-dimethylbenzylamine
(dmba) represents good choice to prepare new ortho-cyclopalla-
dated complexes with promising in vivo and in vitro cytotoxicity
[6,22,23]. Some cyclopalladated complexes based on biphosphinic
ligands were also reported by Rodrigues et al. [24] and these palla-
dacycle–dppe complexes have been investigated for their antitu-
mor activity in a syngeneic B16F10 murine melanoma model. In
our present work, we describe the synthesis, spectroscopic and
structural characterization of three cyclopalladated complexes,
chloro bridging palladacycle 1a, mononuclear palladacycle 2a
and biphosphinic palladacycle 2c. The cytotoxicity of the mononu-
clear palladacycle 2b, which was previously characterized [25],
was reported here. We have also evaluated the in vitro cytotoxic
activity of the compounds 2a, 2b and 2c against the Hela, HT-29,
K562 and MDA-MB-468 human cancer cell lines. For comparison
purpose, the cytotoxicity of cisplatin, a standard antitumor drug,
was evaluated under the same conditions.
Platinum-based antitumor drugs like cisplatin, carboplatin and
oxaliplatin are the most active and widely used clinical agents
for the treatment of advanced cancer. However, severe side effects
such as nephrotoxicity, neurotoxicity, and drug resistance force the
limitation of the dose as well as further use of them in clinical
treatment [1–4]. Non-platinum metal complexes with potential
for the clinical treatment such as those of ruthenium, gallium,
and gold have demonstrated impressive antitumor properties in
preclinical studies [5]. Palladium(II) complexes are intriguing alter-
native candidates for metallo-antitumor drugs due to their struc-
tural and thermodynamic similarities to platinum(II) complexes
[6,7]. Several studies demonstrate that palladium derivates exhibit
a noticeable cytotoxic activity, similarly to standard platinum-
based drugs used as a reference, and show fewer side effects
relative to other heavy metal anticancer compounds [8]. They
show ligand-exchange kinetics 105 times greater than the Pt(II)
analogous [9], which may facilitate the hydrolysis of the leaving
groups that dissociate readily in solution, before the complex
reaches the pharmacological target [10,11]. To overcome their high
lability, chelating ligands have been used to afford high thermody-
⇑
Corresponding author. Tel.: +98 3113913239; fax: +98 3113912350.
E-mail address: karami@cc.iut.ac.ir (K. Karami).
0277-5387/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.poly.2012.11.002

188
K. Karami et al. / Polyhedron 50 (2012) 187–192
2.5. Crystallography
2. Experimental
2.1. General
X-ray diffraction experiments were done at 100 K with the use
of Agilent SuperNova single crystal diffractometer (Mo K radia-
a
tion). Analytical numeric absorption correction using a multifac-
eted crystal model based on expressions derived by R.C. Clark &
J.S. Reid was made [26]. The structures were solved by direct meth-
ods using the SHELXS97 program and refined with the use of SHELXL
(Sheldrick 2008) program. Hydrogen atoms were added in the
calculated positions and were riding on their respective carbons
during the refinement.
Starting materials and solvents were purchased from Sigma–
Aldrich or Alfa Aesar and used without further purification.
Cisplatin was gifted from Isfahan University of Medical Sciences.
Infrared spectra were recorded on a FT-IR JASCO 680 spectropho-
tometer in the spectral range 4000–400 cmÀ1 using the KBr pellets
technique. NMR spectra were measured on a Bruker spectrometer
at 400.13 MHz (1H) and 161.97 MHz (31P) using standard pulse
sequences at 298 K. Elemental analysis was performed on a Leco,
CHNS-932 apparatus. Palladacycles 1b, 1c and [Pd{(C,N)-C6H4CH2
2.6. Cell culture and MTT assay
NH(Et)}(l-OAc)]2 were obtained using procedure described earlier
[25].
Hela (human cervix carcinoma), HT-29 (colon cancer cell line),
K562 (leukemia cancer cell line) and MDA-MB-468 (human breast
carcinoma) were purchased from Pasture Institute, Tehran, Iran.
They were grown in PRMI 1640 was supplemented with 10% of
fetal calf serum, 5 mL of penicillin/streptomycin (50 IU mLÀ1 and
2.2. Synthesis of [Pd2{(C,N)-C6H4CH2NH(Et)}2(
l-Cl)2] (1a)
500
l
gmLÀ1, respectively), NaHCO3 (1 g) and 5 mL of
L-glutamine
To a suspension of the [Pd{(C,N)-C6H4CH2NH(Et)}(
l-OAc)]2
(0.10 g, 0.17 mmol) in methanol was added excess NaCl and the
resulting mixture stirred for 12 h at room temperature. A green
precipitate was formed which was filtered and washed with water
and then air-dried to give 1a. Yield: 64%. IR (KBr, cmÀ1):
(2 mM). Completed media was sterilized through 0.22
l
m microbi-
ological filters after preparation and kept at 4 °C before using.
The cytotoxic effects of complexes 2aÀ2c against Hela, HT-29,
K562 and MDA-MB-468 cell lines were determined by a rapid col-
orimetric assay using 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyl
tetrazolium bromide (MTT) for cell growth inhibition and com-
pared with untreated control [27]. The test is based on the reduc-
tion of the yellow tetrazolium salt MTT to a violet formazan
product via the mithocondrial succinate dehyrogenase in living
cells. The color can then be quantified by spectrophotometric
means. The am⁄⁄⁄ount of violet color produced is directly propor-
m
(NH) = 3233, 3194. 1H NMR (DMSO-d6, ppm): d = 1.18 (t, 3H,
3
CH3, JHH = 6.8 Hz), 2.9 (m, 2H, CH2), 3.78 (dd, Ha, CHaH,
3
2
2JHH = 15.2 Hz, JHH = 2.8 Hz), 4.23 (dd, Hb, CHbH, JHH = 14.8 Hz,
3JHH = 5.2 Hz), 6.18 (sbr, 1H, NH), 6.87–7.64 (m, C6H4, JHH = 9.2 -
3
Hz). Anal. Calc. for C18H24N2Cl2Pd2: C, 39.15; H, 4.3; N, 5.07. Found:
C, 39.17; H, 4.25; N, 5.02%.
tional to the number of viable cells. Briefly 200 lL of cells
(1 Â 105 cells/mL) were seeded in 96-well micro plates and incu-
2.3. Synthesis of [Pd(C,N)-C6H4CH2NH(Et)Cl(Py)] (2a)
bated for 24 h (37 °C, 5% CO2 air humidified). Then, 20 lL of final
concentration of each compound was added and incubated for an-
other 72 h in the same condition. To evaluate cell survival, each
To a suspension of palladacycle 1a (0.05 g, 0.09 mmol) in
dichloromethane (15 mL) was added pyridine (14.6 lL,
well was incubated with 20
lL of MTT solution (5 mg/mL in phos-
0.18 mmol). The resulting solution was stirred for 6 h and then fil-
tered through a plug of MgSO4. The filtrate was concentrated to ca.
2 mL and then n-hexane (15 mL) was added to precipitate 2a as a
pale yellow solid, which was collected and air-dried. Yield: 62%. IR
phate-buffered saline) for 3 h and afterward, 150
lL of the media
of each well was gently replaced with DMSO and mixed to dissolve
insoluble formazan crystals. The MTT-formazan absorption was
measured at 540 nm using an ELISA plate reader. The percentage
of inhibition was calculated using the ratio between the absor-
bance of treated and untreated cells.
(KBr, cmÀ1):
m
(NH) = 3136, 3117. 1H NMR (DMSO-d6, ppm):
d = 1.19 (m, 3H, CH3), 1.24 (m, 3H, CH3), 2.93 (m br, 4H, CH2),
2
3
3.81 (m, 2Ha, CHaH), 4.12 (dd, Hb, CHbH, JHH = 15 Hz, JHH = 6 Hz),
2
3
4.23 (dd, Hb, CHbH, JHH = 14.8 Hz, JHH = 5.6 Hz), 5.88 (d, C6H4,
3JHH = 7.2 Hz), 6.07 (s br, 1H, NH), 6.19 (s br, 1H, NH), 6.67 (t, Py,
3JHH = 6.8 Hz), 6.86–7.43 (m, C6H4), 7.54–8.81 (m, Py). Anal. Calc.
for C14H17N2ClPd: C, 47.34; H, 4.82; N, 7.88. Found: C, 46.89; H,
4.67; N, 7.67%.
3. Results and discussion
3.1. Synthesis and characterization of cyclopalladated complexes
We have previously described the formation of five-membered,
acetato-bridged dinuclear palladacycles of the general formula
2.4. Synthesis of [Pd2(C,N-dmba)2(l-dppe)(Cl)2] (2c)
[Pd(benzylamine)(l-OAc)]2 from the reaction of the secondary
benzylamines PhCH2NH(Et) or PhCH2N(Me)2 with Pd(OAc)2 [25].
Treatment of acetato-bridged complexes with an excess of NaCl
in methanol afforded the corresponding chloro-bridged dimers
1a, 1b and 1c. The mononuclear palladacycles 2a and 2b [25] were
obtained by the reaction of 1a and 1b with two equivalents of Py
(Pyridine) and PPh3, respectively (Scheme 1). The complexes were
fully characterized by elemental analysis, IR and NMR spectrosco-
pies. The crystal structure of 2a has been also solved by X-ray
diffraction method.
To a suspension of the palladacycle 1c (0.08 g, 0.14 mmol) in
dichloromethane (15 mL) was added dppe (0.06 g, 0.14 mmol).
The reaction mixture was stirred for 2 h at room temperature
and then filtered through a plug of MgSO4. The filtrate was con-
centrated to ca. 2 mL and to this concentrated solution, n-hex-
ane (15 mL) was added to precipitate a bright yellow solid,
which was collected and air-dried. White crystals of 2c were
obtained from CH2Cl2-hexane. Yield: 85%. 1H NMR (CDCl3,
ppm): d = 1.7 (s br, 2H, CH2), 2.78 (s br, 12H, CH3), 4.02 (s br,
4H, CH2 (dppe)), 6.36–6.9 (m, 8H, C6H4), 7.28–7.92 (m, 20H,
Ph);31P-{1H} NMR (CDCl3, ppm): d = 37.4 (s). Anal. Calc. for C44-
H48N2P2Cl2Pd2: C, 55.5; H, 5.08; N, 2.94. Found: C, 54.67; H,
5.02; N, 2.90%.
The 1H NMR spectrum of 1a shows only one set of signals,
which indicates that the dinuclear palladacycle 1a consists of only
one geometrical isomer in the solution phase which we propose to
be the anti type isomer, as has been reported for most halogen-
bridged dimers containing orthopalladated amines [28,29]. In the

K. Karami et al. / Polyhedron 50 (2012) 187–192
189
Scheme 1. Representation of the cleavage reaction of the dimeric cyclopalladated complexes 1a and 1b by pyridine and PPh3.
IR spectrum of 2a, the
m
(NÀH) band (that is sensitive to complex-
crystallize in the monoclinic P21/n space group. Fig. 1 shows an OR-
TEP view of the X-ray molecular structure of 2a and also gives
selected bond lengths and angles. The mononuclear complex 2a
crystallizes with two independent molecules (hereafter called
molecule A and B) in the asymmetric unit. The X-ray molecular
structure confirms the structure proposed upon 1H NMR analysis.
Each palladium metal is coordinated in a distorted square-planar
geometry by a chloride anion, a N atom of a pyridine ligand and
ation) is appeared at 3136 and 3117 cmÀ1 for asymmetric and
symmetric stretching, respectively, whereas for N-coordination, a
lowering of the
m
(NÀH) bond is expected [30]. In the 1H NMR spec-
tra of the mononuclear complexes 2a and 2b, the methylene pro-
tons are diastereotopic resulting in formation of two separated
signals. Moreover, the 1H NMR spectra show similar patterns for
the H3ÀH5 aromatic protons of amine, but H6 is significantly
shifted to lower frequencies for 2a (5.88 ppm) and 2b (6.05 ppm)
because of the anisotropic shielding from the phenyl or pyridine
ring [31]. Concerning the 1H NMR spectrum of 2a, two sets of sig-
nals owing to the two diastreoisomers are observed. The nitrogen
atom of benzylamine is a chiral center which can has R and S con-
figurations. The ratio of these stereoisomers is at 1:1 on the basis of
the intensity ratio of the corresponding signals.
a
chelating N-benzylethylamine-C,N moiety forming a five-
membered cyclopalladated ring through the N1, C3 atoms for mol-
ecule A and N3, C17 atoms for molecule B. The deviations of C3 and
C17 from the planes formed by N1, Pd1, N2, Cl1 and N3, Pd2, N4,
Cl2 are 0.130 and 0.108 Å for molecules A and B, respectively.
The angles around each palladium deviate from the ideal value
due to the small bite angle of the cyclometalated ligand. For in-
stance, in the molecule A, the N1ÀPd1ÀC3 bite angle is 81.32(9)°,
while the opposite angle N2ÀPd1ÀCl1 of 88.95(6)° deviates from
the ideal value of 90°. Due to these steric constraints, the other
two angles around the Pd center were opened up and were signif-
The dimeric palladacycle 1c reacted with an equivalent of dppe
to afford a bright yellow solid. Analysis by 1H and 31P NMR spec-
troscopies showed the possible presence of a by-product 3c
(Scheme 2). In the 1H NMR spectrum, minor signals for the meth-
ylene protons of dppe and chelated benzylamine were observed at
2.60 and 4.25 ppm, which was attributed to 3c. Moreover, the 31P
NMR spectroscopy showed the appearance of a major signal at
37.43 ppm (s), corresponding to the dppe-bridged dimer 2c, as well
as a trace amount of a 3c displaying doublets centered at 40.7 and
60.6 ppm. The formation of monomeric by-products was observed
in the synthesis of the other dppe-bridged complexes [32,33]. The
structure of 2c, which could be isolated in pure form by recrystal-
lization, was confirmed by NMR spectroscopy, elemental analysis,
and single crystal X-ray diffraction.
icantly
larger
than
90°;
N1ÀPd1ÀCl1 = 96.19(6)°
and
N2ÀPd1ÀC3 = 93.57(9)°. The dihedral angles between the two
planes formed by N1, Pd1, C3 and N2, Pd1, Cl1 for molecule A
and N3, Pd2, C17 and N4, Pd2, Cl2 for molecule B are 3.62 and
3.54°, respectively. The PdÀC bond distances (1.982(2) and
1.978(2) Å for A and B, respectively) are within the range usually
reported for five-membered palladacycles [34]. In the crystal, the
adjacent molecules are linked by an intermolecular hydrogen bond
between the chlorine atom and the NH group (Fig. 2).
Biphosphinic palladacycle 2c crystallizes with one molecule in
the asymmetric unit. Fig. 3 shows an ORTEP view of 2c and the
selected bond lengths and angles. The center of mass of the
bridged dimer lies on an inversion center and only half of the mol-
ecule is crystallographically unique. The Pd1. . .Pd1i distance of
8.1652(4) Å suggests no interaction between the two Pd atoms,
so two metal centers in the dimer are not directly bonded. The
coordination sphere around the each palladium(II) center is com-
pleted by a chloro group trans-positioned to the carbopalladated
site and a phosphorus atom from the dppe ligand trans to the N1
3.2. Crystal structure of complexes 2a and 2c
To further clarify the coordination environment around the me-
tal center, representative molecular structures of 2a and 2c have
been ascertained by X-ray diffraction studies. Single crystals of pal-
ladacycles 2a and 2c were obtained by slow evaporation of a con-
centrated CH2Cl2Àhexane solution. The crystal data and structural
refinement parameters are listed in Table 1. Both palladacycles
Scheme 2. Synthesis of a dppe bridged palladacycle 2c.

190
K. Karami et al. / Polyhedron 50 (2012) 187–192
Table 1
X-ray crystallography data.
atom increases the PdÀN length. The PdÀCPalladate bond distance in
2c (2.022(2) Å) also lies within the normal range for palladium
dmba complexes [23].
2a
2c
Empirical formula
Formula weight
T (K)
Crystal system
Space group
a (Å)
C
14H17ClN2Pd
C44H48Cl2N2P2Pd2
950.48
100(1)
monoclinic
P21/n
8.7620(7)
23.0810(12)
10.4370(6)
90
104.14(1)
90
2046.82(362)
2
1.12
1.542
355.15
100(1)
monoclinic
P21/n
11.9483(1)
16.8268(2)
14.0423(1)
90
92.391(1)
90
2820.77(5)
8
1.49
1.656
1396
2.95–28.86
6947
3.3. Cytotoxicity
The cytotoxic activity of cyclopalladated complexes 2aÀ2c were
evaluated by means of the standard MTT-dye reduction assay
which is a widely used method in biological evaluation. Recently,
new palladium (II) complexes were assessed using this method
[38].
The complexes 2aÀ2c were tested against four human cancer
cell lines: Hela, HT-29, K562, and MDA-MB-468. The results of
cytotoxic activity in vitro are expressed as IC50 À the concentration
required to inhibit a 50% of the cell growth when the cells are ex-
posed to the compounds (Table 2). Cisplatin was included in the
assay as a positive control. The complexes were not readily soluble
in water hence they were first dissolved in DMSO (dimethylsulfox-
ide) which is effective in accelerating the rate of chloride displace-
ment from a complex [39], so fairly good relationship generally
could be seen between activity and solubility of the complexes.
b (Å)
c (Å)
a
(°)
b (°)
c
(°)
V (Å3)
Z
l
(mmÀ1
)
Dcal (Mg mÀ3
F(000)
)
964
2.97–28.81
3882
h ranges (°)
Independent reflections
Data/restraints/
6947/0/325
3882/0/235
parameters
Goodness-of-fit on F2
Final R indices
1.098
2.243
R1 = 0.0264,
wR2 = 0.0622
R1 = 0.0281,
wR2 = 0.0630
R1 = 0.0222,
wR2 = 0.0613
R1 = 0.0231,
wR2 = 0.061
Palladacycles 2aÀ2c have displayed IC50 values in a
lM range bet-
R indices (all data)
ter than that of the antitumor drug cisplatin. Bridged biphosphinic
palladacycle 2c was more effective than mononuclear palladacy-
cles 2a and 2b, especially against the K562 cell line with an IC50
of 1.4 lM, which maybe partly ascribed to its greater solubility
and lipophilicity that may facilitate transport through the cellular
membranes. The lipophilicity of the bridged palladacycle 2c can
be related to the presence of two bulky PPh2 groups from dppe.
In addition, the dppe bridge leads to the more flexibility in the
structure and makes more interactions with DNA.
Palladacycle 2c was found to be 24.4, 17.8, 5.9 and 2 times more
cytotoxic than cisplatin against the Hela, HT-29, K562 and MDA-
MB-468 human cancer cell lines, respectively. In another study
bridged biphosphinic palladacycle of 1,4 benzodiazepine was
atom, resulting in a slightly distorted square-planar geometry. The
Pd atom deviates very slightly (0.055 Å) from the plane containing
C16, N1, Cl1 and P1. The dihedral angle between the two planes
formed by C15, N1, C16, Pd1 and C15, C14, N1 is 30.50°. The bond
angle at Pd1 involving the bidentate ligand N1ÀPd1ÀC16 equals
83.25(7)°, is smaller than the other three bond angles at the palla-
dium center. Other cyclopalladated compounds bearing the C, N-
chelated dmba ligand exhibit comparable NÀPdÀC angles
[23,34,35]. In comparison of 2a and 2c, the PdÀN distance
(2.155(15) Å) for 2c is longer than the Pd1ÀN1 (2.076(2) Å) and
Pd2ÀN3 (2.071(2) Å) distances for 2a, due to the greater trans
influence of the P atom with respect to the N2 and N4 atoms
[36]. The PdÀN distance (2.155(15) Å) for 2c is also longer than
the analogous distances reported in other bridged biphosphinic
palladacycles (2.086(5)À2.099(8) Å) [32,37]. These data suggested
that the sterically demanding of the benzyl groups at the nitrogen
tested against K562 cell [34] and IC50 value of 4.3 lM was reported
which is in agreement with our result of palladacycle 2c against
the same cell line. A slightly decreasing in the activity of the mono-
nuclear complex 2b compared to 2a is probably related to the pres-
ence of three bulky phenyl groups in this complex which sterically
hinder the metalÀDNA interactions and also prevent direct hydro-
gen bonding with the biological molecules. The IC50 values for
three palladacycles with different cell lines in our study ranged
Fig. 1. ORTEP diagram for palladacycle 2a with ellipsoids drawn at the 70% probability level. The hydrogen atoms have been omitted for clarity. Selected bond lengths (Å), and
angles (°): Pd1ÀCl1 2.429(6), Pd1ÀN2 2.052(2), Pd1ÀN1 2.076(2), Pd1ÀC3 1.982(2), C3ÀPd1ÀN1 81.32(9), C3ÀPd1ÀN2 93.57(9), N2ÀPd1ÀCl1 88.95(6), N1ÀPd1ÀCl1
96.19(6), N1ÀPd1ÀN2 174.84(8), C3ÀPd1ÀCl1 175.70(7) (molecule A); Pd2ÀCl2 2.430(6), Pd2ÀN4 2.041(2), Pd2ÀN3 2.071(2), Pd2ÀC17 1.978(2), C17ÀPd2ÀN3 82.81(9),
C17ÀPd2ÀN4 93.05(9), N4ÀPd2ÀCl2 87.69(6), N3ÀPd2ÀCl2 96.52(6), N3ÀPd2ÀN4 174.70(8), C17ÀPd2ÀCl2 178.67(8) (molecule B).

K. Karami et al. / Polyhedron 50 (2012) 187–192
191
Fig. 2. Part of the crystal packing of 2a. The adjacent molecules are linked through intermolecular N–HÁ Á ÁCl hydrogen bonds (dotted lines).
Fig. 3. ORTEP diagram for palladacycle 2c with ellipsoids drawn at the 70% probability level. The hydrogen atoms have been omitted for clarity. The center of mass of the
dimeric molecule lies on an inversion center. The symmetry transformation used to generate equivalent atoms is: (i) Àx, Ày, Àz. Selected bond lengths (Å), and angles (°):
Pd1ÀCl1 2.424(5), Pd1ÀP1 2.255(5), Pd1ÀN1 2.155(15), Pd1ÀC16 2.022(2), P1ÀC1 1.842(2), C1ÀC1i 1.525(3), C16ÀPd1ÀN1 83.25(7), C16ÀPd1ÀP1 93.4(5), P1ÀPd1ÀCl1
93.7(17), N1ÀPd1ÀCl1 89.7(5), N1ÀPd1ÀP1 176.4(5), C16ÀPd1ÀCl1 170.09(5), C1ÀP1ÀPd1 110.6(6), P1ÀC1ÀC1i 116.63(17), C14ÀN1ÀPd1 106.9(11), C22ÀN1ÀPd1
115.5(12), Pd1ÀN1ÀC14ÀC15 32.16(17), Pd1ÀC16ÀC15ÀC14 12.9(2), P1ÀPd1ÀC16ÀC17 13.2(18).
Table 2
4. Conclusion
Cytotoxicity data (IC50) of the complexes 2a, 2b, 2c and control compound (cisplatin)
against Hela, HT-29, K562 and MDA-MB-468 cancer cell lines.
Herein, the synthesis and characterization of new palladacycles
Complex
IC50 value (
Hela
lM
SD)
were reported. The structure of cyclopalladated complexes 2a and
2c was confirmed by the single-crystal X-ray diffraction. In the
structures, the palladium atom shows a slightly distorted square-
planar geometry. The biological properties of the complexes
2aÀ2c were investigated by evaluation of their antitumor activity.
The results suggested that the three complexes exhibit noticeable
cytotoxic activity towards the all cell lines. They show inhibitory
HT-29
K562
MDA-MB-468
2a
2b
2c
Cisplatin
7.5 0.6
7.7 0.4
2.1 0.05
51.3 2.8
4.3 0.04
5.3 0.28
2.2 0.04
39.2 3.1
3.7 0.04
3.3 0.04
1.4 0.06
8.3 0.6
2.4 0.05
3.3 0.05
2.3 0.01
4.8 0.07
effect against tumor cell lines in low lM ranges which are compa-
from 1.4 to 7.7
l
M, which are clinically achievable doses. Thus,
rable with a standard metal-based chemotherapeutical drug, cis-
platin. Further studies of the DNA binding properties of these
complexes will be necessary to understand the mechanism of
action.
2aÀ2c are considered as agents with potential antitumor activity,
and can therefore be candidates for further stages of screening
in vitro and/or in vivo.

192
K. Karami et al. / Polyhedron 50 (2012) 187–192
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