Synthesis, characterization and in vitro antitumour activity of a series of novel platinum(II) complexes bearing Schiff base ligands

Article abstract of DOI:10.1016/j.ejmech.2012.03.053

A series was neutral platinum(II) complexes bearing OCH₃- or F-substituted 3,4-bis(4-fluorophenyl)-1,6-bis(2-hydroxyphenyl)-2,5-diazahexa-1, 5-dienes (diarylsalenes) were synthesized and tested for in vitro antitumour activity. The growth inhibitory effects depended on the configuration and the substitution pattern of the salicylidene moiety. The lead compound [meso-3,4-bis(4-fluorophenyl)-1,6-bis(2-hydroxyphenyl)-2,5-diazahexa-1,5-diene] platinum(II) (1-Pt) reduced the cell growth of MCF-7 (IC₅₀ = 7.6 μM) and MDA-MB 231 cells (IC₅₀ = 10.0 μM), but was inactive against HT-29 cells at the used concentration range (IC₅₀ > 20 μM). The change of the configuration (meso→d,l) at the 1,2-diimino-1,2-diarylethane bridge and methoxy substitution led to completely inactive compounds, while fluorine substituents increased the antiproliferative effects depending on their position (3-F < 5-F < 4-F < 6-F). Complex 10-Pt (6-F: IC₅₀(MCF-7) = 1.5 μM, IC₅₀(MDA-MB 231) = 1.3 μM, IC₅₀ (HT-29) = 2.6 μM) was as active as cisplatin (IC₅₀(MCF-7) = 1.6 μM, IC₅₀(MDA-MB 231) = 1.5 μM, IC₅₀(HT-29) = 4.1 μM).

Full text of DOI:10.1016/j.ejmech.2012.03.053

European Journal of Medicinal Chemistry 53 (2012) 168e175
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis, characterization and in vitro antitumour activity of a series of novel
platinum(II) complexes bearing Schiff base ligands
,
Maria Proetto a, Wukun Liu a, Adelheid Hagenbach b, Ulrich Abram b, Ronald Gust c
*
a Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Str. 2þ4, 14195 Berlin, Germany
b Institute of Chemistry and Biochemistry, Freie Universität Berlin, Fabeckstrasse 34-36, 14195 Berlin, Germany
c Institute of Pharmacy, University of Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria
a r t i c l e i n f o
a b s t r a c t
Article history:
A series was neutral platinum(II) complexes bearing OCH3- or F-substituted 3,4-bis(4-fluorophenyl)-1,6-
bis(2-hydroxyphenyl)-2,5-diazahexa-1,5-dienes (diarylsalenes) were synthesized and tested for in vitro
antitumour activity. The growth inhibitory effects depended on the configuration and the substitution
pattern of the salicylidene moiety. The lead compound [meso-3,4-bis(4-fluorophenyl)-1,6-bis(2-
hydroxyphenyl)-2,5-diazahexa-1,5-diene]platinum(II) (1-Pt) reduced the cell growth of MCF-7
Received 22 November 2011
Received in revised form
20 March 2012
Accepted 27 March 2012
Available online 4 April 2012
(IC50 ¼ 7.6
m
M) and MDA-MB 231 cells (IC50 ¼ 10.0
mM), but was inactive against HT-29 cells at the
M). The change of the configuration (meso/d,l) at the 1,2-diimino-
used concentration range (IC50 > 20
m
Keywords:
Schiff base platinum complexes
Diarylsalene
Cytotoxicity
Synthesis
1,2-diarylethane bridge and methoxy substitution led to completely inactive compounds, while fluorine
substituents increased the antiproliferative effects depending on their position (3-F < 5-F < 4-F < 6-F).
Complex 10-Pt (6-F: IC50(MCF-7) ¼ 1.5
m
M, IC50(MDA-MB 231) ¼ 1.3
M, IC50(MDA-MB 231) ¼ 1.5
Ó 2012 Elsevier Masson SAS. All rights reserved.
m
M, IC50 (HT-29) ¼ 2.6
m
mM).
M) was as
active as cisplatin (IC50(MCF-7) ¼ 1.6
m
m
M, IC50(HT-29) ¼ 4.1
1. Introduction
bases (diarylsalenes) and others containing the N2O2 donor set are
capable of forming stable complexes with transition metal ions (e.g.
Co, Fe, Ni [10e13]; for a [diarylsalene]cobalt complexes see [14]).
Considering that in the diastereomeric [1,2-diamino-1,2-bis(4-
fluorophenyl)ethane]platinum(II) complexes the neutral ligand
has previously been identified as a carrier for the PtCl2 moiety
[15], 1-Pt (see Scheme 1) was designed as lead compound for
the [diarylsalene]platinum(II) series. Ligand modifications on
1-Pt included meso/d,l stereomerization of the 1,2-diimino-1,2-
diarylethane bridge (2-Pt, see Scheme 1) as well as OCH3 and F
substitution in the salicylidene moiety (3-Pt to 6-Pt, and 7-Pt to 10-
Pt respectively).
In vitro antitumour activities of the platinum compounds have
been validated against the MCF-7 human breast cancer cell line
and the effect of ligand substitution on cytotoxicity has been
investigated. The most active compounds were additionally tested
against MDA-MB 231 and HT-29 cells.
Since the discovery of its biological activity in the early 1960s
[1], cisplatin has become one of the most widely used and effective
antineoplastic agents. Today, more than 30 years after approval,
platinum-based drugs, e.g. cisplatin and carboplatin, still play
a central role in cancer chemotherapy [2,3]. However, several
disadvantages particularly related to general toxicity which leads to
undesirable side effects and to drug-resistance phenomena limit
their clinical use [4,5]. These restrictions and the fact that some
tumoral diseases are not sensitive to platinum agents [3] forced the
development of novel anticancer agents, combining platinum(II)
with suitable carrier ligands [6e8].
Over the past years, promising results have been obtained for
platinum complexes bearing
a substituted 1,2-diaminoethane
backbone (e.g. 1,2-diamino-1,2-diarylethane) as non-leaving
group [7,9]. It has been shown that appropriate substituents on
the aromatic rings could increase the cytotoxicity of the complexes.
These interesting results induced us to synthesize platinum(II)
complexes bearing Schiff base ligands derived from 1,2-diamino-
1,2-diarylethanes and substituted salicylaldehydes. These Schiff
2. Results
2.1. Synthesis and structural characterization
The synthetic route to [diarylsalene]platinum(II) derivatives is
outlined in Scheme 1. The Schiff bases were synthesized according
* Corresponding author. Tel.: þ43 512 507 58200; fax: þ43 512 507 58299.
E-mail address: ronald.gust@uibk.ac.at (R. Gust).
0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2012.03.053

M. Proetto et al. / European Journal of Medicinal Chemistry 53 (2012) 168e175
169
R
Config.
Compounds
R
Config.
Compounds
H
meso
d,l
1, 1-Pt
2, 2-Pt
3, 3-Pt
4, 4-Pt
5, 5-Pt
6-OCH3
3-F
meso
meso
meso
meso
meso
6, 6-Pt
7, 7-Pt
8, 8-Pt
9, 9-Pt
10, 10-Pt
H
3-OCH3
4-OCH3
5-OCH3
meso
meso
meso
4-F
5-F
6-F
Scheme 1. Synthetic route to [diarylsalene]platinum(II) complexes and their substitution patterns.
to a previously published method [14]. The diastereomerically
pure 1,2-diamino-1,2-bis(4-fluorophenyl)ethanes [16e19] were
reacted with two equivalents of the respective salicylaldehyde. The
subsequent coordination to platinum was performed according to
Tong et al. [20] with some modifications: the complexes were
generated from the gently heated reaction mixture of the tetra-
dentate ligands, potassium carbonate and potassium tetra-
chloroplatinate in DMSO.
(
d
¼ 12.60e14.30). It is important to emphasize that the resonance
of the OH group is downfield-shifted relative to the signal for
phenolic protons of regular H bonds [21]. This paramagnetic shift is
as expected for Resonance-Assisted Hydrogen Bonds (RAHBs)
[21,22]. Substituents (F or OCH3) located in ortho- or para-position
shifted the OH signal to a higher field (5:
that of the meta-derivatives (6:
compare the effects of fluorine and methoxy substitution for each
position (Fig. S2: ligands 5 and 9). We observed that an electron
donating substituent like OCH3 had a more pronounced shielding
effect on the OH proton than F (9:
diamagnetic shift (5:
¼ 12.41).
d
¼ 12.41) compared to
d
¼ 13.97) (Fig. S2). It is possible to
The coordination was confirmed by NMR spectroscopy, mass
spectrometry and X-ray crystallographic studies. In the case of
the diarylsalene ligands, there is a free rotation around the central
CeC bond. This leads to three staggered conformations: two
structures with a gauche- and one with an anti-conformation.
Previous crystallographic studies showed that 3,4-diaryl-1,6-bis(2-
hydroxyphenyl)-2,5-diazahexa-1,5-diene in meso-configuration
adapts an anti-conformation [21], in which the azomethine protons
(NCH) are located above the aryl groups (Fig. 1) and suffer
a shielding that reflects upfield of the signals of the above
mentioned protons. This phenomenon was used to distinguish
between meso- and d,l-isomers. The NCH protons of d,l-3,4-bis(4-
fluorophenyl)-1,6-bis(2-hydroxyphenyl)-2,5-diazahexa-1,5-diene
(2) which are not influenced in the same way showed a resonance
d
¼ 12.68) causing a larger
d
The coordination of the diarylsalene ligands to platinum(II), and
the building of square-planar chelate complexes led to changes in
the 1H NMR spectra allowing the characterization of the
compounds. The resonance signal of the phenolic OH groups
completely disappeared upon coordination in all cases. This
confirms the bonding of oxygen to the metal ions (CeOeM). The
resonance signals of the 1,2-diarylethane moiety, as well as the
signal of the NCH proton shifted in different directions (Fig. S3).
Those of the aromatic protons and the azomethine proton suffered
a diamagnetic shift, while the ones at the ethane bridge are para-
magnetic shifted.
in the 1H NMR spectra at
Fig. S1).
d
¼ 8.56 (compared to
d
¼ 8.45 in 1, see
In addition, the 13C NMR spectra of the selected compounds 1
and 1-Pt were studied. Upon coordination of 1 to platinum(II) the
azomethine carbons as well as the fluorine bound carbons (FeCAr)
While the resonance of the azomethine proton was nearly
identical for all meso-diarylsalenes (
d
¼ 8.30e8.70), the position
(ortho, meta or para), much more than the kind of substituent (F or
were upfield shifted, while the CH resonances of 1-Pt appeared at
lower field compared to 1. Unlike the shifts observed in the 1H NMR
spectra, the changes in the 13C NMR were only minimal.
The formation of complexes was further supported by positive
mode ESI high resolution mass spectrometry, which documented
a base peak corresponding to the [M þ Na]þ or [M þ K]þ ions.
To gain insight into the coordination chemistry and structural
parameters of the [diarylsalene]platinum(II) complexes, 9-Pt was
isolated as single crystal by slow evaporation of a concentrated
methanol solution and was characterized by X-ray diffraction. Its
crystal structure is shown in Fig. 2 together with the numbering
scheme for the atoms.
OCH3) located at the salicylidene moiety, affected the OH signals
A summary of crystal data, experimental details and refinement
methods are given in Table 1.
Fig. 1. Newman projection of 1 in the anti-conformation.

170
M. Proetto et al. / European Journal of Medicinal Chemistry 53 (2012) 168e175
Fig. 2. A: X-ray molecular structure of 9-Pt. The hydrogen atoms are omitted for clarity. B: Crystal packing diagram of 9-Pt, where complexes are arranged in pairs and in a head-to-
tail fashion.
The crystal structure shows that in 9-Pt the Schiff base ligand (9)
is four-fold coordinated at the platinum(II) via the azomethine
nitrogens and the oxygen atom of the hydroxyl groups. The plat-
inum atom resides in a square-planar geometry. The bond angles at
the platinum atom (N1ePteN2, N1ePteO1, N2ePteO2 and
O1ePteO2) lie in the range of 85.0e94.9ꢀ. The average PteN and
PteO distances of 1.927 and 1.991 Å respectively, resemble those
reported for similar platinum(II) complexes bearing the N2O2
ligand donor set [23e25].
Concerning the crystal packing, the molecules seem to be
arranged in a head-to-tail fashion with intermolecular pep stack-
ing interactions mainly between the salicylidene moieties (see
Fig. 2 right).
MCF-7 human breast cancer cells. IC50 values determined after
96 h of incubation are shown in Table 2. The most active
compounds were additionally tested against MDA-MB 231 and
HT-29 cells.
Variations on the salicylidene moiety determined the activity of
the complexes at the MCF-7 cell line. On the one hand, the intro-
duction of methoxy groups gave inactive compounds at the used
concentrations. On the other hand, the substitution with fluorines
resulted in active complexes in which the IC50 values depended
on the F-position on the ring. While 3-F substitution (7-Pt) led to
a complex which did not influence the tumour cell growth, the
shift of the fluorine from the 3- into the 6-position (10-Pt) enor-
mously increased the antiproliferative effects. Complex 10-Pt
(IC50
compound 1-Pt, but caused cytotoxicity comparable to that of
cisplatin (IC50 ¼ 1.6 M). The isomers 8-Pt (4-F) and 9-Pt (5-F)
reduced the growth of MCF-7 cells to a much lower extend
M). It is interesting to note that the meso/d,l
¼
1.5 mM) was not only more active than the lead
2.2. Antiproliferative effects
m
The [diarylsalene]platinum(II) complexes and the established
antitumour drug cisplatin were tested for in vitro activity against
(IC50 ¼ 7.8 and 12.7
m
stereoisomerization of the 1,2-diimino-1,2-diarylethane bridge led
to inactive compounds within the tested range of concentrations.
Table 1
Substances which presented IC50 values <20
mM were time-
Crystal data and structure refinement for 9-Pt.
dependently tested for growth inhibitory effects against MCF-7
cells (Fig. 3) and for cytotoxicity (IC50) against MDA-MB 231 and
HT-29 cells (Table 2).
Crystal system
Space group
Unit cell dimensions
Monoclinic
P21/n
a (Å) 12.075(2)
b (Å) 18.559(2)
c (Å) 11.839(2)
2533.5(7)
4
1.860
5.602
1372
Yellow
a
b
g
(ꢀ) 90.00(1)
(ꢀ) 107.27(1)
(ꢀ) 11.84(1)
In contrast to cisplatin, which reached its maximum effect
towards the end of the test (Fig. S4), the onset of activity of
the [diarylsalene]platinum(II) complexes was observed earlier
(48e72 h) occasionally followed by a recuperation of the cells. In
the case of 1-Pt, the cell population already started to recover after
the initial damage. Because exponential cell growth is guaranteed
for at least 250 h of incubation, the rise of the growth curve can be
explained by the development of drug-resistance [26]. The
recovery is also observed for 9-Pt and at low concentrations (0.63
V (Å3)
Z
rcalcd (g cmꢁ3
m
)
(MoKa) (mmꢁ1
F(000)
)
Crystal colour
Crystal shape
Block
Crystal size (mm3)
0.16 ꢂ 0.12 ꢂ 0.10
Reflections collected
Independent reflections
Absorption correction
Max. and min. transmission
Refinement method
14473
and 1.25
It is worthy to mention that 10-Pt caused cytocidal effects (T/
corr < 0%) at concentrations of 5 and 10 M which can be hold until
mM) for 10-Pt.
6755 (Rint ¼ 0.1085)
Integration
0.6083 and 0.4751
C
m
Full-matrix least-squares on F2
6755/0/346
the end of the experiment. Such growth inhibition could not be
observed with cisplatin (Fig. S4).
Data/restrains/parameters
Goodness of fit on F2
0.670
At the MDA-MB 231 cell line (Table 2), 1-Pt (IC50 ¼ 10.0
8-Pt (IC50 ¼ 5.3 M) and 10-Pt (IC50 ¼ 1.3 M) were as active as
against MCF-7 cells, while 9-Pt was inactive (IC50 > 20 M).
Interestingly, only 8-Pt (IC50 ¼ 6.7 M) and 10-Pt (IC50 ¼ 2.6 M)
mM),
Final R indices [I > 2
s
(I)]
R1 ¼ 0.0428, wR2 ¼ 0.0601
R1 ¼ 0.1560, wR2 ¼ 0.0757
1.656 and ꢁ1.723
CCDC-859077
R indices (all data)
m
m
Largest diff. peak and hole (e Åꢁ3
Deposit number
)
m
m
m

M. Proetto et al. / European Journal of Medicinal Chemistry 53 (2012) 168e175
171
Table 2
Cytotoxicity (IC50 values [
m
M]) of [diarylsalene]platinum(II) complexes on the MCF-7 and MDA-MB 231 breast cancer as well as HT-29 colon carcinoma cell lines.a
MCF-7
MDA-MB 231
HT-29
MCF-7
MDA-MB 231
ndb
HT-29
ndb
1-Pt
2-Pt
3-Pt
4-Pt
5-Pt
6-Pt
7.6 ꢃ 2.9
>20.0
>20.0
>20.0
>20.0
>20.0
10.0 ꢃ 1.7
>20.0
ndb
7-Pt
8-Pt
9-Pt
10-Pt
Cisplatin
>20.0
ndb
7.8 ꢃ 1.1
12.7 ꢃ 2.0
1.5 ꢃ 0.1
1.6 ꢃ 0.1
5.3 ꢃ 2.0
6.7 ꢃ 1.3
ndb
ndb
>20.0
>20.0
ndb
ndb
1.3 ꢃ 0.3
1.5 ꢃ 0.1
2.6 ꢃ 0.5
4.1 ꢃ 0.3
ndb
ndb
ndb
ndb
a
The IC50 values represent the concentration results in a 50% decrease in cell growth after 96 h incubation and was calculated as mean of at least two independent
experiments.
b
nd: Not determined.
reduced the growth of HT-29 cells. This might be an indication that
the substituents at the salicylidene moiety can also determine
tumour selectivity which however must be confirmed in an
extended SAR study. Furthermore, it would be of interest to study
especially the effects of 10-Pt against cisplatin-resistant cells. This
complex was active at all cell lines used; at HT-29 cells it was even
more potent than cisplatin.
configured ligand of the lead structure 1-Pt with its d,l-configured
isomer led to a completely inactive compound (2-Pt) at the tested
range of concentrations. It has been recently observed for similar
substituted [diarylsalene]cobalt complexes, that the respective
meso-configured compounds were enriched in higher amounts in
the tumour cells than the corresponding d,l-configured complexes
[14], and therefore a carrier mediated cellular uptake has been
proposed. Considering the similarities between ligands of the
reported cobalt and our synthesized platinum complexes, it is
reasonable to propose that the observed inactivity of 2-Pt is due to
decreased cellular accumulation (when compared to 1-Pt).
3. Discussion
The
synthesized
[diarylsalene]platinum(II)
complexes
The influence of a substituted salicylidene moiety on cyto-
toxicity is pronounced and modulated the activity. While the
incorporation of methoxy groups drastically reduced the in vitro
antitumour effects, complexes bearing a fluorine-substituted
salicylidene moiety presented variable cytotoxic activity
displayed cytotoxic potency against MCF-7 and MDA-MB 231
human breast cancer as well as against HT-29 colon carcinoma
cells, depending on the configuration and substitution pattern of
the ligands. The configuration of the 1,2-diimino-1,2-diarylethane
bridge played an essential role. Replacement of the meso-
1-Pt
8-Pt
120
120
100
80
60
40
20
0
100
80
60
40
20
0
-20
-20
0
20
40
60
80
100
120
140
160
0
20
40
60
80
100
120
140
160
Incubation time [h]
Incubation time [h]
1.25 µM
2.5 µM
5 µM
10 µM
20 µM
0.63 µM
1.25 µM
2.5 µM
5 µM
10 µM
9-Pt
10-Pt
120
100
80
120
100
80
60
60
40
40
20
20
0
0
-20
-20
0
20
40
60
80
100
120
140
160
0
20
40
60
80
100
120
140
160
Incubation time [h]
Incubation time [h]
1.25 µM
2.5 µM
5 µM
10 µM
20 µM
0.63 µM
1.25 µM
2.5 µM
5 µM
10 µM
Fig. 3. Time-dependent antiproliferative effects of 1-Pt, 8-Pt, 9-Pt and 10-Pt on MCF-7 cells.

172
M. Proetto et al. / European Journal of Medicinal Chemistry 53 (2012) 168e175
depending on the position of the substituent. It has been
demonstrated by 1H NMR spectroscopy that electron donating
groups (e.g. OCH3) have more pronounced shielding effects on
the OH proton than fluorine substituents, when a specific ring
position is compared. If this effect is due to the changed electron
density at the oxygen atom, it might have also an influence on
the respective PteO bond. Thus, the low activity of the methoxy-
substituted complexes could be explained by the strengthening
of the PteO bond, the increase of energy needed for a ring
opening and therefore, the decrease in reactivity towards its
proposed target, the DNA. Nevertheless, this effect cannot be
generalized. While the 1H NMR resonance signals of the hydroxyl
groups are much more affected by the position than by the kind
of substituent, the growth inhibitory effects depend mainly on
the kind of substituents at the 1,2-diarylethane.
Ar0H-3, Ar0H-5); 7.27e7.41 (m, 8H, ArH-4, ArH-6, Ar0H-2, Ar0H-6);
8.45 (s, 2H, NCH); 13.03 (s, 2H, ArOH). 13C NMR (DMSO-d6):
d
¼ 166.94 (C]N); 160.67,160.20 (FeCAr); 136.60 (d); 133.24,132.40,
130.33 (d), 119.39, 119.04, 116.95, 115.78, 115.57 (CAr); 77.25 (CH).
5.2.1.2. d,l-3,4-Bis(4-fluorophenyl)-1,6-bis(2-hydroxyphenyl)-2,5-
diazahexa-1,5-diene [2]. 2 was obtained from d,l-1,2-diamino-
1,2-bis(4-fluorophenyl)ethane (3.98 mmol, 989 mg) and salicy-
laldehyde (7.97 mmol, 972 mg). Yield: 1.3 g (2.85 mmol, 72%) of
yellow crystals. 1H NMR (DMSO-d6):
d
¼ 5.11 (s, 2H, CH);
6.81e6.89 (m, 4H, ArH-3, ArH-5); 7.07e7.15 (t, 3J ¼ 8.81 Hz, 4H,
Ar0H-3, Ar0H-5); 7.27e7.38 (m, 8H, ArH-4, ArH-6, Ar0H-2, Ar0H-6);
8.56 (s, 2H, NCH); 13.15 (s, 2H, ArOH).
5.2.1.3. meso-3,4-Bis(4-fluorophenyl)-1,6-bis(2-hydroxy-3-methoxy-
phenyl)-2,5-diazahexa-1,5-diene [3]. 3 was obtained from meso-
1,2-diamino-1,2-bis(4-fluorophenyl)ethane (0.35 mmol, 86 mg)
and 3-methoxysalicylaldehyde (0.69 mmol, 97 mg). Yield:
129 mg (0.26 mmol, 75%) of light yellow crystals. 1H NMR
4. Conclusion
Novel [diarylsalene]platinum(II) complexes were successfully
synthesized and characterized. It has been demonstrated that
substitution with electron donation groups terminates the cyto-
toxic activity, while fluorine substitution can enhance the anti-
proliferative effects. It is presumed that these effects could be
partially originated by changes on reactivity of the complexes
related to the electron density on the PteO bonds. However, the
missing correlation between this expected reactivity and the
cytotoxicity evidences the involvement of more specific processes
or interactions of the complexes outside or inside the tumour cells.
Further experiments related to the target of the complexes (such as
DNA interaction studies) and to the intracellular accumulation
(drug uptake/efflux studies) will help to clarify to influence of the
substituents on the cytotoxic effects.
(DMSO-d6):
d
¼ 3.77 (s, 6H, OCH3); 5.08 (s, 2H, CH); 6.76e6.84
(t, 2H, 3J ¼ 7.87 Hz, ArH-5); 6.87e6.97 (dd, 3J ¼ 7.90 Hz,
4J
¼
1.30 Hz, 2H, ArH-4); 7.00e7.08 (dd, 3J
¼
8.00 Hz,
4J ¼ 1.20 Hz, 2H, ArH-6); 7.12e7.21 (t, J ¼ 8.81 Hz, 4H, Ar0H-3,
Ar0H-5); 7.30e7.44 (m, 4H, Ar0H-2, Ar0H-6); 8.44 (s, 2H, NCH);
13.21 (s, 2H, ArOH).
3
5.2.1.4. meso-3,4-Bis(4-fluorophenyl)-1,6-bis(2-hydroxy-4-methoxy-
phenyl)-2,5-diazahexa-1,5-diene [4]. 4 was obtained from meso-
1,2-diamino-1,2-bis(4-fluorophenyl)ethane (0.18 mmol, 44 mg)
and 4-methoxysalicylaldehyde (0.35 mmol, 53 mg). Yield: 70 mg
(0.14 mmol, 75%) of yellow crystals. 1H NMR (DMSO-d6):
d
¼ 3.75 (s,
6H, CH3); 4.98 (s, 2H, CH); 6.36e6.40 (d, 4J ¼ 2.28 Hz, 2H, ArH-3);
4
6.40e6.45 (dd, 3J ¼ 8.54 Hz, J ¼ 2.36 Hz, 2H, ArH-5); 7.10e7.19 (t,
5. Experimental section
3J ¼ 8.81 Hz, 4H, Ar0H-3, Ar0H-5); 7.19e7.25 (d, 3J ¼ 8.57 Hz, 2H,
ArH-6); 7.26e7.34 (m, 4H, Ar0H-2, Ar0H-6); 8.32 (s, 2H, NCH); 13.54
(s, 2H, ArOH).
5.1. General procedures
The following instrumentation was used: 1H NMR spectra:
Bruker ADX 400 spectrometer operated at 400 MHz (internal
standard, tetramethylsilane); ESI-TOF spectra: Agilent 6210 ESI-
TOF, Agilent Technologies, Santa Clara, CA, USA. Chemicals were
obtained from SigmaeAldrich (Germany) and used without further
purification. The 1,2-diamino-1,2-diarylethanes were synthesized
as described earlier [16e19]. Reactions were all monitored by TLC,
performed on silica gel plates 60 F254 (Merck, Darmstadt/
Germany). Visualization on TLC was achieved by UV light.
5.2.1.5. meso-3,4-Bis(4-fluorophenyl)-1,6-bis(2-hydroxy-5-methoxy-
phenyl)-2,5-diazahexa-1,5-diene [5]. 5 was obtained from meso-
1,2-diamino-1,2-bis(4-fluorophenyl)ethane (0.22 mmol, 55 mg)
and 5-methoxysalicylaldehyde (0.44 mmol, 67 mg). Yield: 90 mg
(0.17 mmol, 79%) of yellow crystals. 1H NMR (DMSO-d6):
d
¼ 3.67 (s,
6H, CH3); 5.06 (s, 2H, CH); 6.77e6.83 (d, 3J ¼ 8.47 Hz, 2H, ArH-3);
6.90e6.99 (m, 4H, ArH-4, ArH-6); 7.12e7.21 (t, 3J ¼ 8.77 Hz, 4H,
Ar0H-3, Ar0H-5); 7.30e7.39 (m, 4H, Ar0H-2, Ar0H-6); 8.41 (s, 2H,
NCH); 12.41 (s, 2H, ArOH).
5.2. Syntheses
5.2.1.6. meso-3,4-Bis(4-fluorophenyl)-1,6-bis(2-hydroxy-6-methoxy-
phenyl)-2,5-diazahexa-1,5-diene [6]. 6 was obtained from meso-
1,2-diamino-1,2-bis(4-fluorophenyl)ethane (0.54 mmol, 133 mg)
and 6-methoxysalicylaldehyde (1.07 mmol, 163 mg). Yield: 226 mg
5.2.1. General procedure for the synthesis of meso- and d,l-3,4-
bis(4-fluorophenyl)-1,6-bis(2-hydroxyphenyl)-2,5-diazahexa-1,5-
diene derivatives
An amount of one equivalent of the respective 1,2-diamino-1,2-
diarylethane was suspended in acetonitrile and reacted with two
equivalents of the respective salicylaldehyde. The reaction mixture
was heated to reflux for 6 h. The solvent was reduced by half, and
the diimine was subsequently allowed to crystallize. The crystals
were filtered off, washed with diethyl ether, and dried over P2O5.
(0.44 mmol, 83%) of yellow crystals. 1H NMR (DMSO-d6):
d
¼ 3.75
(s, 6H, CH3); 5.16 (s, 2H, CH); 6.37e6.49 (m, 4H, ArH-3, ArH-5);
3
7.12e7.21 (t, J ¼ 8.82 Hz, 4H, Ar0H-3, Ar0H-5); 7.23e7.29 (t, 2H,
3J ¼ 8.82 Hz, ArH-4); 7.31e7.39 (m, 4H, Ar0H-2, Ar0H-6); 8.70 (s, 2H,
NCH); 13.97 (s, 2H, ArOH).
5.2.1.7. meso-3,4-Bis(4-fluorophenyl)-1,6-bis(2-hydroxy-3-fluoro-
phenyl)-2,5-diazahexa-1,5-diene [7]. 7 was obtained from meso-
1,2-diamino-1,2-bis(4-fluorophenyl)ethane (0.35 mmol, 86 mg)
and 3-fluorosalicylaldehyde (0.69 mmol, 97 mg). Yield: 129 mg
(0.26 mmol, 75%) of light yellow crystals. 1H NMR (DMSO-d6):
5.2.1.1. meso-3,4-Bis(4-fluorophenyl)-1,6-bis(2-hydroxyphenyl)-2,5-
diazahexa-1,5-diene [1]. 1 was obtained from meso-1,2-diamino-
1,2-bis(4-fluorophenyl)ethane (0.40 mmol, 99 mg) and salicy-
laldehyde (0.80 mmol, 98 mg). Yield: 166 mg (0.36 mmol, 91%) of
d
¼ 5.18 (s, 2H, CH); 6.80e6.88 (m, 2H, ArH-5); 7.15e7.23 (m, 6H,
yellow crystals. 1H NMR (DMSO-d6):
d
¼ 5.09 (s, 2H, CH);
ArH-6, Ar0H-3, Ar0H-5); 7.26e7.35 (m, 2H, ArH-4); 7.35e7.44 (m,
6.82e6.92 (m, 4H, ArH-3, ArH-5); 7.10e7.22 (t, 3J ¼ 8.81 Hz, 4H,
4H, Ar0H-2, Ar0H-6); 8.49 (s, 2H, NCH); 13.51 (s, 2H, ArOH).

M. Proetto et al. / European Journal of Medicinal Chemistry 53 (2012) 168e175
173
5.2.1.8. meso-3,4-Bis(4-fluorophenyl)-1,6-bis(2-hydroxy-4-fluoro-
phenyl)-2,5-diazahexa-1,5-diene [8]. 8 was obtained from meso-
1,2-diamino-1,2-bis(4-fluorophenyl)ethane (0.41 mmol, 104 mg)
and 4-fluorosalicylaldehyde (0.84 mmol, 117 mg). Yield: 161 mg
(0.33 mmol, 80%) of a light yellow powder. 1H NMR (DMSO-d6):
5.2.2.3. [meso-3,4-Bis(4-fluorophenyl)-1,6-bis(2-hydroxy-3-methoxy-
phenyl)-2,5-diazahexa-1,5-diene]platinum(II) [3-Pt]. 3-Pt was
obtained from meso-3,4-bis(4-fluorophenyl)-1,6-bis(2-hydroxy-
3-methoxyphenyl)-2,5-diazahexa-1,5-diene (3) (0.19 mmol,
137 mg) and potassium tetrachloroplatinate (0.19 mmol, 79 mg).
Yield: 79 mg (0.11 mmol, 61%) of a yellow powder. 1H NMR (DMSO-
d
¼ 5.08 (s, 2H, CH); 6.65e6.75 (m, 4H, ArH-3, ArH-5); 7.11e7.21 (t,
3J ¼ 8.80 Hz, 4H, Ar0H-3, Ar0H-5); 7.30e7.36 (m, 4H, Ar0H-2, Ar0H-6);
d6):
d
¼ 3.82 (s, 6H, OCH3); 5.54 (s, 2H, CH); 6.48e6.56 (t, 2H,
7.39e7.46 (m, 2H, ArH-6); 8.44 (s, 2H, NCH); 13.69 (s, 2H, ArOH).
3J ¼ 7.84 Hz, ArH-5); 6.96e7.02 (m, 2H, ArH-4); 7.06e7.25 (m, 10H,
ArH-6, Ar0H-2, Ar0H-3, Ar0H-5, Ar0H-6); 8.23 (s, 2H, NCH). HRMS
(þ)-ESI m/z [M þ K]þ calcd for C30H24F2KN2O4Ptþ: 748.0989;
found: 748.1033.
5.2.1.9. meso-3,4-Bis(4-fluorophenyl)-1,6-bis(2-hydroxy-5-fluoro-
phenyl)-2,5-diazahexa-1,5-diene [9]. 9 was obtained from meso-
1,2-diamino-1,2-bis(4-fluorophenyl)ethane (0.34 mmol, 85 mg)
and 5-fluorosalicylaldehyde (0.68 mmol, 95 mg). Yield: 110 mg
(0.22 mmol, 66%) of dark yellow crystals. 1H NMR (DMSO-d6):
5.2.2.4. [meso-3,4-Bis(4-fluorophenyl)-1,6-bis(2-hydroxy-4-methoxy-
phenyl)-2,5-diazahexa-1,5-diene]platinum(II)
[4-Pt]. 4-Pt
was
d
¼ 5.09 (s, 2H, CH); 6.85e6.91 (dd, 3J ¼ 9.01 Hz, 4J ¼ 4.05 Hz, 2H,
obtained from meso-3,4-bis(4-fluorophenyl)-1,6-bis(2-hydroxy-4-
methoxyphenyl)-2,5-diazahexa-1,5-diene (4) (0.08 mmol, 44 mg)
and potassium tetrachloroplatinate (0.08 mmol, 35 mg). Yield:
20 mg (0.03 mmol, 35%) of a yellow powder. 1H NMR (DMSO-d6):
ArH-3); 7.08e7.23 (m, 6H, ArH-4, Ar0H-3, Ar0H-5); 7.23e7.29 (dd,
3J ¼ 8.85 Hz, J ¼ 3.11 Hz, 2H, ArH-6); 7.29e7.42 (m, 4H, Ar0H-2,
4
Ar0H-6); 8.41 (s, 2H, NCH); 12.68 (s, 2H, ArOH).
d
¼ 3.77 (s, 6H, CH3); 5.45 (s, 2H, CH); 6.20e6.26 (dd, 3J ¼ 8.81 Hz,
5.2.1.10. meso-3,4-Bis(4-fluorophenyl)-1,6-bis(2-hydroxy-6-fluoro-
phenyl)-2,5-diazahexa-1,5-diene [10]. 10 was obtained from meso-
1,2-diamino-1,2-bis(4-fluorophenyl)ethane (0.35 mmol, 89 mg)
and 6-fluorosalicylaldehyde (0.71 mmol, 100 mg). Yield: 75 mg
4J ¼ 2.28 Hz, 2H, ArH-5); 6.46e6.50 (d, 4J ¼ 2.21 Hz, 2H, ArH-3);
3
7.05e7.13 (t, J ¼ 8.76 Hz, 4H, Ar0H-3, Ar0H-5); 7.17e7.24 (m, 4H,
Ar0H-2, Ar0H-6); 7.27e7.32 (d, 3J ¼ 8.88, 2H, ArH-6); 8.05 (s, 2H,
NCH). HRMS (þ)-ESI m/z [M þ K]þ calcd for C30H24F2KN2O4Ptþ:
748.0989; found: 748.0999.
(0.15 mmol, 43%) of yellow crystals. 1H NMR (DMSO-d6):
d
¼ 5.28 (s,
2H, CH); 6.62e6.75 (m, 4H, ArH-3, ArH-5); 7.15e7.24 (t, 3J ¼ 8.81 Hz,
4H, Ar0H-3, Ar0H-5); 7.32e7.42 (m, 6H, ArH-4, Ar0H-2, Ar0H-6); 8.67
(s, 2H, NCH); 13.70 (s, 2H, ArOH).
5.2.2.5. [meso-3,4-Bis(4-fluorophenyl)-1,6-bis(2-hydroxy-5-methoxy-
phenyl)-2,5-diazahexa-1,5-diene]platinum(II)
[5-Pt]. 5-Pt
was
obtained from meso-3,4-bis(4-fluorophenyl)-1,6-bis(2-hydroxy-5-
methoxyphenyl)-2,5-diazahexa-1,5-diene (5) (0.10 mmol, 54 mg)
and potassium tetrachloroplatinate (0.10 mmol, 43 mg). Yield:
25 mg (0.03 mmol, 35%) of a yellow powder. 1H NMR (DMSO-d6):
5.2.2. General procedure for the synthesis of the [3,4-bis(4-fluoro-
phenyl)-1,6-bis(2-hydroxyphenyl)-2,5-diazahexa-1,5-diene]
platinum(II) complexes
Two equivalents of K2CO3 were dissolved in water, and the
resulting solution was added slowly to a solution of one equivalent
of the ligand in dry DMSO. Afterwards, a solution of one equivalent
of potassium tetrachloroplatinate in water was added dropwise.
The mixture was heated for 5 h, keeping the temperature of the
reaction below 60 ꢀC. The mixture was allowed to cool to room
temperature and the solid matter was filtered off.
d
¼ 3.63 (s, 6H, CH3); 5.53 (s, 2H, CH); 6.89e6.94 (d, 3J ¼ 9.23 Hz, 2H,
ArH-3); 6.95e6.98 (d, 4J ¼ 3.14 Hz, 2H, ArH-6); 7.08e7.19 (m, 6H,
ArH-4, Ar0H-3, Ar0H-5); 7.19e7.26 (m, 4H, Ar0H-2, Ar0H-6); 8.24
(s, 2H, NCH). HRMS (þ)-ESI m/z [M
þ
Na]þ calcd for
C30H24F2N2NaO4Ptþ: 732.1250; found: 732.1246.
5.2.2.6. [meso-3,4-Bis(4-fluorophenyl)-1,6-bis(2-hydroxy-6-methoxy-
phenyl)-2,5-diazahexa-1,5-diene]platinum(II) [6-Pt]. 6-Pt was
5.2.2.1. [meso-3,4-Bis(4-fluorophenyl)-1,6-bis(2-hydroxyphenyl)-
2,5-diazahexa-1,5-diene]platinum(II) [1-Pt]. 1-Pt was obtained
from meso-3,4-bis(4-fluorophenyl)-1,6-bis(2-hydroxyphenyl)-2,5-
diazahexa-1,5-diene (1) (0.20 mmol, 91 mg) and potassium tetra-
chloroplatinate (0.20 mmol, 82 mg). Yield: 69 mg (0.11 mmol, 53%)
obtained from meso-3,4-bis(4-fluorophenyl)-1,6-bis(2-hydroxy-
6-methoxyphenyl)-2,5-diazahexa-1,5-diene (6) (0.32 mmol,
163 mg) and potassium tetrachloroplatinate (0.32 mmol, 130 mg).
Yield: 30 mg (0.04 mmol, 13%) of a brown powder. 1H NMR (DMSO-
d6):
d
¼ 3.73 (s, 6H, CH3); 5.42 (s, 2H, CH); 6.13e6.22 (d, 3J ¼ 7.91 Hz,
of a yellow powder. 1H NMR (DMSO-d6):
d
¼ 5.55 (s, 2H, CH);
2H, ArH-5); 6.53e6.58 (d, 3J ¼ 8.68 Hz, 2H, ArH-3); 7.23e7.30 (t,
3J ¼ 8.84 Hz, 4H, Ar0H-3, Ar0H-5); 7.31e7.37 (t, 3J ¼ 8.33, 2H, ArH-4);
7.69e7.75 (m, 4H, Ar0H-2, Ar0H-6); 8.75 (s, 2H, NCH). HRMS (þ)-ESI
m/z [M þ K]þ calcd for C30H24F2KN2O4Ptþ: 748.0989; found:
748.0965.
6.53e6.63 (t, 3J ¼ 7.27 Hz, 2H, ArH-5); 6.95e7.03 (d, 3J ¼ 8.53 Hz, 2H,
ArH-3); 7.07e7.15 (t, 3J ¼ 8.79 Hz, 4H, Ar0H-3, Ar0H-5); 7.20e7.27 (m,
4H, Ar0H-2, Ar0H-6); 7.39e7.52 (m, 4H, ArH-4, ArH-6); 8.26 (s, 2H,
NCH). 13C NMR ([D7]DMF):
d
¼ 163.6, 163.4 (C]N); 156.8, 156.7
(FeCAr); 134.6, 134.4, 134.3, 134.2, 131.7, 122.9, 121.5, 121.3, 115.9,
115.8, 115.5, 115.4 (CAr); 79.1, 79.0 (CH). HRMS (þ)-ESI m/z
5.2.2.7. [meso-3,4-Bis(4-fluorophenyl)-1,6-bis(2-hydroxy-3-fluoro-
phenyl)-2,5-diazahexa-1,5-diene]platinum(II) [7-Pt]. 7-Pt was
obtained from meso-3,4-bis(4-fluorophenyl)-1,6-bis(2-hydroxy-3-
fluorophenyl)-2,5-diazahexa-1,5-diene (7) (0.19 mmol, 93 mg) and
potassium tetrachloroplatinate (0.19 mmol, 79 mg). Yield: 79 mg
[M
þ
Na]þ calcd for C28H20F2N2NaO2Ptþ: 672.1038; found:
672.1001.
5.2.2.2. [d,l-3,4-Bis(4-fluorophenyl)-1,6-bis(2-hydroxyphenyl)-2,5-
diazahexa-1,5-diene]platinum(II) [2-Pt]. 2-Pt was obtained from d,l-
3,4-bis(4-fluorophenyl)-1,6-bis(2-hydroxyphenyl)-2,5-diazahexa-1,
5-diene (2) (0.20 mmol, 91 mg) and potassium tetrachloroplatinate
(0.20 mmol, 82 mg). Yield: 98 mg (0.15 mmol, 75%) of a yellow
(0.11 mmol, 61%) of a yellow powder. 1H NMR (DMSO-d6):
d
¼ 5.62
(s, 2H, CH); 6.51e6.64 (m, 2H, ArH-5); 7.06e7.19 (t, 3J ¼ 8.70 Hz, 4H,
Ar0H-3, Ar0H-5); 7.19e7.39 (m, 6H, ArH-6, Ar0H-2, Ar0H-6);
7.38e7.52 (m, 2H, ArH-3); 8.35 (s, 2H, NCH). HRMS (þ)-ESI m/z
powder. 1H NMR (DMSO-d6):
d
¼ 5.28 (s, 2H, CH); 6.56e6.67 (t,
[M
þ
Na]þ calcd for C28H18F4N2NaO2Ptþ: 708.0850; found:
3J ¼ 7.34 Hz, 2H, ArH-5); 6.93e7.02 (d, 3J ¼ 7.41 Hz, 2H, ArH-3);
708.0852.
3
7.22e7.34 (t, J ¼ 8.81 Hz, 4H, Ar0H-3, Ar0H-5); 7.40e7.54 (m, 4H,
ArH-4, ArH-6); 7.69e7.83 (m, 4H, Ar0H-2, Ar0H-6); 8.52 (s, 2H, NCH).
HRMS (þ)-ESI m/z [M þ Na]þ calcd for C28H20F2N2NaO2Ptþ:
672.1038; found: 672.1004.
5.2.2.8. [meso-3,4-Bis(4-fluorophenyl)-1,6-bis(2-hydroxy-4-fluoro-
phenyl)-2,5-diazahexa-1,5-diene]platinum(II) [8-Pt]. 8-Pt was
obtained from meso-3,4-bis(4-fluorophenyl)-1,6-bis(2-hydroxy-4-

174
M. Proetto et al. / European Journal of Medicinal Chemistry 53 (2012) 168e175
fluorophenyl)-2,5-diazahexa-1,5-diene (8) (0.19 mmol, 94 mg) and
potassium tetrachloroplatinate (0.19 mmol, 79 mg). Yield: 79 mg
supplemented with 5% foetal bovine serum (FBS; Biochrom,
Germany) in a humidified atmosphere (5% CO2) at 37 ꢀC. The
experiments were performed according to established procedures
(0.11 mmol, 61%) of a yellow powder. 1H NMR (DMSO-d6):
d
¼ 5.55
(s, 2H, CH); 6.46e6.54 (m, 2H, ArH-5); 6.73e6.80 (dd, 3J ¼ 12.06 Hz,
with some modifications [26,28,29]. In 96 well plates, 100 mL of
3
4J ¼ 2.27 Hz, 2H, ArH-3); 7.06e7.15 (t, J ¼ 8.81 Hz, 4H, Ar0H-3,
a cell suspension in culture medium at 7500 cells/mL (MCF-7 and
MDA-MB 231) or 3000 cells/mL (HT-29) were plated into each well
and were incubated for three days under cell culture conditions.
After the addition of various concentrations of the test compounds,
cells were incubated for up to appropriate incubation time. Then
the medium was removed, the cells were fixed with gluta-
rdialdehyde solution 1% and stored under phosphate buffered
saline (PBS) at 4 ꢀC. Cell biomass was determined by a crystal violet
staining, followed by extracting of the bound dye with ethanol and
a photometric measurement at 590 nm. Mean values were calcu-
lated and the effects of the compounds were expressed as %
Treated/Controlcorr values according to the following equation:
Ar0H-5); 7.18e7.28 (m, 4H, Ar0H-2, Ar0H-6); 7.50e7.58 (m, 2H, ArH-
6); 8.26 (s, 2H, NCH). HRMS (þ)-ESI m/z [M þ Na]þ calcd for
C28H18F4N2NaO2Ptþ: 708.0850; found: 708.0866.
5.2.2.9. [meso-3,4-Bis(4-fluorophenyl)-1,6-bis(2-hydroxy-5-fluoro-
phenyl)-2,5-diazahexa-1,5-diene]platinum(II) [9-Pt]. 9-Pt was
obtained from meso-3,4-bis(4-fluorophenyl)-1,6-bis(2-hydroxy-5-
fluorophenyl)-2,5-diazahexa-1,5-diene (9) (0.16 mmol, 77 mg) and
potassium tetrachloroplatinate (0.16 mmol, 65 mg). Yield: 93 mg
(0.13 mmol, 82%) of a dark yellow powder. 1H NMR (DMSO-d6):
3
d
¼ 5.56 (s, 2H, CH); 6.94e7.03 (dd, J ¼ 9.27 Hz, 4J ¼ 4.81 Hz, 2H,
3
ArH-3); 7.07e7.16 (t, J ¼ 8.82 Hz, 4H, Ar0H-3, Ar0H-5); 7.18e7.25
(m, 4H, Ar0H-2, Ar0H-6); 7.30e7.46 (m, 4H, ArH-4, ArH-6); 8.29 (s,
T ꢁ C0
T=Ccorr½%ꢄ ¼
ꢂ 100
Na]þ calcd for
C ꢁ C0
2H, NCH). HRMS (þ)-ESI m/z [M
þ
C28H18F4N2NaO2Ptþ: 708.0850; found: 708.0853.
(C0 control cells at the time of compound addition; C control
cells at the time of test end; T probes/samples at the time of test
end). The IC50 value was determined as the concentration causing
50% inhibition of cell proliferation and calculated as mean of at least
two independent experiments (OriginPro 8).
5.2.2.10. [meso-3,4-Bis(4-fluorophenyl)-1,6-bis(2-hydroxy-6-fluoro-
phenyl)-2,5-diazahexa-1,5-diene]platinum(II) [10-Pt]. 10-Pt was
obtained from meso-3,4-bis(4-fluorophenyl)-1,6-bis(2-hydroxy-6-
fluorophenyl)-2,5-diazahexa-1,5-diene (10) (0.13 mmol, 64 mg)
and potassium tetrachloroplatinate (0.13 mmol, 53 mg). Yield:
48 mg (0.07 mmol, 54%) of a yellow powder. 1H NMR (DMSO-d6):
Acknowledgement
d
¼ 5.67 (s, 2H, CH); 6.37e6.48 (dd, 3J ¼ 10.90 Hz, 4J ¼ 8.05 Hz, 2H,
ArH-5); 6.81e6.90 (d, 3J ¼ 8.79 Hz, 2H, ArH-3); 7.08e7.20
This work was supported by the Deutsche Forschungsgemeins-
chaft (DFG) within FOR 630 “Biological function of organometallic
compounds”.
3
(t, J ¼ 8.73 Hz, 4H, Ar0H-3, Ar0H-5); 7.20e7.31 (m, 4H, Ar0H-2,
Ar0H-6); 7.39e7.50 (m, 2H, ArH-4); 8.46 (s, 2H, NCH). HRMS (þ)-ESI
m/z [M þ Na]þ calcd for C28H18F4N2NaO2Ptþ: 708.0850; found:
708.0853.
Appendix. Supplementary data
5.3. X-ray Crystallography
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.ejmech.2012.03.053.
The intensities for the X-ray determinations were collected on
an STOE IPDS 2T instrument with Mo K
a
radiation (
l
¼ 0.71073 Å)
References
at 200 K. Standard procedures were applied for data reduction and
absorption correction. Structure solution and refinement were
performed with SHELXS97 and SHELXL97 [27]. Hydrogen atom
positions were calculated for idealized positions and treated with
the “riding model” option of SHELXL. More details on data collec-
tions and structure calculations are contained in Table 1. Selected
bond lengths and angles are summarized in Table 3.
[1] B. Rosenberg, L. Van Camp, T. Krigas, Inhibition of cell division in Escherichia
coli by electrolysis products from a platinum electrode, Nature 205 (1965)
698e699.
[2] N.J. Wheate, S. Walker, G.E. Craig, R. Oun, The status of platinum anticancer
drugs in the clinic and in clinical trials, Dalton Trans. 39 (2010) 8113e8127.
[3] L. Kelland, The resurgence of platinum-based cancer chemotherapy, Nat. Rev.
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tance, Oncogene 22 (2003) 7265e7279.
[5] L.P. Martin, T.C. Hamilton, R.J. Schilder, Platinum resistance: the role of DNA
repair pathways, Clin. Cancer Res. 14 (2008) 1291e1295.
[6] R. Gust, W. Beck, G. Jaouen, H. Schönenberger, Optimization of cisplatin for the
treatment of hormone dependent tumoral diseases. Part 1: use of steroidal
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[7] R. Gust, W. Beck, G. Jaouen, H. Schönenberger, Optimization of cisplatin for the
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G. Jaouen, S. Mundwiler, R. Alberto, D. Osella, Platinum(II) and technetium(I)
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Table 3
Selected bond lengths (Å) and angles (ꢀ) in 9-Pt.
Pt(1)eN(1)
Pt(1)eO(1)
N(1)eC(8)
N(2)eC(14)
1.922(7)
1.959(6)
1.28(1)
1.50(1)
1.32(1)
85.4(3)
178.8(3)
93.9(3)
Pt(1)eN(2)
Pt(1)eO(2)
N(1)eC(9)
N(2)eC(15)
1.932(7)
2.022(6)
1.511(9)
1.28(1)
1.317(9)
94.9(3)
O(1)eC(1)
O(2)eC(21)
N(1)ePt(1)eN(2)
N(1)ePt(1)eO(2)
N(2)ePt(1)eO(2)
N(1)ePt(1)eO(1)
N(2)ePt(1)eO(1)
O(1)ePt(1)eO(2)
179.1(3)
85.0(3)
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