Synthesis, characterization, and cytotoxicities of platinum(II) complexes bearing pyridinecarboxaldimines containing bulky aromatic groups

Article abstract of DOI:10.1016/j.ica.2004.07.039

Six platinum dichloride pyridinecarboxaldimine complexes containing bulky aryl groups have been prepared and characterized fully. Cytotoxicities of the complexes have been investigated against OV2008 (human ovarian carcinoma) and the analogous cisplatin-r

Full text of DOI:10.1016/j.ica.2004.07.039

Inorganica Chimica Acta 358 (2005) 63–69
www.elsevier.com/locate/ica
Synthesis, characterization, and cytotoxicities of
platinum(II) complexes bearing pyridinecarboxaldimines
containing bulky aromatic groups
a
Maren L. Conrad , Jennifer E. Enman , Stephen J. Scales , Haiwen Zhang ,
a
a
a
a
Christopher M. Vogels , Mazen T. Saleh , Andreas Decken , Stephen A. Westcott
b
c
a,
*
a
Department of Chemistry, Mount Allison University, 63C York Street, Sackville, Canada NB E4L 1G8
b
Department of Biology and Biochemistry, Mount Allison University, Sackville, Canada NB E4L 1G7
c
Department of Chemistry, University of New Brunswick, Fredericton, Canada NB E3B 5A3
Received 13 May 2004; accepted 24 July 2004
Available online 21 August 2004
Abstract
Condensation of 2-pyridinecarboxaldehyde with several primary amines containing bulky aryl groups gave the corresponding
pyridinecarboxaldimines (N-N0). Addition of these ligands to [PtCl2(coe)]2 (coe = cis-cyclooctene) gave complexes of the type cis-
PtCl2(N-N0) in moderate yields. The platinum complexes have been examined for their potential cytotoxicities against OV2008
(human ovarian carcinoma) and the analogous cisplatin-resistant cell line C13.
ꢀ 2004 Elsevier B.V. All rights reserved.
Keywords: Pyridinecarboxaldimines; Cytotoxicity; Platinum; Aromatic; Anticancer
1. Introduction
Steric crowding from the methyl group is believed to de-
crease the rates of hydrolysis and substitution reactions
of AMD473 by effectively shielding the platinum atom
and thereby permitting high selectivity in binding to
DNA [10]. The primary mechanism of action in these
platinum drugs is believed to arise from the metalꢀs
interaction with DNA.
We have begun to develop AMD473 analogues by
replacing the NH3 group with a pendant imine group.
Previous studies have shown that the platinum complex
derived from aniline, 2 (Fig. 1), has shown considerable
activity against the hormone independent human mam-
mary carcinoma cell line MDA-MB 231 [11]. Varying
the aniline functionality allows us to design compounds
with a wide range of physical and chemical properties
that may provide steric congestion around the platinum
atom. As well, the use of bidentate ligands prevents
trans-labilization and undesired displacement of the lig-
ands by sulfur and nitrogen donors in biomolecules,
Cisplatin, cis-[PtCl2(NH3)2], and a few related plati-
num-based complexes are currently used as anticancer
agents against testicular and ovarian malignancies [1–
7]. There are several limitations to platinum therapy,
however, such as neural and kidney toxicity as well as
intrinsic and acquired resistance of tumor cells to the
drugs [1]. These complications have provided incentive
for further research into the development of platinum-
based complexes with increased solubility and enhanced
specificity towards cancer cells. Recent studies have
shown that cis-amminedichloro(2-methylpyridine)plati-
num(II) (AMD473 or ZD0473, Fig. 1) shows considera-
ble cytotoxicity in cisplatin-resistant cell lines [8,9].
*
Corresponding author. Tel.: +1 506 364 2372/2351; fax: +1 506
364 2313.
E-mail address: swestcott@mta.ca (S.A. Westcott).
0020-1693/$ - see front matter ꢀ 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.ica.2004.07.039

64
M.L. Conrad et al. / Inorganica Chimica Acta 358 (2005) 63–69
Hz, 1H, Ar), 8.05 (t of d, JH–H = 7, 2 Hz, 1H, Ar),
7.19–7.17 (ov m, 3H, Ar), 2.23 (s, 6H, CH3); 13C{1H}
d: 174.6, 157.1, 149.8, 146.1, 141.3, 131.3, 130.6, 130.5,
128.3, 128.2, 18.1. IR (nujol): 2949, 2902, 2860, 1601,
1562, 1462, 1377, 1301, 1267, 1232, 1184, 1159, 1111,
1039, 974, 939, 897, 847, 804, 764, 733. C14H14N2Cl2Pt
requires C, 35.29; H, 2.97; N, 5.88. Found: C, 35.26;
H, 2.76; N, 5.42%.
N
N
N
NH3
Cl
Pt
Pt
Cl
Cl
Cl
2
1
Fig. 1. Structure of AMD473 (1) and complex 2.
2.2.2. Compound 4
A CH2Cl2 (2 mL) solution of ligand (0.04 g, 0.17
mmol) was added to [PtCl2(coe)]2 (0.06 g, 0.08 mmol)
in CH2Cl2 (3 mL) at 0 ꢁC. The reaction was allowed
to proceed for 5 h at which point solvent was removed
under vacuum to give an orange solid. The resulting
solid was then triturated with hexane (3 · 10 mL) to af-
ford 4 (0.06 g, 74%) as a red–orange solid. M.p. 272–
276 ꢁC (decomposition). Spectroscopic NMR data (in
CDCl3): 1H d: 9.94 (d, JH–H = 7 Hz, JH–Pt = 42 Hz,
1H, Ar), 8.78 (s, JH–Pt = 94 Hz, 1H, C(H )‚N), 8.27
(t, JH–H = 7 Hz, 1H, Ar), 7.97 (d, JH–H = 7 Hz, 1H,
Ar), 7.87 (t, JH–H = 7 Hz, 1H, Ar), 7.32 (t, JH–H = 7
Hz, 1H, Ar), 7.22 (d, JH–H = 7 Hz, 2H, Ar), 2.90–
2.60 (2nd order m, 4H, CH2CH3), 1.26 (t, JH–H = 8
Hz, 6H, CH2CH3); 13C{1H} d: 174.5, 156.8, 149.9,
144.8, 141.4, 136.7, 130.8, 130.5, 128.7, 126.1, 23.9,
14.4. IR (nujol): 2943, 2906, 2872, 1712, 1462, 1377,
1304, 1232, 1159, 1109, 1038, 972, 810, 766, 723, 608.
C16H18N2Cl2Pt requires C, 38.09; H, 3.60; N, 5.55.
Found: C, 38.29; H, 3.52; N, 5.46%.
interactions believed responsible for some of the adverse
side effects associated with cisplatin [1–3]. We report
herein our results on the synthesis and initial cytotoxic-
ity testing of cis-dichloro(pyridin-2-ylcarboxaldi-
mine)platinum(II) compounds containing bulky aryl
groups.
2. Experimental
2.1. General procedures and methods
Reagents and solvents used were obtained from Ald-
rich Chemicals. K2PtCl4 was purchased from Precious
Metals Online Ltd and [PtCl2(coe)]2 was made by an
established procedure [12]. Pyridinecarboxaldimine lig-
ands were prepared as previously reported [13]. NMR
spectra were recorded on a JEOL JNM-GSX270 FT
and a Varian Mercury Plus 200 NMR spectrometer.
1H NMR chemical shifts are reported in ppm and are
referenced to residual protons in deuterated solvent at
270 and 200 MHz. 13C NMR chemical shifts are refer-
enced to solvent carbon resonances as internal standards
at 68 and 50 MHz. Multiplicities are reported as singlet
(s), doublet (d), triplet (t), septet (sept), multiplet (m),
broad (br), and overlapping (ov). Infrared spectra were
obtained using a Mattson Genesis II FT-IR spectrome-
ter and are reported in cmꢀ1. Melting points were meas-
2.2.3. Compound 5
A CH2Cl2 (2 mL) solution of ligand (0.08 g, 0.30
mmol) was added to [PtCl2(coe)]2 (0.11 g, 0.14 mmol) in
CH2Cl2 (3 mL) at 0 ꢁC. The reaction was allowed to
proceed for 5 h at which point solvent was removed under
vacuum to give an orange solid. The resulting solid was
then triturated with hexane (3 · 10 mL) to afford 5
(0.08 g, 54%) as a red–orange solid. M.p. 260–264 ꢁC
(decomposition). Spectroscopic NMR data (in DMSO-
d6): 1H d: 9.49 (d, JH–H = 7 Hz, JH–Pt = 40 Hz, 1H, Ar),
9.47 (s, JH–Pt = 97 Hz, 1H, C(H)‚N), 8.47 (t, JH–H = 7
Hz, 1H, Ar), 8.24 (d, JH–H = 7 Hz, 1H, Ar), 8.06 (t,
JH–H = 7 Hz, 1H, Ar), 7.36 (t, JH–H = 7 Hz, 1H, Ar), 7.26
(d, JH–H = 7 Hz, 2H, Ar), 3.15 (sept, JH–H = 7 Hz, 2H,
CH(CH3)2), 1.27 (d, JH–H = 7 Hz, 6H, CH(CH3)2), 1.10
(d, JH–H = 7 Hz, 6H, CH(CH3)2); 13C{1H} d: 173.9,
156.7, 150.0, 143.0, 141.6, 141.5, 130.9, 130.5, 129.1,
123.6, 28.0, 24.5, 23.2. IR (nujol): 2931, 2856, 1712,
1462, 1377, 1302, 1230, 1157, 1109, 1043, 972, 935, 806,
768, 723, 604. C18H22N2Cl2Pt requires C, 40.60; H,
4.17; N, 5.26. Found: C, 40.60; H, 3.88; N, 5.13%.
ured uncorrected with
a
Mel-Temp apparatus.
Microanalyses for C, H, and N were carried out at Gue-
lph Chemical Laboratories Ltd. (Guelph, Ont.).
2.2. Procedures
2.2.1. Compound 3
A CH2Cl2 (2 mL) solution of ligand (0.06 g, 0.29
mmol) was added to [PtCl2(coe)]2 (0.10 g, 0.13 mmol)
in CH2Cl2 (3 mL) at 0 ꢁC. The reaction was allowed
to proceed for 5 h at which point a precipitate was col-
lected by suction filtration and washed with Et2O (3 · 5
mL) to afford 3 (0.09 g, 73%) as an orange solid. M.p.
106–109 ꢁC (decomposition). Spectroscopic NMR data
1
(in DMSO-d6): H d: 9.48 (d, JH–H = 7 Hz, JH–Pt = 38
2.2.4. Compound 6
A CH2Cl2 (2 mL) solution of ligand (0.06 g, 0.31
mmol) was added to [PtCl2(coe)]2 (0.11 g, 0.14 mmol)
Hz, 1H, Ar), 9.29 (s, JH–Pt = 96 Hz, 1H, C(H)‚N),
8.47 (t of d, JH–H = 7, 2 Hz, 1H, Ar), 8.18 (d, JH–H = 7

M.L. Conrad et al. / Inorganica Chimica Acta 358 (2005) 63–69
65
in CH2Cl2 (3 mL) at 0 ꢁC. The reaction was allowed to
2.3. X-ray crystallography
proceed for 5 h at which point an orange precipitate was
collected by suction filtration and washed with Et2O
(3 · 10 mL) to afford 6 (0.08 g, 52%) as an orange solid.
M.p. 256–260 ꢁC (decomposition). Spectroscopic NMR
data (in DMSO-d6): 1H d: 9.47 (d, JH–H = 7 Hz,
JH–Pt = 42 Hz, 1H, Ar), 9.29 (s, JH–Pt = 97 Hz, 1H,
C(H)‚N), 8.46 (t of d, JH–H = 7, 2 Hz, 1H, Ar), 8.21
(d, JH–H = 7 Hz, 1H, Ar), 8.02 (t of d, JH–H = 7, 2 Hz,
1H, Ar), 7.32 (m, 3H, Ar), 7.21 (m, 1H, Ar), 2.35 (s,
3H, CH3); 13C{1H}: 173.6, 157.5, 149.7, 147.3, 141.2,
132.2, 130.6, 130.4, 130.2, 128.8, 126.7, 124.0, 18.2. IR
(nujol): 2966, 2945, 2888, 2844, 1714, 1462, 1377,
1304, 1184, 1155, 1111, 1041, 972, 941, 901, 769, 721,
521. C13H12N2Cl2Pt requires C, 33.77; H, 2.62; N,
6.06. Found: C, 33.24; H, 2.40; N, 5.68%.
Crystals of 5 and 7 were grown from saturated
CH2Cl2 solutions at 5 ꢁC. Single crystals were coated
with Paratone-N oil, mounted using a glass fibre and
frozen in the cold stream of the goniometer. A hemi-
sphere of data were collected on a Bruker AXS P4/
SMART 1000 diffractometer using x and h scans with
a scan width of 0.3ꢁ and 30 s (5) and 20 s (7) exposure
times. The detector distance was 6 cm (5) and 5 cm
(7). The data were reduced [14] and corrected for
absorption [15]. The structures were solved by direct
methods and refined by full-matrix least squares on F2
[16]. All non-hydrogen atoms were refined anisotropi-
cally. Hydrogen atoms were located in Fourier differ-
ence maps and refined isotropically.
2.4. Cell culture
2.2.5. Compound 7
A CH2Cl2 (2 mL) solution of ligand (0.06 g, 0.26
mmol) was added to [PtCl2(coe)]2 (0.10 g, 0.13 mmol)
in CH2Cl2 (3 mL) at 0 ꢁC. The reaction was allowed
to proceed for 5 h at which point a precipitate was
collected by suction filtration and washed with Et2O
(3 · 10 mL) to afford 7 (0.08 g, 62%) as an orange so-
lid. M.p. 170–174 ꢁC (decomposition). Spectroscopic
NMR data (in DMSO-d6): 1H d: 9.50 (d, JH–H = 7
Hz, JH–Pt = 40 Hz, 1H, Ar), 9.46 (s, JH–Pt = 95 Hz,
1H, C(H)‚N), 8.46 (t of d, JH–H = 7, 2 Hz, 1H,
Ar), 8.26 (d, JH–H = 7 Hz, 1H, Ar), 8.04–8.01 (ov m,
5H, Ar), 7.64–7.61 (ov m, 3H, Ar); 13C{1H} d:
173.2, 157.7, 149.7, 145.5, 141.3, 133.1, 132.7, 130.3,
130.2, 128.9, 128.3, 128.1, 127.7, 127.6, 123.8, 122.6.
IR (nujol): 2966, 2945, 2891, 2845, 1712, 1462, 1377,
1269, 1169, 974, 939, 893, 862, 823, 758, 723.
C16H12N2Cl2Pt requires C, 38.56; H, 2.43; N, 5.62.
Found: C, 38.20; H, 2.26; N, 5.45%.
OV2008 (human ovarian carcinoma) and the analo-
gous cisplatin-resistant cell line C13 were a generous gift
from Dr. Barbara C. Vanderhyden of the Centre for
Cancer Therapeutics, Ottawa Regional Cancer Centre,
Ont., Canada. Both cell lines were cultured in complete
RPMI-1640 medium with
L-glutamine, supplemented
with 5% fetal bovine serum, penicillin (50 units/mL),
and streptomycin (50 mg/mL). Cells were incubated in
a humidified atmosphere of 5% CO2 at 37 ꢁC and were
subcultured twice weekly using trypsin-EDTA.
2.5. Cell growth inhibition assay
Cells were seeded in 96-well plates at a concentration
of 0.1–1.0 · 104 cells/well in 200 lL of complete media
and incubated for 24 h at 37 ꢁC in a 5% CO2 atmosphere
to allow for cell adhesion. Stock solutions (15 mM) of
the compounds made in DMSO were filter sterilized,
then diluted to 10 mM in phosphate buffered saline
(PBS, 0.02 M phosphate, 0.11 M NaCl, pH 7.0, sterile).
The 10 mM solutions were diluted to 50 lM and 1.4 mM
in complete media for treatment against OV2008 and
C13 cell lines, respectively. Precisely 20 lL of compound
solutions were added to 180 lL of fresh media in wells to
give final concentrations of 5 lM against OV2008 and
140 lM for C13. All assays were performed in two inde-
pendent sets of quadruplicate tests. Control groups con-
taining no drug were run in each assay, along
with standards of cisplatin and a previously studied
cis-dichloro(pyridin-2-ylcarboxaldimine)platinum(II)
complex (2).
2.2.6. Compound 8
A CH2Cl2 (2 mL) solution of ligand (0.08 g, 0.28
mmol) was added to [PtCl2(coe)]2 (0.10 g, 0.13 mmol)
in CH2Cl2 (3 mL) at 0 ꢁC. The reaction was allowed
to proceed for 5 h at which point a precipitate was col-
lected by suction filtration and washed with Et2O (3 · 10
mL) to afford 8 (0.09 g, 63%) as an orange solid. M.p.
362–363 ꢁC (decomposition). Spectroscopic NMR data
1
(in DMSO-d6): H d: 9.52 (ov m, 2H, Ar & C(H)‚N),
8.69 (s, 2H, Ar), 8.48 (t, JH–H = 7 Hz, 1H, Ar), 8.28
(d, JH–H = 7 Hz, 1H, Ar), 8.20–8.15 (ov m, 4H, Ar),
8.02 (t, JH–H = 7 Hz, 1H, Ar), 7.60–7.57 (ov m, 3H,
Ar); 13C{1H} d: 173.1, 157.7, 149.7, 145.7, 141.2,
138.2, 132.4, 132.3, 130.9, 130.6, 130.3, 130.2, 128.7,
128.6, 128.3, 127.7, 126.8, 126.7, 124.0, 122.5. IR (nujol):
2974, 2881, 2839, 1712, 1462, 1377, 1159, 903, 756, 474.
C20H14N2 Cl2Pt requires C, 43.80; H, 2.58; N, 5.11.
Found: C, 43.61; H, 2.43; N, 5.00%.
Following 48 h of exposure, each well was carefully
rinsed with 200 lL PBS buffer. MTT solution (50 lL,
1 mg/mL ddH2O) along with 200 lL of fresh, complete
media were added to each well, and plates were incu-
bated for 45 min. Following incubation, the media was
removed and the purple formazan precipitate in each

66
M.L. Conrad et al. / Inorganica Chimica Acta 358 (2005) 63–69
well was solubilized in 200 lL DMSO. Absorbances
were measured using a VersaMax tunable microplate
reader (Molecular Devices) at 570 nm. Reduction of cell
proliferation was determined as a fraction of the absorb-
ance values for each drug treatment (T) to the mean
absorbance of the no-drug control (C), and calculated
using the expression 1ꢀT/C · 100%. Data from the sep-
arate trials were combined using a t-test (p < 0.05).
one groove and allow formation of a drug-DNA adduct
[31]. While the platinum center in cisplatin based drugs
is believed to bind preferentially with the N-7 positions
of the purine bases in DNA, incorporation of a planar
side group, as in 7 and 8, may allow these platinum com-
plexes to interact directly with DNA or via an intercala-
tion mechanism. Related (terpyridine)platinum(II)
complexes containing tethered 9-aminoacridine groups
have also been found to be competitive and reversible
inhibitors of trypanothione reductase from Trypano-
soma cruzi, the causative agent of Chagasꢀ disease [32].
In this study, complexes 3–8 have been characterized
by a number of physical methods, including multinu-
clear NMR spectroscopy. A significant downfield shift
3. Results and discussion
3.1. Synthesis and structures
1
The addition of a primary amine to commercially
available 2-pyridinecarboxaldehyde to afford the corre-
sponding pyridin-2-ylcarboxaldimine ligand is a well-
known route to a versatile class of bidentate ligands
[17–27]. Variation of the amine allows for the facile de-
sign of ligands and platinum complexes with different
physical and chemical properties. In this study, the me-
tal complexes 3–8 (Fig. 2) were prepared by addition of
the pyridinecarboxaldimine ligands to CH2Cl2 solutions
of [PtCl2(coe)]2 (coe = cis-cyclooctene) [12,13].
Complexes 7 and 8 contain aromatic side groups and
are of particular interest as recent studies have shown
that structurally similar planar or semiplanar chro-
mophores, such as acridine, play an important role in
the class of DNA-intercalating anticancer drugs [28].
For instance, amsacrine, a 9-anilinoacridine analogue,
and ledakrin, a nitroacridine, are used to treat specific
tumors such as L1210, and several derivatives such as
the 4-carboxamidoacridine DACA (XR5000), imidazo-
acridinones, and pyrazolo[3,4,5-kl]nitroacridine (PZA
or NSC366140) are currently undergoing clinical trials
[28]. The observed cytotoxicity of these chromophores
may also be related to potent enzyme inhibition as re-
lated studies have shown that topoisomerase [29] and
telomerase [30] activities may be strongly affected by
acridines. The affinity of acridines for DNA has also
been used to prepare intercalating alkylating agents,
which interact by positioning the alkylating group in
in the H NMR is observed for the imine sp2 proton
upon coordination of the ligand to the metal center.
For instance, the singlet at d 8.35 ppm for the free ligand
derived from 2-pyridinecarboxaldehyde and 2,6-diiso-
propylaniline shifts to 9.47 ppm in complex 5. Platinum
satellites are also observed for this resonance
(JH–Pt = 97 Hz) upon complexation of the ligand to
the metal. Similar trends are observed for the pyridine
hydrogen alpha to the nitrogen atom as the chemical
shift changes from d 8.74 to 9.49 ppm (JH–Pt = 40 Hz).
Interestingly, two distinct methyl resonances are ob-
1
served in the H (d 1.27 and 1.10 ppm) and 13C NMR
(d 24.5 and 23.2 ppm) spectra for the magnetically
inequivalent isopropyl groups.
Complex 5 has also been characterized by an X-ray
diffraction study (Fig. 3). Crystallographic data are gi-
ven in Table 1 and selected bond lengths and angles pro-
vided in Table 2. The nitrogen–platinum bonds of
˚
˚
2.0147(19) A (pyridine) and 1.998(2) A(imine) are simi-
lar to those reported in other iminopyridine platinum
systems [33–35]. Slightly longer Pt–N bond distances
are observed in related five coordinate Pt(II) [36,37]
and Pt(IV) complexes [38]. The imine C(6)–N(7) dis-
˚
tance is 1.288(3) A and is in the range of accepted car-
bon–nitrogen double bonds [39]. Interestingly, the
aromatic ring on the imine nitrogen is almost perpendic-
ular to the N(1)–Pt–N(7) plane (87.6ꢁ), a trend that is
observed in related diimine systems [40]. Indeed, this
1/2 [PtCl2(coe)]2
N
N
R
N
R
N
CH2Cl2
Pt
Cl
Cl
coe = cis-cyclooctene
3: R = 2,6-Me2C6H3
4: R = 2,6-Et2C6H3
5: R = 2,6-iPr2C6H3
6: R = 2-MeC6H4
7: R= 2-naphthyl
8: R = 2-anthracene
Fig. 2. Synthesis of platinum complexes 3–8.

M.L. Conrad et al. / Inorganica Chimica Acta 358 (2005) 63–69
67
Table 2
Selected bond lengths (A) and angles (ꢁ) for 5 and 7
˚
5
7
Pt–N(1)
Pt–N(7)
2.0147(19)
1.998(2)
2.2857(7)
2.2850(7)
1.445(4)
1.288(3)
1.451(3)
2.008(5)
2.014(5)
Pt–Cl(1)
Pt–Cl(2)
C(5)–C(6)
C(6)–N(7)
N(7)–C(8)
2.2689(17)
2.2816(16)
1.437(9)
1.282(8)
1.438(8)
N(7)–Pt–N(1)
N(7)–Pt–Cl(1)
N(1)–Pt–Cl(1)
N(7)–Pt–Cl(2)
N(1)–Pt–Cl(2)
Cl(1)–Pt–Cl(2)
C(1)–N(1)–C(5)
C(1)–N(1)–Pt
C(5)–N(1)–Pt
N(7)–C(6)–C(5)
C(6)–N(7)–C(8)
C(6)–N(7)–Pt
C(8)–N(7)–Pt
79.79(8)
80.1(2)
173.82(6)
95.11(6)
95.12(6)
174.24(15)
94.22(15)
97.43(15)
176.82(14)
88.31(7)
118.5(6)
127.5(4)
114.1(4)
118.4(5)
119.4(5)
114.2(4)
126.4(4)
174.72(6)
90.05(3)
118.5(2)
Fig. 3. A view of complex 5, with displacement ellipsoids drawn at the
30% probability level. H atoms have been omitted.
127.28(18)
114.18(16)
117.2(2)
Table 1
Crystallographic data collection parameters for 5 and 7
119.0(2)
115.38(18)
125.65(15)
Complex
5
7 Æ CH2Cl2
Formula
Fw
C18H22Cl2N2Pt
532.37
C17H14Cl4N2Pt
583.19
Crystal system
Space group
monoclinic
P2(1)/c
orthorhombic
P2(1)2(1)2(1)
7.6821(6)
11.9842(9)
19.7118(16)
90
˚
a (A)
10.0457(8)
12.517(1)
14.7766(12)
94.633(1)
1852.0(3)
4
˚
b (A)
˚
c (A)
b (ꢁ)
3
˚
V (A )
1814.7(2)
4
2.135
Z
Dcalc (mgmꢀ3
)
1.909
0.075 · 0.075 · 0.4
198(1)
Crystal size (mm3)
Temperature (K)
0.1 · 0.2 · 0.425
198(2)
Radiation Mo Ka(k)
0.71073
7.865
10424
0.71073
8.322
11961
l (mmꢀ1
)
Total reflections
Total unique reflections
Number of variables
Rint
3251
296
4060
217
Fig. 4. A view of complex 7, with displacement ellipsoids drawn at the
30% probability level. H atoms and the solvent molecule have been
omitted.
0.0231
2.03 to 24.99
0.0562
1.99 to 27.50
h Range (ꢁ)
Largest differenceꢀ3
˚
Peak/hole, (eA
)
0.775/ꢀ0.239
1.069
0.0138
2.357/ꢀ1.857
1.040
0.0321
S (Goodness-of-fit) on F2
R1a(I > 2r (I))
of 5, the isopropyl groups are rotated to minimize steric
interaction between the two methyl groups and the
metallacycle.
wR2b(all data)
0.0343
0.0779
2
w ¼ 1=½r2ðF o2Þ þ ð0:0151 ꢁ PÞ þ ð0:7172 ꢁ PÞꢂð5Þ and w ¼ 1=½r2ðF 2oÞþ
2
ð0:0418 ꢁ PÞ ꢂð7Þ, where P ¼ ðmaxðF 2; 0Þ þ 2 ꢁ F c2Þ=3.
jj F o j ꢀ j F c jj = j F ooj.
P
P
As mentioned previously, complexes 7 and 8 are of
special interest due to their extended planar ring sys-
tems. We have carried out an X-ray diffraction study
on the naphthalene complex 7 (Fig. 4). Bond distances
and angles are similar to those found in complex 5 ex-
cept the naphthalene ring is twisted 52ꢁ out of the plane
held by the pyridylimine platinum dichloride fragment
due to increased packing forces in the crystal in compar-
ison to the non-benzannelated analogue 5.
a
R1 ¼
P
P
2
1=2
b
wR2 ¼ ð ½wðF 2o ꢀ F c2Þ = ½F 4oꢂꢂÞ
.
structural feature has been used to create active and
selective catalyst precursors for the polymerization of
a olefins, where ortho substitution of the aniline group
with bulky groups is believed to shield and stabilize
the metal center. The structure of the related [PtCl2(R-
pea)] (pea = 1,(2-pyridyl)ethylamine) has been reported
recently, where the methyl group of the backbone lies
in an equatorial plane and results in a close contact with
the pyridine, which would otherwise not be present if the
methyl group were in the axial position [41]. In the case
3.2. Cytotoxic activity
We have tested the cytotoxic activity of the platinum
complexes against both cisplatin-sensitive and cisplatin-

68
M.L. Conrad et al. / Inorganica Chimica Acta 358 (2005) 63–69
Table 3
Cancer Centre, Ont., Canada) for providing us with
the OV2008 and C13 cell lines.
Percent reduction of cell proliferation of cisplatin-sensitive (OV2008)
and cisplatin-resistant (C13) cancer cells to compounds at 5 and
140 lM, respectively
Entry
Compound
OV2008
C13
Appendix A. Supplementary material
1
2
3
4
5
6
7
8
Cisplatin
44 11
41
37
86
95
8
8
6
2
2
3
4
5
6
7
8
21
40 10
3
Full crystallographic data in CIF format have been
deposited with The Director, CCDC, 12 Union Road,
Cambridge, CB2 1EZ, UK (fax: +44-1223-366033;
e-mail: deposit@ccdc.cam.ac.uk or http://www.ccdc.ca-
m.ac.uk) and are available on request, quoting deposi-
tion numbers 237684 and 237839 for compounds 5
and 7, respectively. Supplementary data associated with
this article can be found, in the online version at
doi:10.1016/j.ica.2004.07.039.
19 11
0
0
0
79 19
77
93
6
1
6
7
11 11
resistant human ovarian cells (Table 3), OV2008 and
C13, respectively, at concentrations corresponding to
cisplatinꢀs IC50 value against either cell line [42–46].
Interestingly, only compounds 3 and 4 (Entries 3 and
4, respectively) showed any appreciable activity against
cisplatin-sensitive cells OV2008. More remarkable, how-
ever, was the observation that almost all compounds
showed substantial activity against the cisplatin-resist-
ant cell line C13 (Entries 3–7). Only compound 8, con-
taining the bulky anthracene unit did not show any
appreciable activity (Entry 8). While these initial studies
have shown that some compounds display promise
against the cisplatin-resistant cell line, further in vitro
studies are needed to address the structure activity rela-
tionships in these complexes in order to design a potent
drug candidate.
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