Synthesis, characterization and anticancer properties of (salicylaldiminato)platinum(II) complexes

Article abstract of DOI:10.1016/j.ica.2014.02.028

Twelve new (salicylaldiminato)platinum(II) complexes have been prepared, characterized and examined for their in vitro cytotoxic properties against three human glioma cell lines LN18, LN405 and Hs683. Initial biotesting was done on platinum complexes 1-6, which display a wide range of physicochemical properties. Whereas introduction of aromatic rings in the complexes did not seem to have a significant impact on bioactivities, the length of the aliphatic group positively correlated with cytotoxicity in all cell lines. Complexes 2 and 3 were found to be particularly potent against LN18 cells as demonstrated by stronger cell growth inhibition when compared to cisplatin. These initial findings led us to develop an additional series of mono (salicylaldiminato) platinum(II) complexes 7-12, which were subjected to additional cytotoxicity studies but were less cytotoxic compared to the bis Schiff base complexes. These organometallic compounds could serve as interesting starting points for the development of novel therapeutic strategies to treat brain tumors.

Full text of DOI:10.1016/j.ica.2014.02.028

Inorganica Chimica Acta 415 (2014) 88–94
Contents lists available at ScienceDirect
Inorganica Chimica Acta
journal homepage: www.elsevier.com/locate/ica
Synthesis, characterization and anticancer properties
of (salicylaldiminato)platinum(II) complexes
Alyssa E. Patterson a, Jessica J. Miller a, Brittany A. Miles a, Erin L. Stewart a, Josée-Marie E.J. Melanson a,
Christopher M. Vogels a, Amanda M. Cockshutt a, Andreas Decken b, Pier Morin Jr. c,
,
⇑
Stephen A. Westcott a,
⇑
a Department of Chemistry and Biochemistry, Mount Allison University, Sackville, NB E4L 1G8, Canada
b Department of Chemistry, University of New Brunswick, Fredericton, NB E3B 5A3, Canada
c Département de chimie et biochimie, Université de Moncton, Campus de Moncton, Moncton, NB E1A 3E9, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
Twelve new (salicylaldiminato)platinum(II) complexes have been prepared, characterized and examined
for their in vitro cytotoxic properties against three human glioma cell lines LN18, LN405 and Hs683. Initial
biotesting was done on platinum complexes 1–6, which display a wide range of physicochemical prop-
erties. Whereas introduction of aromatic rings in the complexes did not seem to have a significant impact
on bioactivities, the length of the aliphatic group positively correlated with cytotoxicity in all cell lines.
Complexes 2 and 3 were found to be particularly potent against LN18 cells as demonstrated by stronger
cell growth inhibition when compared to cisplatin. These initial findings led us to develop an additional
series of mono (salicylaldiminato)platinum(II) complexes 7–12, which were subjected to additional cyto-
toxicity studies but were less cytotoxic compared to the bis Schiff base complexes. These organometallic
compounds could serve as interesting starting points for the development of novel therapeutic strategies
to treat brain tumors.
Received 13 November 2013
Received in revised form 9 February 2014
Accepted 16 February 2014
Available online 5 March 2014
Keywords:
Cancer
Glioma
Platinum
Salicylaldimine
Schiff base
Ó 2014 Elsevier B.V. All rights reserved.
1. Introduction
Although modest improvements have been made over the past
fifty years, most of this work has involved varying either the inert
Cisplatin (Fig. 1a) is a remarkably small molecule that has made
a huge impact in medicinal chemistry. Indeed, this simple coordi-
nation complex has achieved considerable success in the treatment
of ovarian, testicular, head and neck, bladder, cervical and small
cell lung cancer [1]. Unfortunately, cisplatin has several serious
side effects, such as oto-, neuro-, and nephrotoxicity, which de-
crease its overall effectiveness in cancer therapy [2]. Since its dis-
covery, a plethora of second generation platinum complexes
based on the structure of cisplatin, such as [PtCl2(cis-1,4-DACH)]
(Fig. 1b) and carboplatin (Fig. 1c), have been developed and exam-
ined for their potential anticancer properties. The mechanism of
action of these platinum drugs is believed to arise by initial ligand
substitution with the anionic ligands (chlorides or carboxylates) by
molecules of water to give a charged platinum molecule. Coordina-
tion of the metal to nitrogenous bases of DNA, most likely through
the N7 of guanine, interferes with cell replication and ultimately
causes them to undergo apoptosis, or programmed cell death.
amine ligands or the labile chloride ligands in an effort to enhance
delivery of the platinum metal to the cancerous cells [3].
An interesting recent development has been in the combined
use of radiotherapy and platinum chemotherapy for the treatment
of glioblastomas [4–9]. The synergy between cancer treatments en-
ables the reduction of platinum dose and thereby diminishes side
effects. Gliomas are classified into four clinical grades and glioblas-
toma multiforme (GBM) is the most aggressive, whereby the med-
ian survival period for patients diagnosed with a GBM is only
twelve months. Unfortunately, tumors infiltrate into regions of
the brain that render complete surgical extraction difficult.
Although some improvements in the prognosis of GBM patients
have been observed using chemotherapeutic agents, such as cis-
platin and its derivatives, the search for novel agents to treat
GBM is of utmost importance in an effort to improve this combined
form of therapy.
While the coordination chemistry of most transition metals (i.e.
Co, Cu, Pd, Ni, etc.) containing simple salicylaldimines has been
extensively studied [10], it is somewhat surprising that relatively
little is known about the corresponding platinum complexes
⇑
Corresponding authors. Tel.: +1 506 364 2372 (S.A. Westcott).
E-mail address: swestcott@mta.ca (S.A. Westcott).
http://dx.doi.org/10.1016/j.ica.2014.02.028
0020-1693/Ó 2014 Elsevier B.V. All rights reserved.

A.E. Patterson et al. / Inorganica Chimica Acta 415 (2014) 88–94
89
Multiplicities are reported as singlet (s), doublet (d), triplet (t),
multiplet (m), broad (br), and overlapping (ov) with coupling
constants (J) reported in hertz. FT-IR spectra were obtained with
a Thermo Fisher Scientific Nicolet iS5 FT-IR spectrometer in ATR
mode and are reported in cmꢀ1. Melting and decomposition
points were measured uncorrected with a Mel-Temp apparatus.
Elemental analyses for C, H, and N were carried out at Guelph
Chemical Laboratories (Guelph, ON) and Laboratoire d’Analyse
Élémentaire de l’Université de Montréal (Montréal, QC).
Fig. 1. Common platinum anticancer agents.
2.2. General procedure for the synthesis of complexes 1–6
Table 1
Crystallographic data-collection parameters.
Under an atmosphere of dinitrogen, a hexane solution of n-BuLi
(0.5 M equivalent) was added to a toluene solution of the appropri-
ate Schiff base. Upon stirring the reaction mixture for 8 h, a toluene
Complex
3
4
Formula
C
30H44N2O2Pt
C26H20N2O2Pt
587.53
monoclinic
C2/m
11.867(3)
10.079(3)
9.657(3)
90
113.208(5)
90
Molecular weight
Crystal system
Space group
a (Å)
b (Å)
c (Å)
659.76
monoclinic
P21/c
14.739(2)
5.6317(8)
17.185(2)
90
97.515
90
1414.2(3)
2
1.549
(5 mL) solution of [PtCl2(g
2-coe)]2 (0.25 M equivalents, coe = cis-
cyclooctene) was added and the mixture was heated at reflux for
18 h. Upon cooling to RT, the reaction was transferred to ambient
conditions and passed through a plug of silica. Removal of solvent
under vacuum afforded crude products as orange-red solids. Com-
plexes 1 and 4–6 were isolated upon recrystallization from a min-
imum amount of hot toluene, filtered and then stored at 5 °C
whereas compounds 2 and 3 were similarly isolated from hexane.
a
(°)
b (°)
c
(°)
V (Å3)
1061.5(5)
2
1.838
Z
qcalc (Mg mꢀ3
)
2.2.1. Di-(2-((isopentylimino)methyl)phenolato-j
2-N,O)platinum(II)
(1)
Crystal size (mm3)
T (K)
0.57 ꢁ 0.10 ꢁ 0.10
0.15 ꢁ 0.15 ꢁ 0.03
198(1)
188(1)
Radiation
Mo K
(k = 0.71073 Å)
4.989
Mo K
(k = 0.71073 Å)
6.635
a
a
A toluene solution of the Schiff base (612 mg, 3.20 mmol) was
deprotonated with n-BuLi (2.0 mL of a 1.6 M solution in hexanes,
l
(mmꢀ1
)
3.20 mmol) and added to a toluene solution of [PtCl2(g
2-coe)]2
Total reflections
9105
3519
(600 mg, 0.80 mmol). Yellow-orange solid; yield: 710 mg (77%);
mp: 279–281 °C. 1H NMR (CDCl3) d (ppm): 7.91 (s, JH–Pt = 59.8 Hz,
2H, CH@N), 7.35–7.22 (ov m, 4H, Ar), 6.88 (d, JH–H = 8.7 Hz, 2H,
Ar), 6.57 (t, JH–H = 7.7 Hz, 2H, Ar), 3.86 (br t, JH–H = 6.2 Hz, 4H,
NCH2), 1.73–1.69 (ov m, 6H, CH2 and CH(CH3)2), 0.96 (d, JH–H = 5.4 -
Hz, 12H, CH(CH3)2). 13C{1H} NMR (CDCl3) d (ppm): 163.5 (C–O),
158.8 (C@N), 133.7, 133.4, 120.9, 120.3, 115.7, 57.2 (N–CH2), 41.7
(NCH2CH2), 26.5 (CH(CH3)2), 22.9 (CH3). IR (Nujol) (cmꢀ1): 2945
Total unique reflections
Number of variables
h Range (°)
3126
183
2.39–27.49
1.027 and ꢀ1.163
1244
140
2.29–27.50
3.304 and ꢀ1.174
Largest difference peak and hole
(e Å3)
S (Goodness of fit (GOF)) on F2
1.130
0.0348
0.0971
1.182
0.0261
0.0633
a
R1 (I > 2
r
(I))
b
wR2 (all data)
a
R1
wR2 = (
(3) and 1/[
=
R
||Fo| ꢀ |Fc||/
R
|Fo|.
[wF4o])1/2 2(Fo2) + (0.0313ꢂP)2 + (1.9366ꢂP)]
, where w = 1/[r
R
[w(F2oF2c)2]/
R
b
(s), 2901 (s), 2859 (s), 1616 (s, mC@N), 1597 (m), 1537 (m), 1465
r
2(F2o) + (0.0439ꢂP)2] (4), where P = (max (Fo2, 0) + 2ꢂF2c)/3.
(s), 1450 (s), 1405 (m), 1377 (m), 1354 (w), 1320 (m), 1200 (w),
1147 (w), 1126 (w), 910 (w), 752 (s), 735 (w). Anal. Calc. for C24H32-
N2O2Pt (575.66): C, 50.07; H, 5.61; N, 4.87. Found: C, 50.25; H,
5.80; N, 4.61%.
[11–16]. In one study, tetradentate salen-type platinum complexes
have been reported and examined primarily for their potential to
be used as electroluminescent devices [15]. More relevant to this
study is a recent report that has shown that complexes of this type
can also be used to inhibit the growth of MCF-7 and MDA-MB 231
cancer cells [16]. These results, along with our interest in designing
new families of biologically-active platinum complexes [17], led us
to develop a series of easily prepared Schiff base platinum com-
plexes derived from salicylaldehyde and a variety of primary
amines with different physicochemical properties.
2.2.2. Di-(2-((hexylimino)methyl)phenolato-j
2-N,O)platinum(II) (2)
A toluene solution of the Schiff base (656 mg, 3.20 mmol) was
deprotonated with n-BuLi (2.0 mL of a 1.6 M solution in hexanes,
3.20 mmol) and added to a toluene solution of [PtCl2(g
2-coe)]2
(600 mg, 0.80 mmol). Yellow-orange solid; yield: 821 mg (85%);
mp: 186–187 °C. 1H NMR (CDCl3) d (ppm): 7.90 (s, JH–Pt = 59.9 Hz,
2H, CH@N), 7.32 (ddd, JH–H = 8.4, 6.9, 1.7 Hz, 2H, Ar), 7.25 (dd,
JH–H = 7.7, 1.7 Hz, 2H, Ar), 6.87 (d, JH–H = 8.4 Hz, 2H, Ar), 6.57
(ddd, JH–H = 7.7, 6.9, 1.0 Hz, 2H, Ar), 3.83 (t, JH–H = 6.9 Hz, 4H,
NCH2), 1.81 (quint, JH–H = 6.9 Hz, 4H, NCH2CH2), 1.41–1.23 (ov m,
12H, (CH2)3), 0.87 (t, JH–H = 6.9 Hz, 6H, CH3). 13C{1H} NMR (CDCl3)
d (ppm): 163.5 (C–O), 158.7 (C@N), 133.7, 133.5, 120.8, 120.4,
115.7, 59.0 (N–CH2), 32.5, 31.7, 26.7, 22.7, 14.2 (CH3). IR (Nujol)
2. Experimental
2.1. General methods
(cmꢀ1): 2919 (s), 2854 (s), 1616 (s,
mC@N), 1538 (s), 1467 (s),
Reagents and solvents used were obtained from Aldrich Chem-
1431 (s), 1405 (w), 1321 (s), 1203 (m), 1148 (m), 750 (s), 735
(m). Anal. Calc. for C26H36N2O2Pt (603.72): C, 51.72; H, 6.02; N,
4.64. Found: C, 51.96; H, 5.99; N, 4.34%.
icals. [PtCl2(g
2-coe)]2 (coe = cis-cyclooctene) [18] and the Schiff
bases [19] were synthesized according to literature procedures.
NMR spectra were recorded on a JEOL JNM-GSX400 FT NMR spec-
trometer. 1H NMR chemical shifts are reported in ppm and are ref-
erenced to residual protons in deuterated solvent at 400 MHz. 13C
NMR chemical shifts are referenced to solvent carbon resonances
as internal standards at 100 MHz. 19F NMR chemical shifts are
referenced to CF3CO2H as an external standard at 376 MHz.
2.2.3. Di-(2-((octylimino)methyl)phenolato-j
2-N,O)platinum(II) (3)
A toluene solution of the Schiff base (747 mg, 3.20 mmol) was
deprotonated with n-BuLi (2.0 mL of a 1.6 M solution in hexanes,
3.20 mmol) and added to a toluene solution of [PtCl2(
(600 mg, 0.80 mmol). Yellow-orange solid; yield: 897 mg (85%);
g
2-coe)]2

90
A.E. Patterson et al. / Inorganica Chimica Acta 415 (2014) 88–94
mp: 158–159 °C. 1H NMR (CDCl3) d (ppm): 7.90 (s, JH–Pt = 53.9 Hz,
2H, CH@N), 7.32 (ddd, JH–H = 8.4, 6.7, 1.7 Hz, 2H, Ar), 7.24 (dd,
JH–H = 7.9, 1.7 Hz, 2H, Ar), 6.87 (d, JH–H = 8.4 Hz, 2H, Ar), 6.57
(ddd, JH–H = 7.9, 6.7, 1.0 Hz, 2H, Ar), 3.83 (t, JH–H = 6.9 Hz, 4H,
NCH2), 1.81 (quint, JH–H = 6.9 Hz, 4H, NCH2CH2), 1.44–1.18 (ov m,
20H, (CH2)5), 0.85 (t, JH–H = 6.9 Hz, 6H, CH3). 13C{1H} NMR (CDCl3)
d (ppm): 163.5 (C–O), 158.7 (C@N), 133.7, 133.5, 120.8, 120.4,
115.6, 59.0 (N–CH2), 32.5, 31.9, 29.5, 29.4, 27.0, 22.7, 14.2 (CH3).
2.3. General procedure for the synthesis of complexes 7–12
Under an atmosphere of dinitrogen, a hexane solution of n-BuLi
(1 M equivalent) was added to a toluene (5 mL) solution of the
appropriate Schiff base. Upon stirring the reaction mixture for
3 h at RT, a toluene (20 mL) suspension of [PtCl2(g
2-coe)]2 (0.5 M
equivalents) was added and the mixture was stirred at RT for
18 h. After removal of the reaction from the inert atmosphere,
the suspension was passed through a plug of alumina to remove
the lithium salts and the solvent was removed under vacuum to af-
ford the desired platinum complexes.
IR (Nujol) (cmꢀ1): 2927 (s), 2854 (s), 1616 (s,
mC@N), 1538 (m),
1466 (s), 1451 (s), 1405 (w), 1377 (w), 1354 (w), 1322 (s), 1198
(w), 1148 (w), 914 (w), 751 (m), 736 (w). Anal. Calc. for C30H44N2-
O2Pt (659.84): C, 54.60; H, 6.73; N, 4.25. Found: C, 54.76; H, 7.01;
N, 4.05%.
2.3.1. (Chlorido)(
methyl)phenolato-
g
2-cis-cyclooctene)(2-((2-ethyl-1-hexylimino)-
2-N,O)platinum(II) (7)
j
2.2.4. Di-(2-((phenylimino)methyl)phenolato-j
2-N,O)platinum(II) (4)
A toluene solution of the Schiff base (373 mg, 1.60 mmol) was
deprotonated with n-BuLi (1.0 mL of a 1.6 M solution in hexanes,
A toluene solution of the Schiff base (631 mg, 3.20 mmol) was
1.60 mmol) and added to a toluene solution of [PtCl2(g
2-coe)]2
deprotonated with n-BuLi (2.0 mL of a 1.6 M solution in hexanes,
(600 mg, 0.80 mmol). Orange oil. Yield: 743 mg (81%). 1H NMR
(CDCl3): d = 7.76 (s, JHPt = 67.6 Hz, 1H, C(H)@N), 7.33 (ddd,
JHH = 8.4, 6.8, 1.8 Hz, 1H, Ar), 7.25 (dd, JHH = 8.0, 1.8 Hz, 1H, Ar),
6.85 (d, JHH = 8.4 Hz, 1H, Ar), 6.65 (ddd, JHH = 8.0, 6.8, 0.8 Hz, 1H,
Ar), 5.45 (br m, JHPt = 57.2 Hz, 2H, HC@CH), 4.08 (dd, JHH = 7.0,
7.0 Hz, 2H, NCH2), 2.44 (m, 2H, CH2 (coe)), 2.30 (m, 2H, CH2
(coe)), 2.10 (m, 1H, CH), 1.81 (m, 2H, CH2 (coe)), 1.59–1.50 (ov m,
6H, CH2 (coe)), 1.33–1.23 (ov m, 8H, CH2 (2-ethyl-1-hexyl)),
0.94–0.86 (ov m, 6H, CH3) ppm. 13C{1H} NMR (CDCl3): d = 163.6
(C–O), 161.4 (C@N), 135.7, 134.4, 120.1, 119.8, 116.9, 94.3 (s,
JCPt = 163.2 Hz, C@C), 67.1 (N–CH2), 40.4, 29.8, 28.9, 28.4, 26.6,
25.8 (br), 23.3, 23.2, 14.3, 10.6. IR (Nujol) (cmꢀ1): 2956 (m), 2923
3.20 mmol) and added to a toluene solution of [PtCl2(
(600 mg, 0.80 mmol). Orange solid; yield: 771 mg (82%); decompo-
sition point: 288–294 °C. 1H NMR (CDCl3) d (ppm): 8.01 (s, JH–Pt
64.6 Hz, 2H, CH@N), 7.46–7.34 (ov m, 10H, Ar), 7.24–7.17 (ov m,
g
2-coe)]2
=
4H, Ar), 6.51 (ddd, JH–H = 7.9, 6.7, 1.0 Hz, 2H, Ar), 6.12 (d, JH–H
=
8.8 Hz, 2H, Ar). 13C{1H} NMR (CDCl3) d (ppm): 163.8 (C–O), 159.6
(C@N), 149.9, 134.4, 133.8, 128.2, 126.7, 124.8, 121.0, 120.7,
116.1. IR (Nujol) (cmꢀ1): 2963 (m), 2868 (m), 1602 (s,
mC@N),
1524 (s), 1461 (s), 1440 (s), 1316 (s), 1178 (s), 1143 (m), 758 (s),
691 (s). Anal. Calc. for C26H20N2O2Pt (587.56): C, 53.15; H, 3.44;
N, 4.77. Found: C, 52.94; H, 3.41; N, 4.60%.
(m), 1608 (s,
mC@N), 1540 (m), 1468 (m), 1447 (m), 1403 (w),
2.2.5. Di-(2-((4-methoxyphenylimino)methyl)phenolato-j2
N,O)platinum(II) (5)
-
1380 (w), 1357 (w), 1318 (m), 1172 (w), 1150 (m), 1130 (w),
1039 (w), 1024 (w), 975 (w), 908 (w), 849 (w), 816 (w), 752 (s),
734 (s), 667 (w), 612 (w). Anal. Calc. for C23H36NClOPt (573.07):
C, 48.20; H, 6.33; N, 2.44. Found: C, 47.95; H, 6.34; N, 2.40%.
A toluene solution of the Schiff base (727 mg, 3.20 mmol) was
deprotonated with n-BuLi (2.0 mL of a 1.6 M solution in hexanes,
3.20 mmol) and added to a toluene solution of [PtCl2(g
2-coe)]2
2.3.2. (Chlorido)(
phenolato-
2-N,O)platinum(II) (8)
g
2-cis-cyclooctene)(2-((decylimino)methyl)-
(600 mg, 0.80 mmol). Burgundy solid; yield: 901 mg (87%); decom-
position point: 223–228 °C. 1H NMR (CDCl3) d (ppm): 7.99 (s, JH–Pt
j
= 60.4 Hz, 2H, CH@N), 7.31–7.18 (ov m, 8H, Ar), 6.93 (d, JH–H
=
A toluene solution of the Schiff base (418 mg, 1.60 mmol) was
8.9 Hz, 4H, Ar), 6.50 (ddd, JH–H = 7.9, 7.0, 1.0 Hz, 2H, Ar), 6.22
deprotonated with n-BuLi (1.0 mL of a 1.6 M solution in hexanes,
(d, JH–H = 8.9 Hz, 2H, Ar), 3.88 (s, 6H, OCH3). 13C{1H} NMR (CDCl3)
1.60 mmol) and added to a toluene solution of [PtCl2(g
2-coe)]2
(600 mg, 0.80 mmol). Orange oil. Yield: 788 mg (82%). 1H NMR
(CDCl3): d = 7.89 (s, JHPt = 66.6 Hz, 1H, C(H)@N), 7.34 (ddd,
JHH = 8.4, 6.8, 1.8 Hz, 1H, Ar), 7.26 (dd, JHH = 8.0, 1.8 Hz, 1H, Ar),
6.87 (d, JHH = 8.4 Hz, 1H, Ar), 6.65 (ddd, JHH = 8.0, 6.8, 1.0 Hz, 1H,
Ar), 5.49 (br m, JHPt = 56.4 Hz, 2H, HC@CH), 4.17 (t, JHH = 7.4 Hz,
2H, NCH2), 2.47 (m, 2H, CH2 (coe)), 2.31 (m, 2H, CH2 (coe)), 1.90–
1.82 (br m, 4H, CH2 (decyl and coe)), 1.59–1.51 (ov m, 6H, CH2
(coe)), 1.33–1.27 (ov m, 14H, CH2 (decyl)), 0.89 (t, JHH = 6.0 Hz,
3H, CH3) ppm. 13C{1H} NMR (CDCl3): d = 163.3 (C–O), 161.0
(C@N), 135.7, 134.4, 120.0, 119.5, 116.8, 94.4 (s, JCPt = 158.8 Hz,
C@C), 63.2 (N–CH2), 32.9, 32.1, 29.9, 29.8, 29.6 (2C), 28.9, 26.8,
26.6, 25.8 (br), 22.9, 14.4 (CH3). IR (Nujol) (cmꢀ1): 2925 (s), 2855
d
(ppm): 163.8 (C–O), 159.6 (C@N), 158.3 (C–OCH3), 143.2,
134.3, 133.7, 125.7, 120.9, 120.8, 116.0, 113.2, 55.7 (OCH3). IR
(Nujol) (cmꢀ1): 2971 (s), 2881 (s), 2838 (s), 1600 (s,
C@N), 1539
m
(w), 1506 (s), 1464 (s), 1442 (s), 1377 (m), 1304 (s), 1250 (m),
1181 (m), 1149 (w), 1125 (w), 839 (s), 750 (s). Anal. Calc. for
C28H24N2O4Pt (647.62): C, 51.93; H, 3.74; N, 4.33. Found: C,
52.21; H, 3.50; N, 4.16%.
2.2.6. Di-(2-((4-fluorophenylimino)methyl)phenolato-j2
N,O)platinum(II) (6)
-
A toluene solution of the Schiff base (689 mg, 3.20 mmol) was
deprotonated with n-BuLi (2.0 mL of a 1.6 M solution in hexanes,
3.20 mmol) and added to a toluene solution of [PtCl2(
g
2-coe)]2
(s), 1613 (s, mC@N), 1460 (m), 1377 (m), 722 (w). Anal. Calc. for C25-
(600 mg, 0.80 mmol). Bright orange solid; yield: 838 mg (84%);
decomposition point: 245–247 °C. 1H NMR (CDCl3) d (ppm): 8.00
(s, JH–Pt = 62.4 Hz, 2H, CH@N), 7.34–7.22 (ov m, 8H, Ar), 7.15–7.07
(ov m, 4H, Ar), 6.53 (ddd, JH–H = 7.9, 6.9, 1.0 Hz, 2H, Ar), 6.19
(d, JH–H = 8.9 Hz, 2H, Ar). 13C{1H} NMR (CDCl3, 50 °C) d (ppm):
164.0 (C–O), 161.4 (d, JCF = 246 Hz, C–F), 159.8 (C@N), 145.9 (d,
JCF = 3 Hz), 134.6, 133.7, 126.3 (d, JCF = 8 Hz), 120.9, 120.6, 116.2,
114.8 (d, JCF = 23 Hz). 19F{1H} NMR (CDCl3) d (ppm): ꢀ116.2. IR
H40NClOPt (601.12): C, 49.95; H, 6.71; N, 2.33. Found: C, 49.93; H,
6.90; N, 2.25%.
2.3.3. (Chlorido)(
phenolato-
2-N,O)platinum(II) (9)
g
2-cis-cyclooctene)(2-((hexadecylimino)methyl)-
j
A toluene solution of the Schiff base (553 mg, 1.60 mmol) was
deprotonated with n-BuLi (1.0 mL of a 1.6 M solution in hexanes,
1.60 mmol) and added to a toluene solution of [PtCl2(g
2-coe)]2
(Nujol) (cmꢀ1): 2943 (m), 2855 (m), 1604 (s,
m
C@N), 1589 (s),
(600 mg, 0.80 mmol). Further purified by passing a Et2O solution
of the complex through a plug of alumina. Orange oil. Yield:
866 mg (79%). 1H NMR (CDCl3): d = 7.88 (s, JHPt = 66.2 Hz, 1H,
C(H)@N), 7.32 (ddd, JHH = 8.6, 6.8, 1.6 Hz, 1H, Ar), 7.26 (dd,
JHH = 7.8, 1.6 Hz, 1H, Ar), 6.85 (d, JHH = 8.6 Hz, 1H, Ar), 6.63 (ddd,
1531 (m), 1499 (s), 1465 (s), 1441 (s), 1379 (m), 1353 (w), 1308
(m), 1226 (m), 1178 (s), 1146 (s), 1125 (m), 1093 (w), 837 (s),
762 (m). Anal. Calc. for C26H18N2F2O2Pt (623.54): C, 50.08; H,
2.92; N, 4.49. Found: C, 49.91; H, 2.77; N, 4.72%.

A.E. Patterson et al. / Inorganica Chimica Acta 415 (2014) 88–94
91
JHH = 7.8, 6.8, 1.0 Hz, 1H, Ar), 5.47 (br m, JHPt = 56.0 Hz, 2H, HC@CH),
4.15 (t, JHH = 7.6 Hz, 2H, NCH2), 2.46 (m, 2H, CH2 (coe)), 2.29 (m, 2H,
CH2 (coe)), 1.90–1.74 (br m, 4H, CH2 (hexadecyl and coe)), 1.58–
1.51 (ov m, 6H, CH2 (coe)), 1.31–1.25 (ov m, 26H, CH2 (hexadecyl)),
0.88 (t, JHH = 6.0 Hz, 3H, CH3) ppm. 13C{1H} NMR (CDCl3): d = 163.2
(C–O), 161.0 (C@N), 135.6, 134.4, 120.0, 119.5, 116.8, 94.2 (s,
JCPt = 160.2 Hz, C@C), 63.1 (N–CH2), 32.9, 32.2, 30.0 (4C), 29.9
(3C), 29.8, 29.6, 29.5, 28.9, 26.7, 26.6, 25.8 (br), 22.9, 14.4 (CH3).
(600 mg, 0.80 mmol). Recrystallization from
a
CH2Cl2/hexane
(5 mL:2 mL) solution afforded 12 as a yellow solid. Yield: 731 mg
(80%); decomposition point: 75–78 °C. 1H NMR (CDCl3): d = 7.83
(s, JHPt = 69.6 Hz, 1H, C(H)@N), 7.24 (ddd, JHH = 8.4, 7.0, 1.8 Hz,
1H, Ar), 7.17 (dd, JHH = 7.8, 1.8 Hz, 1H, Ar), 6.77 (d, JHH = 8.4 Hz,
1H, Ar), 6.57 (ddd, JHH = 7.8, 7.0, 1.0 Hz, 1H, Ar), 5.41 (br m,
JHPt = 57.2 Hz, 2H, HC@CH), 5.10 (m, 1H, NCH), 2.40 (m, 2H, CH2
(coe)), 2.22 (m, 2H, CH2 (coe)), 2.01 (m, 2H, CH2 (coe)), 1.75–1.43
(ov m, 20H, CH2 (cyclooctyl + coe)) ppm. 13C{1H} NMR (CDCl3):
d = 162.7 (C–O), 159.2 (C@N), 135.5, 134.2, 120.7, 119.8, 116.8,
93.7 (s, JCPt = 158.7 Hz, C@C), 66.1 (N–CH), 36.0, 28.9, 26.6, 26.5,
26.3, 25.7 (br), 25.1. IR (Nujol) (cmꢀ1): 2918 (m), 2848 (m), 1610
IR (Nujol) (cmꢀ1): 2918 (s), 2850 (m), 1610 (s,
mC@N), 1540 (m),
1469 (m), 1448 (m), 1402 (w), 1358 (w), 1327 (m), 1203 (w),
1150 (w), 1130 (w), 1025 (w), 959 (w), 912 (w), 847 (w), 751 (s),
735 (m), 594 (w). Anal. Calc. for C31H52NClOPt.Et2O (759.40): C,
55.36; H, 8.23; N, 1.84. Found: C, 55.28; H, 7.96; N, 2.04%.
(s,
mC@N), 1539 (m), 1469 (m), 1449 (m), 1412 (w), 1337 (m),
1199 (w), 1150 (w), 1028 (w), 913 (w), 752 (s), 600 (w). Anal. Calc.
for C23H34NClOPt (571.05): C, 48.37; H, 6.00; N, 2.45. Found: C,
48.53; H, 6.10; N, 2.37%.
2.3.4. (Chlorido)(
phenolato-
2-N,O)platinum(II) (10)
g
2-cis-cyclooctene)(2-(octadecylimino)methyl)-
j
A toluene solution of the Schiff base (598 mg, 1.60 mmol) was
deprotonated with n-BuLi (1.0 mL of a 1.6 M solution in hexanes,
2.4. Stability testing of platinum complexes in DMSO-d6
1.60 mmol) and added to a toluene solution of [PtCl2(g
2-coe)]2
(600 mg, 0.80 mmol). Further purified by passing a Et2O solution
of the complex through a plug of alumina. Orange oil. Yield:
959 mg (84%). 1H NMR (CDCl3): d = 7.89 (s, JHPt = 65.8 Hz, 1H,
C(H)@N), 7.33 (ddd, JHH = 8.4, 6.8, 1.8 Hz, 1H, Ar), 7.25 (dd,
JHH = 8.0, 1.8 Hz, 1H, Ar), 6.86 (d, JHH = 8.4 Hz, 1H, Ar), 6.64 (ddd,
JHH = 8.0, 6.8, 1.0 Hz, 1H, Ar), 5.48 (br m, JHPt = 57.2 Hz, 2H, HC@CH),
4.16 (t, JHH = 7.6 Hz, 2H, NCH2), 2.46 (m, 2H, CH2 (coe)), 2.25 (m, 2H,
CH2 (coe)), 1.90–1.74 (br m, 4H, CH2 (octadecyl and coe)), 1.57–
1.50 (ov m, 6H, CH2 (coe)), 1.31–1.25 (ov m, 30H, CH2 (octadecyl)),
0.88 (t, JHH = 6.0 Hz, 3H, CH3) ppm. 13C{1H} NMR (CDCl3): d = 163.3
(C–O), 161.0 (C@N), 135.7, 134.4, 120.0, 119.5, 116.8, 94.3 (s,
JCPt = 158.8 Hz, C@C), 63.2 (N–CH2), 32.9, 32.2, 30.0 (6C), 29.8
(4C), 29.6, 29.5, 28.9, 26.8, 26.6, 25.8 (br), 23.0, 14.4 (CH3). IR (Nu-
Compounds 2, 4, and 11 were dissolved in DMSO-d6 and ana-
lyzed by 1H and 13C{1H} NMR spectroscopy. The degree of decom-
position over time was determined by comparing the NMR spectra
collected after 1, 24, and 96 h.
2.5. X-ray diffraction studies
Crystals of 3 and 4 were grown from a saturated toluene solu-
tion stored at 5 °C. Single crystals were coated with Paratone-N
oil, mounted using a polyimide MicroMount, and frozen in the cold
stream of the goniometer. A hemisphere of data was collected on a
Bruker AXS P4/SMART 1000 diffractometer using
with a scan width of 0.3° and 10 s (3) and 30 s (4) exposure times.
The detector distance was 5 cm. For 3, the data were reduced (SAINT)
x and / scans
jol) (cmꢀ1): 2920 (s), 2850 (s), 1610 (s,
m
C@N), 1540 (m), 1469 (s),
1448 (s), 1358 (w), 1328 (m), 1202 (w), 1150 (w), 1130 (w),
1025 (w), 959 (w), 912 (w), 847 (w), 817 (w), 751 (m), 729 (m),
594 (w). Anal. Calc. for C33H56NClOPt.Et2O (787.46): C, 56.43; H,
8.45; N, 1.78. Found: C, 56.36; H, 8.33; N, 1.92%.
[20] and corrected for absorption (SADABS) [21]. The structure was
solved by direct methods and refined by full-matrix least squares
on F2
(SHELXTL) [22]. The octyl group was disordered and the site
occupancies determined using an isotropic model as 0.6 (C(8)–
C(15)) and 0.4 (C(80)–C(150)) and fixed in subsequent refinement
cycles. For 4, the crystal was a multiple twin and the orientation
matrix for the major component was determined (CELL_NOW) [23].
Solving the structure in a lower symmetry space group or larger
cell setting did not alleviate the disorder. The data were reduced
2.3.5. (Chlorido)(
ethylimino)methyl)phenolato-
g
2-cis-cyclooctene)(2-((2-(1-cyclohexenyl)-
2-N,O)platinum(II) (11)
j
A toluene solution of the Schiff base (367 mg, 1.60 mmol) was
deprotonated with n-BuLi (1.0 mL of a 1.6 M solution in hexanes,
1.60 mmol) and added to a toluene solution of [PtCl2(
g
2-coe)]2
(
SAINT) [20] and corrected for absorption (TWINABS) [24]. The struc-
ture was solved by direct methods and refined by full-matrix least
squares on F2
SHELXTL) [22]. The ligand was disordered over two
(600 mg, 0.80 mmol). Orange oil. Yield: 710 mg (78%). 1H NMR
(CDCl3): d = 7.74 (s, JHPt = 60.5 Hz, 1H, C(H)@N), 7.32 (ddd,
JHH = 8.4, 6.8, 1.8 Hz, 1H, Ar), 7.21 (dd, JHH = 7.8, 1.8 Hz, 1H, Ar),
6.85 (d, JHH = 8.4 Hz, 1H, Ar), 6.62 (ddd, JHH = 7.8, 6.8, 1.0 Hz, 1H,
Ar), 5.46 (s, 1H, C@CH), 5.27 (br m, JHPt = 71.5 Hz, 2H, HC@CH),
4.23 (t, JHH = 7.3 Hz, 2H, NCH2), 2.47 (m, 2H, CH2 (coe)), 2.41 (t,
J = 7.3 Hz, 2H, NCH2CH2), 2.26 (m, 2H, CH2 (coe)), 1.98 (m, 2H,
CH2 (cyclohexenyl)), 1.90 (m, 2H, CH2 (cyclohexenyl)), 1.81 (m,
2H, CH2 (coe)), 1.62–1.43 (ov m, 10H, CH2 (coe + cyclohexenyl))
ppm. 13C{1H} NMR (CDCl3): d = 163.2 (C–O), 161.3 (C@N), 135.6,
134.3, 134.0, 125.1, 120.0, 119.4, 116.8, 94.4 (s, JCPt = 162.2 Hz,
C@C), 61.3 (N–CH2), 40.9, 29.0, 28.9, 26.6, 25.8 (br), 25.6, 23.2,
(
sites, generated by symmetry operators of the space group. All
non-hydrogen atoms were refined using anisotropic displacement
parameters. Hydrogen atoms were included in calculated positions
and refined using a riding model. Bond distances and thermal
parameters within the side chain of 3 were restrained.
2.6. Cell cultures
Human glioma cells LN18, LN405 and Hs683 were maintained
in an incubator at 37 °C and 5% CO2 in DMEM supplemented with
10% FBS (foetal bovine serum) and antibiotics (Invitrogen) and
have been described elsewhere [25]. All cell lines were kind gifts
of Adrian Merlo (Laboratory of Molecular Neuro-oncology, Univer-
sity of Basel, Basel, Switzerland).
22.6. IR (Nujol) (cmꢀ1): 2920 (m), 2851 (m), 1611 (s,
mC@N), 1541
(m), 1471 (m), 1446 (m), 1401 (w), 1358 (w), 1327 (m), 1174
(w), 1148 (w), 1129 (w), 1009 (w), 915 (m), 842 (w), 746 (s), 734
(m), 619 (w). Anal. Calc. for C23H32NClOPt (569.04): C, 48.55; H,
5.67; N, 2.46. Found: C, 49.16; H, 5.77; N, 2.31%.
2.7. MTT assays
2.3.6. (Chlorido)(
phenolato-
2-N,O)platinum(II) (12)
g
2-cis-cyclooctene)(2-((cyclooctylimino)methyl)-
j
10000 cells were seeded in triplicates in 96-wells plates in
A toluene solution of the Schiff base (370 mg, 1.60 mmol) was
200
CO2. Medium was replaced with medium containing 0.5
complexes dissolved in DMSO (or DMF) and further incubated for
l
L of cell medium and incubated for 24 h at 37 °C and 5%
deprotonated with n-BuLi (1.0 mL of a 1.6 M solution in hexanes,
l
M of
1.60 mmol) and added to a toluene solution of [PtCl2(g
2-coe)]2

92
A.E. Patterson et al. / Inorganica Chimica Acta 415 (2014) 88–94
48 h. Complexes were substituted for DMSO (or DMF) in control
wells. Following incubation, 20 L of a 5 mg/mL solution of MTT
in PBS was added to each well. Cells and MTT were incubated for
3 h and removed afterwards. Stained cells were re-suspended in
100 lL of a 1:24 1 M HCl/95% EtOH and read at 560 nm on a Vari-
stretch in the FT-IR spectra has also shifted (Schiff base is at
1620 cmꢀ1) to a slightly lower wavenumber (approximately
m
m
l
1605–1615 cmꢀ1 for metal complexes) and elemental analyses
are consistent with a bis Schiff base formulation. Also of note, is
the absence of the broad OH peak in the FT-IR spectra when the li-
gands are coordinated to platinum. Complexes 3 and 4 have been
characterized by single crystal X-ray diffractions studies, the
molecular structures of both square planar complexes are shown
in Fig. 2 (Table 1). Bond distances and angles are similar to those
found in the related bis salicylaldoximato trans-(N,N)-[Pt(o-OC6H4-
CH@NOH)2], where the Pt–N distance is 1.974(6) Å and the Pt–O
bond is 1.978(5) Å [27]. The C@N bonds are N1–C1 1.282(7) Å (3)
and 1.302(11) Å (4), respectively, suggesting a significant double
bond character. In comparison the related C–N singles bonds from
the amine group are N1–C8 1.480(7) Å (3) and 1.449(10) Å (4). As
with related species, only one isomer is observed where the imine
nitrogens are trans to one another. Complexes 1–6 were stable in
DMSO for days, but eventually decomposed to give a number of
unidentified platinum complexes, including platinum metal,
resulting from disassociation of the Schiff base ligand. The poor
solubilities associated with 1–6 precludes their potential use as
therapeutics, where one the major difficulties, and hence side ef-
fects, associated with cisplatin is its limited solubility in both aque-
ous and organic media. As such, a novel family of complexes was
prepared containing only one Schiff base ligand and an organic sol-
uble cyclooctene (coe) ligand. Introduction of a cyclooctene group
to platinum is known to vastly enhance the solubilities of the cor-
responding complexes in simple organic solvents [18].
oskan (Scanlab). All data presented are mean standard error of
the mean (SEM).
3. Results and discussion
3.1. Chemistry
Addition of n-BuLi to the readily prepared salicylaldimine li-
gands followed by addition of [PtCl2(
tene) afforded the
g
2-coe)]2 (coe = cis-cyclooc-
corresponding
bis(salicylaldiminato)platinum(II) complexes 1–6 in good yields
(Scheme 1). Compounds 1–3 contain aliphatic chains of various
lengths to increase the lipophilicity of the platinum complexes to
overcome some of the drawbacks associated with cisplatin ther-
apy. Indeed, considerable effort has been directed towards improv-
ing the lipophilicity of the metal complex by encapsulating the
drug in liposomes [26]. On the other hand, compounds 4–6 contain
aromatic rings with electron donating (5) and electron withdraw-
ing (6) groups in the para position in order to assess the role elec-
tronic effects may play on bioactivities. Compounds 1–6 were only
sparing soluble in polar organic solvents (i.e. DMSO, DMF, etc.) and
completely insoluble in water.
A series of mono Schiff base organometallic complexes 7–12
was prepared from organic soluble long chain alkyl amines and sal-
icylaldehyde (Scheme 2) and characterized by multinuclear NMR
and FT-IR spectroscopy and elemental analyses. Although com-
plexes 7–12 showed no appreciable solubility in water, these orga-
nometallic derivatives are now soluble in common organic
solvents such as dichloromethane and THF. Multinuclear NMR
spectroscopic data confirmed the presence of a bound cyclooctene
All new complexes have been characterized by multinuclear
NMR and FT-IR spectroscopy, as well as elemental analyses. A sig-
nificant upfield shift in the 1H NMR spectra from d 9 ppm to 8 ppm
is observed for the imine proton upon coordination of the ligand to
the d8 metal center. Likewise, the imine carbon (N@C) in the
13C{1H} NMR spectra has shifted only marginally from d 160 ppm
to 163 ppm upon complexation. No peaks are observed for the
cyclooctene group suggesting that two equivalents of the salicylal-
diminato ligands are bound to platinum. The diagnostic C@N
Scheme 1. Synthesis of complexes 1–6.
Scheme 2. Synthesis of complexes 7–12.
Fig. 2. Ball and stick diagrams of the molecular structures of complexes 3 (a) and 4 (b) with hydrogen atoms omitted for clarity. Selected bond distances: Pt–N(1) 2.018(4),
Pt–O(1) 1.985(4) Å (3); Pt–N(1) 1.995(8), Pt–O(1) 1.977(5) Å (4).

A.E. Patterson et al. / Inorganica Chimica Acta 415 (2014) 88–94
93
aggressive than its GBM counterpart, and have been characterized
elsewhere [29]. Unfortunately, the poor solubilities of 1–6 allowed
a maximum concentration of only 0.5 lM. The length of the
aliphatic R group in complexes 1–3 was associated with an
increase in cytotoxicity in all three cell lines tested when compared
to cisplatin (Fig. 3), a compound with a long history of therapeutic
use in high-grade gliomas [30,31]. Complex 3, the one possessing
the longest aliphatic and most lipophilic chain, was particularly
cytotoxic to all three glioma cell models. Introduction of aromatic
rings in the platinum complexes 4–6, however, did not lead to any
significant cytotoxic effects on glioma cells.
Owing to the increased solubilities, the cytotoxic activities of
the six new organometallic complexes were examined in greater
detail, using cisplatin as a control, against the same three glioma
cell lines performed at final concentrations of 100, 10 and 1 lM.
Fig. 3. Cytotoxic effects of platinum complexes in three glioma cell lines.
%
Overall, the results (Fig. 4) showed that four complexes 7, 8, 11,
and 12 all exhibited greater cytotoxic activity than cisplatin against
all three cell lines. In contrast, the platinum complexes with the
longest saturated lipophilic chains, hexadecyl (9) and octadecyl
(10), had the least potent cytotoxic effect. Of significance is the
observation that complex 11 displayed greater cytotoxicity against
Viability standard error is expressed as an average of triplicates.
group, as the 1H NMR data showed a broad peak at around d
5.5 ppm attributed to the olefinic C–H bonds with platinum cou-
pling (JH–Pt = 57 Hz), suggesting that the cyclooctene unit is still
coordinated to the metal center, and showing the expected plati-
num satellites. Similarly, the coordinated alkene shows up at about
d 94 ppm in the 13C NMR spectra, consistent with a platinum
bound alkene. Like the bis Schiff base complexes, the diagnostic
C@N stretch in the FT-IR spectra also shifted to a lower wavenum-
LN18 at 10 lM than cisplatin at 100 lM. The cytotoxicities of all
platinum complexes against the less aggressive oligodendrocytom-
a cell line (Hs683) were similar to that observed against the other
GBM models. Further studies are needed, however, to determine
the structure–activity relationship of these complexes and the role
of the alkene group, the results of which will be published in due
course.
ber (approximately m
1610 cmꢀ1 for metal complexes) and elemen-
tal analyses are consistent with a mono Schiff base cyclooctene
formulation. The absence of a broad OH peak in the FR-IR spectra
was also noted when the ligands were coordinated to platinum.
Unfortunately, all attempts to isolate single crystals for an X-ray
diffraction study to confirm the structure of these complexes
proved unsuccessful. A previous study in our laboratory, however,
showed that the nitrogen atom is trans to the alkene group of the
cyclooctene group [28]. Once again, complexes 7–12 were stable
in DMSO or DMF for days at room temperature, but upon heating
to 60 °C small amounts of decomposition products were observed.
Interestingly, it appears that the Schiff base ligand becomes unco-
ordinated and decomposes back to the starting aldehyde and
amine. No evidence was observed by multinuclear NMR spectros-
copy, however, for free cyclooctene, suggesting that this ligand re-
mains bound to the platinum center.
4. Conclusions
In summary, two novel families of platinum complexes were
prepared and evaluated for their in vitro cytotoxic potential in
three brain tumor cell lines LN18, LN405 and Hs683. Complexes
possessing moderately long aliphatic chains, while being able to
maintain solubility in physiological media, were particularly cyto-
toxic to all three glioma cell models. The ability to readily alter the
salicylaldiminato ligands will allow us to generate a wide range of
potentially useful platinum chemotherapeutic agents with various
physical and chemical properties, which will be the subject of fur-
ther studies, along with studies to understand the mechanism of
action in these new complexes.
3.2. In vitro tests
Acknowledgements
Initial tests were conducted on the first class of platinum com-
plexes 1–6, using cisplatin as a standard, for their cytotoxic prop-
erties against three glioma cell lines using the MTT method.
LN405 and LN18 are two GBM cell lines with distinct PTEN, p14/
ARF and p16 tumor suppressors expression status [25]. Hs683 cells
are derived from a human oligodendroglioma, a glioma less
We thank NSERC, MAU, and U de M for the financial support.
AEP thanks the Beatrice Hunter Cancer Research Foundation for a
summer grant. Dan De Lion Durant is thanked for his expert tech-
nical assistance and anonymous reviewers for the very helpful
suggestions.
Fig. 4. Cytotoxicity of cisplatin and novel platinum complexes 7–12 against glioblastoma cell line (a) LN18 (b) LN405, and (c) Hs683 at 100, 10 and
Viability standard error is expressed as an average of triplicates.
1 lM. %

94
A.E. Patterson et al. / Inorganica Chimica Acta 415 (2014) 88–94
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graphic data for 3 and 4. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via http://
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