Synthesis, characterization, and cytotoxicities of palladium(II) and platinum(II) complexes containing fluorinated pyridinecarboxaldimines

Article abstract of DOI:10.1016/j.poly.2004.06.013

Sixteen palladium and platinum dichloride pyridinecarboxaldimine complexes containing fluorine have been prepared and characterized fully. Cytotoxicities of the complexes have been investigated against OV2008 (human ovarian carcinoma) and the analogous ci

Full text of DOI:10.1016/j.poly.2004.06.013

Polyhedron 23 (2004) 2169–2176
www.elsevier.com/locate/poly
Synthesis, characterization, and cytotoxicities of palladium(II)
and platinum(II) complexes containing fluorinated
pyridinecarboxaldimines
a
Stephen J. Scales , Haiwen Zhang , Paul A. Chapman , Ciara P. McRory ,
a
a
a
a
a
b
c
Eric J. Derrah , Christopher M. Vogels , Mazen T. Saleh , Andreas Decken ,
a,
*
Stephen A. Westcott
a
Department of Chemistry, Mount Allison University, 63C York Street, Sackville, NB, Canada E4L 1G8
Department of Biology and Biochemistry, Mount Allison University, Sackville, NB, Canada E4L 1G7
b
c
Department of Chemistry, University of New Brunswick, Fredericton, NB, Canada E3B 5A3
Received 9 May 2004; accepted 9 June 2004
Available online 29 July 2004
Abstract
Condensation of 2-pyridinecarboxaldehyde with several primary amines containing fluorine groups gave the corresponding py-
ridinecarboxaldimines (N-N0). Addition of these ligands to [MCl2(coe)]2 (M = Pd, Pt; coe = cis-cyclooctene) gave complexes of the
type cis-MCl2(N-N0) [Pd (3), Pt (4)] in moderate to high yields. All palladium and platinum complexes were examined for their po-
tential cytotoxicities against OV2008 (human ovarian carcinoma) and the analogous cisplatin-resistant C13.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Keywords: Pyridinecarboxaldimine; Cytotoxicity; Platinum; Palladium; Fluorine
1. Introduction
dine)platinum(II) (AMD473 or ZD0473, Fig. 1) shows
considerable cytotoxicity in cisplatin-resistant cell lines
[8,9]. Steric crowding from the methyl group is believed
to decrease the rates of hydrolysis and substitution reac-
tions 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 in-
teraction with DNA.
We have begun to develop AMD473 analogues by re-
placing the NH3 group with a pendant imine group. Pre-
vious 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
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 an incen-
tive for further research into the development of plati-
num-based complexes with increased solubility and
enhanced specificity towards cancer cells. Recent studies
have shown that cis-amminedichloro(2-methylpyri-
*
Corresponding author. Tel.: +1-506-364-2351/2372; fax: +1-506-
364-2313.
E-mail address: swestcott@mta.ca (S.A. Westcott).
0277-5387/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.poly.2004.06.013

2170
S.J. Scales et al. / Polyhedron 23 (2004) 2169–2176
plet (t), quartet (q), multiplet (m), broad (br) and over-
lapping (ov). Infrared spectra were obtained using a
Mattson Genesis II FT-IR spectrometer and are reported
in cmꢀ1. Melting points were measured uncorrected with
a Mel-Temp apparatus. Microanalyses for C, H and N
were carried out at Guelph Chemical Laboratories Ltd.
(Guelph, Ont.).
N
N
N
NH3
Cl
Pt
Pt
Cl
Cl
Cl
2
1
Fig. 1. Structure of AMD473 (1) and complex 2.
2.2. General procedure for the preparation of metal
complexes
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, in-
teractions 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-ylcarboxaldimine)-
palladium(II) and -platinum(II) compounds containing
bulky fluorinated aryl groups (Fig. 2).
A CH2Cl2 (5 ml) solution of ligand (0.55 mmol) was
added to the appropriate [MCl2(coe)]2 (where M = Pd or
Pt) (0.25 mmol) in CH2Cl2 (5 ml). The reaction mixture
was stirred for 5 h at room temperature and the precip-
itate was collected by suction filtration and washed with
CH2Cl2 (3 · 5 ml) to afford the metal complex.
2.2.1. Compound 3a
Yield: 80% as an orange solid; m.p. 280–281 ꢁC (de-
composition). Spectroscopic NMR data (in DMSO-
d6): 1H d: 9.05 (d, J = 6 Hz, 1H, Ar), 8.89 (s, 1H,
C(H)‚N), 8.43 (t of d, J = 8, 1 Hz, 1H, Ar), 8.23 (d,
J = 8 Hz, 1H, Ar), 7.97 (t of d, J = 6, 1 Hz, 1H, Ar),
7.48–7.27 (ov m, 4H, Ar); 13C{1H} d: 175.7, 155.9,
154.5 (d, JC–F = 274 Hz, CF), 150.9, 142.0, 135.6 (d,
JC–F = 12 Hz), 130.7 (d, JC–F = 8 Hz), 130.5, 130.2,
125.7, 124.9 (d, JC–F = 4 Hz), 116.4 (d, JC–F = 20 Hz);
19F{1H} d: ꢀ118.4. IR (nujol): 2949, 2904, 2860, 1581,
1460, 1377, 1250, 1228, 1159, 1101, 955, 798, 771, 739.
Anal. Calc. for C12H9N2Cl2FPd: C, 38.16; H, 2.41; N,
7.42. Found: C, 38.20; H, 2.29; N, 7.13%.
2. Experimental
2.1. General procedures and methods
Reagents and solvents used were obtained from Ald-
rich Chemicals. PdCl2 and K2PtCl4 were purchased
from Precious Metals Online Ltd. and [PdCl2(coe)]2
and [PtCl2(coe)]2 were made by established procedures
[12]. Pyridinecarboxaldimine ligands were prepared as
previously reported [13]. NMR spectra were recorded
on a JEOL JNM-GSX270 FT NMR or Varian Mercury
1
Plus 200 NMR spectrometer. H NMR chemical shifts
are reported in ppm and are referenced to residual pro-
tons in deuterated solvent at 270 and 200 MHz. 13C
NMR chemical shifts are referenced to solvent carbon
resonances as internal standards at 68 and 50 MHz.
19F NMR chemical shifts are referenced to CF3CO2H.
Multiplicities are reported as singlet (s), doublet (d), tri-
2.2.2. Compound 3b
Yield: 76% as an orange solid; m.p. 278–280 ꢁC (de-
composition). Spectroscopic NMR data (in DMSO-
d6): 1H d: 9.05 (d, J = 6 Hz, 1H, Ar), 8.80 (s, 1H,
C(H)‚N), 8.42 (t, J = 8 Hz, 1H, Ar), 8.21 (d, J = 8
Hz, 1H, Ar), 7.96 (t, J = 6 Hz, 1H, Ar), 7.55–7.47 (m,
R1
R2
R1
R2
1/2 [MCl2(coe)]2
N
R3
N
N
R3
N
CH2Cl2
M
coe = cis-cyclooctene
R5
R4
R5
R4
Cl
Cl
a: R1 = F, R2 = R3 = R4 = R5 = H
b: R2 = F, R1 = R3 = R4 = R5 = H
c: R3 = F, R1 = R2 = R4 = R5 = H
d: R1 = CF3, R2 = R3 = R4 = R5 = H
e: R2 = CF3, R1 = R3 = R4 = R5 = H
f: R3 = CF3, R1 = R2 = R4 = R5 = H
g: R2 = R4 = CF3, R1 = R3 = R5 = H
h: R1 = R2 = R3 = R4 = R5 = F
3: M = Pd
4: M = Pt
Fig. 2. Synthesis of palladium and platinum complexes 3–4.

S.J. Scales et al. / Polyhedron 23 (2004) 2169–2176
2171
1H, Ar), 7.34–7.24 (ov m, 3H, Ar); 13C{1H} d: 174.0,
2.2.6. Compound 3f
161.7 (d, JC–F = 245 Hz, CF), 156.2, 150.7, 148.8 (d,
JC–F = 10 Hz), 141.9, 130.6 (d, JC–F = 9 Hz), 130.3,
129.9, 120.7, 115.9, (d, JC–F = 21 Hz), 112.4 (d, JC–
F = 25 Hz); 19F{1H} d: ꢀ112.8. IR (nujol): 2951, 2927,
2854, 1591, 1460, 1377, 1360, 1300, 1269, 1252, 1228,
1167, 1138, 980, 897, 856, 796, 771, 723, 692. Anal. Calc.
for C12H9N2Cl2FPd: C, 38.16; H, 2.41; N, 7.42. Found:
C, 38.22; H, 2.13; N, 7.25%.
Yield: 65% as an orange solid; m.p. 301–302 ꢁC (de-
composition). Spectroscopic NMR data (in DMSO-
d6): 1H d: 9.06 (d, J = 6 Hz, 1H, Ar), 8.83 (s, 1H,
C(H)‚N), 8.42 (t of d, J = 8, 1 Hz, 1H, Ar), 8.22 (d,
J = 8 Hz, 1H, Ar), 7.97 (t of d, J = 6, 1 Hz, 1H, Ar),
7.87 (d, J = 8 Hz, 2H, Ar), 7.63 (d, J = 8 Hz, 2H, Ar);
13C{1H} d: 174.4, 156.3, 150.7, 150.4, 142.0, 130.4,
130.0, 129.1 (q, JC–F = 35 Hz), 126.0 (q, JC–F = 4 Hz),
125.6, 124.5 (q, JC–F = 274 Hz, CF3); 19F{1H} d:
ꢀ60.8. IR (nujol): 3074, 2870, 1460, 1377, 1186, 1169,
1107, 966, 854, 766, 721, 607. Anal. Calc. for
C13H9N2Cl2F3Pd: C, 36.51; H, 2.13; N, 6.55. Found:
C, 36.66; H, 1.97; N, 6.45%.
2.2.3. Compound 3c
Yield: 60% as an orange solid; m.p. 328 ꢁC (decom-
position). Spectroscopic NMR data (in DMSO-d6): H
1
d: 9.05 (d, J = 6 Hz, 1H, Ar), 8.75 (s, 1H, C(H)‚N),
8.40 (t, J = 8 Hz, 1H, Ar), 8.20 (d, J = 8 Hz, 1H, Ar),
7.94 (t, J = 6 Hz, 1H, Ar), 7.51–7.46 (m, 2H, Ar),
7.34–7.28 (m, 2H, Ar); 13C{1H} d: 173.4, 162.2 (d, JC–
F = 246 Hz, CF), 156.4, 150.6, 143.9 (d, JC–F = 2 Hz),
141.9, 130.1, 129.7, 126.8 (d, JC–F = 9 Hz), 115.6 (d,
JC–F = 22 Hz); 19F{1H} d: ꢀ113.0. IR (nujol): 3109,
3041, 3016, 2920, 1597, 1579, 1498, 1479, 1308, 1296,
1242, 1228, 1196, 1157, 1103, 960, 850, 806, 795, 768,
579. Anal. Calc. for C12H9N2Cl2FPd: C, 38.16; H,
2.41; N, 7.42. Found: C, 37.98; H, 2.10; N, 7.10%.
2.2.7. Compound 3g
Yield: 60% as an orange solid; m.p. 358–360 ꢁC (de-
composition). Spectroscopic NMR data (in DMSO-
d6): 1H d: 9.07 (d, J = 6 Hz, 1H, Ar), 8.98 (s, 1H,
C(H)‚N), 8.45 (t of d, J = 8, 1 Hz, 1H, Ar), 8.27 (d,
J = 8 Hz, 1H, Ar), 8.24 (s, 1H, Ar), 8.19 (s, 2H, Ar),
8.00 (t of d, J = 6, 1 Hz, 1H, Ar); 13C{1H} d: 175.7,
156.1, 150.9, 148.2, 142.1, 130.8, 130.6 (q, JC–F = 34
Hz), 130.3, 126.1, 123.5 (q, JC–F = 274 Hz, CF3), 122.6
(q, JC–F = 4 Hz); 19F{1H} d: ꢀ61.2. IR (nujol): 3107,
3020, 2951, 2922, 2854, 1371, 1358, 1292, 1279, 1242,
1184, 1174, 1126, 970, 901, 881, 777, 702, 683. Anal.
Calc. for C14H8N2Cl2F6Pd: C, 33.92; H, 1.63; N, 5.65.
Found: C, 33.50; H, 1.39; N, 5.43%.
2.2.4. Compound 3d
Yield: 70% as an orange solid; m.p. 324–326 ꢁC (de-
composition). Spectroscopic NMR data (in DMSO-
d6): 1H d: 9.04 (d, J = 6 Hz, 1H, Ar), 8.97 (s, 1H,
C(H)‚N), 8.44 (t of d, J = 8, 1 Hz, 1H, Ar), 8.25 (d,
J = 8 Hz, 1H, Ar), 8.01 (t of d, J = 6, 1 Hz, 1H, Ar),
7.82–7.76 (ov m, 2H, Ar), 7.61 (t, J = 8 Hz, 1H, Ar),
7.51 (d, J = 8 Hz, 1H, Ar); 13C{1H} d: 175.2, 155.6,
151.2, 145.3, 142.1, 133.5, 130.6 (2C), 129.0, 126.8 (q,
JC–F = 5 Hz), 126.2, 124.5 (q, JC–F = 274 Hz, CF3),
122.2 (q, JC–F = 30 Hz); 19F{1H} d: ꢀ55.9. IR (nujol):
3074, 3014, 2952, 2925, 2854, 1593, 1471, 1456, 1319,
1296, 1269, 1203, 1155, 1124, 1055, 1034, 984, 768,
571. Anal. Calc. for C13H9N2Cl2F3Pd: C, 36.51; H,
2.13; N, 6.55. Found: C, 36.57; H, 1.98; N, 6.54%.
2.2.8. Compound 3h
Yield: 65% as an orange solid; m.p. 288 ꢁC (decom-
position). Spectroscopic NMR data (in DMSO-d6): H
1
d: 9.21 (s, 1H, C(H)‚N), 9.04 (d, J = 6 Hz, 1H, Ar),
8.46 (t, J = 8 Hz, 1H, Ar), 8.34 (d, J = 8 Hz, 1H, Ar),
8.06 (t, J = 6 Hz, 1H, Ar); 19F{1H} d: ꢀ145.4 (d, JF–
F = 19 Hz), ꢀ154.2 (t, JF–F = 19 Hz), ꢀ162.8 (t, JF–
F = 9 Hz). IR (nujol): 3095, 3016, 2951, 2924, 2856,
1591, 1512, 1470, 1433, 1352, 1294, 1221, 1103, 1009,
995, 960, 885, 793, 781. Anal. Calc. for
C12H5N2Cl2F5Pd: C, 32.06; H, 1.12; N, 6.23. Found:
C, 31.91; H, 0.83; N, 5.99%.
2.2.5. Compound 3e
Yield: 65% as an orange solid; m.p. 346–348 ꢁC (de-
composition). Spectroscopic NMR data (in DMSO-
d6): 1H d: 9.06 (d, J = 6 Hz, 1H, Ar), 8.85 (s, 1H,
C(H)‚N), 8.42 (t, J = 8 Hz, 1H, Ar), 8.23 (d, J = 8
Hz, 1H, Ar), 7.97 (t, J = 6 Hz, 1H, Ar), 7.85 (s, 1H,
Ar), 7.80 (m, 1H, Ar), 7.77–7.68 (ov m, 2H, Ar);
13C{1H} d: 175.0, 156.8, 151.3, 148.2, 142.5, 130.8,
130.5 (2C), 129.9 (q, JC–F = 32 Hz), 129.4, 128.7 (q,
JC–F = 274 Hz, CF3), 126.1 (q, JC–F = 4 Hz), 122.0 (q,
JC–F = 4 Hz); 19F{1H} d: ꢀ61.0. IR (nujol): 3074,
3014, 2953, 2854, 1593, 1450, 1362, 1329, 1238, 1184,
1159, 1117, 1068, 808, 773, 700, 658. Anal. Calc. for
C13H9N2Cl2F3Pd: C, 36.51; H, 2.13; N, 6.55. Found:
C, 36.23; H, 2.11; N, 6.33%.
2.2.9. Compound 4a
Yield: 65% as an orange solid; m.p. 282 ꢁC (decom-
position). Spectroscopic NMR data (in DMSO-d6): H
1
d: 9.51 (s, JH–Pt = 92 Hz, 1H, C(H)‚N), 9.47 (d, JH–
H = 6 Hz, JH–Pt = 40 Hz, 1H, Ar), 8.47 (t, JH–H = 8
Hz, 1H, Ar), 8.25 (d, JH–H = 8 Hz, 1H, Ar), 8.04 (t,
JH–H = 6 Hz, 1H, Ar), 7.50–7.31 (ov m, 4H, Ar);
13C{1H} d: 175.4, 157.1, 154.9 (d, JC–F = 250 Hz, CF),
149.8, 141.4, 135.4 (d, JC–F = 12 Hz), 131.1 (d, JC–
F = 8 Hz), 130.8 (2C), 126.5, 124.9 (d, JC–F = 4 Hz),
116.5 (d, JC–F = 20 Hz); 19F{1H} d: ꢀ120.0. IR (nujol):
2941, 2902, 2860, 1589, 1558, 1493, 1456, 1377, 1348,
1300, 1250, 1228, 1159, 1101, 937, 856, 800, 766, 739,

2172
S.J. Scales et al. / Polyhedron 23 (2004) 2169–2176
667, 596. Anal. Calc. for C12H9N2Cl2FPt: C, 30.91; H,
1.95; N, 6.01. Found: C, 30.44; H, 1.73; N, 5.68%.
9.48 (d, JH–H = 6 Hz, JH–Pt = 40 Hz, 1H, Ar), 9.45 (s,
JH–Pt = 88 Hz, 1H, C(H)‚N), 8.47 (t of d, JH–H = 8, 1
Hz, 1H, Ar), 8.26 (d, JH–H = 8 Hz, 1H, Ar), 8.02 (t of
d, JH–H = 6, 1 Hz, 1H, Ar), 7.90 (s, 1H, Ar), 7.85–7.75
(ov m, 3H, Ar); 13C{1H} d: 174.5, 157.6, 149.7, 147.6,
141.4, 130.6, 130.5, 130.2 (q, JC–F = 31 Hz), 130.0,
129.2, 128.3 (q, JC–F = 274 Hz, CF3), 126.0 (q, JC–F = 4
Hz), 121.9 (q, JC–F = 4 Hz); 19F{1H} d: ꢀ61.0. IR (nujol):
2943, 2910, 2860, 1460, 1377, 1327, 1240, 1182, 1161,
1117, 1066, 941, 808, 771, 700, 660, 596. Anal. Calc. for
C13H9N2Cl2F3Pt: C, 30.24; H, 1.76; N, 5.43. Found: C,
30.20; H, 1.50; N, 5.43%.
2.2.10. Compound 4b
Yield: 81% as an orange solid; m.p. 286 ꢁC (decom-
position). Spectroscopic NMR data (in DMSO-d6): H
1
d: 9.48 (d, JH–H = 6 Hz, JH–Pt = 47 Hz, 1H, Ar), 9.40
(s, JH–Pt = 91 Hz, 1H, C(H)‚N), 8.45 (t, JH–H = 8 Hz,
1H, Ar), 8.24 (d, JH–H = 8 Hz, 1H, Ar), 8.01 (t, JH–
H = 6 Hz, 1H, Ar), 7.60–7.52 (m, 1H, Ar), 7.40–7.29
(ov m, 3H, Ar); 13C{1H} d: 174.0, 161.8 (d, JC–F = 247
Hz, CF), 157.5, 149.7, 148.7 (d, JC–F = 10 Hz), 141.3,
130.7, 130.5, 130.4, 121.2 (d, JC–F = 3 Hz), 116.2 (d,
JC–F = 21 Hz), 112.7 (d, JC–F = 25 Hz); 19F{1H} d:
ꢀ112.7. IR (nujol): 2931, 2912, 2856, 1593, 1460, 1377,
1358, 1300, 1269, 1252, 1230, 1138, 984, 897, 858, 796,
769, 694. Anal. Calc. for C12H9N2Cl2FPt: C, 30.91; H,
1.95; N, 6.01. Found: C, 31.27; H, 1.65; N 6.00%.
2.2.14. Compound 4f
Yield: 85% as an orange solid; m.p. 300 ꢁC (decom-
position). Spectroscopic NMR data (in DMSO-d6): H
1
d: 9.48 (d, JH–H = 6 Hz, JH–Pt = 40 Hz, 1H, Ar), 9.43
(s, JH–Pt = 97 Hz, 1H, C(H)‚N), 8.47 (t of d,
JH–H = 8, 1 Hz, 1H, Ar), 8.26 (d, JH–H = 8 Hz, 1H,
Ar), 8.03 (t of d, JH–H = 6, 1 Hz, 1H, Ar), 7.92 (d,
JH–H = 8 Hz, 2H, Ar), 7.68 (d, JH–H = 8 Hz, 2H, Ar);
13C{1H} d: 174.4, 157.5, 149.7, 149.5, 141.3, 130.6,
130.5, 130.2 (q, JC–F = 31 Hz), 126.5 (q, JC–F = 274
Hz, CF3), 126.0 (2C); 19F{1H} d: ꢀ60.8. IR (nujol):
2958, 2939, 2883, 1416, 1325, 1201, 1111, 1066, 856,
825, 808, 760, 731, 700, 685, 669, 606, 596, 515. Anal.
Calc. for C13H9N2Cl2F3Pt: C, 30.24; H, 1.76; N, 5.43.
Found: C, 29.98; H, 1.42; N, 5.22%.
2.2.11. Compound 4c
Yield: 85% as an orange solid; m.p. 327 ꢁC (decom-
position). Spectroscopic NMR data (in DMSO-d6): H
1
d: 9.47 (d, JH–H = 6 Hz, JH–Pt = 40 Hz, 1H, Ar), 9.34
(s, JH–Pt = 93 Hz, 1H, C(H)‚N), 8.45 (t of d, JH–
H = 8, 1 Hz, 1H, Ar), 8.23 (d, JH–H = 8 Hz, 1H, Ar),
8.00 (t of d, JH–H = 6, 1 Hz, 1H, Ar), 7.56–7.51 (ov m,
2H, Ar), 7.39–7.33 (ov m, 2H, Ar); 13C{1H} d: 172.8,
161.8 (d, JC–F = 250 Hz, CF), 157.1, 149.1, 143.3 (d,
JC–F = 2 Hz), 140.7, 129.8, 129.7, 126.6 (d, JC–F = 9
Hz), 115.0 (d, JC–F = 23 Hz); 19F{1H} d: ꢀ112.7. IR (nu-
jol): 2951, 2939, 2914, 2852, 1462, 1377, 1298, 1244,
1228, 1157, 1101, 1059, 1039, 972, 947, 932, 920, 850,
806, 766, 752, 586. Anal. Calc. for C12H9N2Cl2FPt: C,
30.91; H, 1.95; N, 6.01. Found: C, 30.75; H, 1.69; N,
5.72%.
2.2.15. Compound 4g
Yield: 60% as an orange solid; m.p. 338 ꢁC (decom-
position). Spectroscopic NMR data (in DMSO-d6): H
1
d: 9.59 (s, JH–Pt = 85 Hz, 1H, C(H)‚N), 9.49 (d,
JH–H = 6 Hz, JH–Pt = 40 Hz, 1H, Ar), 8.49 (t, JH–H = 8
Hz, 1H, Ar), 8.31 (d, JH–H = 8 Hz, 1H, Ar), 8.27 (s,
1H, Ar), 8.25 (s, 2H, Ar), 8.05 (t, JH–H = 6 Hz, 1H,
Ar); 13C{1H} d: 175.6, 157.4, 149.9, 148.1, 141.5,
130.9, 130.6 (q, JC–F = 34 Hz), 130.4, 126.5, 123.5 (q,
J = 274 Hz, CF3), 123.1 (q, JC–F = 4 Hz); 19F{1H} d:
ꢀ61.2. IR (nujol): 2935, 2904, 2870, 1460, 1377, 1290,
1173, 1126, 974, 900, 847, 773. Anal. Calc. for
C14H8N2Cl2F6Pt: C, 28.77; H, 1.38; N, 4.80. Found:
C, 28.57; H, 1.16; N, 4.57%.
2.2.12. Compound 4d
Yield: 75% as an orange solid; m.p. 315 ꢁC (decom-
position). Spectroscopic NMR data (in DMSO-d6): H
1
d: 9.59 (s, JH–Pt = 90 Hz, 1H, C(H)‚N), 9.48 (d, JH–
H = 6 Hz, JH–Pt = 40 Hz, 1H, Ar), 8.48 (t, JH–H = 8
Hz, 1H, Ar), 8.30 (d, JH–H = 8 Hz, 1H, Ar), 8.06 (t,
JH–H = 6 Hz, 1H, Ar), 7.88–7.79 (ov m, 2H, Ar), 7.67
(t, JH–H = 8 Hz, 1H, Ar), 7.54 (d, JH–H = 8 Hz, 1H,
Ar); 13C{1H} d: 174.9, 163.2, 156.9, 150.1, 141.5,
133.4, 131.1, 130.9, 129.4, 127.1, 126.9 (q, JC–F = 5
Hz), 125.0 (q, JC–F = 274 Hz, CF3), 122.9 (q, JC–F = 30
Hz); 19F{1H} d: ꢀ56.2. IR (nujol): 2945, 2902, 2868,
1560, 1460, 1377, 1317, 1306, 1271, 1234, 1201, 1163,
1124, 1055, 1032, 968, 781, 762, 723, 596. Anal. Calc.
for C13H9N2Cl2F3Pt: C, 30.24; H, 1.76; N, 5.43. Found:
C, 29.81; H, 1.69; N, 5.25%.
2.2.16. Compound 4h
Yield: 60% as an orange solid; m.p. 302 ꢁC (decompo-
1
sition). Spectroscopic NMR data (in DMSO-d6): H d:
9.85 (s, JH–Pt = 82 Hz, 1H, C(H)‚N), 9.47 (d,
JH–H = 6 Hz, JH–Pt = 38 Hz, 1H, Ar), 8.50 (t, JH–H = 8
Hz, 1H, Ar), 8.40 (d, JH–H = 8 Hz, 1H, Ar), 8.14 (t,
JH–H = 6 Hz, 1H, Ar); 19F{1H} d: ꢀ145.9 (d, J = 19
Hz), ꢀ153.6 (t, J = 19 Hz), ꢀ162.6 (t, J = 19 Hz). IR (nu-
jol): 3041, 3016, 2960, 2939, 2864, 1512, 1471, 1433, 1350,
1292, 1223, 1105, 1026, 1011, 993, 939, 887, 779, 667.
Anal. Calc. for C12H5N2Cl2F5Pt: C, 26.77; H, 0.94; N,
5.21. Found: C, 26.53; H, 0.75; N, 5.15%.
2.2.13. Compound 4e
Yield: 65% as an orange solid; m.p. 336 ꢁC (decompo-
1
sition). Spectroscopic NMR data (in DMSO-d6): H d:

S.J. Scales et al. / Polyhedron 23 (2004) 2169–2176
2173
2.3. X-ray crystallography
measured using a VersaMax tunable microplate reader
(Molecular Devices) at 570 nm. Reduction of cell prolif-
eration was determined as a fraction of the absorbance
values for each drug treatment (T) to the mean absorb-
ance of the no-drug control (C), and calculated using the
expression 1 ꢀ T/C · 100%. Data from the separate tri-
als were combined using a t test (P < 0.05).
Crystals of 3dÆDMF were grown from a saturated
DMF solution at 20 ꢁC. Single crystals were coated with
Paratone-N oil, mounted using a glass fibre and frozen
in the cold stream of the goniometer. A hemisphere of
data was collected on a Bruker AXS P4/SMART 1000
diffractometer using x and h scans with a scan width
of 0.3ꢁ and 10 s exposure time. The detector distance
was 4 cm. The data were reduced [14] and corrected
for absorption [15]. The structure was 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.
3. Results and discussion
3.1. Synthesis and structure
The addition of a primary amine to commercially
available 2-pyridinecarboxaldehyde to afford the corre-
sponding pyridinecarboxaldimine ligand is a well-
known route to a versatile class of bidentate ligands
[17–27]. Variation of the amine therefore allows for
the facile design of ligands and subsequent metal com-
plexes with different physical and chemical properties.
In this study, the metal complexes 3–4 (Fig. 2) were pre-
pared by addition of the pyridin-2-ylcarboxaldimine lig-
ands to CH2Cl2 solutions of [MCl2(coe)]2 (M = Pd, Pt;
coe = cis-cyclooctene) [12,13]. Palladium complexes
were also prepared because of recent interest for their
anticancer potential. Compounds of the type [Pd(en)Cl2]
and [Pd(en)L] (en = ethylenediamine; L = malonato,
methylmalonato, dimethylmalonato and 1,1-cyclob-
utanedicarboxylato) were recently shown to bind to
DNA in a manner similar to that proposed for cisplatin
[28].
2.4. Cell culture
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, where 20 ll of compound so-
lutions were added to 180 ll of fresh medium 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-di-
chloro(pyridin-2-ylcarboxaldimine)platinum(II) com-
plex (2) [11].
Complexes containing fluorine groups are of particu-
lar interest as substitution of hydrocarbon fragments
with C–F moieties can dramatically alter the properties
of biologically active compounds and can influence the
metabolism and distribution of drug molecules in the
body [29–31]. For instance, substitution of fluorine on
the aromatic ring of the neurotransmitter norepineph-
rine produces large differences in its adrenergic activities
[32].
In this study, complexes 3–4 have been characterized
by a number of physical methods, including multinu-
clear NMR spectroscopy. A significant downfield shift
1
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 8.59 ppm for the free ligand
derived from 2-pyridinecarboxaldehyde and 4-fluoroan-
iline shifts to 9.34 ppm in complex 4c. Platinum satellites
are also observed for this resonance (JH–Pt = 93 Hz) up-
on complexation of the ligand to the metal. Similar
trends are observed for the pyridine hydrogen a to the
nitrogen atom as the chemical shift changes from d
8.71 to 9.47 ppm (JH–Pt = 40 Hz). The 19F NMR spectra
for compounds 3–4 are similar to analogous palladium
and platinum complexes containing fluorinated imines
[33–36]. For instance, three distinct resonances appear
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 me-
dia were added to each well, and plates were incubated
for 45 min. Following incubation, the medium was re-
moved and the purple formazan precipitate in each well
was solubilized in 200 ll DMSO. Absorbances were

2174
S.J. Scales et al. / Polyhedron 23 (2004) 2169–2176
Table 1
Crystallographic data collection parameters for 3dÆDMF
Complex
Formula
3dÆDMF
C16H16Cl2F3N3OPd
Formula weight
Crystal system
Space group
500.62
triclinic
ꢀ
P1
˚
a (A)
7.9624(5)
9.4425(5)
12.8704(7)
77.022(1)
76.213(1)
89.263(1)
914.93(9)
2
˚
b (A)
˚
c (A)
a (ꢁ)
b (ꢁ)
c (ꢁ)
3
˚
V (A )
Z
Dcalc (Mg mꢀ3
)
1.817
0.375 · 0.30 · 0.15
173(1)
Fig. 3. A view of molecule 3dÆDMF, with displacement ellipsoids
drawn at the 30% probability level. H atoms and the molecule of DMF
have been omitted for clarity.
Crystal size (mm3)
T (K)
Radiation
Mo Ka (k = 0.71073)
1.346
7377
l (mmꢀ1
)
Total reflections
Total unique reflections
Number of variables
Rint
4769
299
in the aromatic region for complexes 3, 4h, derived from
pentafluoroaniline, and coupling constants are in the ex-
pected range for analogous compounds [37]. It is inter-
esting to note, however, that metal complexes 3, 4h
were unstable in DMSO and decomposed after ca. 12
h to give a number of unidentified products, precluding
the acquisition of 13C NMR data. As late metals are
known to activate the C–F bond in related pentafluoro-
pyridine [38], it is plausible that compounds 3, 4h are
also decomposing via a similar mechanism [39,40].
Complex 3dÆDMF has also been characterized by an
X-ray diffraction study (Fig. 3). Crystallographic data
are given in Table 1 and selected bond lengths and an-
gles provided in Table 2. The nitrogen–palladium bonds
0.0244
h Range (ꢁ)
Largest difference peak/hole (e A
2.22–30.00
0.918/ꢀ0.2828
1.063
ꢀ3
˚
)
S (Goodness-of-fit) on F2
a
R1 (I>2r(I))
wR2 (all data)
0.0272
0.0703
b
P
P
a
R1 = iFojꢀjFci/ jFoj.
P
P
2
1=2
b
wR2 ¼ ð ½wðF 2o ꢀ F c2Þ = ½F 4oꢁꢁÞ
,
where w ¼ 1=½r2ðF o2Þþ
2
ð0:0354 ꢂ PÞ þ ð0:2668 ꢃ PÞꢁ, where P ¼ ðmaxðF 2o; 0Þ þ 2 ꢂ F c2Þ=3.
Table 2
˚
˚
˚
Selected bond lengths (A) and angles (ꢁ) for 3dÆDMF
of 2.0296(15) A (pyridine) and 2.0181(16) A (imine) are
similar to those reported in other imine palladium sys-
tems [41–43]. The imine C(7)–N(8) distance of 1.286(2)
Pd–N(8)
Pd–N(1)
2.0181(16)
2.0296(15)
2.2663(5)
2.2841(5)
1.327(2)
1.357(2)
1.286(2)
1.424(2)
1.325(2)
1.334(3)
1.341(3)
Pd–Cl(1)
Pd–Cl(2)
˚
A is in the range of accepted carbon–nitrogen double
bonds [44]. Interesting, the aromatic ring on the imine
nitrogen is almost perpendicular to the N(1)–Pd–N(8)
plane (83.4ꢁ), a trend that is observed in related diimine
platinum systems [45]. Indeed, this structural feature has
been used to create active and selective catalyst precur-
sors 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-pyr-
idyl)ethylamine) has been reported recently [46], where
the methyl group of the backbone lies in an equatorial
plane and results in a close contact between it and the
pyridine, which would otherwise not be present if the
methyl group were in the axial position. In the case of
N(1)–C(6)
N(1)–C(2)
C(7)–N(8)
N(8)–C(9)
C(15)–F(2)
C(15)–F(1)
C(15)–F(3)
N(8)–Pd–N(1)
N(8)–Pd–Cl(1)
N(1)–Pd–Cl(1)
N(8)–Pd–Cl(2)
N(1)–Pd–Cl(2)
Cl(1)–Pd–Cl(2)
C(6)–N(1)–C(2)
C(6)–N(1)–Pd
80.39(6)
93.28(5)
173.64(4)
174.97(4)
94.66(5)
91.673(19)
118.60(17)
128.69(14)
112.68(12)
106.7(2)
C(2)–N(1)–Pd
˚
3dÆDMF, a closest contact of Pd with F is 3.387 A,
F(2)–C(15)–F(1)
F(2)–C(15)–F(3)
F(1)–C(15)–F(3)
F(2)–C(15)–C(10)
F(1)–C(15)–C(10)
F(3)–C(15)–C(10)
where the trifluoromethyl group is canted over the plane
of the metal center. This observation suggests that com-
plexes with CF3 groups in the ortho position of the imine
aryl ring may shield the metal atom in a similar way to
AMD473.
106.8(2)
105.64(19)
112.02(18)
112.97(19)
112.2(2)

S.J. Scales et al. / Polyhedron 23 (2004) 2169–2176
2175
3.2. Cytotoxic activity
to address the structure activity relationships in these
complexes in order to design a potent drug candidate.
We have tested the cytotoxic activity of all the new pal-
ladium and platinum complexes against both cisplatin-
sensitive and cisplatin-resistant human ovarian cells
(Table 3), OV2008 and C13, respectively, at concentra-
tions corresponding to cisplatinꢀs IC50 value against
either cell line [47–49]. While marginal activity was
observed for palladium complexes against cisplatin-
sensitive cells OV2008, most of the analogous platinum
complexes showed significantly less activity. Indeed, the
platinum complexes 4a and 4h, which contain a F group
in the a position showed no activity against the cisplatin-
sensitive cell line. In contrast, however, is the observation
that 4d, with a bulky CF3 group in the a position, showed
considerable activity against OV2008 while 4e showed no
activity with the CF3 group in the meta position. More
remarkable is that almost all palladium and platinum
complexes displayed substantial activity against cisplatin-
resistant cell lines C13. Only compound 4a does not
show any significant activity. Compound 3d, with the
CF3 group in the ortho position of the aryl group, was
significantly more active than its platinum analogue
4d. The platinum compounds 4e and 4g contain a CF3
moiety in the meta position and show enhanced activi-
ties towards C13 as compared to OV2008. Interestingly,
increased activities were observed for both metal com-
plexes when the CF3 group was bound in the para posi-
tion (complexes 3f and 4f show the greatest activity
against C13). While these initial studies have shown that
some compounds show promise against the cisplatin-
resistant cell line, further in vitro studies are needed
4. Conclusion
Pyridinecarboxaldimines derived from the condensa-
tion of 2-pyridinecarboxaldehyde and fluorine-contain-
ing amines have been prepared in high yields and used
as ligands for palladium and platinum salts. The result-
ing metal complexes have shown considerable cytotoxic-
ity against the OV2008 (human ovarian carcinoma)
cisplatin-resistant C13 cell line. Future work in this area
will continue to develop bulkier metal complexes con-
taining highly fluorinated groups.
Acknowledgements
Thanks are gratefully extended to the Research
Corporation (Cottrell College Science Award),
NSERC, Canada Research Chair/Canadian Founda-
tion for Innovation/Atlantic Innovation Fund pro-
grams and Mount Allison University for financial
support. We also thank Roger Smith, Dan Durant
and Barbie Sears (MAU) for expert technical assist-
ance, Dr. Barbara C. Vanderhyden of the Centre
for Cancer Therapeutics (Ottawa Regional Cancer
Centre, Ont., Canada) for providing us with the
OV2008 and C13 cell lines, and anonymous reviewers
for helpful comments.
Appendix A. Supplementary material
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 www: http//www.
ccdc.cam.ac.uk) and are available on request, quoting
deposition number 237107 for compound 3dÆDMF.
Supplementary data associated with this article can be
found, in the online version at doi:10.1016/j.poly.2004.
06.013.
Table 3
Percent reduction of cell proliferation of cisplatin-sensitive (OV2008)
and cisplatin-resistant (C13) cancer cells to compounds at 5 and 140
lM, respectively (n = 8; SD)
Compound
OV2008
C13
cisplatin
2
44 11
41
37
78
31
31
8
8
8
9
7
21
25 11
21
3
3a
3b
3c
7
28 12
28 10
20 11
24 12
23 10
3d
3e
79 11
29 16
83 15
39 15
56 13
3f
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