Facile preparation of mono-, Di- and mixed-carboxylato platinum(IV) complexes for versatile anticancer prodrug design

Article abstract of DOI:10.1002/chem.201203159

Facile strategies were developed for the versatile functionalization of platinum(IV) axial sites, allowing for easy accessibility to unsymmetric mono- and mixed-carboxylato, as well as symmetric di-substituted platinum(IV) complexes. The first method involves the direct oxidation and carboxylation of the platinum(II) center using an appropriate peroxide and the carboxylate of choice to firstly yield a monocarboxylato monohydroxido platinum(IV) complex. This platinum(IV) intermediate can undergo further carboxylation to give rise to a mixed-carboxylato platinum(IV) complex. The second method involves the activation of the carboxylate of choice by a common carbodiimide coupling reagent, and its reaction with a dihydroxido platinum(IV) precursor to give the monocarboxylato platinum(IV) complex. Uronium salts can be employed to promote efficient dicarboxylation of the dihydroxido platinum(IV) precursor. Lastly, an axial azide pendant group was demonstrated to be suitable for orthogonal "click" conjugation reactions. Copyright

Full text of DOI:10.1002/chem.201203159

DOI: 10.1002/chem.201203159
Facile Preparation of Mono-, Di- and Mixed-Carboxylato Platinum(IV)
Complexes for Versatile Anticancer Prodrug Design
[
a]
[a]
[b]
[a]
Jenny Z. Zhang, Paul Bonnitcha, Ezequiel Wexselblatt, Alice V. Klein,
[
c]
[b]
[a]
Yousef Najajreh, Dan Gibson,* and Trevor W. Hambley*
Abstract: Facile strategies were devel-
oped for the versatile functionalization
of platinum(IV) axial sites, allowing for
easy accessibility to unsymmetric
mono- and mixed-carboxylato, as well
as symmetric di-substituted plati-
monocarboxylato monohydroxido plat-
inum(IV) complex. This platinum(IV)
intermediate can undergo further car-
boxylation to give rise to a mixed-car-
boxylato platinum(IV) complex. The
second method involves the activation
of the carboxylate of choice by a
common carbodiimide coupling re-
agent, and its reaction with a dihydrox-
ido platinum(IV) precursor to give the
monocarboxylato platinum(IV) com-
plex. Uronium salts can be employed
to promote efficient dicarboxylation of
the dihydroxido platinum(IV) precur-
sor. Lastly, an axial azide pendant
group was demonstrated to be suitable
for orthogonal “click” conjugation re-
actions.
ACHTUNGTRENNUNGn um(IV) complexes. The first method
involves the direct oxidation and car-
boxylation of the platinum(II) center
using an appropriate peroxide and the
carboxylate of choice to firstly yield a
Keywords: carboxylation · ligands ·
platinum · prodrugs · synthesis
Introduction
Despite the favorable characteristics demonstrated by
platinum(IV) complexes, past drug design strategies have
failed to deliver platinum(IV) complexes that exhibit suffi-
cient advantages over established platinum(II) agents to
enable their progression past the Phase III clinical trial
Platinum(IV)-based anticancer compounds hold enormous
potential for overcoming many of the limitations facing ex-
isting platinum(II)-based chemotherapies. Platinum(IV)
complexes are more inert than platinum(II) complexes,
making them more resistant to unwanted side-reactions in
the body. Moreover, they are regarded as prodrugs since
they require activation by bioreduction to release the cyto-
toxic platinum(II) component. Importantly, they contain two
axial ligands, which can be used to influence the reduction
[6]
stage. A significant hindrance to innovative platinum(IV)
drug design is the limiting nature of the available methods
for the functionalization of the axial ligands. Currently, func-
tionalization is most commonly carried out using anhydrides
and acyl chlorides, which undergo direct carboxylation reac-
[
1]
[7]
tions with platinum(IV) axial hydroxido ligands. The reli-
ance on such reagents limits the choice of ligands that can
be introduced to the platinum(IV) axial sites to mostly
simple aliphatic and aromatic moieties. In order to install
more interesting biofunctional groups, such as carbon nano-
[
2]
[3]
kinetics, lipophilicity, cellular accumulation, and activi-
[
4]
ty of the platinum species. Since the axial ligands are re-
leased upon reduction, they can be further exploited in drug
design to confer pharmacological advantages to the plati-
num component without interfering with the cytotoxic mode
[
5,8]
carriers and estrogen receptor targeting molecules,
cyclic
[5]
of action.
anhydrides have been used to firstly introduce a pendant
carboxylate group onto the platinum aixal positions, which
can then be coupled with amine-containing groups through
an extra amide-formation step. Although this strategy can
be employed in cases where suitable amine groups are pres-
ent on the ligand, the coupling of ligands of high complexity,
such as peptide groups with multiple unprotected amines,
[
a] Dr. J. Z. Zhang, Dr. P. Bonnitcha, A. V. Klein, Prof. T. W. Hambley
School of Chemistry, The University of Sydney
Sydney, N.S.W. (Australia)
Fax : (+61)9351-3329
[9]
has proven to be more challenging and low yielding. The
emergence of more facile and versatile functionalization
methods is expected to significantly accelerate platinum(IV)
drug development. Alternative pendant functional groups,
E-mail: t.hambley@chem.usyd.edu.au
[
b] E. Wexselblatt, Prof. D. Gibson
Institute for Drug Research, School of Pharmacy
The Hebrew University, Jerusalem (Israel)
E-mail: dang@ekmd.huji.ac.il
including imines, have been suggested to afford more versa-
[
c] Prof. Y. Najajreh
[10]
tile conjugation reactions;
however, these require addi-
Anti-Cancer Drugs Research Laboratory
Faculty of Pharmacy, Al-Quds University
Jerusalem, P.O. Box 20002 Abu-Dies (Palestine)
tional ligand modifications to include partnering hydrazide
or aminooxy groups.
Another factor constraining platinum(IV) drug design is
the favored generation of symmetric platinum(IV) com-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203159.
1672
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Chem. Eur. J. 2013, 19, 1672 – 1676

FULL PAPER
plexes (dicarboxylation), largely because of the high reactiv-
ity of anhydrides and acyl chlorides. This duplication of
functionality is usually unnecessary and strategically limiting
for drug design. The ability to readily introduce different
functionalities at each of the axial sites would enable the de-
velopment of more sophisticated platinum(IV) prodrugs, in
which the two axial sites can serve different but complemen-
tary purposes to enhance drug efficacy or to facilitate drug
metabolism studies. Mixed-carboxylato platinum(IV) com-
plexes had been previously synthesized by combining two
different anhydrides with a dihydroxido platinum(IV) pre-
strategies can be applied to platinum(IV) derivatives of
diam(m)inedichlorido platinum(II) complexes.
Monocarboxylato Pt complexes were generated by two
IV
different synthetic routes. The more robust of the two
(Scheme 1: Method 1, Table 1 and Table 2) is based on the
mechanism first described by Abbott et al. and involves a
one-pot synthesis containing a large excess of the carboxylic
acid, a smaller excess of a peroxo oxidizing agent (hydrogen
[11]
[2a]
II
peroxide or tert-butyl hydrogen peroxide ) and the Pt
precursor. Our approach was based on the assumption that
II
the peroxide oxidizes the Pt , adding one hydroxido ligand
[7a]
cursor in a one-pot reaction; such a strategy lacks control
and is low yielding, and more controlled alternatives have
been lacking. However, reliable strategies for the generation
of unsymmetric monocarboxylato monohydroxido plati-
to its coordination sphere whereas the other axial ligand is
ACHTUNGTRENNUNGn um(IV) complexes have been reported in the literature,
and these can be used to form the important first step in the
generation of mixed carboxylato platinum(IV) complexes.
The oxidation of platinum(II) by H O intrinsically gives
2
2
rise to unsymmetric platinum(IV) complexes in which one
of the axial hydroxido ligands originates from the H O , and
2
2
[11]
the other from the solvent. This effect was verified in re-
actions using alcohol and acetic acid as solvents, with mono-
alkoxido/acetato platinum(IV) complexes having been selec-
[12]
tively generated. Although reliable, this method limits the
choice of the axial ligands to those that can be derived from
simple alcohols and carboxylic acids that exist as liquids at
room temperature; this limitation must be overcome if this
strategy is to be used in effective platinum(IV) drug design.
In an alternative strategy, monocarboxylato platinum(IV)
complexes have also been selectively generated using anhy-
drides and a dihydroxido platinum(IV) precursor with bulky
[13]
equatorial amine groups;
however, the platinum(IV)
Scheme 1. Reaction pathways for the formation of symmetric and unsym-
metric platinum(IV) complexes. Method 1 involves the oxidation of a
platinum(II) precursor (1) with a large excess of a carboxylic acid and a
smaller excess of a suitable peroxide to generate a monocarboxylato plat-
inum(IV) complex (2). Method 2 involves the use of a common carbodi-
products generated by this method are inherently resistant
to further carboxylation reactions. As it stands, more
straightforward and versatile strategies for the manipulation
of one or both of the axial sites will greatly facilitate pro-
gressive platinum(IV) drug development.
Herein, we report novel synthetic strategies for the gener-
ation of new platinum(IV) complexes with a diverse range
of mono-, di- and mixed-axial carboxylato ligands. A pend-
ant conjugation strategy exploiting the versatility of click
chemistry is also described as a mode to introduce more
complex biofunctionalities to the platinum(IV).
AHCTUNGERTNNUNGi mide coupling reagent to generate a monocarboxylato platinum(IV)
complex (2), following which another carboxylato group can be added in
situ using another activated carboxylate to generate a mixed-carboxylato
platinum(IV) complex (5). Method 3 involves the use of a uronium salt
in a one-pot reaction with the desired carboxylate and a platinum(IV)
precursor (3), to generate a dicarboxylato platinum(IV) complex (4).
Table 1. Generation of monocarboxylato platinum(IV) complexes using
hydrogen peroxide (Method 1).
Results and Discussion
In the context of platinum(IV) prodrugs, high kinetic inert-
ness is essential for minimizing premature reduction and
loss of pharmacological advantages to the platinum compo-
nent. Recently, it was reported that dicarboxylato oxalipla-
tin-based platinum(IV) complexes exhibit unusually slow
rates of reduction, which has not been observed in cisplatin-
based platinum(IV) analogues. As such, the conditions re-
ported in the present study were optimized using predomi-
nantly oxaliplatin-based platinum compounds; however, the
1
Product
R
Yield [%]
2
a
ÀCH
3
79
31
83
34
53
2b
2c
À
2 4 3
ACHTUNGTRENNGU( CH ) CH
[2a]
ÀCH Br
2
2
4
d
c
À1-naphthyl
(di) ÀCH
2
Br
Chem. Eur. J. 2013, 19, 1672 – 1676
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1673

D. Gibson, T. W. Hambley et al.
Table 2. Generation of monocarboxylato platinum(IV) complexes using
tert-butyl hydrogen peroxide (Method 1).
In some cases, such as that of bromoacetic acid, the reac-
tion occurs very rapidly, and prolonged reaction times or the
addition of larger excesses of the carboxylic acid resulted in
the formation of the di-substituted platinum(IV) complex
1
95
(
Table 1, 4c).
track this reaction and it was observed that the mono-
AHCTUNGTREGbNNNU romoacetato platinum(IV) complex is formed at 1 h, fol-
Pt NMR spectroscopy was employed to
lowed by the full conversion to the dicarboxylato complex
at time points beyond 3 h. This result can be explained by
a
b
1
Product
R
–
R
–
R
Yield
%]
[
the acidic nature of bromoacetato ligand (pK 2.9), which
a
[
a]
can protonate the remaining hydroxido ligand on the mono-
carboxylato complex, forming an aqua ligand that can be
easily displaced by another carboxylate. This is consistent
with the observations that the generation of diacetato and
hexanoato complexes was not observed at time points of up
to 3 days into the reaction, since both acetic and hexanoic
2
2
2
a
ÀCH
ÀCH
ÀCH
3
3
3
60
63
93
k
l
–piperidine
–piperidino
piperidine
–piperidino
piperidine
ÀNH
3
2
ÀNH
A
H
U
G
R
N
U
)
)
CH
CH
2
3
3
3
3
2
m
ÀNH
2
A
H
N
T
E
N
G
2
ÀCH
2
CH
3
89
[
2a]
[
a] Reported previously by Zhang et al.
acids have higher pK values of approximately 4.8. It should
a
be noted that the degree of conversion was determined by
1
95
likely “picked up” from the surrounding solvent, in this case
the carboxylic acid, which is present in large excess. Using
hydrogen peroxide as the oxidizing agent, acetic acid
performing Pt NMR spectroscopy on the reaction mixture
(in situ), which is different to the actual isolated yields.
In instances where the ligand is too scarce to be used in
large excess, an alternative monocarboxylation route
(Scheme 1: Method 2, Table 3) can be used. This method
(
liquid), hexanoic acid (oil), bromoacetic acid (solid) and
naphthyleneacetic acid (solid) were all selectively mono-
functionally added to the platinum using this method. In
cases where the carboxylic acid reagent is a solid or an oil, a
minimal volume of THF or acetonitrile was used to solubi-
lize the starting materials in the reaction mixture. Minimum
volumes of 30% (w/v) hydrogen peroxide (<5 equiv) were
used to minimize the water content in the reactions to mini-
mize formation of the dihydroxido product.
Table 3. Generation of monocarboxylato platinum(IV) complexes using
activated carboxylates (Method 2).
The extent of product conversion is somewhat dependent
on the solubility of the platinum(II) starting material in the
reaction mixtures. The reaction mixture for 2c is the most
polar and acidic, and was observed to greatly solubilize the
platinum(II) precursor, giving rise to an overall high yield.
The lower solubility of the platinum(II) starting material in
the 2b and 2d reaction mixtures, and the higher lipophilicity
of the products gave rise to more difficult isolation and
lower overall yields.
Another option is to use tert-butyl hydrogen peroxide (5m
in decane) as the oxidizing agent. This has the benefit of en-
abling the use of completely non-aqueous media, avoiding
the formation of the dihydroxido platinum(IV) side product
and affording higher compatibility with platinum complexes
and ligands that exhibit poor aqueous solubility. Monocar-
boxylation reactions of trans-platinum(II) complexes using
the organic oxidizing agent and aliphatic acids resulted in
quantitative conversions and good yields. Representative ex-
amples are presented in Table 2.
1
Product
R
Yield [%]
2
b
À
A
H
U
G
R
N
U
G
2
)
4
CH
3
40
64
49
2e
ÀCH N
2
3
4
e
(di) ÀCH
2 3
N
uses common carbodiimide coupling reagents to activate the
carboxylic acid, which is then added slowly to a dihydroxido
platinum(IV) precursor to generate the monocarboxylato
platinum(IV) complex. The formation of the different plati-
num(IV) species was also conveniently tracked in situ using
1
95
Pt NMR spectroscopy. The peak corresponding to the
monocarboxylato platinum(IV) complex is typically about
100 ppm downfield of the dihydroxido platinum(IV) com-
plex, and the dicarboxylato peak appears approximately an-
other 200 ppm downfield of the monocarboxylato plati-
AHCTUNGTRENNUNG
The major advantage of direct oxidative addition of plati-
num(II) complexes to yield monocarboxylated plati
complexes is that it exploits the higher solubility of plati-
num(II) complexes (either in water or organic solvents)
over the dihydroxido platinum(IV) derivatives, which are
often insoluble in common solvents, thus providing a route
to the preparation of compounds that were previously not
accessible.
A
H
U
G
R
N
U
G
poor solubility of the dihydroxido oxaliplatin–platinum(IV)
precursor in organic solvents. The quantity of activated car-
boxylic acid required to exclusively generate the monocar-
boxylato complex was variable; 2.5 equiv excess of large lip-
ophilic carboxylic acids, such as hexanoic acid and Fmoc-
glycine, were required for optimal conversion into the
ACHTUNGTRENNUNG
mono ACHUTNGRNEUNGc arboxylato platinum(IV) complex (with some dihy-
1674
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Chem. Eur. J. 2013, 19, 1672 – 1676

Carboxylato Platinum(IV) Complexes as Anticancer Prodrugs
FULL PAPER
droxido platinum(IV) starting material remaining). The use
of larger excesses resulted in formation of some dicarboxyl-
ACHTUNGTRENNUNGa to platinum(IV) complexes. In contrast, 1.1 equivalents of
azidoacetic acid and naphthyleneacetic acid, were required
for the optimal conversion into the monocarboxylato plati-
num(IV) complex. The exclusive generation of the di-substi-
tuted species was found to require much larger excesses of
the carboxylic acid (>6 equiv for hexanoic acid and
Mixed-carboxylato platinum(IV) complexes can be relia-
bly generated following the isolation of the monosubstituted
product using Method 1, or in situ using Method 2. For ex-
ample, 5a was generated following the isolation of the
mono ACHUTNGRNEUNGa cetato platinum(IV) complex, synthesized using
Method 1, and further carboxylation with azidoacetic acid
using a carbodiimide activating agent. In the instance of 5b,
for which Method 2 was firstly employed to generate the
monoazido complex, succinic anhydride and base could be
combined with the reaction mixture in situ to generate the
mixed-carboxylato platinum(IV) complex. In the latter case,
>
4 equiv for azidoacetic acid), and is consistent with previ-
ous observations suggesting that the remaining hydroxido
[12d]
ligand is less reactive.
Method 2 most likely proceeds via the formation of an O-
acylisourea or anhydride intermediate. In the absence of an-
other activating agent and base, this intermediate is reactive
enough to directly couple to the first hydroxido axial ligand,
but less so to the remaining hydroxido ligand. Although this
method is lower yielding due to the low solubility of the di-
hydroxido platinum(IV) precursor in DMF, it uses mild re-
action conditions, requires a smaller quantity of ligand and
is more versatile. Further optimization efforts exploring car-
boxylate activating reagents with different properties, such
as the water soluble EDC, different solvent systems and re-
action conditions, are expected to improve the reaction
yields.
the yields have yet to be optimized AHCTUNGTERNNUN(G Table 5).
Table 5. Generation of mixed-carboxylato platinum(IV) complexes.
1
2
Product
R
R
Yield [%]
5
5b
5c
a
ÀCH
3
ÀCH
2
N
3
84
29
52
Efficient generation of symmetrical dicarboxylato plati-
ÀCH N
Àsuccinate
2
3
ÀCH
Àanthraquinone
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
num(IV) complexes can be achieved with the addition of
base and activating agents, such as hydroxybenzotriazole
HOBT) in Method 2. A more convenient alternative is to
3
(
use uronium salts, such as O-(benzotriazol-1-yl)-N,N,N’,N’-
tetramethyluronium tetrafluoroborate (TBTU; Scheme 1:
Method 3, Table 4, compounds 4a, 4b, 4d and 4 f) in one-
An attractive alternative to the currently reported pend-
ant coupling reactions is the use of orthogonal click reac-
tions. Click reactions are known for their reliability and high
[14]
yielding nature.
Platinum(II) complexes have previously
been functionalized with azide groups on the non-leaving
positions for conjugation to organic scaffolds modified with
Table 4. Generation
Method 3).
of
dicarboxylato
platinum(IV)
complexes
(
[15]
alkyne click partner groups. We have shown that azides
can be readily incorporated into platinum(IV) complexes
using the aforementioned methods (complexes 2e and 5a)
and that alkyne functional groups can be introduced to the
desired ligand and then readily clicked onto the axial ligands
of the platinum(IV) complexes. An anthraquinone moiety
was chosen for conjugation to the pendant platinum(IV)
azide group. Anthraquinones are known DNA intercalators
that exhibit intrinsic fluorescence, and have been conjugated
to platinum(II) complexes in the past to serve as biocarriers,
1
Product
R
Yield [%]
4
4
4
4
a
b
d
f
ÀCH
(CH ) CH
3
3
60
67
82
84
[16]
À
A
H
U
G
R
N
U
G
as well as fluorescent tags for biodistribution studies. In
this example, the anthraquinone was tethered to an alkyne
group via a short alkyl linker, which was then treated with
2
4
À1-naphthyl
ÀGly-Fmoc
5
a in the presence of a CuI catalyst (Scheme 2). The reac-
tion was stopped at 1 h and the platinum(IV)–anthraqui-
pot reactions with the desired carboxylic acid and base. The
use of uronium salts reliably gave rise to reasonable yields
and straightforward isolation of the platinum(IV) products
due to the high solubility of the byproducts in organic sol-
vents. This strategy bypasses the need for anhydrides and
acyl chlorides, the generation of which require additional
preparative steps and in the latter case requires harsh reac-
tion conditions which lead to byproduct formation.
none conjugate (5c) was isolated by HPLC.
Conclusion
In conclusion, a diverse range of ligands can be readily cou-
pled onto one or both of the axial positions of platinum(IV)
complexes using the strategies described. Importantly, the
Chem. Eur. J. 2013, 19, 1672 – 1676
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www.chemeurj.org
1675

D. Gibson, T. W. Hambley et al.
by the Australian Research Council through Discovery grant
DP110100461.
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1
95
[
[
General procedure for Method 2: The platinum(IV) precursor (trans-
[
Pt(OH)
2
ox ACHTUNGTRENNUNG( R,R-chxn)]) was suspended in DMF. Carboxylic acid (1–
2
.5 equiv) was combined with DCC (1.1–2.6 equiv) in DMF. Once a
white precipitate had fully formed (after ~15 min), the reaction mixture
was centrifuged and the supernatant was added to the platinum(IV) pre-
cursor. The mixture was stirred for 16 h or until the reaction had pro-
1
95
ceeded to completion (monitored using Pt NMR spectroscopy). The re-
action mixture was filtered, and the volume of the filtrate was reduced to
a slurry under high vacuum. The DCU byproduct was precipitated with
water. The white precipitate was removed by filtration, and the volume
of the filtrate was reduced under high vacuum. A minimal amount of
MeOH was added to dissolve the residue, and diethyl ether was added to
precipitate the platinum(IV) product. The platinum(IV) solid was collect-
ed by centrifugation and washed with an ethanol/diethyl ether mixture
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(1:4).
General procedure for Method 3: trans-[Pt(OH)
2
ox AHCTUNGTERNNUNG( R,R-chxn)] was stir-
[
14] H. C. Kolb, K. B. Sharpless, Drug Discovery Today 2003, 8, 1128–
137.
red in DMF with carboxylic acid (3 equiv), triethylamine (3 equiv) and
TBTU (3 equiv). The mixture was filtered, the filtrate was collected, and
DMF was removed under high vacuum. Addition of ethanol/water (1:1)
to the residue resulted in precipitation of the desired product, which was
collected by filtration and washed with diethyl ether.
1
[
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Acknowledgements
We would like to thank the Australian–Israel Scientific Exchange Foun-
dation for their financial support. D.G. thanks the Israel Science Founda-
tion for financial support (grant 1332/10). This work was also supported
Received: September 6, 2012
Published online: December 18, 2012
1676
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