Design, synthesis, characterisation and chemical reactivity of mixed-ligand platinum(ii) oxadiazoline complexes with potential cytotoxic properties

Article abstract of DOI:10.1039/c0dt00360c

A series of mixed ligand platinum(ii) oxadiazoline complexes bearing 7-nitro-1,3,5-triazaadamantane (7-NO₂TAA) as a labile and reactive nitrogen ligand has been synthesised from easily accessible starting materials. [2+3] cycloaddition of nitrones R¹R²C-N ⁺(Me)O^- to only one of the nitrile ligands in trans-[PtX₂(PhCN)₂] (X = Cl, Br) results in the selective formation of mono-oxadiazoline complexes trans-[PtX₂(PhCN){NC(Ph)-O- N(Me)-CR¹R²}] from which the remaining nitrile can be replaced by 7-NO₂TAA. The resulting complexes trans-[PtX ₂(7-NO₂TAA) {NC(Ph)-O-N(Me)-CR¹R²}] and their precursors were characterised by elemental analysis, IR and multinuclear NMR spectroscopy. The suitability of the target complexes as anticancer agents was extrapolated from their general chemical reactivity. They are stable in DMSO, but react with thiols and undergo aquation of a chloro ligand. In the absence of a competing ligand, the coordinated 7-NO ₂TAA ligand slowly hydrolyses in an aqueous medium under release of formaldehyde, and this could induce bioactivity independent of the one typically found with platinum compounds. With nitrogen heterocycles such as pyridine a slow exchange of the 7-NO₂TAA ligand occurs. A combined DFT/AIM study confirms the reaction observed in the experiment and predicts that other nitrogen heterocycles such as DNA nucleobases should react in the same way. Moreover, the 7-NO₂TAA should be even more labile in an aqueous medium where protonation of the remaining amines can occur. A PM6 molecular modelling study suggests that the PtCl(oxadiazoline) fragment formed after release of one chloro and the labile 7-NO₂TAA ligand fits well into the DNA groove and is able to form d(GpG) intrastrand crosslinks similar to the ones observed with cisplatin. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/c0dt00360c

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PAPER
www.rsc.org/dalton | Dalton Transactions
Design, synthesis, characterisation and chemical reactivity of mixed-ligand
platinum(II) oxadiazoline complexes with potential cytotoxic properties
Gabriele Wagner,*a Anthony Marchantb and James Sayerb
Received 22nd April 2010, Accepted 7th June 2010
First published as an Advance Article on the web 26th July 2010
DOI: 10.1039/c0dt00360c
A series of mixed ligand platinum(II) oxadiazoline complexes bearing 7-nitro-1,3,5-triazaadamantane
(7-NO2TAA) as a labile and reactive nitrogen ligand has been synthesised from easily accessible starting
materials. [2+3] cycloaddition of nitrones R1R2C–N+(Me)O- to only one of the nitrile ligands in
trans-[PtX2(PhCN)2] (X = Cl, Br) results in the selective formation of mono-oxadiazoline complexes
1
2
=
trans-[PtX2(PhCN){N C(Ph)–O–N(Me)–CR R }] from which the remaining nitrile can be replaced by
1
2
=
7-NO2TAA. The resulting complexes trans-[PtX2(7-NO2TAA) {N C(Ph)–O–N(Me)–CR R }] and
their precursors were characterised by elemental analysis, IR and multinuclear NMR spectroscopy.
The suitability of the target complexes as anticancer agents was extrapolated from their general
chemical reactivity. They are stable in DMSO, but react with thiols and undergo aquation of a chloro
ligand. In the absence of a competing ligand, the coordinated 7-NO2TAA ligand slowly hydrolyses in an
aqueous medium under release of formaldehyde, and this could induce bioactivity independent of the
one typically found with platinum compounds. With nitrogen heterocycles such as pyridine a slow
exchange of the 7-NO2TAA ligand occurs. A combined DFT/AIM study confirms the reaction
observed in the experiment and predicts that other nitrogen heterocycles such as DNA nucleobases
should react in the same way. Moreover, the 7-NO2TAA should be even more labile in an aqueous
medium where protonation of the remaining amines can occur. A PM6 molecular modelling study
suggests that the PtCl(oxadiazoline) fragment formed after release of one chloro and the labile
7-NO2TAA ligand fits well into the DNA groove and is able to form d(GpG) intrastrand crosslinks
similar to the ones observed with cisplatin.
Natile successfully introduced Pt(II) compounds with imino-type
Introduction
ligands, which were synthesised in the metal coordination sphere
by condensation of acetone to a platinum-ammine precursor,9 or
by alcoholysis of a coordinated nitrile.10
We recently found that D4-1,2,4-oxadiazoline complexes
such as the trans-[PtCl2(D4-1,2,4-oxadiazoline)2] and trans-
[PtCl2(nitrile)(D4-1,2,4-oxadiazoline)] compounds shown in
Scheme 1 exhibit in vitro cytotoxicities in platinum-sensitive
human cancer cell lines which are comparable to those of
cisplatin and carboplatin, and their activity is retained in cisplatin-
resistant cells.11 D4-1,2,4-Oxadiazoline complexes can be synthe-
Platinum based anticancer agents such as cisplatin, carboplatin
and oxaliplatin are widely used in the treatment of human cancers,1
and a variety of combinatorial chemotherapy regimens are in
place for the treatment of ovarian, testicular, colon, head and
neck cancer, as well as other solid tumor types.2 Their clinical
success, however, is often limited by the occurrence of resistance
and severe side effects and, in the case of cisplatin, a dose
limiting toxicity. In this light, the search is ongoing for new and
improved platinum drugs with a high activity combined with less
toxic side effects, an extended spectrum of activity to difficult-to-
treat tumours, and an ability to overcome intrinsic and acquired
resistance of cancer cells to currently used drugs. The past decades
have seen the discovery of a number of compounds with high in
vitro activity in the sub-micromolar range,3 the development of
tumour-seeking complexes,4 as well as compounds that overcome
cisplatin resistance, among which trans-configured complexes are
prominent.5 For instance, Pt(IV) complexes bearing NH3 and
aliphatic amines have been studied in Kelland’s team,6 and Pt(II)
complexes with aromatic nitrogen heterocycles or one ammine or
a sulfoxide were pioneered by Farrell.7 Branched aliphatic amines
as ligands were explored in Navarro-Ranninger’s group,8 whereas
sised straightforwardly by cycloaddition of nitrones across the
4
≡
C N bond of Pt-coordinated nitriles to give trans-[PtCl4(D -1,2,4-
oxadiazoline)2]12 and trans-[PtCl4(nitrile)(D4-1,2,4-oxadiazoline)]
compounds13 where the metal is a Pt(IV) center. Analogous
Pt(II) complexes14–16 and other mixed ligand Pt(II) complexes
aSolid State Chemistry, Institute of Physics, University of Augsburg,
Universita¨tsstr. 1, D-86135 Augsburg, Germany. E-mail: gabriele.wagner@
physik.uni-augsburg.de; Tel: +49 (0) 821 598 3270
bChemical Sciences, FHMS, University of Surrey, Guildford, Surrey, United
Kingdom GU2 7XH
Scheme 1 Pt(II) oxadiazoline complexes with potent in vitro cytotoxicity
(R = H, OH, OCH2CH2OMe; R1 = H, OH).11
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such as trans-[PtCl2(heterocycle)(D4-1,2,4-oxadiazoline)]13 and cis-
[PtCl2(sulfoxide)(D4-1,2,4-oxadiazoline)] can be prepared as well,
the latter ones also in an enantiomerically enriched form when
a chiral sulfoxide is employed.17 Given the ease with which
the substitution pattern of the oxadiazoline ligand can be var-
ied, a combinatorial chemistry approach can help to optimise
pharmaceutically relevant properties such as solubility, polarity
or cell uptake, or to enhance the DNA binding by secondary
binding mechanisms. This could render this class of compounds
particularly promising for medicinal applications.
Cytotoxic platinum compounds with a Cl,Cl,N,N coordination
sphere are thought to bind to the DNA after loss of the labile
chloro ligands whereas the nitrogen ligands remain unaffected.
Herein, we report on our approach to design trans-configured
mixed ligand Pt(II) oxadiazoline complexes with a labile nitrogen
ligand whose reactivity is enhanced in an aqueous medium. This
can be achieved if this ligand is labilised upon protonation at
the nearly neutral pH of the cytoplasm,18 or able to undergo
slow hydrolysis. Concomitant loss of a labile chloro ligand then
allows for DNA inter- and intrastrand adducts similar to the
ones formed by cisplatin, except that now a cis-PtCl(oxadiazoline)
moiety attaches to the DNA rather than a cis-Pt(NH3)2 fragment.
The compounds, although initially trans-configured, could mimic
the mode of action of classical cis-configured platinum drugs,
but still retain the oxadiazoline moiety for the fine-tuning of the
pharmacological properties.
Synthesis of the compounds
The synthesis of the target compounds 5a–5l was straightforward
and followed the outline shown in Scheme 2. The starting
complexes trans-[PtCl2(PhCN)2] (2a) and trans-[PtBr2(PhCN)2]
(2b) were prepared from PtCl2 or PtBr2 and hot benzoni-
trile as described previously.13 Reaction with one equiva-
lent of nitrones 1a–1f provided the mono-cycloadducts trans-
1
2
=
[PtX2(PhCN)(N C(Ph)–O–N(Me)–CR R )] 3a–3l with high se-
lectivity and in good yields. With the methoxy substituted nitrones
1a–1d, this reaction took place at room temperature within 10–
20 h. The nitrones 1e and 1f are less reactive and 3–4 days at room
temperature or 20 h at 60 ◦C were required for the reaction to
complete. The halogen attached to the platinum in the starting
benzonitrile complex has little influence on the reactivity of the
coordinated nitriles. This is also expected because the halogen
and the nitrile are in cis position to each other and there is
1
little electronic communication between them. The IR, H and
13C NMR data are in good agreement with those of similar
compounds described previously,13,16 and confirm the presence of
one coordinated nitrile and one oxadiazoline moiety. The 195Pt
NMR chemical shift reports on the nature of the coordinated
halogens (-2229 to -2232 ppm for the chloro complexes 3a–3f,
-2679 to -2708 for the bromo compounds 3g–3l).
The ligand 7-nitro-1,3,5-triazaadamantane 4 was synthe-
sised from nitromethane, paraformaldehyde and ammonium
acetate as shown in Scheme 3, using a procedure described in
the literature.22 Alternatively, this compound can be prepared
from nitromethane, formic acid and hexamethylenetetramine,23
or from aqueous ammonia, paraformaldehyde and tris(hydro-
xymethyl)nitromethane.22a
Results and discussion
As a protonatable ligand we opted for the 1,3,5-triazaadamantane
derivative 4 (7-NO2TAA), shown in Scheme 2. Tertiary amines
bind to Pt(II) moderately strongly, and protonation at the unco-
ordinated nitrogens ought to weaken the Pt–N bond to facilitate
the release of the ligand since the nitrogens are close enough to
each other to communicate. Other adamantyl-type ligands have
been used before in anticancer-active transition metal compounds,
e.g. Pt(IV) complexes bearing an adamantylamine moiety,19 or
Ru complexes with a 1,3,5-triaza-7-phosphaadamantane ligand,20
but with a different intention. The variable oxadiazoline part
is used to explore the effect of substituents. Both chloro and
bromo compounds were prepared in this work, because the bromo
analogue of cisplatin is known to be also active and less toxic than
cisplatin itself.21
Scheme 3 Synthesis of 7-nitro-1,3,5-triazaadamantane 4.
The reaction of the mono-oxadiazoline complexes 3a–3l with
one equivalent of 4 results in a ligand exchange and selective
replacement of the nitrile ligand. A similar reactivity has been
observed previously with stoichiometric amounts of aromatic
nitrogen heterocycles,13 but this is the first example where such
a reaction occurs with a tertiary aliphatic amine and an excess
of amine relative to platinum. The resulting mixed ligand oxa-
diazoline/triazaadamantane Pt(II) complexes 5a–5l were charac-
terised by TLC, elemental analysis, IR and NMR spectroscopy.
Additionally, the Pt content of 5a was determined by thermo-
gravimetric analysis of the residue after complete combustion.
Compounds 5 are significantly more polar than their precursors
3, as evidenced from their lower Rf value on TLC (e.g., 5a:
≡
0.12; 3a: 0.50 on SiO2/CH2Cl2). In the IR spectrum the C N
stretch is no longer present, indicating that the nitrile has been
=
replaced. The oxadiazoline can be identified by its C N stretching
vibration at 1634–1645 cm-1, and the presence of a coordinated
triazaadamantane ligand is confirmed by the asymmetric NO2
stretch at 1538 cm-1 (vs. 1520 cm-1 in the free ligand). The 1H and
13C NMR spectra show the typical signals of one oxadiazoline
and one triazaadamantane ligand whose NMR designation is
Scheme 2 Synthesis of the PtX2(7-NO2TAA)(oxadiazoline) complexes 5.
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was isolated and characterised as the 2 : 1 complex 6a where
two PtCl2(oxadiazoline) moieties bind to one and the same
triazaadamantane ligand. Its 195Pt signal is virtually the same as for
5a and also the 1H and 13C signals of the oxadiazoline part of the
molecule are very similar. The triazaadamantane ligand, however,
shows a signal pattern clearly distinct from 5a but consistent with
the involvement of two amino groups in metal coordination. Thus,
the two protons Ha and Ha¢ appear at a relatively high chemical
shift of 5.06 and 5.24 ppm as a result of the deshielding effect of
two neighbouring platinum moieties. Protons Hb and Hb¢ (4.3 and
4.74 ppm, 2 H each) and those in positions Hc and Hc¢ (4.01 and
4.21 ppm, 2 H each) are flanked by one platinum moiety only and
are less deshielded. The two protons Hd at a fairly low chemical
shift of 3.52 ppm are more shielded than in 5a. Similar trends are
observed in the corresponding 13C signals of 6a.
Scheme 4 1H and 13C NMR numbering of the coordinated 7-ni-
tro-1,3,5-triazaadamantane ligand in compounds 5 (top) and 6 (bottom).
shown in Scheme 4. The coordinated triazaadamantane produces
1
two H signals for the C–CH2–N groups at 3.66 (s, 4 Hd/d¢) and
4.29 ppm (s, 2 Hc). The axial and equatorial N–CH2–N protons
appear at 3.88 and 4.23 (1 Hb/b¢ each), 4.68 and 4.81 ppm (2 Ha/a¢
each), as broad doublets with a geminal coupling of 12.8–13.8 Hz.
Compared to free 4 (3.83 (s, 6H, C–CH2–N), 4.12 (d, 13,2 Hz, 3H,
N–CH2–N equatorial), 4.48 (d, 13,2 Hz, 3H, N–CH2–N axial)), the
coordinated ligand is reduced in symmetry from C3v to Cs, and the
protons close to the platinum center are more deshielded, whereas
the remote set of protons experiences a stronger shielding than in
4. The 13C pattern consists of four CH2 signals at approximately 58
(2 C–CH2–N, Cd), 64 (1 C–CH2–N, Cc), 71 (1 N–CH2–N, Cb) and
80 ppm (2 N–CH2–N, Ca), and one quaternary carbon Ce at about
73 ppm. Again, the platinum atom deshields the nearer carbons
with respect to the uncoordinated ligand 4 (59.7 (C–CH2–N), 72.6
Computational analysis of the ligand–Pt bond strengths in 2a, 3a
and 5a and related compounds
For a better understanding of the chemical reactivity of com-
pounds 2, 3 and 5 and to establish evidence for the postulated
weakening of the Pt–N bond upon protonation of the other
amino nitrogens of the triazaadamantane ligand, a DFT study
of compounds 2a, 3a, 5a and the mono- and diprotonated
forms 5a–H+ and 5a–2H+ was undertaken, using the B3LYP
functional, the LANL08 basis set for Pt and Cl, and 6-31G* for
all other atoms. This and similar computational methods have
been used for other DFT studies of related compounds before,25,26
and the geometry optimised structures compare well with the
structures of related compounds examined by single crystal X-ray
diffraction.13,14,17 Since bond distances do not always accurately
reflect the strength of a bond, other parameters such as bond
orders and the charge density at the bond critical point were used
as additional indicators. The latter property was obtained from a
topological analysis of the charge densities27 and the results are
summarised in Table 1.
1
(C–NO2), 73.4 (N–CH2–N). The H and 13C patterns together
with the elemental analysis provide evidence that only one of
the amino nitrogens of the triazaadamantane is coordinated to
a platinum center and a mononuclear 1 : 1 complex had formed,
in spite of the initial equivalence of the three amino groups of
1
ligand 4. The oxadiazoline ligands exhibit a H and 13C NMR
pattern similar to the one seen in the precursor compounds 3a–
3l. However, it is worth mentioning that the methoxy groups in
positions 2 and 6 of the aromatic substituent attached to the
oxadiazoline ligand are not equivalent in 5c, 5d, 5i and 5j, nor
are the triazaadamantane protons Hc. This is ascribed to hindered
rotation of the methoxy-substituted aromatic ring relative to the
As expected from molecular orbital considerations, the Pt–Cl
bonds of all compounds show similar properties and there is little
influence from the nitrogen ligands in a cis-position to them. The
properties of the Pt–N bonds, however, depend sensitively on the
1
Table 1 Bond distances and electronic properties of the Pt–N and Pt–Cl
bonds in compounds 2a, 3a, 5a, monoprotonated 5a–H+ and diprotonated
5a–2H+
oxadiazoline. In the same sense, the broad H and 13C signals of
the 6-position in the 2- and 2,4-derivatives 5a, 5b, 5g and 5h can be
attributed to conformational changes in the NMR dynamic range.
If the NMR spectra are run at 333 K (60 ◦C), these broad signals
sharpen due to faster conformational exchange. The 195Pt NMR
signal of the chloro compounds 5a–5f appears at a higher chemical
shift than in 3a–3f. This is the expected trend when a nitrile
ligand is exchanged by an amine although the change in chemical
shift for 5a–5f is smaller (approx. 70 ppm) than the one observed
for replacement of a nitrile with an aromatic amine (approx 200
ppm).13,16 The 195Pt NMR signal of the bromo compounds 5g–5l
reports more sensitively on the nature of the coordinated ligands
and large downfield shifts of about 200 ppm relative to 3g–3l are
observed. Similar effects have been reported for other platinum
bromo compounds.24
Bond
Property
2a
3a
5a
5a–H+ 5a–2H+
˚
Pt–N(nitrile) Dist/A
Bond order
1.950 1.958
0.320 0.301
0.8824 0.8591
3
˚
rBCP (e/A )
˚
Pt–N(oxa)
Dist/A
2.026 2.035 2.008 1.989
0.382 0.354 0.405 0.458
0.7960 0.7792 0.8489 0.9086
Bond order
3
˚
rBCP (e/A )
˚
Pt–N(TAA) Dist/A
Bond order
2.135 2.182 2.234
0.420 0.334 0.253
0.6450 0.5551 0.4768
3
˚
rBCP (e/A )
˚
Pt–Cl(1)
Pt–Cl(2)
Dist/A
2.426 2.434 2.447 2.433 2.443
0.899 0.855 0.818 0.843 0.812
0.4770 0.4665 0.4513 0.4670 0.4590
2.424 2.428 2.435 2.429 2.413
0.901 0.888 0.876 0.860 0.879
0.4785 0.4710 0.4668 0.4683 0.4854
Bond order
3
˚
rBCP (e/A )
˚
Dist/A
In the synthesis of 5a–5l a small amount (up to 10%) of
a byproduct is formed which can be easily separated off by
chromatography. For the reaction of 3a with 4 this product
Bond order
rBCP (e/A )
3
˚
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Table 2 Calculated bond distances and electronic properties of the Pt–N
and Pt–Cl bonds in compounds 5a, 7a, 8a and 9a
nature of the nitrogen ligand itself, as well as the nature of the
ligand in the trans-position to it. The Pt–N bond parameters
suggest that the coordination of the nitrile in 3a is weaker, as
compared to 2a. This is plausible because the oxadiazoline ligand
in the trans-position to it acts as an electron donor, making the Pt
center less Lewis acidic and less prone to accept electrons from the
nitrile lone pair. In consequence, the nitrile in 3a is less activated
towards cycloaddition with a nitrone, and this explains why the
reaction with 2a can be stopped at the mono-cycloadduct 3a. The
nitrile in 3a should also be more labile and easier to exchange,
which is indeed observed in the experiment when 3a is reacted
with the amine 4 to form 5a. A comparison of 3a with 5a suggests
that the Pt–N bond to the oxadiazoline does not change much
upon ligand exchange, whereas the newly introduced 7-NO2-TAA
ligand seems to bind relatively weakly, as evidenced by the longer
bond distance and the low charge density in the bond critical point.
The bond order is comparatively high, but this can be attributed
to the different hybridisation of the nitrogen lone pair (sp3 vs. sp2),
where a better overlap is expected with increasing p-character.
When 5a is protonated at the free amino groups of the 7-NO2-
TAA ligand to form 5a–H+ and 5a-2H+, the Pt–N bond to 7-
NO2-TAA weakens with increasing degree of protonation and
the Pt–N bond to the oxadiazoline concomitantly strengthens.
Hence, the reactivity of 5 towards a replacement of the 7-NO2-
TAA ligand should be enhanced upon protonation. A similar
effect is expected when a Lewis acidic Pt moiety coordinates to
the 7-NO2-TAA ligand, and this explains the preferred formation
of a 1 : 1 (Pt:7-NO2-TAA) complex such as 5a over coordination
of two Pt moieties to the 7-NO2-TAA, as in 6a.
Bond
Property
5a
7a
8a
9a
˚
Pt–N(oxa)
Dist/A
2.035
0.354
0.7792
2.135
0.420
0.6450
2.447
0.818
0.4513
2.435
0.876
0.4668
2.040
0.357
0.7666
2.051
0.387
0.7591
2.435
0.838
0.4631
2.429
0.869
0.4678
2.034
0.360
0.7733
2.030
0.330
0.7751
2.435
0.861
0.4635
2.432
0.880
0.4648
2.037
0.363
0.7702
2.044
0.366
0.7585
2.443
0.814
0.4551
2.421
0.894
0.4748
Bond order
3
˚
rBCP (e/A )
˚
Pt–N(ligand)
Pt–Cl(1)
Dist/A
Bond order
3
˚
rBCP (e/A )
˚
Dist/A
Bond order
3
˚
rBCP (e/A )
˚
Pt–Cl(2)
Dist/A
Bond order
rBCP (e/A )
3
˚
To assess the possibility of replacement of the 7-NO2-TAA
ligand by nitrogen heterocycles such as pyridine or DNA nucle-
obases typically acting as targets for platinum binding in biological
systems, the bond properties of the pyridine complex 7a and
the analogous guanine and adenine complexes 8a and 9a (see
Scheme 5) were calculated and the results are summarised in
Table 2. The pyridine ligand in 7a binds far more strongly than
the 7-NO2-TAA ligand in 5a, suggesting that a ligand exchange
should be feasible, at least as long as the steric effects in the
coordination sphere are small enough not to adversely affect the
thermodynamics and the kinetics of the reaction. Accordingly,
one might expect ligand exchange with the purine nucleobases
guanine or adenine if 5a was to form DNA adducts. This can
be inferred from the very good agreement of the calculated Pt–N
bond parameters of the pyridine complex 7a and the complexes
with guanine or adenine (8a and 9a), suggesting similar reactivities
and properties.
Scheme
5
Synthesis of trans-PtCl2(oxadiazoline)(pyridine) 7a and
structures of the calculated complexes trans-PtCl2(oxadiazoline)
(5-methyl-guanine) 8a and trans-PtCl2(oxadiazoline)(5-methyladenine) 9a;
R1 = H; R2 = 2-methoxyphenyl.
fragment fits into the groove of the DNA double helix. Moreover,
the oxadiazoline ligand may allow for additional binding with the
DNA, e.g through intercalation of the aromatic substituents with
the nucleobases, or by hydrogen bonding to the DNA backbone,
leading to a higher stability of the adduct.
We addressed these issues in a molecular modelling study
with the semiempiric PM6 parametrisation29 as implemented in
MOPAC2009.30 This method has been used successfully for the
modelling of other biologically relevant systems such as proteins
and nucleobases.31 The input was generated from Lippard’s
DNA duplex dodecamer, d(CCTCTGGTCTCC. GGAGACCA-
GAGG), containing a cis-diammineplatinum(II) d(GpG) 1,2-
intrastrand cross-link at the central guanine pair. The structure of
this complex has been determined in solution by high-resolution
2D NMR spectroscopy and restrained molecular dynamics
refinement,32 and the coordinates can be obtained from the RSCB
Protein Data Bank.33 The Pt(NH3)2 moiety was replaced by the
PtCl(oxadiazoline) fragment present in 5a and hydrogens were
added to the phosphates to reduce the charges on the backbone.
This structure was subjected to a geometry optimisation of the
newly added hydrogens only, followed by a geometry optimisation
of the PtCl(oxadiazoline) moiety only. The result is shown in Fig. 1
and demonstrates that the PtCl(oxadiazoline) moiety fits well into
Molecular modelling of the DNA binding of the
PtCl(oxadiazoline) fragment
Cisplatin is thought to act primarily through formation of 1,2-
intrastrand d(GpG) adducts with the DNA, where the binding of
a cis-Pt(NH3)2 moiety to the N7 of two adjacent guanine bases
forces the DNA double helix to bend into a U-shaped turn.28
If compounds such as 5a reacted under loss of ligand 4 and
a chloride, as postulated, one might expect the remaining cis-
PtCl(oxadiazoline) moiety to form similar 1,2-intrastrand d(GpG)
adducts. Whether these are bent (and thus dysfunctional to the cell)
depends on how well the comparatively large PtCl(oxadiazoline)
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the groove of the bent DNA helix, and seems not to impose much
strain.
Fig. 2 Orthogonal views (a) and (b) of the structure of the d(GpG)
intrastrand crosslink with a PtCl(oxadiazoline) moiety after full geometry
optimisation of all atoms. For colour coding see Fig. 1.
Chemical reactivity of [PtCl2(oxadiazoline)(7-NO2-TAA)]
complexes
Fig. 1 Orthogonal views (a) and (b) of the structure of the d(GpG)
A basic investigation of the chemical reactivity of 5a was un-
dertaken to confirm some of the predictions made on the basis
of the computational study, and to further assess the potential of
compounds of this type for medicinal applications. The hypothesis
that complexes 5 react with nitrogen heterocycles by replacement
of the 7-NO2-TAA ligand was supported by the selective formation
of the mixed PtCl2(oxadiazoline)(pyridine) complex 7a in the
reaction of 5a with one equivalent of pyridine. The analytical and
spectroscopic data of 7a confirm the absence of the 7-NO2-TAA
and the presence of a pyridine ligand, and agree well with those of a
similar mixed PtCl2(oxadiazoline)(pyridine) complex synthesised
by a different route.13 The reaction of 5a with pyridine to give 7a
requires 96 h at 37 ◦C and is slower than the replacement of a
nitrile from a related mixed oxadiazoline/nitrile complex (24 h at
intrastrand crosslink with
a PtCl(oxadiazoline) moiety; only the
PtCl(oxadiazoline) moiety was geometry optimised whereas the DNA
fragment, taken from the corresponding cisplatin adduct,32 was held
fixed. Purple: phosphate–deoxyribose backbone; green: G; blue: A; red:
C; yellow: T; green spheres: Pt and Cl; black: oxadiazoline ligand, with
spheres depicting O(red), N (blue) and C (grey). The oxadiazoline ligand
is the one present in compound 5a.
Upon full geometry optimisation (Fig. 2) the U-turn of the
DNA double helix widened a little and the oxadiazoline ligand
changed its conformation, but the overall shape is very similar to
the previous one where the DNA coordinates were held fixed in
the positions of the cis-diammineplatinum(II) d(GpG) intrastrand
cross-link. This can also be seen in Fig. 3 where a best fit overlay
of the two structures is shown.
◦
60 C).13 This is also expected from the calculated properties of
The oxadiazoline ligand spans about 2/3 through the double
strand, with the phenyl group close to the phosphate backbone of
one strand and the 2-methoxyphenyl group near the nucleobases
of the other one. With this particular oxadiazoline, no evidence
for intercalation or hydrogen bonding was found. However, the
model suggests sites where the introduction of substituents may
cause such additional bonding, and this could help with the
design of more effective compounds in the future, and a better
understanding of the activity of similar oxadiazoline complexes
studied previously.11 The most cytotoxic complex described in
that paper bears an OH at the phenyl group that comes close
to the phosphate backbone in the model presented here, and this
might reflect in a stronger DNA binding through hydrogen bond
formation.
the Pt–N bond in 7a as compared to 3a, described in the previous
section.
The reactivity of 5a towards thiols, represented by N-acetyl-L-
cysteine methyl ester, was studied as a model for the reactions with
cysteine, methionine and glutathione, which were suggested as an
important detoxification route for platinum compounds, but also
as a pathway for the generation of compounds with enhanced renal
toxicity.34 With 5a, an unselective reaction took place within 48 h
at room temperature, to form a number of so far uncharacterized
compounds, part of which precipitated as a brownish material. It
can be concluded that thiols do react and will certainly affect the in
vivo toxicity, the general metabolism and drug clearance pathways.
DMSO is a common solvent in medicinal chemistry, not only
for the investigation of the biological activity of organic drug
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Fig. 3 Orthogonal views (a) and (b) of the best fit of the cis-PtCl(oxadiazoline) d(GpG) intrastrand crosslinks shown in Fig. 2 (DNA in red, Pt moiety
in orange: fully optimised structure) and Fig. 1 (DNA in green, Pt moiety in blue: DNA conformation as in the cisplatin-adduct, only the Pt moiety was
geometry optimised).
candidates but also for platinum compounds, although their
affinity for sulfoxides is fairly high. Cisplatin, for example, is
known to react with DMSO within a few hours to produce the less
cytotoxic cationic complex cis-[Pt(NH3)2(Cl)(DMSO)]+.35 In view
of these observations, the stability in DMSO should be generally
checked for potential drug candidates before cytotoxicities are
assessed. Compound 5a is stable in DMSO for several weeks at
room temperature and occupies an intermediate position between
trans-[PtCl2(oxadiazoline)2] compounds which are unchanged for
months, and the trans-[PtCl2(oxadiazoline)(nitrile)] complexes
which react within hours.11 The first signs of replacement of
the azaadamantane ligand by DMSO became apparent after six
weeks with the emergence of signals of the free 7-NO2-TAA
ligand in the 1H NMR spectrum. After three months the progress
of the reaction was sufficient to reveal a new 195Pt signal at
-2966 ppm, at a similar chemical shift as the one observed for
cis-[PtCl2(oxadiazoline)(DMSO)] compounds synthesized via a
different route.17 Complex 5a thus closely mirrors the reactivity of
[PtCl2(oxadiazoline)(nitrile)] with DMSO,11 except that the ligand
exchange is significantly slower. After prolonged reaction times
(more than six months), an increasing number of compounds was
detected by NMR spectroscopy. Among these a small amount of
cis-[PtCl2(DMSO)2] was identified on the basis of its 195Pt NMR
signal at -3440 ppm (lit. -3442 ppm36). Several 195Pt signals in
the range of -3040 to -3160 ppm and -2100 to -2280 ppm were
tentatively assigned to complexes of the general type [PtCl2(N-
ligand)(DMSO)] or [PtCl(N-ligand)2(DMSO)]+, and [PtCl2(N-
ligand)2], respectively.
Aquation, i.e. chloride replacement by an aqua ligand, is a
necessary requirement for cisplatin to be biologically active,37 and
occurs when the drug passes from the relatively high chloride
concentration in the blood plasma to the cell cytoplasm, where
the chloride concentration is significantly lower. The rates and
extent of aquation of platinum compounds are usually measured
by NMR techniques, based on the identification and quantitative
determination of the different species in solution from the cross
peaks in the [1H,15N] HMQC, for which 15N-labelled compounds
are required and a proton has to be attached to the nitrogen.38
Compounds like 5, lacking NH groups, cannot be studied by this
method. Alternatively, the molar conductivity has been used as
evidence for aquation of platinum(II) iminoether compounds,39 on
the basis that replacement of a chloro by an aqua ligand generates
ionic species which enhance the conductivity. The chloro complex
5a and its bromo counterpart 5g were dissolved in dry DMSO and
the conductivity was measured at regular intervals over a period
of one week. The conductivity was negligibly low and unchanged
with time, indicating the absence of ionic species. However, when
water was added to these samples, the conductivity of 5a increased
within 7 days to stabilise at a final molar conductivity of 30–37
X-1 mol-1 cm2, which is in a range expected for a 1 : 1 electrolyte in
7752 | Dalton Trans., 2010, 39, 7747–7759
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DMSO or aqueous solution.40 Compound 5g, in contrast, did not
show any conductivity even after 4 weeks. This observation is in
agreement with previous reports that bromo compounds aquate
to a lesser extent than the corresponding chloro compounds21 and
also excludes processes such as hydrolysis of the organic ligands
as the source of ion formation because this should be similar in
5a and 5g. Also protonation of the azaadamantane ligand can be
ruled out because this should have occurred instantaneously upon
addition of water in both 5a and 5g.
pounds are promising candidates as cytotoxic agents in cancer
therapy for a number of reasons: Firstly, there is precedence that
Pt(II) oxadiazoline complexes have indeed cytotoxic properties,11
and the compounds presented in this work are equally easy
to modify at the oxadiazoline moiety for an optimisation of
the pharmacological properties. The azaadamantane ligand can
be selectively replaced by heterocycles such as pyridine, and
DFT/AIM calculations suggest that this reaction should be
enhanced in an aqueous medium when the azaadamantane is
protonated. A similar ligand replacement should be feasible with
purine nucleobases of the DNA, so that DNA binding is very
likely to happen in the cell. After the exchange of a labile adjacent
chloro ligand, d(GpG) intrastrand adducts analogous to the ones
observed with cisplatin can be formed, and these have been shown
in a PM6 molecular modelling study to cause a similar distortion
of the DNA conformation.
However, there are also some issues that might question the
medicinal properties. Although the compounds are comparatively
stable in DMSO which is used as a common solvent for medicinal
studies, they do react in an aqueous medium and with thiols.
Since thiol-containing compounds are fairly widespread in the
body and also thought to contribute to the metabolism and the
toxicity of platinum compounds, this reaction needs to be studied
in more detail and also kept in mind when the bioactivity of the
compounds is evaluated. Secondly, the release of formaldehyde
from the coordinated azaadamatane is an ambiguous issue. On
one hand, it could add a second mode of action different from
the DNA binding observed with Pt compounds and thus help to
overcome resistance, but the fact that formaldehyde is classified as
carcinogenic may restrict its medicinal use. Lastly, since the TAA
ligand is released from the complex it will be necessary to study
its biological activity in some depth, before a decision about the
potential use of the platinum compounds discussed in this work
can be made.
The 7-NO2-TAA ligand 4 is closely related to hexamethylene
tetramine, which is known to release formaldehyde at pH <6.8.41
A similar reaction is conceivable with the platinum complexes
5 where 4 acts as a ligand. Formaldehyde can be detected with
phloroglucinol in alkaline medium, with a detection limit of
about 0.00122%,42 in a setup adapted from the literature43 where
nitrogen is bubbled through a flask containing the analyte and
then through two micro impingers containing a freshly prepared
solution of the test reagent. After 1 h the solutions from both
impingers were analysed for their orange coloration (which should
be intense in the first and negligible in the second sample for a
positive result). Alternatively, formaldehyde can be detected with
Schiff’s test (fuchsin/sodium bisulfite solution) by the violet–red
colour formed, using the same apparatus. The reliability of the
two methods was checked with blind tests with aqueous formalde-
hyde solution, hexamethylene tetramine in acidic medium (both
positive), hexamethylene tetramine in alkaline solution and the
blank solvents water or aqueous DMSO (all three negative). No
formaldehyde was detected with ligand 4 in aqueous DMSO, but
the test became positive upon addition of 1 N H2SO4 to the
analyte, indicating that the release of formaldehyde is promoted
by acid. With compound 5a, where ligand 4 is bound to a Lewis
acidic Pt(II) center, the activation is strong enough to cause a slow
formaldehyde release at neutral pH values already. The detection
after about 2 h suggests a low equilibrium concentration, but since
the formaldehyde is continuously removed from the equilibrium
by the nitrogen stream and accumulates in the test solution it can
be detected reproducibly after prolonged reaction time.
Experimental section
Computational details
The formation of formaldehyde could have a positive effect
on the pharmacological properties of platinum compounds such
as 5, because the release of a toxic compound could help to
overcome resistance effects by introduction of a second mode of
action which is independent of the action of the Pt center itself.
On the other hand, one should keep in mind that formaldehyde
has been classified as carcinogenic in humans by the IARC
working group in 2004.44 In spite of this, hexamethylene tetramine
is still in use as a bacteriostatic in infections of the urinal
DFT calculations were carried out with the PC GAMESS/Firefly
package,46 which is partially based on the GAMESS(US) source
code.47 Results were visualised with MacMOLPlt.48 Molecu-
lar geometries were fully optimised using the B3LYP hybrid
functional,49 in its implementation which is based on the VWN1
formula.50 The LANL08 core potential basis set51 was used for Pt
and Cl and the 6-31G* basis set52 for all other atoms. Mayer bond
orders53 were calculated as implemented in PC GAMESS/Firefly.
The topological analysis of the charge densities27 was performed
with the software package AIMPAC.54 Molecular modelling of
the DNA binding was performed with the program package
MOPAC2009,30 using the PM6 parametrisation29 and a modified
BFGS routine recommended for large molecules,55 as implemented
in the program. For the graphical evaluation the program MolMol
2 K.2 was used.56
R
tracts (in drugs such as Hiprexꢀ), and its mode of action is
attributed exactly to the release of formaldehyde. Interestingly,
the use of hexamethylene tetramine in combination with cisplatin
in squamous cell carcinoma has been reported.45 The results
suggested a cisplatin sensitivity-enhancing effect of hexamethylene
tetramine, which might also operate with the platinum compounds
suggested in this work.
Materials and instrumentation. Solvents and reagents were
obtained from commercial sources and used as received. Trans-
[PtX2(PhCN)2] 2a–2b,13 nitrone 1f,13 nitrones 1a–1e57 and 7-
nitro-1,3,5-triazaadamantane 422a were synthesised according to
published methods. C, H and N elemental analyses were run on a
Concluding Remarks
This work presents the facile synthesis of trans-configured mixed
ligand platinum(II) oxadiazoline complexes with a labile and
reactive 1-nitro-1,3,5-triazaadamantane ligand. The target com-
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Dalton Trans., 2010, 39, 7747–7759 | 7753
©

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(CH of PhC N), 122.7 (Cq of PhC N), 165.2 (C N). 195Pt NMR
in CDCl3, d (ppm): -2229 (680 Hz).
=
=
=
Leeman CE 440 automatic analyser. Thermogravimetric analyses
were carried out on a TA Instruments Q500 thermoanalyser, at
heating rates of 10 K min-1 over a range of 20 to 800 ◦C and
in an N2 atmosphere, followed by a switch to synthetic air. The
Pt content of the sample was calculated from the weight of the
residue. Conductivities were measured with a WTW Cond315i
conductivity meter and a TetraCon325 conductivity cell. Infrared
spectra (4000–400 cm-1) were recorded on Perkin Elmer 2000
FTIR, Nicolet Avatar 320 FT-IR and Bruker Equinox 55 FT-IR
spectrometers in KBr pellets. 1H, 13C and 195Pt NMR spectra were
acquired on Bruker DRX 500 and Bruker AV 300 spectrometers
at ambient temperature. 195Pt chemical shifts are given relative to
aqueous K2[PtCl4] = -1630 ppm, with half height line widths in
parentheses.
trans-(Benzonitrile)-dichloro[2,3-dihydro-3-(2,6-dimethoxyph-
enyl)-2-methyl-5-phenyl-1,2,4-oxadiazole-jN4]platinum
(3c).
Yield 79%. Elemental analysis calculated for C24H23Cl2N3O3Pt:
C 43.19; H 3.47; N 6.29; found: C 43.28; H 3.33; N 6.17. IR
(selected bands), cm-1: 3064, 3003, 2967 and 2939 n(C–H), 2839
n(C–H of OMe), 2289 n(C N), 1645 and 1597 m n(C N and
C C). H NMR in CDCl3, d (ppm): 3.06 (s, 3H, NMe), 3.67 (s,
3H) and 4.01 (s, 3H)(2 ¥ OMe), 6.75 (s, 1H, N–CH–N), 6.56 (d,
8.3 Hz, 1H), 6.66 (d, 8.3 Hz, 1H) and 7.33 (t, 8.4 Hz, 1H)(aryl-H
of N–CH(Ar)–N), 7.47 (t, 7.5 Hz, 2H) and 7.67 (m, 3H)(aryl-H
of PhC N–Pt), 7.58 (t, 7.5 Hz, 2H), 7.65 (m, 1H) and 8.92 (d,
7.1 Hz, 2H)(aryl-H of PhC N). 13C NMR in CDCl3, d (ppm):
≡
=
1
=
≡
=
48.4 (NMe), 56.1 and 56.8 (2 ¥ OMe), 86.9 (N–CH–N), 104.2,
105.2 and 131.4 (CH of N–CH(Ar)–N), 112.9, 158.7 and 160.6 (Cq
Synthesis of the mixed nitrile/oxadiazoline complexes
≡
of N–CH(Ar)–N), 129.4, 133.6 and 134.7 (CH of PhC N–Pt),
Trans-PtX2(PhCN)2 2a or 2b (0.1 mmol) and the corresponding
nitrone 1a–1f (0.1 mmol) were dissolved in chloroform (1 ml) and
stirred at room temperature for 48 h. The solvent was evaporated
and the residual crude products were purified by chromatography
on silica using CH2Cl2 (3a–3e and 3g–3k) or CH2Cl2–ethyl acetate
98 : 2 (3f and 3l) as eluent.
≡
≡
110.1 (Cq of PhC N–Pt), 116.4 (C N), 128.7, 130.5 and 134.8
(CH of PhC N), 123.0 (Cq of PhC N), 164.2 (C N). 195Pt NMR
in CDCl3, d (ppm): -2231 (620 Hz).
=
=
=
trans-(Benzonitrile)-dichloro[2,3-dihydro-3-(2,4,6-trimethox-
yphenyl)-2-methyl-5-phenyl-1,2,4-oxadiazole-jN4]platinum (3d).
Yield 89%. Elemental analysis calculated for C25H25Cl2N3O4Pt:
C 43.05; H 3.61; N 6.02; found: C 43.21; H 3.41; N 5.91. IR
trans-(Benzonitrile)-dichloro[2,3-dihydro-3-(2-methoxyphenyl)-
(selected bands), cm-1: 3068, 3007 and 2974 n(C–H), 2844 n(C–H
2-methyl-5-phenyl-1,2,4-oxadiazole-jN4]platinum
(3a). Yield
1
≡
=
of OMe), 2293 n(C N), 1631 m n(C N). H NMR in CDCl3, d
(ppm): 3.03 (s, br., 3H, NMe), 3.65 (s, 3H), 3.80 (s, 3H) and 3.98
(s, 3H)(3 ¥ OMe), 6.64 (s, br., 1H, N–CH–N), 6.11 (s, 1H) and
6.20 (s, 1H)(aryl-H of N–CH(Ar)–N), 7.48 (t, 7.8 Hz, 2H) and
7.67 (m, 3H)(aryl-H of PhC N–Pt), 7.59 (t, 7.8 Hz, 2H), 7.66 (m,
1H) and 8.92 (d, 7.5 Hz, 2H)(aryl-H of PhC N). 13C NMR in
CDCl3, d (ppm): 48.3 (NMe), 55.4, 56.1 and 56.8 (3 ¥ OMe), 87.1
(N–CH–N), 91.0 and 91.8 (CH of N–CH(Ar)–N), 106.0, 159.5,
161.6 and 162.6 (Cq of N–CH(Ar)–N), 129.5, 133.5 and 133.7
75%. Elemental analysis calculated for C23H21Cl2N3O2Pt: C 43.34;
H 3.32; N 6.59; Pt 30.60; found: C 43.16; H 3.22; N 6.45. TGA
(residue) Pt 30.71. IR (selected bands), cm-1: 3065, 3006 and
≡
2972 n(C–H), 2841 n(C–H of OMe), 2294 n(C N), 1629 m
n(C N). H NMR in CDCl3, d (ppm): 3.08 (s, br., 3H, NMe),
1
≡
=
=
3.92 (s, 3H, OMe), 6.44 (s, br., 1H, N–CH–N), 6.97 (d, 8.0 Hz,
1H), 7.01 (t, 8.0 Hz, 1H), 7.39 (td, 8.0 Hz, 1.5 Hz, 1H) and 7.53
(s, br., 1H)(aryl-H of N–CH(Ar)–N), 7.49 (t, 7.8 Hz, 2H) and
≡
7.68 (m, 3H)(aryl-H of PhC N–Pt), 7.61 (t, 7.8 Hz, 2H), 7.69
≡
≡
≡
=
(CH of PhC N–Pt), 110.2 (Cq of PhC N–Pt), 116.5 (C N),
(m, 1H) and 8.99 (dd, 7.9 Hz, 1.9 Hz, 2H)(aryl-H of PhC N).
13C NMR in CDCl3, d (ppm): 47.5 (NMe), 56.0 (OMe), 90.6
(N–CH–N), 111.3, 120.7, 129.7 and 130.9 (CH of N–CH(Ar)–N),
124.1 and 157.9 (Cq of N–CH(Ar)–N), 129.5, 133.6 and 135.0
=
=
128.7, 130.5 and 134.8 (CH of PhC N), 123.3 (Cq of PhC N),
164.0 (C N). 195Pt NMR in CDCl3, d (ppm): -2230 (640 Hz).
=
trans-(Benzonitrile)-dichloro[2,3-dihydro-3-(2-furyl)-2-methyl-
5-phenyl-1,2,4-oxadiazole-jN4]platinum (3e). Yield 65%. Ele-
mental analysis calculated for C20H17Cl2N3O2Pt: C 40.21; H 2.87;
N 7.03; found: C 40.18; H 2.66; N 6.98. IR (selected bands), cm-1:
≡
≡
≡
(CH of PhC N–Pt), 110.0 (Cq of PhC N–Pt), 116.7 (C N),
=
=
128.8, 130.8 and 134.2 (CH of PhC N), 122.6 (Cq of PhC N),
165.5 (C N). 195Pt NMR in CDCl3, d (ppm): -2229 (740 Hz).
=
≡
3115, 3063, 3005 and 2968 n(C–H), 2290 n(C N), 1630 s and 1599
trans-(Benzonitrile)-dichloro[2,3-dihydro-3-(2,4-dimethoxyphe-
1
=
=
m n(C N and C C). H NMR in CDCl3, d (ppm): 3.05 (s, br., 3H,
NMe), 6.15 (s, br., 1H, N–CH–N), 6.44 (dd, 3.4 Hz, 1.9 Hz, 1H),
6.84 (d, 3.3 Hz, 1H) and 7.51 (m, 1H)(furyl-H), 7.51 (t, 7.8 Hz, 2H)
nyl)-2-methyl-5-phenyl-1,2,4-oxadiazole-jN4]platinum
(3b).
Yield 70%. Elemental analysis calculated for C24H23Cl2N3O3Pt:
C 43.19; H 3.47; N 6.29; found: C 43.01; H 3.31; N 6.27. IR
(selected bands), cm-1: 3063, 3003 and 2966 n(C–H), 2837 n(C–H
≡
and 7.69 (m, 3H)(aryl-H of PhC N–Pt), 7.60 (t, 7.8 Hz, 2H), 7.70
(m, 1H) and 8.99 (d, 7.5 Hz, 2H)(aryl-H of PhC N). 13C NMR
in CDCl3, d (ppm): 46.8 (NMe), 87.9 (N–CH–N), 110.8, 111.5
and 144.1 (CH of N–CH(furyl)-N), 147.8 (Cq of N–CH(furyl)-N),
129.5, 133.6 and 135.0 (CH of PhC N–Pt), 109.8 (Cq of PhC N–
=
≡
=
=
of OMe), 2289 n(C N), 1615 and 1590 m n(C N and C C).
1H NMR in CDCl3, d (ppm): 3.05 (s, br., 3H, NMe), 3.80 (s,
3H) and 3.89 (s, 3H)(2 ¥ OMe), 6.33 (s, br., 1H, N–CH–N), 6.51
(s, 1H), 6.52 (d, 8.0 Hz, 1H) and 7.43 (“s”, br., 1H)(aryl-H of
N–CH(Ar)–N), 7.49 (t, 7.4 Hz, 2H) and 7.67 (m, 3H)(aryl-H
≡
≡
≡
=
Pt), 116.9 (C N), 128.8, 130.9 and 134.5 (CH of PhC N), 121.9
(Cq of PhC N), 165.3 (C N). 195Pt NMR in CDCl3, d (ppm):
-2248 (650 Hz).
=
=
≡
of PhC N–Pt), 7.60 (t, 7.4 Hz, 2H), 7.67 (m, 1H) and 8.97 (d,
7.4 Hz, 2H)(aryl-H of PhC N). 13C NMR in CDCl3, d (ppm):
=
47.2 (NMe), 55.5 and 55.9 (2 ¥ OMe), 90.5 (N–CH–N), 99.1,
104.3 and 130.7 (CH of N–CH(Ar)–N), 116.6, 159.0 and 162.1 (Cq
trans-(Benzonitrile)-dichloro[2,3-dihydro-3-ethoxycarbonyl-3-
ethoxycarbonyl-methyl-2-methyl-5-phenyl-1,2,4-oxadiazole-jN4]
platinum (3f). Yield 74%. Anal. Calcd for C23H25Cl2N3O5Pt: C,
40.07; H, 3.65; N, 6.09. Found: C, 40.10; H, 3.67; N, 5.83. IR
≡
of N–CH(Ar)–N), 129.4, 133.6 and 134.8 (CH of PhC N–Pt),
≡
≡
109.9 (Cq of PhC N–Pt), 116.7 (C N), 128.7, 130.7 and 134.0
7754 | Dalton Trans., 2010, 39, 7747–7759
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-1
≡
=
spectrum (selected bands), cm : 2289 w n(C N), 1739 s n(C O),
4.02 (s, 3H)(2 ¥ OMe), 6.79 (s, 1H, N–CH–N), 6.55 (d, 8.0 Hz,
1H), 6.65 (d, 8.2 Hz, 1H) and 7.32 (t, 8.0 Hz, 1H)(aryl-H of
N–CH(Ar)-N), 7.47 (t, 7.6 Hz, 2H) and 7.67 (m, 3H)(aryl-H
1
=
1623 m n(C N). H NMR (500 MHz, CDCl3) d (ppm): 1.31 (t,
7.1 Hz, 3H) and 1.33 (t, 7.1 Hz, 3H)(2 ¥ OCH2CH3), 3.06 (s, 3H,
NMe), 3.56 (d, 17.5 Hz, 1H) and 4.88 (d, 17.5 Hz, 1H)(CH2), 4.27
(m, 3H) and 4.34 (m, 1H)(2 ¥ OCH2CH3), 7.53 (t, 8.0 Hz, 2H),
7.70 (m, 1H) and 7.74 (d, 8.0 Hz, 2H)(PhC N), 7.61 (t, 7.5 Hz,
2H), 7.70 (m, 1H) and 8.85 (d, 7.5 Hz, 2H)(N C–Ph). 13C NMR
(125.7 MHz, CDCl3) d (ppm): 14.1 and 14.4 (2 ¥ OCH2CH3), 39.7
(CH2), 42.0 (NMe), 61.6 and 63.3 (2 ¥ OCH2CH3), 92.2 (N–C–
N), 109.9 (Cq, N CPh), 116.8 (N C), 122.5 (Cq, N CPh), 129.0
≡
of PhC N–Pt), 7.59 (t, 7.6 Hz, 2H), 7.65 (m, 1H) and 8.94 (d,
7.5 Hz, 2H)(aryl-H of PhC N). 13C NMR in CDCl3, d (ppm):
=
≡
48.5 (NMe), 56.1 and 57.0 (2 ¥ OMe), 87.5 (N–CH–N), 104.4,
105.2 and 131.4 (CH of N–CH(Ar)-N), 113.0, 158.8 and 160.7 (Cq
=
≡
of N–CH(Ar)-N), 129.4, 133.7 and 135.5 (CH of PhC N–Pt),
≡
≡
110.3 (Cq of PhC N–Pt), 118.2 (C N), 128.7, 130.6 and 134.8
(CH of PhC N), 123.2 (Cq of PhC N), 164.1 (C N). 195Pt NMR
in CDCl3, d (ppm): -2685 (580 Hz).
≡
≡
=
=
=
=
≡
=
=
(CH, N CPh), 129.6 (CH, N CPh), 131.2 (CH, N CPh), 133.8
≡
≡
=
(CH, N CPh), 134.7 and 135.1 (CH, N CPh and N CPh), 167.9
(C N), 165.9 and 168.1 (C O). 195Pt NMR (107.3 MHz, CDCl3)
trans-(Benzonitrile)-dibromo[2,3-dihydro-3-(2,4,6-trimethoxy-
=
=
d (ppm): -2232 (950 Hz).
phenyl)-2-methyl-5-phenyl-1,2,4-oxadiazole-jN4]platinum
(3j).
Yield 76%. Elemental analysis calculated for C25H25Br2N3O4Pt: C
38.18; H 3.20; N 5.37; found: C 37.93; H 3.18; N 5.14. IR (selected
trans-(Benzonitrile)-dibromo[2,3-dihydro-3-(2-methoxyphenyl)-
2-methyl-5-phenyl-1,2,4-oxadiazole-jN4]platinum
(3g). Yield
bands), cm-1: 3060, 2995, 2955 and 2940 n(C–H), 2839 n(C–H of
82%. Elemental analysis calculated for C23H21Br2N3O2Pt: C 38.03;
H 2.91; N 5.79; found: C 38.07; H 2.75; N 5.63. IR (selected
1
≡
=
=
OMe), 2286 n(C N), 1641 and 1610 m n(C N and C C). H
NMR in CDCl3, d (ppm): 3.05 (s, 3H, NMe), 3.67, 3.80 and 4.00
(s, 3H, 3 ¥ OMe), 6.68 (s, 1H, N–CH–N), 6.09 (d, 1.5 Hz, 1H)
and 6.21 (d, 1.5 Hz, 1H)(aryl-H of N–CH(Ar)-N), 7.48 (t, 7.7 Hz,
bands), cm-1: 3069, 2994 and 2968 n(C–H), 2839 n(C–H of OMe),
1
≡
=
2286 n(C N), 1631 m n(C N). H NMR in CDCl3, d (ppm): 3.10
(s, br., 3H, NMe), 3.92 (s, 3H, OMe), 6.42 (s, br., 1H, N–CH–N),
6.95 (d, 8.3 Hz, 1H), 7.02 (t, 7.6 Hz, 1H), 7.39 (td, 8.3 Hz, 1.5 Hz,
1H) and 7.53 (s, br., 1H)(aryl-H of N–CH(Ar)-N), 7.48 (t, 7.8 Hz,
≡
2H) and 7.67 (m, 3H)(aryl-H of PhC N–Pt), 7.58 (t, 7.8 Hz, 2H),
7.65 (m, 1H) and 8.93 (d, 7.5 Hz, 2H)(aryl-H of PhC N). 13C
=
NMR in CDCl3, d (ppm): 48.3 (NMe), 55.4, 55.9 and 56.8 (3 ¥
OMe), 87.5 (N–CH–N), 90.9 and 91.7 (CH of N–CH(Ar)-N),
105.1, 159.4, 161.5 and 162.6 (Cq of N–CH(Ar)-N), 129.3, 133.6
≡
2H) and 7.66 (m, 3H)(aryl-H of PhC N–Pt), 7.60 (t, 7.8 Hz,
2H), 7.67 (m, 1H) and 8.99 (dd, 7.6 Hz, 1.9 Hz, 2H)(aryl-H
of PhC N). 13C NMR in CDCl3, d (ppm): 47.6 (NMe), 56.0
=
≡
≡
and 135.4 (CH of PhC N–Pt), 110.2 (Cq of PhC N–Pt), 118.1
(OMe), 91.2 (N–CH–N), 111.5, 120.7, 130.1 and 130.9 (CH of
≡
=
(C N), 128.5, 130.5 and 134.7 (CH of PhC N), 123.2 (Cq of
N–CH(Ar)-N), 124.1 and 158.0 (Cq of N–CH(Ar)-N), 129.5,
PhC N), 163.8 (C N). 195Pt NMR in CDCl3, d (ppm): -2685
=
=
≡
≡
133.6 and 134.9 (CH of PhC N–Pt), 110.1 (Cq of PhC N–Pt),
(650 Hz).
≡
=
118.5 (C N), 128.8, 131.3 and 134.0 (CH of PhC N), 122.8 (Cq
of PhC N), 165.0 (C N). 195Pt NMR in CDCl3, d (ppm): -2681
=
=
trans-(Benzonitrile)-dibromo[2,3-dihydro-3-(2-furyl)-2-methyl-
5-phenyl-1,2,4-oxadiazole-jN4]platinum (3k). Yield 62%. Ele-
mental analysis calculated for C20H17Br2N3O2Pt: C 35.00; H 2.50;
N 6.12; found: C 34.91; H 2.39; N 6.01. IR (selected bands), cm-1:
(800 Hz).
trans-(Benzonitrile)-dibromo[2,3-dihydro-3-(2,4-dimethoxyph-
enyl)-2-methyl-5-phenyl-1,2,4-oxadiazole-jN4]platinum
(3h).
≡
3118, 3066, 3009 and 2969 n(C–H), 2287 n(C N), 1633 s and 1600
Yield 70%. Elemental analysis calculated for C24H23Br2N3O3Pt:
C 38.11; H 3.07; N 5.56; found: C 38.17; H 3.03; N 5.42. IR
(selected bands), cm-1: 3060, 3005 and 2968 n(C–H), 2839 n(C–H
1
=
=
m n(C N and C C). H NMR in CDCl3, d (ppm): 3.08 (s, br., 3H,
NMe), 6.14 (s, br., 1H, N–CH–N), 6.43 (dd, 3.3 Hz, 1.8 Hz, 1H),
6.81 (d, 2.7 Hz, 1H) and 7.50 (m, 1H)(furyl-H), 7.51 (t, 7.7 Hz, 2H)
≡
=
=
of OMe), 2286 n(C N), 1622 and 1615 m n(C N and C C).
1H NMR in CDCl3, d (ppm): 3.07 (s, br., 3H, NMe), 3.80 (s,
3H) and 3.89 (s, 3H)(2 ¥ OMe), 6.32 (s, br., 1H, N–CH–N), 6.50
(s, 1H), 6.53 (d, 8.2 Hz, 1H) and 7.45 (“s”, br., 1H)(aryl-H of
N–CH(Ar)-N), 7.49 (t, 7.6 Hz, 2H) and 7.68 (m, 3H)(aryl-H
≡
and 7.67 (m, 3H)(aryl-H of PhC N–Pt), 7.59 (t, 7.6 Hz, 2H), 7.68
(m, 1H) and 9.00 (d, 7.8 Hz, 2H)(aryl-H of PhC N). 13C NMR
=
in CDCl3, d (ppm): 46.9 (NMe), 88.4 (N–CH–N), 110.8, 111.9
and 144.0 (CH of N–CH(furyl)-N), 147.6 (Cq of N–CH(furyl)-N),
≡
≡
129.4, 133.6 and 135.0 (CH of PhC N–Pt), 109.9 (Cq of PhC N–
≡
of PhC N–Pt), 7.60 (t, 7.6 Hz, 2H), 7.67 (m, 1H) and 8.97 (d,
≡
=
Pt), 118.6 (C N), 128.7, 131.0 and 134.4 (CH of PhC N), 122.0
7.2 Hz, 2H)(aryl-H of PhC N). 13C NMR in CDCl3, d (ppm):
=
(Cq of PhC N), 164.9 (C N). 195Pt NMR in CDCl3, d (ppm):
-2708 (750 Hz).
=
=
47.2 (NMe), 55.4 and 55.7 (2 ¥ OMe), 91.1 (N–CH–N), 99.1,
105.8 and 130.9 (CH of N–CH(Ar)-N), 116.6, 159.0 and 162.1 (Cq
≡
of N–CH(Ar)-N), 129.3, 133.6 and 135.2 (CH of PhC N–Pt),
trans-(Benzonitrile)-dibromo[2,3-dihydro-3-ethoxycarbonyl-3-
ethoxycarbonyl-methyl-2-methyl-5-phenyl-1,2,4-oxadiazole-jN4]
platinum (3l). Yield 64%. Anal. Calcd for C23H25Br2N3O5Pt: C,
35.49; H, 3.24; N, 5.40. Found: C, 35.30; H, 3.28; N, 5.06. IR
≡
≡
109.9 (Cq of PhC N–Pt), 118.2 (C N), 128.5, 130.7 and 134.6
(CH of PhC N), 122.7 (Cq of PhC N), 164.5 (C N). 195Pt NMR
in CDCl3, d (ppm): -2679 (850 Hz).
=
=
=
trans - (Benzonitrile) - dibromo[2,3 - dihydro - 3 - (2,6 - dimethoxy-
spectrum (selected bands), cm-1: 3063, 2982 and 2938 n(C–H),
phenyl)-2-methyl-5-phenyl-1,2,4-oxadiazole-jN4]platinum
(3i).
2288 w n(C N), 1739 s n(C O), 1622 m n(C N). H NMR
(500 MHz, CDCl3) d (ppm): 1.28 (t, 7.3 Hz, 3H) and 1.34 (t,
7.3 Hz, 3H)(2 ¥ OCH2CH3), 3.08 (s, 3H, NMe), 3.64 (d, 17.5 Hz,
1H) and 4.82 (d, 17.5 Hz, 1H)(CH2), 4.25 (m, 3H) and 4.35 (m,
1H)(2 ¥ OCH2CH3), 7.53 (t, 8.0 Hz, 2H), 7.71 (m, 1H) and 7.74
1
≡
=
=
Yield 79%. Elemental analysis calculated for C24H23Br2N3O3Pt:
C 38.11; H 3.07; N 5.56; found: C 38.18; H 2.89; N 5.36. IR
(selected bands), cm-1: 3063, 3000 and 2940 n(C–H), 2836 n(C–H
1
≡
=
=
of OMe), 2286 n(C N), 1638 and 1596 m n(C N and C C). H
NMR in CDCl3, d (ppm): 3.07 (s, 3H, NMe), 3.69 (s, 3H) and
≡
(d, 8.0 Hz, 2H)(PhC N), 7.61 (t, 7.5 Hz, 2H), 7.71 (m, 1H) and
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Dalton Trans., 2010, 39, 7747–7759 | 7755
©

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8.84 (d, 7.5 Hz, 2H)(N C–Ph). 13C NMR (125.7 MHz, CDCl3)
d (ppm): 14.0 and 14.4 (2 ¥ OCH2CH3), 39.9 (CH2), 42.2 (NMe),
N–CH(Ar)–N), 124.2 and 157.4 (Cq of N–CH(Ar)–N), 128.5,
=
=
=
130.3 and 133.8 (CH of PhC N), 122.9 (Cq of PhC N), 164.5
=
≡
61.6 and 63.4 (2 ¥ OCH2CH3), 92.3 (N–C–N), 110.0 (Cq, N CPh),
118.6 (N C), 122.7 (Cq, N CPh), 129.0 (CH, N CPh), 129.6
(CH, N CPh), 131.4 (CH, N CPh), 133.7 (CH, N CPh), 134.7
and 135.1 (CH, N CPh and N CPh), 167.9 (C N), 166.0 and
168.0 (C O). 195Pt NMR (107.3 MHz, CDCl3) d (ppm): -2688
(C N). 195Pt NMR in CDCl3, d (ppm): -2160 (910 Hz).
≡
=
≡
trans-Dichloro[2,3-dihydro-3-(2,4-dimethoxyphenyl)-2-methyl-
5-phenyl-1,2,4-oxadiazole-jN4][7-nitro-1,3,5-triazaadamantane-
jN1]platinum (5b). Yield 69%. Elemental analysis calculated for
C24H30Cl2N6O5Pt: C 38.51; H 4.04; N 11.23; found: C 38.39; H
3.97; N 11.00. IR (selected bands), cm-1: 3063, 3005 and 2966 n(C–
=
=
≡
≡
=
=
=
(850 Hz).
=
=
H), 2838 n(C–H of OMe), 1628 and 1615 m n(C N and C C),
1538 n(NO2). 1H NMR in CDCl3, d (ppm): 3.00 (s, br., 3H, NMe),
3.81 (s, 3H) and 3.90 (s, 3H)(2 ¥ OMe), 3.66 (s, 4H)(TAA Hd and
Hd¢), 4.22 (s, 2H, TAA Hc), 3.85 (dm, 13.2 Hz, 1H) and 4.23 (d,
13.2 Hz, 1H)(TAA Hb and Hb¢), 4.56 (dm, 13.2 Hz, 2H) and 4.78
(d, 13.2 Hz, 2H)(TAA Ha and Ha¢), 6.21 (s, br., 1H, N–CH–N), 6.50
(m, 2H) and 7.40 (“s”, br., 1H)(aryl-H of N–CH(Ar)–N), 7.58 (t,
7.6 Hz, 2H), 7.66 (tm, 7.5 Hz, 1H) and 8.89 (d, 7.2 Hz, 2H)(aryl-H
Synthesis of the mixed triazaadamantane/oxadiazoline complexes.
Trans-PtX2(PhCN)(oxadiazoline) 3a–3l (0.1 mmol) and 7-nitro-
1,3,5-triaza-adamantane 4 (0.1 mmol) were dissolved in chloro-
form (1 ml) and stirred at room temperature for 2 weeks. The
solvent was evaporated and the residual crude products were
purified by chromatography on silica using CH2Cl2/diethylether
98 : 2 (5a–5e and 5g–5k) or CH2Cl2/ethyl acetate 92 : 8 (5f and
5l) as eluent. A small amount of a dinuclear side product 6 was
detected in each reaction, and 6a was isolated and characterised.
of PhC N). 13C NMR in CDCl3, d (ppm): 47.1 (NMe), 55.5 and
=
55.9 (2 ¥ OMe), 58.2 (TAA Cd), 62.7 (TAA Cc), 71.6 (TAA Cb),
78.3 (TAA Ca), 73.0 (TAA C–NO2), 90.2 (N–CH–N), 98.9, 104.2
and 130.5 (CH of N–CH(Ar)–N), 117.0, 158.8 and 162.0 (Cq of
trans-Dichloro[2,3-dihydro-3-(2-methoxyphenyl)-2-methyl-5-
phenyl - 1,2,4 - oxadiazole - jN4][7 - nitro - 1,3,5 - triazaadamantane
jN1]platinum (5a). Yield 73%. Elemental analysis calculated for
C23H28Cl2N6O4Pt: C 38.45; H 3.93; N 11.70; Pt 27.15; found: C
38.42; H 4.08; N 11.43. TGA (residue) Pt 27.37. Rf (SiO2/CH2Cl2):
0.12. IR (selected bands), cm-1: 3065, 2991, 2961 and 2923 n(C–
H), 2839 n(C–H of OMe), 1634 m n(C N), 1610 s n(C C), 1539
n(NO2). 1H NMR in CDCl3, d (ppm): 3.03 (s, br., 3H, NMe), 3.92
(s, 3H, OMe), 3.65 (d, 14.1 Hz, 2H) and 3.67 (d, 14.1 Hz, 2H)(TAA
Hd and Hd¢), 4.21 (“s”, 2H, TAA Hc), 3.88 (dm, 13.3 Hz, 1H) and
4.23 (d, 13.3 Hz, 1H)(TAA Hb and Hb¢), 4.56 (dm, 13.3 Hz, 2H)
and 4.78 (d, 13.3 Hz, 2H)(TAA Ha and Ha¢), 6.29 (s, br., 1H,
N–CH–N), 6.95 (d, 8.0 Hz, 1H), 6.98 (t, 7.8 Hz, 1H), 7.38 (td,
7.8 Hz, 1.5 Hz, 1H) and 7.48 (“s”, br., 1H)(aryl-H of N–CH(Ar)-
=
N–CH(Ar)–N), 128.6, 130.5 and 133.8 (CH of PhC N), 123.2 (Cq
of PhC N), 164.7 (C N). 195Pt NMR in CDCl3, d (ppm): -2164
=
=
(650 Hz).
trans-Dichloro[2,3-dihydro-3-(2,6-dimethoxyphenyl)-2-methyl-
5-phenyl-1,2,4-oxadiazole-jN4][7-nitro-1,3,5-triazaadamantane-
jN1]platinum (5c). Yield 82%. Elemental analysis calculated for
C24H30Cl2N6O5Pt: C 38.51; H 4.04; N 11.23; found: C 38.33; H
3.91; N 10.97. IR (selected bands), cm-1: 3054, 2968 and 2941
=
=
=
n(C–H), 2839 n(C–H of OMe), 1645 and 1598 m n(C N and
C C), 1538 n(NO2). H NMR in CDCl3, d (ppm): 3.00 (s, 3H,
1
=
NMe), 3.62 (s, 3H) and 4.02 (s, 3H)(2 ¥ OMe), 3.64 (s, 4H)(TAA
Hd and Hd’), 4.13 (d, 13.6 Hz, 1H) and 4.19 (d, 13.6 Hz, 1H)(TAA
Hc), 3.87 (dm, 13.6 Hz, 1H) and 4.21 (d, 13.6 Hz, 1H)(TAA Hb
and Hb¢), 4.51 (dm, 13.2 Hz, 2H) and 4.73 (d, 13.2 Hz, 2H)(TAA
Ha and Ha¢), 6.62 (s, 1H, N–CH–N), 6.54 (d, 8.0 Hz, 1H), 6.65 (d,
8.0 Hz, 1H) and 7.33 (t, 8.0 Hz, 1H)(aryl-H of N–CH(Ar)–N), 7.58
(t, 7.6 Hz, 2H), 7.64 (m, 1H) and 8.83 (d, 7.6 Hz, 2H)(aryl-H of
N), 7.58 (t, 7.6 Hz, 2H), 7.68 (t, 7.6 Hz, 1H) and 8.89 (dd, 7.7 Hz,
1.8 Hz, 2H)(aryl-H of PhC N). C NMR in CDCl3, d (ppm): 47.4
13
=
(NMe), 56.0 (OMe), 58.31 and 58.35 (TAA Cd), 62.8 (TAA Cc),
71.6 (TAA Cb), 78.37 and 78.42 (TAA Ca), 73.0 (TAA C–NO2),
90.3 (N–CH–N), 111.1, 120.6, 129.5 and 131.0 (CH of N–CH(Ar)–
N), 124.4 and 157.5 (Cq of N–CH(Ar)–N), 128.7, 130.6 and 134.1
PhC N). 13C NMR in CDCl3, d (ppm): 48.6 (NMe), 56.1 and 56.8
=
(CH of PhC N), 123.1 (Cq of PhC N), 164.9 (C N). 195Pt NMR
in CDCl3, d (ppm): -2164 (720 Hz).
=
=
=
(2 ¥ OMe), 58.25 and 58.32 (TAA Cd), 62.6 (TAA Cc), 71.6 (TAA
Cb), 78.2 (TAA Ca), 73.1 (TAA C–NO2), 87.1 (N–CH–N), 104.1,
105.2 and 131.4 (CH of N–CH(Ar)–N), 113.3, 158.7 and 160.8 (Cq
[l-(7-Nitro-1,3,5-triazaadamantane-jN1:jN3]tetrachlorobis[2,3-
dihydro-3-(2-methoxyphenyl)-2-methyl-5-phenyl-1,2,4-oxadiazole-
jN4]diplatinum (6a). Yield 12%. Elemental analysis calculated
for C39H44Cl4N8O6Pt2: C 37.39; H 3.54; N 8.94; found: C 37.33; H
3.60; N 8.61. Rf (SiO2/CH2Cl2): 0.31. IR (selected bands), cm-1:
=
of N–CH(Ar)–N), 128.6, 130.3 and 133.5 (CH of PhC N), 123.5
(Cq of PhC N), 163.6 (C N). 195Pt NMR in CDCl3, d (ppm):
-2170 (520 Hz).
=
=
trans - Dichloro[2,3 - dihydro - 3 - (2,4,6 - trimethoxyphenyl) - 2-
methyl-5-phenyl-1,2,4-oxadiazole-jN4][7-nitro-1,3,5-triazaada-
mantane-jN1]platinum (5d). Yield 77%. Elemental analysis cal-
culated for C25H32Cl2N6O6Pt: C 38.57; H 4.14; N 10.79; found:
C 38.19; H 4.44; N 10.65. IR (selected bands), cm-1: 3008, 2965
3065, 2991, 2961 and 2923 n(C–H), 2839 n(C–H of OMe), 1632
1
=
=
m n(C N), 1610 s n(C C), 1542 n(NO2). H NMR in CDCl3,
d (ppm): 3.03 (s, br., 6H, NMe), 3.92 (s, 6H, OMe), 3.52 (“s”,
2H, TAA Hd), 4.01 (m, 2H) and 4.21 (m, 2H)(TAA Hc and Hc¢),
4.30 (m, 2H) and 4.72 (m, 2H)(TAA Hb and Hb¢), 5.06 (m, 1H)
and 5.24 (m, 1H)(TAA Ha and Ha¢), 6.27 (s, br., 2H, N–CH–N),
6.94 (m, 2H), 6.99 (m, 2H), 7.38 (tm, 7.8 Hz, 2H) and 7.47
(“s”, br., 2H)(aryl-H of N–CH(Ar)–N), 7.59 (m, 4H), 7.67 (“t”,
=
and 2942 n(C–H), 2841 n(C–H of OMe), 1645 m n(C N), 1610 s
n(C C), 1538 n(NO2). H NMR in CDCl3, d (ppm): 2.97 (s, br.,
1
=
3H, NMe), 3.60 (s, 3H), 3.80 (s, 3H) and 4.00 (s, 3H)(3 ¥ OMe),
3.65 (s, 4H)(TAA Hd and Hd¢), 4.23 (d, 14.1 Hz, 1H) and 4.19
(d, 14.1 Hz, 1H)(TAA Hc), 3.86 (dm, 13.4 Hz, 1H) and 4.26 (d,
13.4 Hz, 1H)(TAA Hb and Hb¢), 4.53 (dm, 13.2 Hz, 2H) and 4.74
(d, 13.2 Hz, 2H)(TAA Ha and Ha¢), 6.50 (s, br., 1H, N–CH–N), 6.08
(s, 1H) and 6.20 (s, 1H)(aryl-H of N–CH(Ar)–N), 7.58 (t, 7.6 Hz,
7.6 Hz, 2H) and 8.89 (dm, 7.7 Hz, 4H)(aryl-H of PhC N). 13C
NMR in CDCl3, d (ppm): 47.2 (NMe), 55.7 (OMe), 56.7 (TAA
Cd), 61.7 (TAA Cc), 76.4 (TAA Cb), 79.4 (TAA Ca), 72.8 (TAA
C–NO2), 89.8 (N–CH–N), 110.9, 120.4, 129.1 and 130.8 (CH of
=
7756 | Dalton Trans., 2010, 39, 7747–7759
This journal is
The Royal Society of Chemistry 2010
©

View Online
=
2H), 7.61 (m, 1H) and 8.82 (d, 7.6 Hz, 2H)(aryl-H of PhC N).
3.88 (dm, 13.1 Hz, 1H) and 4.23 (d, 13.1 Hz, 1H)(TAA Hb and Hb¢),
4.68 (dm, 13.2 Hz, 2H) and 4.81 (d, 13.3 Hz, 2H)(TAA Ha and Ha¢),
6.26 (s, br., 1H, N–CH–N), 6.95 (d, 7.8 Hz, 1H), 7.00 (t, 7.8 Hz,
1H), 7.39 (td, 7.8 Hz, 1.5 Hz, 1H) and 7.50 (“s”, br., 1H)(aryl-H of
N–CH(Ar)–N), 7.59 (t, 7.6 Hz, 2H), 7.69 (t, 7.6 Hz, 1H) and 8.91
13C NMR in CDCl3, d (ppm): 48.5 (NMe), 55.4, 56.1 and 56.8 (3 ¥
OMe), 58.26 and 58.33 (TAA Cd), 62.7 (TAA Cc), 71.6 (TAA Cb),
78.2 (TAA Ca), 73.0 (TAA C–NO2), 87.2 (N–CH–N), 90.9 and
91.8 (CH of N–CH(Ar)-N), 106.4, 159.5, 161.7 and 162.6 (Cq of
N–CH(Ar)–N), 128.5, 130.2 and 133.4 (CH of PhC N), 123.6 (Cq
(dd, 7.8 Hz, 1.6 Hz, 2H)(aryl-H of PhC N). 13C NMR in CDCl3,
=
=
of PhC N), 163.4 (C N). 195Pt NMR in CDCl3, d (ppm): -2169
d (ppm): 47.6 (NMe), 56.0 (OMe), 58.2 (TAA Cd), 64.3 (TAA Cc),
71.5 (TAA Cb), 80.38 and 80.45 (TAA Ca), 73.4 (TAA C–NO2),
91.2 (N–CH–N), 111.3, 120.7, 129.4 and 131.2 (CH of N–CH(Ar)–
N), 124.7 and 157.9 (Cq of N–CH(Ar)–N), 128.6, 130.6 and 133.8
=
=
(600 Hz).
trans-Dichloro[2,3-dihydro-3-(2-furyl)-2-methyl-5-phenyl-1,2,4-
oxadiazole-jN4][7 - nitro - 1,3,5 - triazaadamantane-jN1]platinum
(5e). Yield 69%. Elemental analysis calculated for
C20H24Cl2N6O4Pt: C 35.41; H 3.57; N 12.39; found: C 35.26; H
3.31; N 12.12. IR (selected bands), cm-1: 3112, 3061, 2966, 2902
and 2880 w n(C–H), 1634 m n(C N and C C), 1538 n(NO2).
1H NMR in CDCl3, d (ppm): 3.00 (s, br., 3H, NMe), 3.68 (d,
13.6 Hz, 2H) and 3.70 (d, 13.6 Hz, 2H)(TAA Hd and Hd¢), 4.26
(s, 2H, TAA Hc), 3.90 (dm, 13.2 Hz, 1H) and 4.28 (d, 13.2 Hz,
1H)(TAA Hb and Hb¢), 4.60 (dm, 12.8 Hz, 2H) and 4.84 (d,
12.8 Hz, 2H)(TAA Ha and Ha¢), 5.99 (s, br., 1H, N–CH–N),
6.44 (dd, 3.3 Hz, 1.8 Hz, 1H), 6.77 (d, 3.2 Hz, 1H) and 7.50
(m, 1H)(furyl-H), 7.59 (t, 7.8 Hz, 2H), 7.70 (tm, 7.4 Hz, 1H)
(CH of PhC N), 123.3 (Cq of PhC N), 164.3 (C N). 195Pt NMR
in CDCl3, d (ppm): -2471 (840 Hz).
=
=
=
trans-Dibromo[2,3-dihydro-3-(2,4-dimethoxyphenyl)-2-methyl-
5-phenyl-1,2,4-oxadiazole-jN4][7-nitro-1,3,5-triazaadamantane-
jN1]platinum (5h). Yield 63%. Elemental analysis calculated for
C24H30Br2N6O5Pt: C 34.42; H 3.61; N 10.04; found: C 34.23; H
3.55; N 9.81. IR (selected bands), cm-1: 3060, 3007 and 2938 n(C–
=
=
=
=
H), 2839 n(C–H of OMe), 1630 and 1618 m n(C N and C C),
1533 n(NO2). 1H NMR in CDCl3, d (ppm): 3.02 (s, br., 3H, NMe),
3.82 (s, 3H) and 3.90 (s, 3H)(2 ¥ OMe), 3.67 (s, 4H)(TAA Hd
and Hd’), 4.29 (s, 2H, TAA Hc), 3.87 (dm, 13.5 Hz, 1H) and
4.25 (d, 13.5 Hz, 1H)(TAA Hb and Hb¢), 4.69 (dm, 13.0 Hz,
2H) and 4.82 (d, 13.0 Hz, 2H)(TAA Ha and Ha¢), 6.18 (s, br.,
1H, N–CH–N), 6.49 (s, 1H), 6.51 (d, 8.2 Hz, 1H) and 7.43 (“s”,
br., 1H)(aryl-H of N–CH(Ar)–N), 7.58 (t, 7.5 Hz, 2H), 7.64 (m,
and 8.90 (dm, 7.3 Hz, 2H)(aryl-H of PhC N). 13C NMR in
CDCl3, d (ppm): 46.8 (NMe), 58.3 (TAA Cd), 62.8 (TAA Cc), 71.6
(TAA Cb), 78.4 (TAA Ca), 72.9 (TAA C–NO2), 87.9 (N–CH–N),
110.8, 111.3 and 143.9 (CH of N–CH(furyl)–N), 148.1 (Cq of
=
N–CH(furyl)–N), 128.6, 130.6 and 134.2 (CH of PhC N), 122.4
1H) and 8.89 (d, 7.3 Hz, 2H)(aryl-H of PhC N). 13C NMR in
=
=
(Cq of PhC N), 164.8 (C N). 195Pt NMR in CDCl3, d (ppm):
-2187 (580 Hz).
CDCl3, d (ppm): 47.3 (NMe), 55.5 and 55.9 (2 ¥ OMe), 58.15
and 58.18 (TAA Cd), 64.2 (TAA Cc), 71.4 (TAA Cb), 80.26 and
80.34 (TAA Ca), 73.4 (TAA C–NO2), 91.3 (N–CH–N), 98.9, 104.4
and 131.0 (CH of N–CH(Ar)–N), 117.2, 159.1 and 162.1 (Cq of
=
=
trans-Dichloro[2,3-dihydro-3-ethoxycarbonyl-3-ethoxycarbony-
lmethyl-2-methyl-5-phenyl-1,2,4-oxadiazole-jN4][7-nitro-1,3,5-
triazaadamantane-jN1]platinum (5f). Yield 54%. Anal. Calcd for
C23H32Cl2N6O7Pt: C, 35.85; H, 4.19; N, 10.91. Found: C, 35.73; H,
=
N–CH(Ar)–N), 128.4, 130.4 and 133.6 (CH of PhC N), 123.3
(Cq of PhC N), 164.0 (C N). 195Pt NMR in CDCl3, d (ppm):
-2467 (550 Hz).
=
=
3.99; N, 10.76. IR spectrum (selected bands), cm-1: 2989, 2965 and
1
=
=
2935 w n(C–H), 1742 s n(C O), 1628 m n(C N), 1536 n(NO2). H
NMR (500 MHz, CDCl3) d (ppm): 1.26 (t, 7.2 Hz, 3H) and 1.35 (t,
7.2 Hz, 3H)(2 ¥ OCH2CH3), 3.01 (s, 3H, NMe), 3.46 (d, 17.5 Hz,
1H) and 4.66 (d, 17.5 Hz, 1H)(CH2), 4.26–4.32 (m, 4H)(2 ¥
OCH2CH3), 3.71 (s, 4H)(TAA Hd and Hd’), 4.18 (d, 14.1 Hz, 1H)
and 4.23 (d, 14.1 Hz, 1H)(TAA Hc), 3.92 (dm, 13.4 Hz, 1H) and
4.25 (d, 13.4 Hz, 1H)(TAA Hb and Hb¢), 4.61 (dm, 13.2 Hz, 2H)
and 4.85 (d, 13.2 Hz, 2H)(TAA Ha and Ha¢), 7.61 (“t”, 7.6 Hz,
2H), 7.72 (m, 1H) and 8.76 (d, 7.6 Hz, 2H)(N C–Ph). 13C NMR
(125.7 MHz, CDCl3) d (ppm): 14.0 and 14.2 (2 ¥ OCH2CH3), 39.5
(CH2), 42.0 (NMe), 61.5 and 62.9 (2 ¥ OCH2CH3), 58.26 and 58.33
(TAA Cd), 62.7 (TAA Cc), 71.6 (TAA Cb), 78.2 (TAA Ca), 73.0
trans-Dibromo[2,3-dihydro-3-(2,6-dimethoxyphenyl)-2-methyl-
5-phenyl-1,2,4-oxadiazole-jN4][7-nitro-1,3,5-triazaadamantane-
jN1]platinum (5i). Yield 70%. Elemental analysis calculated
C24H30Br2N6O5Pt: C 34.42; H 3.61; N 10.04; found: C 34.18; H
3.48; N 9.79. IR (selected bands), cm-1: 3052, 2966 and 2940 n(C–
=
=
H), 2838 n(C–H of OMe), 1640 and 1605 m n(C N and C C),
1534 n(NO2). H NMR in CDCl3, d (ppm): 3.03 (s, 3H, NMe),
1
3.67 (s, 3H) and 4.05 (s, 3H)(2 ¥ OMe), 3.65 (s, 4H)(TAA Hd and
Hd’), 4.22 (d, 13.8 Hz, 1H) and 4.26 (d, 13.8 Hz, 1H)(TAA Hc),
3.86 (dm, 13.8 Hz, 1H) and 4.25 (d, 13.8 Hz, 1H)(TAA Hb and
Hb¢), 4.67 (dm, 13.0 Hz, 2H) and 4.79 (d, 13.0 Hz, 2H)(TAA Ha
and Ha¢), 6.66 (s, 1H, N–CH–N), 6.53 (d, 8.2 Hz, 1H), 6.66 (d,
8.0 Hz, 1H) and 7.33 (t, 8.1 Hz, 1H)(aryl-H of N–CH(Ar)–N),
7.57 (t, 7.6 Hz, 2H), 7.63 (m, 1H) and 8.85 (d, 7.6 Hz, 2H)(aryl-H
=
=
(TAA C–NO2), 92.2 (N–C–N), 122.5 (Cq, N CPh), 129.6 (CH,
N CPh), 131.2 (CH, N CPh), 135.1 (CH, N CPh and N CPh),
167.9 (C N), 165.9 and 168.7 (C O). 195Pt NMR (107.3 MHz,
=
=
≡
=
of PhC N). 13C NMR in CDCl3, d (ppm): 48.5 (NMe), 56.0 and
=
=
=
CDCl3) d (ppm): -2168 (710 Hz).
56.8 (2 ¥ OMe), 58.12 and 58.17 (TAA Cd), 64.1 (TAA Cc), 71.4
(TAA Cb), 80.19 and 80.22 (TAA Ca), 73.4 (TAA C–NO2), 87.4
(N–CH–N), 104.0, 105.2 and 131.2 (CH of N–CH(Ar)–N), 113.2,
158.6 and 160.7 (Cq of N–CH(Ar)–N), 128.4, 130.3 and 133.4 (CH
trans-Dibromo[2,3-dihydro-3-(2-methoxyphenyl)-2-methyl-5-
phenyl - 1,2,4 - oxadiazole - jN4][7 - nitro - 1,3,5 - triazaadamantane-
jN1]platinum (5g). Yield 70%. Elemental analysis calculated for
C23H28Br2N6O4Pt: C 34.21; H 3.49; N 10.41; found: C 34.08; H
3.22; N 10.07. IR (selected bands), cm-1: 3068, 2988, 2958 and 2920
n(C–H), 2837 n(C–H of OMe), 1631 m n(C N), 1534 n(NO2). H
of PhC N), 123.4 (Cq of PhC N), 163.3 (C N). 195Pt NMR in
CDCl3, d (ppm): -2478 (600 Hz).
=
=
=
1
=
trans - Dibromo[2,3 - dihydro - 3 - (2,4,6 - trimethoxyphenyl) - 2-
methyl - 5 - phenyl - 1,2,4 - oxadiazole - jN4][7 - nitro - 1,3,5-triazaa-
damantane-jN1]platinum (5j). Yield 65%. Elemental analysis
NMR in CDCl3, d (ppm): 3.04 (s, br., 3H, NMe), 3.93 (s, 3H,
OMe), 3.66 (“s”, 4H, TAA Hd and Hd¢), 4.29 (“s”, 2H, TAA Hc),
This journal is
The Royal Society of Chemistry 2010
Dalton Trans., 2010, 39, 7747–7759 | 7757
©

View Online
calculated for C25H32Br2N6O6Pt: C 34.61; H 3.72; N 9.69; found:
C 34.55; H 3.61; N 9.41. IR (selected bands), cm-1: 2999, 2958
Ligand substitution of the mixed triazaadamantane/oxadiazoline
complex 5a.
=
and 2938 n(C–H), 2835 n(C–H of OMe), 1640 m n(C N), 1533
A solution of 5a (0.1 mmol) and pyridine (0.1 mmol) in chlo-
roform (1 ml) was stirred at 37 ◦C for 96 h. The solvent was
evaporated and the residual crude products were purified by
chromatography on silica using CH2Cl2–ethyl acetate 98 : 2 as
eluent.
n(NO2). 1H NMR in CDCl3, d (ppm): 2.98 (s, br., 3H, NMe), 3.62
(s, 3H), 3.80 (s, 3H) and 4.01 (s, 3H)(3 ¥ OMe), 3.65 (s, 4H)(TAA
Hd and Hd’), 4.29 (d, 14.1 Hz, 1H) and 4.24 (d, 14.1 Hz, 1H)(TAA
Hc), 3.86 (dm, 13.4 Hz, 1H) and 4.27 (d, 13.4 Hz, 1H)(TAA Hb
and Hb¢), 4.66 (dm, 13.2 Hz, 2H) and 4.78 (d, 13.2 Hz, 2H)(TAA
Ha and Ha¢), 6.52 (s, br., 1H, N–CH–N), 6.06 (s, 1H) and 6.20 (s,
1H)(aryl-H of N–CH(Ar)–N), 7.58 (t, 7.6 Hz, 2H), 7.62 (m, 1H)
trans-Dichloro[2,3-dihydro-3-(2-methoxyphenyl)-2-methyl-5-
phenyl-1,2,4-oxadiazole-jN4][pyridine-jN1]platinum (7a). Yield
69%. Elemental analysis calculated for C21H21Cl2N3O2Pt: C 41.12;
H 3.45; N 6.85; Pt 31.80; found: C 40.99; H 3.39; N 6.59. TGA
(residue) Pt 32.23. IR (selected bands), cm-1: 3066, 2999, 2964 and
and 8.82 (d, 7.6 Hz, 2H)(aryl-H of PhC N). 13C NMR in CDCl3,
=
d (ppm): 48.7 (NMe), 55.4, 55.9 and 56.8 (3 ¥ OMe), 58.28 and
58.35 (TAA Cd), 64.7 (TAA Cc), 71.5 (TAA Cb), 80.2 (TAA Ca),
73.3 (TAA C–NO2), 87.5 (N–CH–N), 90.8 and 91.7 (CH of N–
CH(Ar)–N), 105.5, 159.4, 161.6 and 162.6 (Cq of N–CH(Ar)–N),
=
2924 n(C–H), 2838 n(C–H of OMe), 1628 and 1605 m n(C N,
C C). H NMR in CDCl3, d (ppm): 3.05 (s, 3H, NMe), 3.73 (s, br.,
1
=
=
=
128.5, 130.4 and 133.4 (CH of PhC N), 123.6 (Cq of PhC N),
3H, OMe), 6.41 (s, br., 1H, N–CH–N), 6.87 (d, 8.1 Hz, 1H), 6.81
(t, 7.8 Hz, 1H), 7.35 (m, 1.5 Hz, 1H) and 7.82 (“s”, br., 1H)(aryl-
H of N–CH(Ar)–N), 7.23 (t, 6.6 Hz, 2H), 7.74 (m, 1H), 7.82 (d,
6.8 Hz, 2H)(pyridine), 7.48 (t, 7.6 Hz, 2H), 7.67 (t, 7.7 Hz, 1H)
and 9.23 (dd, 7.8 Hz, 1.8 Hz, 2H)(aryl-H of PhC N). 13C NMR in
CDCl3, d (ppm): 47.7 (NMe), 56.1 (OMe), 91.5 (N–CH–N), 112.0,
121.1, 129.3 and 131.1 (CH of N–CH(Ar)–N), 124.8 and 158.0 (Cq
of N–CH(Ar)–N), 125.1, 129.7 and 153.3 (CH, pyridine), 129.2,
163.5 (C N). 195Pt NMR in CDCl3, d (ppm): -2477 (620 Hz).
=
trans-Dibromo[2,3-dihydro-3-(2-furyl)-2-methyl-5-phenyl-1,2,4-
oxadiazole - jN4][7 - nitro - 1,3,5 - triazaadamantane - jN1]platinum
(5k). Yield 51%. Elemental analysis calculated for
C20H24Br2N6O4Pt: C 31.31; H 3.15; N 10.95; found: C 31.19;
H 3.01; N 10.71. IR (selected bands), cm-1: 3117, 3063, 2967
=
=
=
and 2887 w n(C–H), 1632 and 1602 m n(C N and C C), 1535
=
=
=
130.8 and 133.9 (CH of PhC N), 123.1 (Cq of PhC N), C N
1
n(NO2). H NMR in CDCl3, d (ppm): 3.01 (s, br., 3H, NMe),
not detected. 195Pt NMR in CDCl3, d (ppm): -2025 (940 Hz).
3.67 (d, 13.6 Hz, 2H) and 3.69 (d, 13.6 Hz, 2H)(TAA Hd and
Hd¢), 4.32 (s, 2H, TAA Hc), 3.90 (dm, 13.2 Hz, 1H) and 4.28 (d,
13.2 Hz, 1H)(TAA Hb and Hb¢), 4.67 (dm, 12.8 Hz, 2H) and 4.87
(d, 12.8 Hz, 2H)(TAA Ha and Ha¢), 6.02 (s, br., 1H, N–CH–N),
6.44 (dd, 3.3 Hz, 1.8 Hz, 1H), 6.79 (d, 3.2 Hz, 1H) and 7.49
(m, 1H)(furyl-H), 7.59 (t, 7.8 Hz, 2H), 7.71 (tm, 7.4 Hz, 1H)
and 8.90 (dm, 7.3 Hz, 2H)(aryl-H of PhC N). 13C NMR in
CDCl3, d (ppm): 46.9 (NMe), 58.3 (TAA Cd), 63.8 (TAA Cc), 71.5
(TAA Cb), 80.2 (TAA Ca), 73.2 (TAA C–NO2), 88.4 (N–CH–N),
110.8, 111.5 and 144.0 (CH of N–CH(furyl)–N), 148.0 (Cq of
Acknowledgements
We are grateful to Johnson Matthey Plc for a loan of platinum
compounds, the University of Augsburg and the Proof of Concept
Fund of the University of Surrey for supporting this work.
=
References
1 (a) L. Kelland, Nat. Rev. Cancer, 2007, 7, 573–584; (b) T. Boulikas,
A. Pantos, E. Bellis and P. Christofis, Cancer Therapy, 2007, 5, 537–
583; (c) Platinum-based Drugs in Cancer Therapy, L. R. Kelland and
N. P. Farrell (ed.), Humana Press Inc., Totowa, NJ, 2000.
2 Clinical Practice Protocols in Oncology Nursing, D. S. Prescher-Hughes
and C. J. Alkhoudairy (ed.), Jones and Bartlett Publishers, Sudbury,
MA, 2007.
3 (a) L. R. Kelland, B. A. Murrer, G. Abel, C. M. Giandomenico, P.
Mistry and K. R. Harrap, Cancer Res., 1992, 52, 822–828; (b) D.
Kovala-Demerzi, A. Boccarelli, M. A. Demerzis and M. Coluccia,
Chemotherapy, 2007, 53, 148–152.
4 for example: M. Galanski, S. Slaby, M. A. Jakupec and B. K. Keppler,
J. Med. Chem., 2003, 46, 4946–4951.
5 (a) E. Wong and C. M. Giandomenico, Chem. Rev., 1999, 99, 2451;
(b) M. D. Hall and T. W. Hambley, Coord. Chem. Rev., 2002, 232,
49; (c) G. Natile and M. Coluccia, Coord. Chem. Rev., 2001, 216–
217, 383; (d) G. Natile and M. Coluccia, Antitumor Active Trans-
Platinum Compounds. Metal Ions in Biological Systems, A. Sigel and
H. Sigel (ed.), Fontis Media, Lausanne, Switzerland/Marcel Dekker,
New York, 2004; (e) G. Natile and M. Coluccia, Anti-Cancer Agents
Med. Chem., 2007, 7, 111–123; (f) U. Kalinowska-Lis, J. Ochocki and
K. Matławska-Wasowska, Coord. Chem. Rev., 2008, 252, 1328–1245;
(g) S. M. Aris and N. P. Farrell, Eur. J. Inorg. Chem., 2009, 1293–1302.
6 (a) L. R. Kelland, C. F. J. Barnard, K. J. Mellish, P. M. Goddard, M.
Valenti, A. Bryant, B. A. Murrer and K. R. Harrap, Cancer Res., 1994,
54, 5618–5622; (b) K. J. Mellish, C. F. J. Barnard, B. A. Murrer and
L. R. Kelland, Int. J. Cancer, 1995, 62, 717–723.
=
N–CH(furyl)–N), 128.6, 130.7 and 134.2 (CH of PhC N), 122.3
(Cq of PhC N), 164.7 (C N). 195Pt NMR in CDCl3, d (ppm):
-2496 (720 Hz).
=
=
trans-Dibromo[2,3-dihydro-3-ethoxycarbonyl-3-ethoxycarbo-
nylmethyl-2-methyl-5-phenyl-1,2,4-oxadiazole-jN4][7-nitro-1,3,5-
triazaadamantane-jN1]platinum (5l). Yield 48%. Anal. Calcd for
C23H32Br2N6O7Pt: C, 32.14; H, 3.75; N, 9.78. Found: C, 32.11;
H, 3.61; N, 9.55. IR spectrum (selected bands), cm-1: 2991, 2963
and 2937 w n(C–H), 1740 s n(C O), 1625 m n(C N), 1533 s
n(NO2). H NMR (500 MHz, CDCl3) d (ppm): 1.24 (t, 7.2 Hz,
3H) and 1.36 (t, 7.2 Hz, 3H)(2 ¥ OCH2CH3), 3.03 (s, 3H, NMe),
3.48 (d, 17.5 Hz, 1H) and 4.62 (d, 17.5 Hz, 1H)(CH2), 4.27–
4.33 (m, 4H)(2 ¥ OCH2CH3), 3.71 (s, 4H)(TAA Hd and Hd’),
4.25 (d, 14.1 Hz, 1H) and 4.26 (d, 14.1 Hz, 1H)(TAA Hc), 3.93
(dm, 13.4 Hz, 1H) and 4.26 (d, 13.4 Hz, 1H)(TAA Hb and Hb¢),
4.69 (dm, 13.2 Hz, 2H) and 4.90 (d, 13.2 Hz, 2H)(TAA Ha and
Ha¢), 7.61 (“t”, 7.6 Hz, 2H), 7.72 (m, 1H) and 8.76 (d, 7.6 Hz,
2H)(N C–Ph). 13C NMR (125.7 MHz, CDCl3) d (ppm): 14.1
and 14.3 (2 ¥ OCH2CH3), 39.8 (CH2), 42.2 (NMe), 61.5 and 62.9
(2 ¥ OCH2CH3), 58.3 (TAA Cd), 64.1 (TAA Cc), 71.5 (TAA Cb),
80.2 (TAA Ca), 73.3 (TAA C–NO2), 92.2 (N–C–N), 122.6 (Cq,
=
=
1
=
7 (a) N. Farrell, T. T. B. Ha, J. P. Souchard, F. L. Wimmer, S. Cros
and N. P. Johnson, J. Med. Chem., 1989, 32, 2240–2241; (b) M. van
Beusichem and N. Farrell, Inorg. Chem., 1992, 31, 634–639.
8 (a) E. I. Montero, S. Diaz, A. M. Gonzales-Vadillo, J. M. Perez,
C. Alonso and C. Navarro-Ranninger, J. Med. Chem., 1999, 42,
=
=
=
N CPh), 129.6 (CH, N CPh), 131.3 (CH, N CPh), 135.2 (CH,
N CPh and N CPh), 167.9 (C N), 166.0 and 168.6 (C O). 195Pt
≡
=
=
=
NMR (107.3 MHz, CDCl3) d (ppm): -2480 (840 Hz).
7758 | Dalton Trans., 2010, 39, 7747–7759
This journal is
The Royal Society of Chemistry 2010
©

View Online
4264–4268; (b) E. I. Montero, J. M. Perez, A. Schwarz, M. A. Fuertes,
J. M. Malinge, C. Alonso, M. Lang and C. Navarro-Ranninger,
ChemBioChem, 2002, 3, 61–67.
9 A. Boccarelli, F. P. Intini, R. Sasanelli, M. F. Sivo, M. Coluccia and G.
Natile, J. Med. Chem., 2006, 49, 829–837.
35 (a) S. J. S. Kerrison and P. J. Sadler, J. Chem. Soc., Chem. Commun.,
1977, 861–863; (b) W. I. Sundquist, K. J. Ahmed, L. S. Hollis and S. J.
Lippard, Inorg. Chem., 1987, 26, 1524–1528; (c) S. J. Fischer, L. M.
Benson, A. Faug, S. Naylor and A. J. Windebank, NeuroToxicology,
2008, 29, 444–452.
10 A. Boccarelli, M. Coluccia, F. P. Intini, G. Natile, D. Locker and M.
Leng, Anticancer Drug Design, 1999, 14, 253–264.
11 H. M. Coley, J. Sarju and G. Wagner, J. Med. Chem., 2008, 51, 135–141.
12 G. Wagner, A. J. L. Pombeiro and V. Yu. Kukushkin, J. Am. Chem.
Soc., 2000, 122, 3106–3111.
13 J. Sarju, J. Arbour, J. Sayer, B. Rohrmoser, W. Scherer and G. Wagner,
Dalton Trans., 2008, 5302–5312.
14 G. Wagner, M. Haukka, J. J. R. Frau´sto da Silva, A. J. L. Pombeiro and
V. Yu. Kukushkin, Inorg. Chem., 2001, 40, 264–271.
15 B. Desai, T. N. Danks and G. Wagner, Dalton Trans., 2003, 2544–2549.
16 B. Desai, T. N. Danks and G. Wagner, Dalton Trans., 2004, 166–171.
17 G. Wagner and M. Haukka, J. Chem. Soc., Dalton Trans., 2001, 2690–
2697.
36 P. Marque´s-Gallego, H. den Dulk, J. Brouwer, H. Kooijman, A. L.
Spek, O. Roubeau, S. J. Teat and J. Reedijk, Inorg. Chem., 2008, 47,
11171–11179.
37 S. J. Berners-Price and T. G. Appleton, Platinum Based Drugs in Cancer
Therapy, L. R. Kelland and N. P. Farrell (Eds), Humana Press, Totowa,
N. J., 2000, pp. 3–35.
38 (a) Y. Z. Liu, F. P. Intini, G. Natile and E. Sletten, J. Chem. Soc., Dalton
Trans., 2002, 3489–3495; (b) G. McGowan, S. Parson and P. J. Sadler,
Inorg. Chem., 2005, 44, 7459–7476; (c) A. C. G. Hotze, Y. Chen, T. W.
Hambley, S. Parsons, N. A. Kratochwil, J. A. Parkinson, V. P. Munk
and P. J. Sadler, Eur. J. Inorg. Chem., 2002, 1035–1039.
39 S. M. Sbovata, F. Bettio, M. Mozzon, R. Bertani, A. Venzo, F.
Benetollo, R. A. Michelin, V. Gandin and C. Marzano, J. Med. Chem.,
2007, 50, 4775–4784.
40 W. Geary, Coord. Chem. Rev., 1971, 7, 81–122.
41 AMA Drug evaluations, 6th ed. American Medical Association,
Chicago, Sept. 1986, 1182.
42 P. Rostock, Langenbeck’s Archives of Surgery, 1929, 217, 264–279.
43 J. V. Das and V. K. Gupta, Fresenius J. Anal. Chem., 1995, 352, 395–
396.
44 (a) V. J. Cogliano, Y. Grosse, R. A. Baan, K. Straif, M. B. Secretan and
F. Ghissassi, Environ. Health Perspect., 2005, 113, 1205–1208; (b) V.
Cogliano, Y. Grosse, R. Baan, K. Straif, B. Secretan and F. Ghissassi,
Lancet Oncol., 2004, 5, 528.
18 J. R. Griffiths, Br. J. Cancer, 1991, 64, 425–427.
ˇ
19 (a) F. Za´k, J. Tura´nek, A. Kroutil, P. Sova, A. Mistr, A. Poulova´, P.
ˇ
ˇ
Mikolin, Z. Za´k, A. Kasˇna´, D. Za´luska´, J. Necˇa, L. Sindlerova´ and
A. Kozub´ık, J. Med. Chem., 2004, 47, 761–763; (b) A. Kozub´ık, V.
ˇ
ˇ
Horva´th, L. Sviha´lkova´-Sindlerova´, K. Soucˇek, J. Hofmanova´, P. Sova,
ˇ
A. Kroutil, F. Za´k, A. Mistr and J. Tura´nek, Biochem. Pharmacol., 2005,
69, 373–383; (c) J. Kaspa´rkova´, O. Nova´kova´, O. Vra´na, F. Intini, G.
Natile and V. Brabec, Mol. Pharmacol., 2006, 70, 1708–1719.
20 (a) C. S. Allardyce, P. J. Dyson, D. J. Ellis and S. L. Heath, Chem.
Commun., 2001, 1396–1397; (b) C. Scolaro, A. Bergamo, L. Brescacin,
R. Delfino, M. Coccietto, G. Laurenczy, T. J. Geldbach, G. Sava and
P. J. Dyson, J. Med. Chem., 2005, 48, 4161–4171.
21 M. J. Claere and J. D. Hoeschele, Bioinorg. Chem., 1973, 2, 187–210.
22 (a) E. B. Hodge, J. Org. Chem., 1972, 37, 320–321; (b) N. W. Gabel,
U.S. Patent 3,301,845 (1967), Chem. Abstr. 67, 21936 (1967); (c) V.
Galik, M. Safar, Z. Kafka and S. Landa, Collect. Czech. Chem.
Commun., 1975, 40, 442–447.
45 S. Masunaga, K. Tano, M. Watanabe, G. Kashino, M. Suzuki, Y.
Kinashi, K. Ono and J. Nakamura, Br. J. Radiol., 2009, 82, 392–400.
46 A. A. Granovsky, PC GAMESS/Firefly version 7.1.C,
http://classic.chem.msu.su/gran/gamess/index.html.
47 M. W. Schmidt, K. K. Baldridge, J. A. Boatz, S. T. Elbert, M. S. Gordon,
J. H. Jensen, S. Koseki, N. Matsunaga, K. A. Nguyen, S. J. Su, T. L.
Windus, M. Dupuis and J. A. Montgomery, J. Comput. Chem., 1993,
14, 1347–1363.
23 M. Safar, V. Galik, Z. Kafka and S. Landa, Collect. Czech. Chem.
Commun., 1975, 40, 2179–2182.
48 B. M. Bode and M. S. Gordon, J. Mol. Graphics Modell., 1998, 16,
24 (a) J. Kramer and K. R. Koch, Inorg. Chem., 2007, 46, 7466–7476;
(b) S. J. Kerrison and P. J. Sadler, J. Magn. Reson., 1978, 31, 321;
(c) P. L. Goggin, R. J. Goodfellow, S. R. Haddock, B. F. Taylor and
I. R. H. Marshall, J. Chem. Soc., Dalton Trans., 1976, 459.
25 (a) G. Wagner, T. N. Danks and B. Desai, Tetrahedron, 2008, 64, 477–
486; (b) G. Wagner, Chem.–Eur. J., 2003, 9, 1503–1510.
26 M. L. Kuznetsov and V. Y. Kukushkin, J. Org. Chem., 2006, 71, 582–
592.
133–138.
49 (a) C. Lee, W. Yang and R. G. Parr, Phys. Rev. B: Condens. Matter,
1988, 37, 785; (b) A. D. Becke, J. Chem. Phys., 1993, 98, 5648; (c) P. J.
Stephens, F. J. Devlin, C. F. Chablowski and M. J. Frisch, J. Phys.
Chem., 1994, 98, 11623–11627.
50 S. H. Vosko, L. Wilk and M. Nusair, Can. J. Phys., 1980, 58, 1200–1211.
51 (a) K. L. Schuchardt, B. T. Didier, T. Elsethagen, L. Sun, V. Gurumoor-
thi, J. Chase, J. Li and T. L. Windus, J. Chem. Inf. Model., 2007, 47,
1045–1052; (b) D. Feller, J. Comp. Chem., 1996, 17, 1571–1586.
52 (a) P. C. Hariharan and J. A. Pople, Theor. Chim. Acta, 1973, 28, 213–
222; (b) M. M. Francl, W. J. Pietro, W. J. Hehre, J. S. Binkley, M. S.
Gordon, D. J. DeFrees and J. A. Pople, J. Chem. Phys., 1982, 77, 3654–
3665.
27 R. F. W. Bader, Atoms in Molecules: A Quantum Theory, Clarendon
Press, Oxford, 1. Edition, 1990.
28 E. R. Jamieson and S. J. Lippard, Chem. Rev., 1999, 99, 2467–2498.
29 J. J. P. Stewart, J. Mol. Model., 2007, 13, 1173–1213.
30 J. J. P. Stewart, J. Comput.-Aided Mol. Des., 1990, 4, 1–105.
See also MOPAC2009 Home Page at http://openmopac.net/
MOPAC2009.html.
31 (a) J. J. P. Stewart, J. Mol. Model., 2009, 15, 765–805; (b) V. I. Danilov,
J. J. P. Stewart and T. van Mourik, J. Biomol. Struct. Dynamics, 2007,
24, 652–653.
32 A. Gelasco and S. J. Lippard, Biochemistry, 1998, 37, 9230–9239.
33 RSCB Protein Data Bank (http://www.rcsb.org/pdb/home/home.do),
PDB ID: 1a84, A. Gelasco and S. J. Lippard, Biochemistry, 1998, 37,
9230–9239.
34 (a) N. Boisdron-Celle, A. Lebouil, P. Allain and E. Gamelin, Bull.
Cancer, 2001, 88, S14–S19; (b) D. M. Townsend, M. Deng, L. Zhang,
M. G. Lapus and M. H. Hanigan, J. Am. Soc. Nephrol., 2003, 14, 1–10.
53 (a) I. Mayer, Int. J. Quantum Chem., 1986, 29, 73–84; (b) I. Mayer,
Int. J. Quantum Chem., 1986, 29, 477–483.
54 (a) F. W. Biegler-Ko¨nig, R. F. W. Bader and T. Tang, J. Comput. Chem.,
1982, 3, 317–328; (b) R. J. Cheeseman, T. A. Keith and R. F. W.
Bader, AIMPAC program package, McMaster University, Hamilton,
ON, 1994.
55 J. J. P. Stewart, THEOCHEM, 1997, 401, 195–205.
56 R. Koradi, M. Billeter and K. Wu¨thrich, J. Mol. Graphics, 1996, 14,
51–55.
57 G. Wagner and T. Garland, Tetrahedron Lett., 2008, 49, 3596–3599. See
also Supplementary Data associated with that article.
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