Synthesis, characterisation and in vitro evaluation of palladium(II) iminophosphine complexes for anticancer activity

Article abstract of DOI:10.1007/s11243-012-9674-4

Palladium(II) complexes have been obtained from the reactions of the iminophosphine ligands, (L1-L7), respectively, with [PdCl₂(COD)] and [PdMeCl(COD)] in CH₂Cl₂ at room temperature. The palladium(II) complexes were charac

Full text of DOI:10.1007/s11243-012-9674-4

Transition Met Chem (2013) 38:165–172
DOI 10.1007/s11243-012-9674-4
Synthesis, characterisation and in vitro evaluation
of palladium(II) iminophosphine complexes for anticancer activity
•
Haleden Chiririwa John R. Moss
•
•
•
Denver Hendricks Reinout Meijboom
Alfred Muller
Received: 2 September 2012 / Accepted: 9 November 2012 / Published online: 14 December 2012
Ó Springer Science+Business Media Dordrecht 2012
Abstract Palladium(II) complexes have been obtained
from the reactions of the iminophosphine ligands, (L1–L7),
respectively, with [PdCl2(COD)] and [PdMeCl(COD)] in
CH2Cl2 at room temperature. The palladium(II) complexes
were characterised using elemental analysis, electro spray
ionisation–mass spectrometry (ESI–MS), NMR (1H and
31P), IR spectroscopy and X-ray diffraction studies. Single-
crystal X-ray diffraction analysis for complexes 2, 7 and 8
revealed that the complexes exhibited a slightly distorted
square planar geometry. In vitro cytotoxic study results
show that the palladium complexes exhibit moderate
activity and block the proliferation of WHCO1 cells with
an IC50 range of 19.02–45.27 lM, and IC50 range of
10.03–68.54 lM for the KYSE450 cell lines.
P donor atoms display a variety of coordination possibilities
beyond those of P–P or N–N ligands [4]. The hard ligand
components can readily dissociate from a soft metal centre
generating a vacant site on the metal ion for substrate bind-
ing. These ligands show a particular behaviour in binding to
soft metal centres such as palladium(II) and platinum(II) that
make their complexes good precursors in catalytic processes
[5–8]. Among the most studied ligands with this character-
istic are the pyridylphosphines and iminophosphines which
have been widely reported in complexes with ruthenium [9],
palladium [10], rhodium [11] and iridium [12]. In the last 3
decades, the interest towards platinum(II) and palladium(II)
complexes containing N and S donor ligands has increased,
resulting in the development of metal-based drugs exhibiting
high anticancer activity together with reduced toxicity,
compared with cisplatin and analogous compounds [13].
The development of palladium anticancer drugs has not
been promising, probably because their design has been
based on structure–activity considerations generated from
platinum antitumor drugs. Bearing in mind that Pd(II)
complexes are about 105 times more reactive than their
Pt(II) analogues, the low antitumoral activity of Pd com-
pounds has been attributed to very rapid hydrolysis of the
leaving groups that dissociate readily in solution, leading to
reactive species far from their pharmacological targets
[14]. Palladium is a suitable candidate for metallodrugs
because it displays structural properties similar to those of
platinum and also exhibits promising cytotoxicity.
Introduction
During recent years, there has been a growing interest in the
chemistry of ligands with both ‘hard’ nitrogen and ‘soft’
phosphorus donor atoms [1–3]. Metal complexes with N and
John R. Moss: Deceased.
H. Chiririwa ꢀ J. R. Moss
Department of Chemistry, University of Cape Town,
Private Bag, Rondebosch 7701, South Africa
H. Chiririwa ꢀ D. Hendricks
As part of our continuing interest in the synthesis of
transition metal complexes of biological molecules, we have
investigated the coordination behaviour of iminophosphines
towards palladium(II), with a view to develop new transition
metal pharmaceuticals. This paper describes the synthesis,
structural characterisation and preliminary biological activ-
ity of palladium iminophosphine complexes.
Division of Medical Biochemistry, University of Cape Town,
Private Bag X3, Observatory 7935, South Africa
H. Chiririwa (&) ꢀ R. Meijboom ꢀ A. Muller
Research Centre for Synthesis and Catalysis, Department of
Chemistry, University of Johannesburg, Auckland Park,
PO Box 524, Johannesburg 2006, South Africa
e-mail: harrychiririwa@yahoo.com
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Transition Met Chem (2013) 38:165–172
Experimental
Each experiment was repeated at least three times.
All manipulations were carried out under an atmosphere of
nitrogen or argon using standard Schlenk techniques. All
other glassware was thoroughly dried at 210 °C for at least
4 h prior to use. [PdCl2(COD)], [PdMeCl(COD)], com-
plexes 1, 2 and ligands L1–L7 were prepared according to
known literature procedures [15–17]. Melting points were
determined on a Kofler hotstage microscope (Reichart
Thermovar) and are uncorrected. Microanalysis data were
obtained using a Carlo Erba EA1108 elemental analyser.
Infrared spectra were recorded on a Perkin-Elmer 1000
FT–IR spectrometer, as KBr discs for solids. All data are
given in wavenumbers (cm-1). 1H, 13C and 31P NMR
spectra were recorded on a Varian Unity-400 instrument.
Mass spectra (EI) were recorded using a JEOL-MATE(II)
GC–MS instrument. X-ray intensity data were collected on
a Nonius Kappa-CCD diffractometer with 1.5 kW graphite
monochromated Mo-Ka radiation.
General procedure for the preparation of palladium(II)
dichloride complexes (1–7)
To a solution of the appropriate ligand (L1–L7) in dry
CH2Cl2 (10 ml) was added an equimolar amount of [PdCl2
(COD)] dissolved in dry CH2Cl2 (10 ml). The reaction was
allowed to stir at room temperature for 4 h before reducing
the solvent to ca 5 ml and precipitating the products using
hexane. The products were filtered off, washed with Et2O
and dried under vacuum.
Complex 1
Yellow crystalline solid. Yield 70 %. m.p.: 158–160 °C.
C22H22Cl2NPd: Found: C, 51.69 %; H, 4.12 %; N, 2.72 %.
Calcd. C, 51.94 %; H, 4.36 %; N, 2.75 %. IR(tC=N, imine:
cm-1): -1632(s). 1H-NMR: (400 MHz, CDCl3) dH 8.85 (s, 1H,
Ha) 7.89 (m, 3H, ArH) 7.66 (dd, 4H, J = 6.3 Hz, J = 7.9 Hz,
ArH) 7.55 (ddd, 7H, J = 2.0 Hz, J = 5.2 Hz, J = 8.5 Hz,
ArH) 2.95 (dddd, 2H, J = 5.4 Hz, J = 8.3 Hz, J = 13.8 Hz,
J = 16.7 Hz, Hb) 1.18 (m, 2H, Hc) 0.53 (t, 3H, J = 7.3 Hz, Hd)
31P NMR: d 30.85 (s). EI–MS: m/z 437.30 [M–2Cl]?.
MTT assay
Thousand five hundred cells were seeded per well in 90 ll
DMEM in 96 well plates. Cells were incubated for 24 h,
then, test samples were plated at a range of concentrations
in 10 ll media, with a final concentration of 0.2 % DMSO.
After 48 h of incubation, the cells were observed under a
phase contrast microscope and the general appearance of
the cells together with confluency status and presence of
precipitate if any was recorded.
Complex 2
Yellow powder. Yield 82 %. m.p. 168–170 °C.
C22H22Cl2NPPd: Found: C, 51.79 %; H, 4.12 %; N, 2.52 %.
Calcd. C, 51.94 %; H, 4.36 %; N, 2.75 %. IR(tC=N, imine:
cm-1): -1630(s). 1H NMR: (dmso-d6) dH 8.02 (s, 1H) 7.72
(m, 2H, ArH) 7.51 (m, 11H, ArH) 6.94 (ddd, 1H, J = 0.5 Hz,
J = 7.7 Hz, J = 10.6 Hz, Ar) 5.57 (dtd, 1H, J = 0.6 Hz,
J = 6.4 Hz, J = 13.0 Hz) 1.16 (d, 6H, J = 6.6 Hz). 31P
NMR: d 31.62 (s). EI–MS: m/z 474.68 [M–Cl]?.
Ten microlitres of MTT reagent was added per well at
the end of the experiment, and the plates incubated for 4 h
at 37 °C. Hundred microlitres of solubilisation solution
was then added to each well, and plates were incubated at
37 °C overnight. After 16 h, the plates were read at
595 nm on an Anthos microplate reader 2001.
Complex 3
IC50 data analysis
Yellow crystalline powder. Yield 75 %. m.p. 200–202 °C.
C31H32Cl2NPPd: Found: C, 59.19 %; H 5.12 %; N 2.42 %.
Calcd. C, 59.39 %; H, 5.15 %; N 2.23 %. IR(tC=N, imine:
cm-1): -1624(s). 1H NMR: (dmso-d6) dH 8.74 (s, 1H,
HC = N) 7.58 (m, 14H ArH) 7.16 (m, 7.16, 4H, ArH) 1.19
(d, 6H, J = 6.7 Hz, –CH3) 0.77 (t, 6H, J = 6.3 Hz, –CH3).
The resulting dose–response curve was analysed by non-
linear regression analysis [nonlinear regression (sigmoidal
dose–response with variable slope)] using GraphPad Prism
version 4.00 for Windows (GraphPad Software, San Diego
California USA, www.graphpad.com) to yield an IC50 value
which is specific for the compound against that particular
cell line. The formula used is as follows:
13C NMR: (dmso-d6) d 169.31, 135.28, 133.94 (d, J
=
CP
11.0 Hz), 132.89, 129.74 (d, JCP = 11.8 Hz), 128.90,
123.80, 28.73, 27.99, 24.31, 23.42. 31P NMR: d 33.34 (s).
EI–MS: m/z 591.44 [M–Cl]?.
ðtop ꢁ bottomÞ
Y =
bottom þ 1 þ 10ðlog IC50ꢁXÞꢂhillslope
where Y is the absorbance reading, X is the concentration of
the compound, top is the maximum absorbance, bottom is
the minimum absorbance (also the absorbance of the med-
ium blank) and the hillslope is the gradient of the curve.
Complex 4
Yellow powder. Yield 76 %. m.p.: 200–202 °C. C26H22Cl2
NPPd: Found: C, 56.26 %; H 3.72 %; N, 2.72 %. Calcd. C,
123

Transition Met Chem (2013) 38:165–172
167
56.09 %; H, 3.98 %; N, 2.52 %. IR(tC=N, imine: cm-1):
-1627(s). 1H-NMR: (400 MHz, d6-dmso) dH 7.81 (m, 1H)
7.63 (m, 1H) 7.49 (m, 1H) 7.09 (m, 1H) 7.08 (m, 1H) 6.91
(dd, 1H, J = 4.6 Hz, J = 10.9 Hz) 6.49 (dd, 1H, J 1.1 Hz,
J = 8.1 Hz) 4.22 (t, 2H, J = 12.6 Hz). 31P NMR: d 34.11 (s).
ca 5 ml and precipitating out the products with hexane,
filtering under gravity and washing the precipitate with dry
Et2O and drying under vacuum for 4 h.
Complex 8
Complex 5
Pale orange powder. Yield 85 %. m.p.: 168–170 °C.
C27H25ClNPPd: Found: C, 60.72 %; H, 4.51 %; N, 2.81 %.
Calcd. C, 60.46 %; H, 4.70 %; N, 2.61 %. IR(tC=N, imine:
cm-1): -1628(s). 1H-NMR: (400 MHz, CDCl3) dH 8.81 (s,
1H, Ha) 7.91 (dd, 1H, J = 4.3 Hz, J = 46.3 Hz, ArH) 7.83
(t, J = 7.6 Hz, ArH) 7.69 (t, 1H, J = 7.4 Hz, ArH) 7.56
(m, 2H, ArH) 7.45 (dt, 4H, J = 2.3 Hz, 7.6 Hz, ArH) 7.29
(m, 1H, ArH) 7.18 (m, 8H, ArH) 7.09 (dd, 1H, J = 7.7 Hz,
J = 10.5 Hz, ArH) 5.10 (s, 2H, Hb) 0.18 (d, 3H,
J = 1.2 Hz, CH3). 31P NMR: d 38.5 (s). EI–MS: m/z
521.75 [M–CH3]?.
Yellow powder. Yield 70 % yield m.p.: 210–212 °C.
C25H21N2PPd: Found: C, 53.69 %; H 3.92 %; N 4.92 %.
Calcd. C, 53.84 %; H, 3.80 %; N 5.02 %. IR(tC=N, imine:
cm-1): -1626(s). 1H-NMR: (400 MHz, d6-dmso) dH 8.82 (s,
1H, Ha) 8.66 (d, 1H, J = 2.3 Hz, Hg) 8.49 (d, 1H,
J = 3.8 Hz, Hf), 8.34 (s, 1H, Ha) 7.91 (dd, 1H, J = 4.1 Hz,
J = 7.3 Hz, He) 7.68 (m, 2H, ArH) 7.55 (dd, 4H,
J = 6.7 Hz, J = 8.3 Hz, ArH) 7.43 (m, 4H, ArH) 7.14 (m,
1H, Hd) 5.45 (s, 2H, Hb) 31P NMR: d 37.4 (s). EI–MS: m/z
557.75 [M]?.
Complex 9
Complex 6
Pale yellow powder. Yield 85 %. m.p.: 178–180 °C.
C26H24ClN2PPd: Found: C, 58.19 %; H, 4.12 %; N,
5.54 %. Calcd. C, 58.12 %; H, 4.50 %; N, 5.21 %.
Yellow powder. Yield 78 %. m.p.: 200–202 °C. C24H20Cl2
NOPPd: Found: C, 52.59 %; H, 3.42 %; N, 2.72 %. Calcd.
C, 52.72 %; H, 3.69 %; N, 2.56 %. IR(tC=N, imine: cm-1):
-1630(s). 1H-NMR: (400 MHz, d6-dmso) 8.72 (s, 1H, Ha)
7.98–8.08 (m, 1H, ArH) 7.75(t, 1H, J = 1.5 Hz, J =
7.7 Hz, ArH) 7.58 (m, 2H, ArH) 7.45 (td, 4H, J = 2.9 Hz,
4.8 Hz, ArH) 7.05 (dd, 1H, J = 8.1 Hz, J = 1.8 Hz, Hf)
7.24 (m, 5H, ArH) 6.55 (d, 1H, J = 2.9 Hz, He) 6.38 (dd,
1H, J = 2.9 Hz, Hd) 5.78 (t, 1H, J = 1.5 Hz, J = 7.7 Hz,
ArH) 5.56 (s, 2H, Hb) 31P NMR: d 32.3(s). EI–MS: m/z
546.71 [M]?.
1
IR(tC=N, imine: cm-1): -1628(s). H NMR: (400 MHz,
CDCl3) dH 8.80 (d, 1H, J = 1.6 Hz, Hf) 8.63 (s, 1H, Ha)
8.47 (dd, 1H, J = 1.6 Hz, J = 4.8 Hz, Hg) 7.88 (ddd, 1H,
J = 1.3 Hz, J = 4.1 Hz, J = 7.6 Hz, ArH) 7.66 (m, 2H,
ArH) 7.79 (tt, 1H, J = 1.4 Hz, J = 7.6 Hz, ArH) 7.52 (m,
2H, ArH) 7.39 (ddd, 4H, J = 2.0 Hz, J = 5.1 Hz,
J = 7.3 Hz, ArH) 5.41 (s, 2H, Hb) 7.11 (m, 6H) 0.26 (d,
3H, J = 3.3 Hz, CH3). 31P NMR: d 37.4 (s) EI–MS: m/z
537.13 [M]?.
Complex 7
Complex 10
Orange crystalline powder. Yield 65 %. m.p. 234–235 °C.
C24H20Cl2NPPdS: Found: C, 51.48 %; H, 3.32 %; N,
2.72 %, S, 5.86. Calcd. C, 51.22 %; H, 3.58 %; N, 2.49 %,
Yellow powder. Yield 75 %. m.p.: 195–196 °C. C25H23
ClNOPPd: Found: C, 57.19 %; H, 4.12 %; N, 2.72 %.
Calc. C, 57.07 %; H, 4.40 %; N, 2.66 %. IR(tC=N, imine:
cm-1): -1631(s). 1H-NMR: (400 MHz, CDCl3) dH 8.65 (s,
1H, Ha) 7.86 (ddd, 1H, J = 1.2 Hz, J = 4.1 Hz,
J = 7.4 Hz, ArH) 7.77 (t, 1H, J = 7.5 Hz, ArH) 7.66 (t,
1H, J = 7.5 Hz, ArH) 7.51 (m, 6H, ArH) 7.34 (m, 4H,
ArH) 7.18 (m, 1H, Hf) 6.43 (m, 1H, Hd) 5.39 (s, 2H, Hb)
0.23 (d, 3H, J = 3.2 Hz, CH3). 31P NMR: d 37.6 (s). EI–
MS: m/z 526.03 [M]?.
1
S, 5.70 %. IR(tC=N, imine: cm-1): -1628(s). H NMR:
(dmso-d6) dH 8.80 (s, 1H) 8.03–7.92 (m, 2H, ArH)
7.86–7.93 (m, 1H, ArH) 7.74 (m, 1H, ArH) 7.52–7.60 (m,
2H, ArH) 7.40 (td, 4H, J = 4.9 Hz, J = 2.9 Hz, ArH) 7.18
(dd, 4H, J = 7.8 Hz, J = 4.9 Hz, ArH) 6.99–7.07 (m, 2H)
6.90 (dd, 1H, J = 2.9 Hz, J = 2.0 Hz) 5.66 (s, 2H). 31P
NMR: d 31.8(s). EI–MS: m/z 562.73 [M]?.
General procedure for the preparation of palladium(II)
Complex 11
chloromethyl complexes (8–11)
Pale yellow powder. Yield 80 %. m.p.: 186–188 °C.
C25H23ClNPPdS: Found: C, 55.19 %; H, 4.08 %; N,
2.38 %; S, 6.05. Calcd. C, 55.36 %; H, 4.27 %; N, 2.58 %;
S, 5.91. IR(tC=N, imine: cm-1): -1629(s). 1H-NMR:
(400 MHz, CDCl3) dH 8.76 (s, 1H, Ha) 7.87 (m, 1H) 7.80
To the appropriate ligand (L4–L7) in dry CH2Cl2 (10 ml)
was added [PdMeCl(COD)] also in dry CH2Cl2 (10 ml) in
an equimolar amount. The reaction was allowed to stir at
room temperature for ca 2 h before reducing the solvent to
123

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Transition Met Chem (2013) 38:165–172
(t, 1H, J = 7.5 Hz) 7.69 (t, 1H, J = 7.5 Hz, Hf) 7.54 (dd,
2H, J = 6.5 Hz, J = 8.2 Hz, ArH) 7.44 (m, 5H, ArH) 7.17
(td, 5H, J = 6.1 Hz, J = 12.2 Hz, ArH) 7.07 (d, 1H,
J = 2.4 Hz, He) 6.96 (dd, 1H, J = 3.5 Hz, J = 5.1 Hz,
Hd) 5.57 (s, 2H, Hb) 0.25 (d, 3H, J = 3.3 Hz, CH3) 31P
NMR: d 37.6 (s). EI–MS: m/z 531.8 [M–CH3]?.
graphic interface X-seed [18]. Crystallographic data for the
structure determinations are listed in Table 1.
Results and discussion
X-ray crystal structure determination
Treatment of the iminophosphine ligands (L1–L7), with
[PdCl2(COD)] in CH2Cl2 at room temperature afforded the
palladium iminophosphine complexes 1–7, respectively,
and palladium methylchloride complexes 8–11 were
obtained from the reaction of ligands (L4–L7) (Scheme 1).
The reaction was allowed to stir in dry CH2Cl2 at room
temperature for 8 h. The solvent was reduced and product
precipitated out with Et2O. Further precipitation was
achieved by allowing the products to crystallize slowly at
-16 °C giving pale yellow/orange crystals in reasonable
yields. These palladium methylchloride complexes are much
more soluble than the palladium dichloride complexes.
Crystals suitable for single-crystal X-ray diffraction for
complexes 2, 7 and 8 were obtained by slow evaporation of
a dmso-d6-CH2Cl2 solution of the complex at room tem-
perature. All X-ray intensity data were collected on a
Nonius Kappa-CCD diffractometer with 1.5 kW graphite
monochromated Mo-Ka radiation.
The structures were solved by direct methods using
SHELXS-97 and refined employing full-matrix least squares
with the programme SHELXL-97 refining on F2. Packing
diagrams were produced using the programme PovRay and
Table 1 Crystal data and structure refinement parameters for complexes 2, 7 and 8
Compound
2
7
8
Empirical formular
Formular weight
T/K
C24H28Cl2NOPPdS
586.81
C24H20Cl2NPPdS
562.74
C27H25ClNPPd
536.30
173(2)
173(2)
173(2)
˚
k/A
0.71073
0.71073
0.7103
Crystal system
Triclinic
P1
Monoclinic
P 21/n
Monoclinic
P 21/n
Space group
Crystal colour and shape
Yellow, plate
8.9935(2)
10.0413(2)
13.9439(3)
91.189(10)
97.957(10)
94.869(10)
1241.93(5))
2
Orange, needle
9.8892(5)
21.6512(12)
10.7050(6)
90
Orange, needle
10.0147(8)
21.8935(18)
10.7478
90
a
b
c
a(deg)
b(deg)
c(deg)
94.7860(10)
90
94.192(2)
90
3
˚
V(A )
2284.1(2)
4
2350.2(3)
4
Z
Densitycalc(mg/ml)
Absorption coefficient (mm-1
F(000)
1.569
1.637
1.516
)
1.128
1.220
0.986
596
1128.0
1088
Crystal size (mm)
0.05 9 0.1 9 0.20
0.10 9 0.26 9 0.46
1.9–30.7
0.03 9 0.12 9 0.13
2.1–28.3
Theta range for data collection (deg) 3.0–28.7
Limiting indices
-12 B h B 12, -13 B k B 13, -14 B h B14, -31 B k B 31,
-18 B 1 B 18
-13 B h B 13, -29 B k B 29,
-14 B 1 B 13
-15 B 1 B 15
Reflections collected/unique
45019/6342 [R(int) = 0.057]
28.66 (99.2 %)
50973/7032 [R(int) = 0.021]
30.670 (99.5 %)
32545/5809 [R(int) = 0.043]
Completeness of theta max. and
min. transmission
28.25 (99.6 %)
Refinement method
Full-matrix least squares on F2
Full-matrix least squares on F2 Full-matrix least squares on F2
Data/restraints/parameters
Goodness-of-fit on F2
6342/0/284
1.059
7032/0/271
1.061
6590/8/270
1.031
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Transition Met Chem (2013) 38:165–172
169
R = (CH2)2CH3
R = (CH)(CH3)2
R = (CH3)C6H3
R = (CH2)C6H5
R = (CH2)C5H4N
R = (CH2)C4H3O
R = (CH2)C4H3S
1
2
3
4
5
6
7
R
R
N
N
[PdCl2(COD)]
DCM, RT
Cl
Cl
Pd
P
P
Ph
Ph
Ph
Ph
R = (CH2)C6H5
R = (CH2)C5H4N 9
R = (CH2)C4H3O 10
8
R
R
N
N
11
R = (CH2)C4H3S
[PdClMe(COD)]
DCM, RT
Cl
CH3
Pd
P
P
Ph
Ph
Ph
Ph
Scheme 1 Synthesis of palladium dichloride complexes
The ligands show a distinctive stretching frequency,
m(C=N) at between 1,629 and 1,636 cm-1 which agrees
with previously reported values for iminophosphine ligands
[19]. Upon complexation, the peaks shift to lower fre-
quencies than in the ligands at 1,624–1,630 cm-1. This is
due to increased electron density on the metal upon coor-
dination of the imine moiety to the metal centre.
The appearance of one signal in the 31P NMR spectra also
suggests that only one species had been formed.
Structural description of complexes 2, 7 and 8
The selected bond lengths and angles for complexes 2 [25],
7 and 8 [26] are summarised in Tables 2, 3 and 4. Their
molecular structures are shown in Figs. 1, 2 and 3.
1
The H NMR spectra of complexes 8–11 showed imine
protons in the region d 8.63–8.81 ppm. The observed upfield
shifts of 0.21–0.28 ppm with respect to the free ligands
further confirmed coordination of the imine nitrogen to the
metal centre. A downfield shift of d 0.18–0.25 ppm was also
observed for the methylene signals, due to the coordination
of the adjacent imine nitrogen thereby deshielding these
protons. No significant chemical shifts were observed for the
olefinic signals of the furyl and the thiophenyl with respect to
those of the free ligands, suggesting that these groups did not
participate in bonding with the metal centre. The 31P NMR
spectra of complexes 8–11 showed the expected downfield
shift to d 37.4–38.5 ppm with respect to the free ligands
which appeared at d -13.2 to -13.9 ppm, due to coordina-
tion of the phosphine moiety to the palladium metal centre.
Table 3 Selected bond distances and angles for the palladium
complex 7
˚
Bond distances (A)
Bond angles(°)
Pd(1)-Cl(2)
Pd(1)-Cl(3)
Pd(1)-P(4)
Pd(1)-N(24)
P (4)-C(5)
P(4)-C(11)
P(4)-C(17)
N(24)-C(23)
2.149(3)
Cl(2)-Pd(1)-Cl(3)
Cl(2)-Pd(1)-P(4)
Cl(2)-Pd(1)-N(24)
Cl(3)-Pd(1)-P(4)
P(4)-Pd(1)-N(24)
Pd(1)-P(4)-C(5)
Pd(1)-P(4)-C(11)
Pd(1)-P(4)-C(17)
88.82(8)
2.3930(12)
2.1904(9)
2.135(3)
1.820(3)
1.812(3)
1.823(3)
1.276(5)
91.49(8)
174.37(11)
176.40(4)
86.38(9)
111.55(11)
120.74(11)
109.32(11)
Table 4 Selected bond distances and angles for the palladium
complex 8
Table 2 Selected bond distances and angles for the palladium
complex 2
˚
Bond distances (A)
Bond angles(°)
˚
Bond distances (A)
Bond angles(°)
Pd(1)-Cl(2)
Pd(1)-P(4)
Pd(1)-N(24)
Pd(1)-C(3)
P (4)-C(5)
P(4)-C(11)
N(24)-C(23)
N(24)-C(25)
2.4035(9)
Cl(2)-Pd(1)-P(4)
Cl(2)-Pd(1)-N(24)
Cl(2)-Pd(1)-C(3)
P(4)-Pd(1)-N(24)
P(4)-Pd(1)-N(24)
Pd(1)-P(4)-C(5)
Pd(1)-P(4)-C(17)
178.09(8)
94.38(8)
Pd(1)-Cl(2)
Pd(1)-Cl(3)
Pd(1)-N(24)
Pd(1)-P(4)
P(4)-C(11)
P(4)-C(17)
N(24)-C(23)
2.3838(6)
Cl(2)-Pd(1)-Cl(3)
Cl(2)-Pd(1)-P(4)
Cl(2)-Pd(1)-N(24)
Cl(3)-Pd(1)-P(4)
Cl(3)-Pd(1)-N(24)
P(4)-Pd(1)-N(24)
90.74(2)
172.6(2)
91.07(5)
92.31(2)
177.29(5)
86.13(5)
2.1940(7)
2.151(2)
2.1232(19)
1.821(3)
1.824(3)
1.280(4)
1.486(4)
2.2826(6)
2.0726(17)
2.2189(6)
1.811(2)
1.820(2)
1.268(3)
88.10(6)
86.76(6)
86.38(9)
111.55(11)
109.32(11)
123

170
Transition Met Chem (2013) 38:165–172
Fig. 1 Molecular structure of
complex 2. All non-hydrogen
atoms were presented with
ellipsoidal model with
probability level 40 %. The
asymmetric unit contains the
organometallic compound and
a DMSO solvent molecule
The coordination around the palladium is slightly dis-
torted from the ideal square planar geometry. The main
distortion is the NPdP bite angle of 86.13(5)° similar to
other palladium complexes with iminophosphines [20].
been observed for similar complexes with iminophos-
phines [20–22].
˚
The Pd–P distances of 2.1940(7) A are within the
expected range and close to the values determined for the
˚
monohalide complex [PdMeCl(L)] (2.1925(9) A and in the
˚
The Pd–P distance (2.2189(6) A) is within the expected
range and the length of the carbon–nitrogen double bond is
also within the expected range.
dihalide complexes of the same ligand studied by Coleman
et al. [23, 24]. The Pd–N distances are similar to those found
for Pd(II) complexes in the same series. The methyl group is
trans to the nitrogen atom of the ligand. The torsion angle
The molecular structure revealed a slightly distorted
square planar geometry around the palladium metal cen-
tre. The ligand was shown to bind in the expected K2-
P^N fashion with a bite angle P(4)-Pd(1)-N(24) of
86.38(9)°. The angle deviated slightly from the expected
90°, presumably due to the strain imposed by the six-
membered chelate ring P(4)-C(17)-C(22)-C(23)-N(24)-
Pd(1). This reduction in the bite angle was compensated
for by an increase in the Cl(2)-Pd(1)-P(4) angle of
91.49(8)°. This deviation of the bite angle from 90° has
˚
Pd(1)-P(4)-C(17)-C(22) = 39.9(2) A indicates that the
=CHC6H4- unit lies above the PdMeCl(P,N) plane.
Preliminary biological evaluation
The palladium complexes synthesised were evaluated for
their cytotoxic activity using the MTT assay to determine
Fig. 3 Molecular structure of 8 showing the atomic numbering
scheme. All non-hydrogen atoms were presented with ellipsoidal
model with probability level 40 %
Fig. 2 Molecular structure of complex 7. All non-hydrogen atoms
were presented with ellipsoidal model with probability level 40 %
123

Transition Met Chem (2013) 38:165–172
171
IC50 values against the oesophageal cancer cell lines
WHCO1 and KYSE450 for selected complexes. Dose–
response curves for each of the complexes were performed
against the cell lines. Each experiment was performed in
triplicate.
activity of some of the palladium(II) complexes could not
be determined due to poor solubility. Further investigations
are under way to increase the solubility of the palladium
complexes and to explore their anticancer activity.
Supplementary materials
In vitro anticancer activity
Crystallographic data for the structural analysis have been
deposited with the Cambridge Crystallographic Data Cen-
tre, CCDC Nos. 825329, 841468 and 818609 for com-
plexes 2, 7 and 8, respectively. Copies of this information
may be obtained free of charge from The Director, CCDC,
12 Union Road, Cambridge CB2 1EZ, UK, Fax: ?44-
1223-336033, e-mail: deposit@ccdc.cam.ac.uk of www:
http://www.ccdc.cam.ac.uk.
The cytotoxicity of the palladium complexes was examined.
In WHCO1 cell lines, complex 2 had the highest activity
with an IC50 value of 19.02 lM and the least active was
complex 10 with an IC50 value of 45.27 lM. In comparison
with cisplatin which has an IC50 of 15–18 lM in WHCO1
cell lines, the palladium complexes described here dis-
played moderate activity against oesophageal cancer cell
lines. In KYSE 450 cells, highest activity was observed with
complex 2 with an IC50 of 10.03 lM and lowest activity
with complex 10 with an IC50 of 68.54 lM as shown in
Table 5.
Acknowledgments Financial support from the University of Cape
Town, the National Research Foundation of South Africa, CANSA,
Project AuTEK (Mintek and Harmony Gold, South Africa) and a
donation of metal salts from the Anglo Platinum Corporation is
gratefully acknowledged.
The palladium complexes 1 and 2 were the dichlorides
which were very soluble in DMSO as compared with the
other dichloride complexes 3–7 which were insoluble.
Complexes 8–11 were the chloromethyl derivatives and
these were very soluble in DMSO. Introduction of a methyl
group into the dichloride complexes increased the solu-
bility of the complexes.
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95 % CI
IC50 in
KYSE450
(lM)
95 % CI
(lM)
1
26.59
19.02
44.14
39.07
45.27
28.50
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15.46–23.42 10.03
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18.45–44.02 10.99
13.81–16.93
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123