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An international journal of inorganic chemistry

www.rsc.org/dalton Number 48  |  28 December 2009  |  Pages 10629–10936

Themed issue: Metal Anticancer Compounds

ISSN 1477-9226
COMMUNICATION
Che, Lau et al. PERSPECTIVE
Dual anti-angiogenic and cytotoxic Lippard and Lovejoy
properties of ruthenium(III) complexes Non-traditional platinum compounds
containing pyrazolato and/or pyrazole for improved accumulation, oral
ligands bioavailability, and tumor targeting 1477-9226(2009)48;1-R
 This paper is published as part of a Dalton Transactions themed issue on:

Metal Anticancer Compounds View Article Online

Guest Editor Peter Sadler

University of Warwick, UK
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Published in issue 48, 2009 of Dalton Transactions

Image reproduced with permission of Chi-Ming Che

Articles published in this issue include:

PERSPECTIVES:

Non-traditional platinum compounds for improved accumulation, oral bioavailability, and tumor
targeting
Katherine S. Lovejoy and Stephen J. Lippard, Dalton Trans., 2009, DOI: 10.1039/b913896j

Metal complexes as photochemical nitric oxide precursors: Potential applications in the treatment
of tumors
Alexis D. Ostrowski and Peter C. Ford, Dalton Trans., 2009, DOI: 10.1039/b912898k

Novel and emerging approaches for the delivery of metallo-drugs

Carlos Sanchez-Cano and Michael J. Hannon, Dalton Trans., 2009, DOI: 10.1039/b912708a

HOT ARTICLE:

Iron(III) complexes of fluorescent hydroxamate ligands: preparation, properties, and cellular

processing
Antonia J. Clarke, Natsuho Yamamoto, Paul Jensen and Trevor W. Hambley, Dalton Trans., 2009,
DOI: 10.1039/b914368h

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 COMMUNICATION
Dual anti-angiogenic and cytotoxic properties of ruthenium(III) complexes
containing pyrazolato and/or pyrazole ligands†
Raymond Wai-Yin Sun,a Miro Fei-Yeung Ng,a Ella Lai-Ming Wong,a Jingfei Zhang,a Stephen Sin-Yin Chui,a
Published on 14 September 2009. Downloaded by Heinrich Heine University of Duesseldorf on 29/11/2013 09:23:55.
Lam Shek,a,b Tai-Chu Lau*b and Chi-Ming Che*a
Received 22nd June 2009, Accepted 2nd September 2009
First published as an Advance Article on the web 14th September 2009
DOI: 10.1039/b912236b
An oxo-bridged diruthenium(III) complex containing pyra-
zolato and pyrazole ligands is stable against ascorbic-acid
reduction, induces apoptosis (60%, 48 h) against HeLa cells at
10 lM level and exhibits promising anti-angiogenic activity at
its sub-cytotoxic concentrations. Other mononuclear ruthe-
nium(III) complexes containing pyrazole ligands [Ru(pz)4 X2 ]+
exhibit dual anti-angiogenic and cytotoxic properties.
Platinum(II) complexes as exemplified by cisplatin and its
derivatives have been widely used for the treatment of various
types of cancer.1 Despite their widespread clinical use, these
complexes suffer from severe toxic side effects and acquired drug
resistance.2 Thus, there are continuing efforts to search for new
bioactive metal complexes including that of platinum,3 gold,4
and ruthenium,5,6 as modern therapeutics. Notably, ruthenium
complexes have received considerable interest for this purpose in
recent years.6 A wide range of ruthenium complexes have been
shown to be anti-tumour active, including RuII arene complexes
[e.g., (h6 -arene)RuII (pta)Cl2 or [(h6 -arene)RuII (en)Cl]+ (pta =
1,3,5-triaza-7-phosphaadamantane, en = ethylenediamine)],7 RuII
pyridocarbazolyl complexes, which target the active site of large
kinase,8 dinuclear RuII triple-stranded helicates that bind and coil
a
Department of Chemistry and Open Laboratory of Chemical Biology of
the Institute of Molecular Technology for Drug Discovery and Synthesis,
The University of Hong Kong, Pokfulam Road, Hong Kong, China. E-mail:
cmche@hku.hk; Fax: (+852) 2857-1586
b
Department of Biology and Chemistry, City University of Hong Kong,
Tat Chee Avenue, Kowloon Tong, Hong Kong, China. E-mail: bhtclau@
cityu.edu.hk
† Electronic supplementary information (ESI) available: Experimental de-
tails; syntheses and characterization of complexes 1-5. UV-vis absorption
spectrum of 1 in CH2 Cl2 (Fig. S1). UV-vis spectra of 1 in a PBS-EtOH
solution (Fig. S2). UV-vis spectra of 1 in a PBS-EtOH solution containing
ascorbic acid (Fig. S3). UV-vis spectral changes of 1 in a PBS-EtOH
solution with increasing concentration of calf-thymus DNA (Fig. S4).
Gel electrophoresis of 100-bp DNA in 2% (w/v) agarose gel showing the
mobilities of the DNA (15.2 mM bp-1 ) in the absence (first lane, left) and the
presence of ethidium bromide (EB), Hoechst33324 (H33324) and 1 (5 and
50 mM) (Fig. S5). Electrophoresis on agarose gel comparing the effect of
CPT and 1 on the relaxation plasmid DNA by human topoisomerase 1
(Fig. S6). UV-vis spectral changes of 1 a PBS-EtOH solution with
increasing concentration of HSA (Fig. S7). Detection of ROS generated
in the untreated and 1-treated HeLa cells (Fig. S8). Cytotoxicity of 1
toward MS1 cells (Fig. S9). Dose-dependent inhibition of the migration of
MS1 cells by 1 (Fig. S10). Cyclic voltammogram of 1 recorded in CH2 Cl2
(Fig. S11). Cyclic voltammogram of 2 recorded in DMF (Fig. S12). Cyclic
voltammogram of 3 recorded in DMF (Fig. S13). Cyclic voltammogram of
4 recorded in DMF (Fig. S14). Inhibition of tube formation by 2, 3, 4 and
5 (Fig. S15). Cyclic voltammogram of 5 recorded in DMF (Fig. S16) and
bond lengths (Å) and angles (◦ ) for 1 (Table S1). CCDC reference number
687112. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/b912236b
10712 | Dalton Trans., 2009, 10712–10716
www.rsc.org/dalton | DaltonView Article Online
Transactions
DNA,9 hexanuclear [Ru6 (p-iPrC6 H4 Me)6 (tpt)2 (dhbq)3 ]6+ (tpt =
2,4,6-tris(pyridine-4-yl)-1,3,5-triazine, dhbq = 2,5-dihydroxy-1,4-
benzoquinonato),10 [RuIII (terpy)X3 ] (terpy = 2,2¢:6¢,6¢¢-terpyri-
dine, X = Cl, Br or I),11 [RuIII (edta)(OH2 /OH)]1-/2- (edta =
ethylenediaminetetraacetato),12 and Na2 [{trans-RuIII Cl4 -
(Me2 SO)}2 (m-L)] (L = heterocyclic bridging ligand).13 Two
ruthenium-based anti-cancer drug leads, imidazolium[trans-
tetrachloro(1H -imidazole)(S-dimethylsulfoxide)ruthenate( III )]
(NAMI-A) and indazolium[trans-RuCl4 (1H-indazole)2 ]
(KP1019), are separately anti-angiogenic and cytotoxic, res-
pectively, and have entered phase I clinical trials.14,15
Bioactive compounds with dual cytotoxic and anti-angiogenic
properties can enhance anti-cancer potency by reducing the
acquired-drug resistance and systematic toxicities generated by
using either a cytotoxic or an anti-angiogenic agent alone.16 Several
clinically-used cytotoxic compounds employed in metronomic
chemotherapy (low doses on a continuous schedule) have recently
been reported to display promising anti-angiogenic properties
in vivo,17 though such examples are sparse in the literature. It
has also been demonstrated that combination of an anti-cancer
agent employed in transarterial chemoembolization (TACE) with
an anti-angiogenic/metastatic agent can significantly prolong
survival of patients having advanced hepatocellular carcinoma
(HCC).18a Notably, TACE involves the direct transportation of
chemotherapeutic agents to the hepatic artery, the latter is the
sole supplier of blood to the HCC tumour.18b Thus, an approach
to a more efficient TACE treatment is to use compounds having
dual cytotoxic and anti-angiogenic properties, which could induce
apoptosis in high-density tumour region with local high-dose
level, and induce anti-angiogenesis to cancer cells in adjacent or
remote areas without damaging the surrounding normal cells or
tissue. In this regard, we are interested to investigate whether
cytotoxic ruthenium complexes can also have significant anti-
angiogenic activity at their sub-cytotoxic levels. We report herein
ruthenium(III) pyrazolate complexes that exhibit dual cytotoxic
and anti-angiogenic activities.
The dinuclear ruthenium(III) complex (1, Ru2 (m2 -O)(m2 -
pz)2 (pz)2 (pzH)4 where pz = pyrazolato and pzH = pyrazole)
was prepared by the reaction of Ru2 (OAc)4 Cl with pyrazole in
MeOH–H2 O (1 : 1, v/v) at room temperature in 88% yield (ESI†).
Deep blue crystals of 1 were obtained by slow evaporation of a
CH2 Cl2 –hexane (1 : 2, v/v) solution. Complex 1 is stable at room
temperature for months. By Evans NMR method,19 the complex is
diamagnetic. Its structure was characterized by X-ray crystallogra-
phy (Fig. 1).‡ Bond lengths and angles are given in the ESI (Table
S1).† As depicted in Fig. 1, the complex contains two symmetry-
inequivalent Ru atoms (Ru1 and Ru2). The Ru1 and Ru2 atoms
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 View Article Online
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Fig. 1 A ball and stick diagram of 1 with a numbering scheme.

Selected bond distances (Å) and angles (◦ ): Ru1 ◊ ◊ ◊ Ru2 3.189, Ru1–O1
1.902, Ru1–N1A 2.064, Ru1–N2A 2.038, Ru1–N3A 2.092, Ru1–N4A
2.104, Ru1–N5A 2.084, Ru2–O1 1.888, Ru2–N1B 2.045, Ru2–N2B 2.063,
Ru2–N6A 2.077, Ru2–N7A 2.108, Ru2–N8A 2.104; Ru1–O–Ru2 114.6◦ .
All hydrogen atoms, water and hexane molecules are omitted for clarity.
N4B and N6B atoms are hydrogen bond acceptors.

are linked together by one m2 -oxo (O1) and two m2 -pyrazolato

ligands. The Ru–O (av. 1.90 Å) and Ru–N distances 2.038– Fig. 2 Crystal packing diagram of 1 showing continuous hydrophobic
2.108 Å are comparable to related values found in the reported channels viewed along the c-axis. Hydrogen atoms are omitted for clarity.
Ru(III) oxo- and dimethylpyrazolato-bridged complex Ru2 (m2 -
O)(m2 -dmp)2 (dmpH)2 (NO)2 Cl (where dmp = dimethylpyrazolato, solution (19 : 1, v/v) containing ascorbic acid (0.1 mM) at room
dmpH = dimethylpyrazole).20 Intramolecular hydrogen bonds temperature, with less than 10% UV-vis spectral change after
(N3B–H3 ◊ ◊ ◊ N4B 2.159 Å, N5B–H5 ◊ ◊ ◊ N4B 2.104 Å and N8B– 72 h (Fig. S2 and Fig. S3, ESI).† This result suggests that ligand
H8 ◊ ◊ ◊ N6B 2.000 Å) between nitrogen atoms of adjacent non- substitution reaction of 1 is insignificant under these conditions.
bridging pyrazolato ligands as well as an intermolecular one The reported cytotoxic ruthenium complexes have IC50 values
(N7B–H7 ◊ ◊ ◊ O1W 1.935 Å) are noted. The oxo bridge of each (dose required for the inhibition of 50% cellular growth) between
complex molecule is H-bonded to a water molecule (O1 ◊ ◊ ◊ O1W ~1 to >200 mM.5–15 In this work, the cytotoxicity of 1 towards
2.694 Å, O1 ◊ ◊ ◊ H1WB 1.843 Å, ∠O1 ◊ ◊ ◊ H1WB–O1W 170.3◦ ). different cancer cell lines including cervical epithelioid carcinoma
Based on the analysis of the Fourier difference map, no apparent (HeLa), nasopharyngeal carcinoma (SUNE1), and normal lung
electron density peak (> 0.3 e Å3 ) could be found near the O1 fibroblast cells (CCD-19Lu) were determined by MTT assays
atom of the oxo-bridge and near the N4B and N6B atoms of (ESI).† Fig. 3 depicts the percentage cell death vs. concentration of
the non-bridging pyrazolate ligands. Thus complex 1 is comprised 1 for an incubation period of 72 h. From these cytotoxicity profiles,
of two ruthenium atoms, one oxo-bridge ligand, four pyrazolato corresponding IC50 values of 1 towards the HeLa and SUNE1
ligands (two are bridging and two are non-bridging) and four cell lines were determined to be 1.5 and 4.4 mM, respectively.
neutral pyrazole ligands. Taken these structural data together Notably, these IC50 values are comparable to that of cisplatin
with the diamagnetic properties, complex 1 is formulated as a (c.f., IC50 (HeLa) = 4.3 mM; IC50 (SUNE1) = 2.3 mM). Using lung
dinuclear Ru2 (III,III) complex with Ru2 (m2 -O)(m2 -pz)2 (pz)2 (pzH)4 fibroblast cells (CCD-19Lu) as model for normal human cells, the
formulation [where pz = pyrazolato and pzH = pyrazole]. IC50 value of 1 was found to be 9.5 mM, revealing that this complex
In the crystal structure, the molecules are connected through exhibits a 2.2- to 6.3-fold in vitro cancer-cell selectivity.
extensive non-covalent C–H ◊ ◊ ◊ p (or N) interactions, leading to
an open framework with hydrophobic channels along the c-
axis (Fig. 2). These channels (with diameter of about 1 nm)
are continuous in one direction and constitute an accessible
void volume of 558 Å3 (4% void fraction). These structural
features enable accommodation of severely disordered hexane
molecule with a half occupancy per molecule of 1.21 Unlike the
hydrophilic channels in zeolites and other micro/mesoporous
materials, facile self-organization of discrete molecular complexes
to form accessible hydrophobic channels in the solid state as in
this case is not common in the literature.
Complex 1 features an intense absorption peak with l max at
589 nm (e = 9.0 ¥ 103 dm3 mol-1 cm-1 , Fig. S1, ESI†) in CH2 Cl2 .
It has a solubility >10 mg mL-1 in CH2 Cl2 , DMSO and EtOH,
and a solubility of ~1 mg mL-1 in phosphate-buffered saline (PBS,
pH 7.0) containing 5% EtOH (v/v). It is stable in PBS–EtOH Fig. 3 Cytotoxic profiles of 1 towards different cell lines.

This journal is © The Royal Society of Chemistry 2009 Dalton Trans., 2009, 10712–10716 | 10713

Since cancer is characterized by uncontrolled cellular prolifer-
ation, there has been considerable interest in chemotherapeutic-
induced apoptosis.22 Using propidium iodide (PI) to assess the
DNA content of cells, the apoptosis-inducing property of 1 in
HeLa cells was examined by flow cytometry. Upon treatment with
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1 (10 mM), 27.7% and 60% of HeLa cells were found to undergo
apoptotic cell death after 24 and 48 h incubation, respectively
(Fig. 4).
Fig. 4 Induction of cell-cycle arrest in HeLa cells after treatment with 1.
Untreated cells and cells treated with 1 (10 mM) were collected at different
time points (24 or 48 h), subjected to propidium iodide (PI) staining and
flow cytometric analysis. G1-phase cells (Dip G1), S-phase cells (Dip S),
G2-phase cells (Dip G2) and apoptotic cells (apoptosis).
Cell-cycle-arrest study was also undertaken. As shown in Fig. 4,
there is an apparent G1-phase cell-cycle arrest, resulting in a
concomitant decrease in the G2-phase population (from 33 to
~2%). On the other hand, no apparent S-phase cell-cycle arrest was
observed upon treatment of HeLa cells with 1 for 48 h. Since DNA
damaging compounds such as cisplatin significantly cause S-phase
cell-cycle arrest and consequently inhibit DNA replication,23 this
finding reveals that 1 could not halt DNA replication in HeLa
cells under the experimental conditions. The direct interaction of
1 with DNA has been examined. We found that 1 weakly interacts
with calf-thymus DNA (ctDNA) with a binding constant of (6.3 ±
0.8) ¥ 103 dm3 mol-1 based on the results from spectrophotometric
titration experiments (Fig. S4, ESI).† Complex 1 also fails to
intercalate DNA (Fig. S5, ESI†) and has no inhibitory activity on
a DNA-binding protein topoisomerase I (Fig. S6, ESI).† Taken
these results altogether, DNA may not be a crucial cellular target of
1 in inducing its cytotoxicity. Besides DNA and topoisomerase I,
1 also displays weak interaction with human serum album (HSA)
with binding constant of (1.2 ± 0.2) ¥ 104 dm3 mol-1 at 298 K
(Fig. S7, ESI).†
A major anti-cancer mechanism involves the generation of reac-
tive oxygen species (ROS). In this study, intracellular production of
10714 | Dalton Trans., 2009, 10712–10716
View Article Online
oxidant(s) upon treatment of HeLa cells with 1 (10 mM) and H2 O2
(10 mM) for 0 to 5 h were examined using dihydrorhodamine-123
(DHRh-123) assay.24 By means of spectrophotometry, the fluo-
rescent signal of rhodamine-123+ (Rh-123+ ), which was generated
by the oxidation of non-fluorescent DHRh-123 in the presence
of ROS, was monitored. We found that 1-treated HeLa cells
did not show any observable increase in fluorescent intensity of
Rh-123+ (Fig. S8, ESI†), revealing that the mechanism of action
was not due to the generation of intracellular ROS. Increasing
level of fluorescent signal (Rh-123+ ) was detected upon treatment
of the HeLa cells with H2 O2 only, but no fluorescent signal was
detected when the HeLa cells had been co-treated with both H2 O2
and 1 (Fig. S8, ESI).† These results reveal that the H2 O2 -induced
Rh-123+ formation is quenched by 1 implying that 1 is an effective
scavenger of ROS.
We further examined the inhibitory activity of 1 towards
nitric oxide (NO) production in lipopolysaccharide stimulated
endothelial cells (MS1). In this study, supernatants of MS1 cells
treated with 1 or vehicle control for 8 h were collected. The NO
present in the supernatants was oxidized to nitrate, and the total
nitrate content was subsequently quantified using a commercially
available NO assay kit.25 Compared to the vehicle control, the
8-h incubation of 1 (10 mM) significantly inhibited the total nitrate
formation by 28.1%, revealing that 1 could significantly inhibit NO
production in vitro. Since a number of ruthenium complexes have
long been known to display promising anti-angiogenic activity by
inhibiting nitric oxide formation,14,15 the anti-angiogenic activity
of 1 has also been investigated.
The initial step of angiogenesis involves endothelial cell
proliferation.26 Under in vitro conditions, endothelial cells are able
to form capillary-like structure on a layer of matrigel, a crude
extract of basal membrane from mouse Engelbreth-Holm-Swarm
tumours, which can be employed as a cell-base model for studying
possible anti-angiogenic activities of different compounds. In this
work, tube-formation assay (8 h) for testing the anti-angiogenic
activity of 1 has been performed. The maximum concentration
of 1 was restricted to 5 mM (Fig. S9, ESI†) in order to maintain
over 95% viability of the endothelial cells after 8 h treatment.
As depicted in Fig. 5, formation of capillary-like structure of the
endothelial cells at 8 h was inhibited by 1, with 24% and 76%
inhibition at concentration of 1.25 mM and 2.5 mM, respectively.
Fig. 5 The anti-angiogenic activity of 1 as revealed from the tube-forma-
tion assay (arrow: selected sites for tube formation).
This journal is © The Royal Society of Chemistry 2009

Notably, incubation of 1 at 5 mM led to >95% distortion of tube
formation.
Wound-healing-migration is an established protocol that allows
examination of cell migration in response to an artificial wound
produced on a cell monolayer.27 Complex 1 showed wound-
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healing capability on MS1 cells in a dose-dependent manner
(Fig. S10, ESI).† A distinct cell migration in the wound area
was found for the vehicle-control group 8 h after wounding,
whereas the 1-treated cells at concentrations of 1.25, 2.5 and 5 mM
demonstrated dose-dependent inhibitory effects on wound healing
under similar conditions. Taken the findings altogether, complex
1 displays promising in vitro anti-angiogenic effect at sub-toxic
concentrations.
In order to investigate whether the dual cytotoxic and anti-
angiogenic properties also present in other ruthenium complexes
with pyrazole or 3-methylpyrazole ligands, complexes 2–4 with
structures depicted in Fig. 6 were prepared.28 Their electrochem-
ical, cytotoxic and anti-angiogenic properties were examined and
compared to that of 1. The cyclic voltammogram of 1 reveals two
reversible couples at E ◦ 1/2 = -0.61 V and -0.96 V vs. Cp2 Fe+/0 ,
which are assigned to the RuIII,III /RuIII,II and RuIII,II /RuII,II couples,
respectively (Fig. S11, ESI).† For complexes 2, 3 and 4, a reversible
RuIII /RuII couple is observed at E ◦ 1/2 = -0.40 V, -0.54 V and
+0.097 vs. Cp2 Fe+/0 , respectively (Fig. S12–S14, ESI).†
Fig. 6 Ruthenium pyrazolyl complexes.
MTT study revealed that complexes 2 and 3 are cytotoxic
towards HeLa cells with IC50 values of 20.3 mM and 2.9 mM,
respectively. Notably, both complexes also display inhibitory
activity towards NO formation (61.0% and 59.7% inhibition vs.
control for 2 and 3, respectively) and promising anti-angiogenic
activity at their sub-toxic concentrations (Fig. S15, ESI).† On the
contrary, complex 4 is considerably less cytotoxic (IC50 = 94.8 mM),
exhibits low NO inhibitory activity (5.9% vs. control) and has
no detectable anti-angiogenic activity at 10 mM level. Cellular
uptake experiments showed that the uptake of Ru to cancer cells
correlated with the cytotoxicity of complexes 1, 2 and 3, revealing
This journal is © The Royal Society of Chemistry 2009
View Article Online
that a higher Ru uptake [cellular Ru content: 3 (19.8 nM) > 1 (17.1
nM) > 2 (10.1 nM)] led to a higher cytotoxic activity (IC50 values:
3 < 1 < 2). We further prepared and examined the cytotoxicity
of cis-[RuII (BiIml)2 (DMSO)2 ](ClO4 )2 (5, BiIml = biimidazole),29
in which case the ruthenium ion is stable in the +2 oxidation
state with considerably higher E ◦ (RuIII/II ) value of +0.45 V vs.
Cp2 Fe+/0 (Fig. S16, ESI).† Similar to 4, this complex displays low
NO inhibitory activity (10.9% vs. control) and is neither cytotoxic
(IC50 value > 100 mM) nor anti-angiogenic.
We have demonstrated that a diruthenium(III) complex (1)
displays dual cytotoxic and anti-angiogenic activities. These dual
properties have also been found in two mononuclear mono-
cationic ruthenium(III) complexes having pyrzaole ligands and
with comparable E ◦ [RuIII /RuII ] values as that of 1 (E ◦ 1/2 = -0.61 V
vs. Cp2 Fe+/0 ). In contrast, the two stable di-cationic ruthenium(II)
complexes 4 and 5 having comparatively high E ◦ [RuIII /RuII ]
values do not display these biological activities.
Notes and references
‡ Crystal data: 1·H2 O·(hexane)0.5 : C108 H148 N64 O8 Ru8 , M = 3279.5, tetrago-
nal, I41 cd, a = 29.596(1) Å, c = 15.253(1) Å, V = 13360.4(6) Å3 , T = 100 K,
Z = 4, m = 7.764 mm-1 , 39 710 collected reflections, 5635 independent
reflections [Rint = 0.038], data/restraints/parameters = 5635/90/444.
Goodness of fit = 1.038. Final R indices: R1 (I > 2s) = 0.059, wR2 =
0.150.
1 (a) L. Kelland, Nat. Rev. Cancer, 2007, 7, 573; (b) M. Galanski, M. A.
Jakupec and B. K. Keppler, Curr. Med. Chem., 2005, 12, 2075.
2 S. van Zutphen and J. Reedijk, Coord. Chem. Rev., 2005, 249, 2845.
3 Selected examples of metal- or platinum-based anti-cancer complexes:
(a) P. C. A. Bruijnincx and P. J. Sadler, Curr. Opin. Chem. Biol., 2008,
12, 197; (b) T. W. Hambley, Dalton Trans., 2007, 4929; (c) Z. Guo and
P. J. Sadler, Angew. Chem., 1999, 111, 1610, (Angew. Chem., Int. Ed.,
1999, 38, 1512).
4 Selected examples of anti-cancer gold complexes: (a) R. W.-Y. Sun and
C.-M. Che, Coord. Chem. Rev., 2009, 253, 1682; (b) R. W.-Y. Sun, D.-L.
Ma, E. L.-M. Wong and C.-M. Che, Dalton Trans., 2007, 4884; (c) M. J.
McKeage, L. Maharaj and S. J. Berners-Price, Coord. Chem. Rev., 2002,
232, 127; (d) C. F. Shaw III, Chem. Rev., 1999, 99, 2589.
5 M. J. Clarke, F. Zhu and D. R. Frasca, Chem. Rev., 1999, 99, 2511.
6 (a) I. Kostova, Curr. Med. Chem., 2006, 13, 1085; (b) M. J. Clarke, in
Metal Ions in Biological Systems, ed. H. Sigel and A. Sigel, Marcel
Dekker, New York, 1980, vol. 11, pp. 231–283.
7 (a) L. Ronconi and P. J. Sadler, Coord. Chem. Rev., 2007, 251, 1633;
(b) H.-K. Liu, S. J. Berners-Price, F. Wang, J. A. Parkinson, J. Xu, J.
Bella and P. J. Sadler, Angew. Chem., 2006, 118, 8333, (Angew. Chem.,
Int. Ed., 2006, 45, 8153); (c) C. Scolaro, A. Bergamo, L. Brescacin, R.
Delfino, M. Cocchietto, G. Laurenczy, T. J. Geldbach, G. Sava and P. J.
Dyson, J. Med. Chem., 2005, 48, 4161; (d) H. Chen, J. A. Parkinson,
S. Parsons, R. A. Coxall, R. O. Gould and P. J. Sadler, J. Am. Chem.
Soc., 2002, 124, 3064; (e) R. E. Morris, R. E. Aird, P. D. S. Murdoch,
H. Chen, J. Cummings, N. D. Hughes, S. Parsons, A. Parkin, G. Boyd,
D. I. Jodrell and P. J. Sadler, J. Med. Chem., 2001, 44, 3616.
8 (a) J. Maksimoska, L. Feng, K. Harms, C. Yi, J. Kissil, R. Marmorstein
and E. Meggers, J. Am. Chem. Soc., 2008, 130, 15764; (b) D. S. Williams,
G. E. Atilla, H. Bregman, A. Arzoumanian, P. S. Klein and E. Meggers,
Angew. Chem., 2005, 117, 2020, (Angew. Chem., Int. Ed., 2005, 44,
1984).
9 G. I. Pascu, A. C. G. Hotze, C. Sanchez-Cano, B. M. Kariuki and M. J.
Hannon, Angew. Chem., 2007, 119, 4452, (Angew. Chem., Int. Ed., 2007,
46, 4374).
10 B. Therrien, G. Suss-Fink, P. Govindaswamy, A. K. Renfrew and P. J.
Dyson, Angew. Chem., 2008, 120, 3833, (Angew. Chem., Int. Ed., 2008,
47, 3773).
11 O. Novakova, J. Kasparkova, O. Vrana, P. M. van Vliet, J. Reedijk and
V. Brabec, Biochemistry, 1995, 34, 12369.
12 D. Chatterjee, A. Mitra, A. Levina and P. A. Lay, Chem. Commun.,
2008, 2864.
Dalton Trans., 2009, 10712–10716 | 10715

13 E. Alessio, E. Iengo, S. Zorzet, A. Bergamo, M. Coluccia, A. Boccarelli
and G. Sava, J. Inorg. Biochem., 2000, 79, 173.
14 E. Alessio, G. Mestroni, A. Bergamo and G. Sava, Curr. Top. Med.
Chem., 2004, 4, 1525.
15 (a) M. Galanski, V. B. Arion, M. A. Jakupec and B. K. Keppler, Curr.
Pharm. Des., 2003, 9, 2078; (b) C. G. Hartinger, S. Zorbas-Seifried,
Published on 14 September 2009. Downloaded by Heinrich Heine University of Duesseldorf on 29/11/2013 09:23:55.
M. A. Jakupec, B. Kynast, H. Zorbas and B. K. Keppler, J. Inorg.
Biochem., 2006, 100, 891.
16 G. Gasparini, R. Longo, M. Fanelli and B. A. Teicher, J. Clin. Oncol.,
2005, 23, 1295, and references therein.
17 R. S. Kerbel and B. A. Kamen, Nat. Rev. Cancer, 2004, 4, 423, and
references therein.
18 (a) H. Graf, C. Jungst, G. Straub, S. Dogan, R.-T. Hoffmann, T. Jakobs,
M. Reiser, T. Waggershauser, T. Helmberger, A. Walter, A. Walli, D.
Seidel, B. Goke and D. Jungst, Digestion, 2008, 78, 34; (b) W. Y. Lau,
S. C. Yu, E. C. Lai and T. W. Leung, Journal of the American College
of Surgeons, 2006, 202, 155.
19 D. F. Evans, J. Chem. Soc., 1959, 2003.
20 D. S. Bohle and E. S. Sagan, Eur. J. Inorg. Chem., 2000, 1609.
21 (a) G. Li, W. Yu and Y. Cui, J. Am. Chem. Soc., 2008, 130, 4582; (b) A.
Fragoso, M. L. Kahn, A. Castiñeiras, J.-P. Sutter, O. Kahn and R. Cao,
10716 | Dalton Trans., 2009, 10712–10716
View Article Online
Chem. Commun., 2000, 1547; (c) A. J. Blake, N. R. Champness, A. N.
Khlobystov, S. Parsons and M. Schröder, Angew. Chem., 2000, 112,
2407, (Angew. Chem., Int. Ed., 2000, 39, 2317).
22 (a) A. Hunt and G. Evan, Science, 2001, 293, 1784; (b) M. O.
Hengartner, Nature, 2000, 407, 770.
23 C. K.-L. Li, R. W.-Y. Sun, S. C.-F. Kui, N. Zhu and C.-M. Che, Chem.–
Eur. J., 2006, 12, 5253.
24 E. L.-M. Wong, G.-S. Fang, C.-M. Che and N. Zhu, Chem. Commun.,
2005, 4578.
25 J. Sun, X. Zhang, M. Broderick and H. Fein, Sensors, 2003, 3, 276.
26 R. Auerbach, R. Lewis, B. Shinners, L. Kubai and N. Akhtar, Clin.
Chem., 2003, 49, 32.
27 M. Li, S. S.-M. Ng, J. Wang, L. Lai, S. Y. Leung, M. Franco, Y. Peng,
M.-L. He, H.-F. Kung and M. C.-M. Lin, Cancer Res., 2006, 66, 1583.
28 The synthesis of 2 has recently been reported. E. Reisner, V. B. Arion, A.
Eichinger, N. Kandler, G. Giester, A. J. L. Pombeiro and B. K. Keppler,
Inorg. Chem., 2005, 44, 6704.
29 The X-ray crystal structure of the cation of 5 has been reported in the
Ph.D thesis of L. Shek, City University of Hong Kong, Hong Kong,
2007. This complex has a distorted octahedral geometry. Two DMSO
ligands are S-bonded to metal center with a cis geometry.
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