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Thermoresponsive organometallic arene ruthenium complexes for tumour targeting
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Thermoresponsive organometallic arene
ruthenium complexes for tumour targeting†
Catherine M. Clavel, Emilia Păunescu, Patrycja Nowak-Sliwinska and Paul J. Dyson*
Received 19th November 2013
Accepted 23rd December 2013
Application of mild hyperthermia can increase the cytotoxicity of anticancer drugs in tumour cells. In this
report, we describe low molecular weight thermoactive ruthenium-based drugs with fluorous chains that
are selectively triggered by mild hyperthermia. The organometallic complexes were prepared,
characterized, and evaluated for their in vitro cytotoxicity against a panel of human cancer cell lines and
DOI: 10.1039/c3sc53185f
non-cancerous immortalized cells. The compounds show considerable chemo-thermal selectivity towards
www.rsc.org/chemicalscience
cancer cells (ca. 5 mM versus >500 mM for healthy cells) for the compound with the longest fluorous chain.
Introduction
Platinum-based anticancer drugs including cisplatin, carboplatin and oxaliplatin lack selectivity towards cancerous cells
and therefore their therapeutic application causes severe sideeffects such as nephrotoxicity,1–3 neurotoxicity,4,5 nausea and
vomiting.6,7 In contrast, ruthenium-based chemotherapeutics
present fewer side-effects compared to platinum-based drugs.
Although ruthenium-based compounds are not currently
employed in the clinic, two ruthenium(III) compounds, namely
KP10198 and NAMI-A,9 completed phase I clinical trials and are
currently in phase II trials. The different toxicity proles of
platinum- and ruthenium-based compounds remain unclear,
although several reasons have been proposed.10 Irrespective of
the full mechanistic differences it is not unreasonable that DNA
targeting by platinum compounds leads to the severe sideeffects due to the ubiquitous nature of this target. Interestingly,
organoruthenium (piano-stool) complexes with the structural
composition [RuII(h6-arene)X2(PTA)] (PTA ¼ 1,3,5-triaza-7phosphaadamantane), known as RAPTA compounds, exhibit
anti-metastatic11 and anti-angiogenic12 properties coupled
with a relatively low toxicity comparable to that observed
for NAMI-A.13
In an effort to improve drug selectivity it is possible to
enhance the activity of a compound at the tumour site by
applying external techniques or inducers.14 One such strategy
combines chemotherapy with tumour localised mild hyperthermia.15–17 A slight increase of the local temperature differentiates tissues, healthy ones adapting easily while cancerous
cells, with a disorganized and compact vascular structure, have
Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de
Lausanne (EPFL), Lausanne, Switzerland. E-mail: paul.dyson@ep.ch
† Electronic supplementary information (ESI) available: Detailed descriptions of
the synthesis and characterization of all compounds, procedures for the
cytotoxicity determination and cell uptake measurements by ICP-MS. See DOI:
10.1039/c3sc53185f
This journal is © The Royal Society of Chemistry 2014
difficulties in dissipating the heat. Some chemotherapeutics
exhibit increased activity under mild hyperthermia (40.5–
42 C),18 even though they are also cytotoxic under normal
conditions, and were not intentionally designed for this application. The thermosensitivity of small molecule drugs can be
enhanced by attaching them to thermoresponsive macromolecules, e.g. liposomal drug carriers19–24 or micelles that are
insoluble at 37 C and become soluble under hyperthermia,
enabling them to cross the cell membrane where they release
their drug content.25,26 Replacing macromolecules with low
molecular weight thermosensitive drugs remains an attractive
alternative approach. As proof of concept, rationally designed
thermoactive derivatives of the organic drug chlorambucil
(CLB)27,28 have been recently designed and were found to be
essentially inactive at 37 C and activated by mild hyperthermia
(41 C) in vitro.29 Recently, the synthesis and biological evaluation (under normal conditions) of some short to medium length
uorous chain bipyridine cisplatin derivatives have been
reported.30,31 Similar types of compounds (amphiphilic uoroalkylated bipyridine platinum and palladium complexes)
have also been tested in liposomal formulations.32–34 Liposomal
formulations of platinum-based drugs, with the rational that
liposomal delivery can increase drug bioavailability and also
accumulation at the tumour site as a consequence of the
enhanced permeability and retention (EPR) effect, are now in
clinical trials.35–38 Herein, ruthenium(II)–arene derivatives
(Fig. 1) modied with uorous chains in order to endow them
with thermoresponsive properties39–41 are described.
The general structure of these new ruthenium(II)–arene
complexes is similar to that of RAPTA-C (Fig. 1) – the PTA ligand
being replaced with the desired uorous or alkyl derivatized
pyridine ligands. The two labile chloride ligands allow activation via hydrolysis following cellular internalization.11,42 Pyridine was selected as the coordinating moiety based on the
widespread use of such ligands in the domain.43–51 The uorous
and alkyl chains are connected to the pyridine ligand via an
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Fig. 1
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Structure of RAPTA-C and the new ruthenium(II)–arene complexes derivatized with alkyl or fluoroalkyl ‘ponytails’.
ester linker that may, in principle, be hydrolysed by intracellular
enzymes such as esterases.41,52,53
Results and discussion
The proposed approach implies a straightforward synthetic
pathway and, consequently, the new derivatives, containing
either an alkyl or uorous chain, were synthesized in two steps
using modied pyridine ligands as shown in Scheme 1. The
pyridine ligands were obtained in good yield (70–87%) using a
standard procedure starting from commercially available 3-pyridine-propionic acid and the corresponding alkyl or uoroalkyl
alcohols. In the second step the pyridine ligands were reacted
with the dimer, [Ru(h6-p-cymene)Cl2]2, in anhydrous, degased
dichloromethane in the dark under an inert atmosphere. The
complexes were isolated by precipitation in good yield (71–87%).
All the compounds have been fully characterized (1H, 13C
and where appropriate 19F NMR spectroscopy, ESI mass spectrometry, IR spectroscopy and elemental analysis: see ESI for
details†). The formation of the ester ligands (both alkyl and
peruoroalkyl derivatives) is accompanied by a deshielding of
around 0.4 ppm of the protons in the alpha position relative to
the oxygen atom, and subsequent complexation to the ruthenium center via the pyridine N-atom is accompanied by a
deshielding of ca. 0.4 ppm for the two pyridine protons in the
alpha position to the nitrogen atom and of a deshielding of ca. 5
ppm for the respective carbon atoms. There is only little change
in position of the proton signals of the p-cymene ring in
comparison to those observed in the parent dimer [Ru(h6-pcymene)Cl2]2. The structures of the compounds were further
corroborated by ESI-MS. The most abundant peaks observed in
the spectra of the ligands are those assigned to [M + H]+ ions,
whereas the spectra of the pyridine Ru(II)-p-cymene complexes
are dominated by species assigned to [M Cl]+ ions. Apart from
Scheme 1
the 19F NMR spectra and the very specic 13C NMR prole, the
presence of the uorous chain is also clearly evidenced from the
IR spectra with the presence of a strong large peak between 1110
and 1250 cm1. A peak at ca. 1730 cm1 conrms the presence
of the ester C]O group.
In vitro anticancer activity
The cytotoxicity of the modied pyridine ligands and their
corresponding complexes has been assessed in various cancer
cell lines (cisplatin-sensitive A2780 and resistant A2780cisR
ovarian carcinoma, MCF-7 and MDA-MBA-231 breast carcinomas and A549 human lung carcinoma) and human embryonic kidney (HEK 293) cells (used as a model for normal cells).
Cytotoxicity studies were carried out at 37 C for 72 hours and at
41 C for 2 hours followed by 70 hours at 37 C to simulate
hyperthermia in the tested cell lines (Table 1).
Distinct thermosensitive behaviour of the compounds is
present, but needs to be evident against the majority of the
tested cancerous cell lines in order to be considered as effective.
In this respect, complex 2c exhibits considerable differences of
up to at least two orders of magnitude (maximum concentrations tested were 500 mM) and hence exhibits ideal thermoresponsive behaviour. In all cases, complex 2c remains inactive at
normal body temperature (IC50 values >500 mM) and becomes
toxic towards tumour cells aer a 2 hour hyperthermia signal
(IC50 values ranging from 5.0 to 42 mM in the various cancer cell
lines). Strikingly, the ligand in 2c, i.e. L2c, shows no thermoactivity or cytotoxicity against the screened cell lines except
on MCF-7 breast cancer with a negligible (non-thermoresponsive) toxicity of 237 mM at 37 C and 284 mM under hyperthermia. Moreover, 2c shows selectivity towards cancerous cells
with a weak cytotoxicity under mild hyperthermia against HEK
293 cells.
Synthesis of ligands L1a–L2c and the ruthenium-p-cymene complexes 1a–2c.
1098 | Chem. Sci., 2014, 5, 1097–1101
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IC50 values determined for the ligands L1a–L2c and complexes 1a–1d and 2a–2c in A2780, A2780cisR, A549, MCF-7, MDA-MB-231 and
HEK 293 cell lines at 37 C and under hyperthermia (2 h at 41 C followed by 70 h at 37 C – labeled 41 C in the table)
Table 1
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A2780 (mM)
A2780cisR (mM)
MCF-7 (mM)
MDA-MB-231 (mM)
A549 (mM)
HEK 293 (mM)
Compound 37 C
41 C
37 C
41 C
37 C
41 C
37 C
41 C
37 C
41 C
37 C
41 C
L1a
L1b
L1c
L1d
L2a
L2b
L2c
1a
1b
1c
1d
2a
2b
2c
263 12
98 7
69 4
40 4
181 12
243 35
>500
23 1
49 1
49 1
15 1
52 2
15 1
10 1
>500
224 23
69 4
88 5
141 9
192 7
>500
114 1
>500
84 1
>500
111 1
25 2
>500
389 27
>500
97 15
>500
>500
>500
>500
482 18
362 14
48 1
27 1
>500
21 1
42 2
>500
>500
315 48
301 75
209 5
>500
237 25
339 73
319 87
>500
>500
>500
38 2
>500
458 16
133 13
110 7
>500
136 1.8
>500
284 31
218 4
108 2
63 4
17 1
70 4
25 2
5.0 0.3
>500
>500
487 9
>500
362 24
>500
>500
328 22
>500
>500
70 8
275 19
36 2
>500
459 27
>500
>500
>500
>500
>500
>500
100 2
473 20
96 8
>500
67 9
31 2
36 5
303 17
>500
96 3
>500
364 8
>500
>500
>500
>500
391 14
>500
355 43
43 1
>500
358 20
323 18
100 9
>500
>500
>500
>500
>500
>500
123 8
42 12
>500
40 2
33 7
>500
>500
189 10
>500
>500
>500
>500
155 17
>500
86 10
>500
270 18
>500
>500
338 3
153 12
206 1
>500
>500
>500
>500
324 10
45 3
42 1
149 9
160 6
>500
132 5
>500
>500
>500
>500
>500
476 164
>500
>500
>500
113 2
>500
>500
44 1
>500
The incorporation of the uorous chain appears to give rise
to the thermoactive effect. Indeed, complex 1c, the hydrocarbon
analogue of 2c, exhibits a totally different prole to 2c. It is
active in some cell lines at 37 C and also moderately toxic
against non-tumourigenic HEK 293 cells with an IC50 value of 86
mM. Complexes with shorter alkyl chains, i.e. 1a and 1b, show
generally poor activity against cancerous and non-cancerous
cells. Complex 1d, with the longest alkyl chain, exhibits good
thermoactivity except in the MDA-MB-231 cell line with an IC50
of 70 mM at 37 C and >500 mM under hyperthermia. Similarly,
its ligand alone, L1d, is only thermoactive in A2780 cells.
Indeed, against A2780cisR and MCF-7 cells, L1d is more active
than the corresponding complex at normal body temperature,
but loses activity under hyperthermia, a behaviour shared with
ligands L1b, L2a, L2b and even complex 2a.
Excluding the cisplatin-resistant cell line, only L2a is less
cytotoxic under hyperthermia against MDA-MB-231 and A459
cells. Ligands L1d and L2b are inactive at both temperatures in
the other cell lines. Ligands with the longest, bulky chains, i.e.
L2b, L2c and L1d, are the least active ligands across the panel of
cell lines. In A2780 cells the alkylated ligands show increasing
cytotoxicity under hyperthermia as the chain length increases,
possibly due to increased lipophilicity.
Compounds containing the shorter uorinated chains do
not exhibit a thermoactivity comparable to 2c. Consequently,
the length of the uorous chain has a signicant impact on the
potential thermoactive behaviour, which is consistent with the
results from the study of chlorambucil modied with uorinated
chains.29 Nevertheless, 2b is remarkably cytotoxic and selective
towards cancerous cells compared to normal cells, whereas the
activity of 2a is not affected by mild hyperthermia in a systematic
manner, presumably due to the short uorous chain.
was used to simulate the hyperthermia signal during a 24 hour
incubation prior to measurement. At 37 C 2c is internalized
three fold more in the A2780 ovarian cancer cell line compared
to the normal HEK 293 cells (Fig. 2). Under mild hyperthermia,
internalization of 2c in A2780 cells increases whereas heat has
little impact on uptake into HEK 293 cells. These data are
consistent with the tumour cell selectivity observed for 2c. It
should be noted, however, that while uptake of 2c into cancer
cells exceeds that in the HEK 293 cells, uptake alone does not
explain the vast differences in cytotoxicity following heat treatment. In this context the difficulties cancer cells have dissipating heat54,55 must also make them more susceptible to cell
death induced by the internalized compound.
Cellular uptake
Cellular uptake studies were conducted on the lead complex, i.e.
2c, to determine the dependency of uptake on temperature in
cancerous and non-cancerous cells. A 2 hour heating at 41 C
This journal is © The Royal Society of Chemistry 2014
Fig. 2 Cellular uptake of 2c in A2780 and HEK 293 cell lines with and
without a 2 hour hyperthermia signal at 41 C. Error bars represent
Standard Deviation.
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Conclusions
Organometallic ruthenium complexes with a long uorous
appendage exert selective cytotoxicity toward tumour cells
under mild hyperthermia. Long uorous chains are required to
obtain relevant thermoresponsive behaviour. For the lead
compound, i.e. 2c, it is noteworthy that the uorous ligand
alone is not cytotoxic under any of the applied conditions
whereas the ruthenium complex demonstrates considerable
differences under normal and thermal conditions (ca. 5 mM
versus >500 mM) and selectivity towards cancer cells over healthy
HEK 293 cells. Discrimination between cancerous and normal
cells may be attributed to more extensive internalization by
cancer cells compared to normal cells combined with the fact
that the tumoural cells are sensitized to the cytotoxic agents
under mild hypothermia. This discovery opens the way towards
the rational design of other thermoactive anticancer drugs.
Acknowledgements
We thank the Swiss National Science Foundation and EPFL for
nancial support.
Notes and references
1 X. Yao, K. Panichpisal, N. Kurtzman and K. Nugent, Am. J.
Med. Sci., 2007, 334, 115–124.
2 N. Pabla and Z. Dong, Kidney Int., 2008, 73, 994–1007.
3 P. D. Sanchez-Gonzalez, F. J. Lopez-Hernandez, J. M. LopezNovoa and A. I. Morales, Crit. Rev. Toxicol., 2011, 41, 803–
821.
4 B. Bhhatarai and P. Gramatica, Chem. Res. Toxicol., 2010, 23,
528–539.
5 R. G. van der Hoop, C. J. Vecht, M. E. L. van der Burg,
A. Elderson, W. Boogerd, J. J. Heimans, E. P. Vries,
J. C. van Houwelingen, F. G. I. Jennekens, W. H. Gispen
and J. P. Neijt, N. Engl. J. Med., 1990, 322, 89–94.
6 L. X. Cubeddu, I. S. Hoffmann, N. T. Fuenmayor and
A. L. Finn, N. Engl. J. Med., 1990, 322, 810–816.
7 B. Bhhatarai and P. Gramatica, Chem. Res. Toxicol., 2010, 23,
277.
8 C. G. Hartinger, M. A. Jakupec, S. Zorbas-Seifried, M. Groessl,
A. Egger, W. Berger, H. Zorbas, P. J. Dyson and B. K. Keppler,
Chemistry & Biodiversity, 2008, 5, 2140–2155.
9 J. M. Rademaker-Lakhai, D. van den Bongard, D. Pluim,
J. H. Beijnen and J. H. M. Schellens, Clin. Cancer Res.,
2004, 10, 3717–3727.
10 C. G. Hartinger and P. J. Dyson, Chem. Soc. Rev., 2009, 38,
391–401.
11 C. Scolaro, A. Bergamo, L. Brescacin, R. Delno,
M. Cocchietto, G. Laurenczy, T. J. Geldbach, G. Sava and
P. J. Dyson, J. Med. Chem., 2005, 48, 4161–4171.
12 P. Nowak-Sliwinska, J. R. van Beijnum, A. Casini,
A. A. Nazarov, G. Wagnieres, H. van den Bergh, P. J. Dyson
and A. W. Griffioen, J. Med. Chem., 2011, 54, 3895–3902.
13 A. Bergamo, C. Gaiddon, J. H. M. Schellens, J. H. Beijnen and
G. Sava, J. Inorg. Biochem., 2012, 106, 90–99.
1100 | Chem. Sci., 2014, 5, 1097–1101
Edge Article
14 N. P. Barry, O. Zava, J. Furrer, P. J. Dyson and B. Therrien,
Dalton Trans., 2010, 39, 5272–5277.
15 C. M. Wendtner, S. Abdel-Rahman, M. Krych, J. Baumert,
L. H. Lindner, A. Baur, W. Hiddemann and R. D. Issels,
J. Clin. Oncol., 2002, 20, 3156–3164.
16 H. I. Robins, J. D. Cohen, C. L. Schmitt, K. D. Tutsch,
C. Feierabend, R. Z. Arzoomanian, D. Alberti, F. d'Oleire,
W. Longo, C. Heiss, et al., J. Clin. Oncol., 1993, 11, 1787–1794.
17 J. A. Dickson and S. K. Calderwood, Nature, 1976, 263, 772–
774.
18 R. D. Issels, Eur. J. Cancer, 2008, 44, 2546–2554.
19 D. Needham, G. Anyarambhatla, G. Kong and
M. W. Dewhirst, Cancer Res., 2000, 60, 1197–1201.
20 L. H. Lindner, M. E. Eichhorn, H. Eibl, N. Teichert,
M. Schmitt-Sody, R. D. Issels and M. Dellian, Clin. Cancer
Res., 2004, 10, 2168–2178.
21 L. Li, T. L. M. ten Hagen, D. Schipper, T. M. Wijnberg,
G. C. van Rhoon, A. M. M. Eggermont, L. H. Lindner and
G. A. Koning, J. Controlled Release, 2010, 143, 274–279.
22 G. Kong, G. Anyarambhatla, W. P. Petros, R. D. Braun,
O. M. Colvin, D. Needham and M. W. Dewhirst, Cancer
Res., 2000, 60, 6950–6957.
23 A. M. Ponce, Z. Vujaskovic, F. Yuan, D. Needham and
M. W. Dewhirst, Int. J. Hyperthermia, 2006, 22, 205–213.
24 S. Unezaki, K. Maruyama, N. Takahashi, M. Koyama,
T. Yuda, A. Suginaka and M. Iwatsuru, Pharm. Res., 1994,
11, 1180–1185.
25 J. Andrew Mackay and A. Chilkoti, Int. J. Hyperthermia, 2008,
24, 483–495.
26 D. E. Meyer, B. C. Shin, G. A. Kong, M. W. Dewhirst and
A. Chilkoti, J. Controlled Release, 2001, 74, 213–224.
27 J. E. Ultmann, G. A. Hyman and A. Gellhorn, JAMA, J. Am.
Med. Assoc., 1956, 162, 178–183.
28 S. Sachanas, G. A. Pangalis, T. P. Vassilakopoulos,
P. Korkolopoulou, F. N. Kontopidou, M. Athanasoulia,
X. Yiakoumis, C. Kalpadakis, G. Georgiou, S. Masouridis,
M. Moschogiannis, P. Tsirkinidis, V. Pappis, S. I. Kokoris,
M. P. Siakantaris, P. Panayiotidis and M. K. Angelopoulou,
Leuk. Lymphoma, 2011, 52, 387–393.
29 C. M. Clavel, O. Zava, F. Schmitt, B. H. Kenzaoui,
A. A. Nazarov, L. Juillerat-Jeanneret and P. J. Dyson, Angew.
Chem., Int. Ed., 2011, 50, 7124–7127.
30 T. T. Chang, S. V. More, N. Lu, J. W. Jhuo, Y. C. Chen, S. C. Jao
and W. S. Li, Bioorg. Med. Chem., 2011, 19, 4887–4894.
31 K. E. Elwell, C. Hall, S. Tharkar, Y. Giraud, B. Bennett, C. Bae
and S. W. Carper, Bioorg. Med. Chem., 2006, 14, 8692–8700.
32 N. Garelli, P. Vierling, J. L. Fischel and G. Milano, Eur. J. Med.
Chem., 1993, 28, 235–242.
33 N. Garelli and P. Vierling, Biochim. Biophys. Acta, 1992, 1127,
41–48.
34 N. Garelli and P. Vierling, Inorg. Chim. Acta, 1992, 194, 247–
253.
35 F. Kratz, I. A. Muller, C. Ryppa and A. Warnecke,
ChemMedChem, 2008, 3, 20–53.
36 D. Peer, J. M. Karp, S. Hong, O. C. FaroKHzad, R. Margalit
and R. Langer, Nat. Nanotechnol., 2007, 2, 751–760.
37 M. J. Hannon, Pure Appl. Chem., 2007, 79, 2243–2261.
This journal is © The Royal Society of Chemistry 2014
View Article Online
Open Access Article. Published on 02 January 2014. Downloaded on 5/2/2026 2:00:06 AM.
This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.
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38 S. Taurin, H. Nehoff and K. Greish, J. Controlled Release,
2012, 164, 265–275.
39 K. Niikura, K. Nambara, T. Okajima, Y. Matsuo and K. Ijiro,
Langmuir, 2010, 26, 9170–9175.
40 F. R. Carrel and P. H. Seeberger, J. Org. Chem., 2008, 73,
2058–2065.
41 B. Hungerhoff, H. Sonnenschein and F. Theil, J. Org. Chem.,
2002, 67, 1781–1785.
42 W. H. Ang, E. Daldini, C. Scolaro, R. Scopelliti, L. JuilleratJeannerat and P. J. Dyson, Inorg. Chem., 2006, 45, 9006–9013.
43 J. G. Malecki, R. Kruszynski, M. Jaworska, P. Lodowski and
Z. Mazurak, J. Organomet. Chem., 2008, 693, 1096–1108.
44 G. Suss-Fink, F. A. Khan, L. Juillerat-Jeanneret, P. J. Dyson
and A. K. Renfrew, J. Cluster Sci., 2010, 21, 313–324.
45 J. Grau, V. Noe, C. Ciudad, M. J. Prieto, M. Font-Bardia,
T. Calvet and V. Moreno, J. Inorg. Biochem., 2012, 109, 72–81.
46 C. A. Vock, C. Scolaro, A. D. Phillips, R. Scopelliti, G. Sava
and P. J. Dyson, J. Med. Chem., 2006, 49, 5552–5561.
47 A. Bacchi, G. Cantoni, M. R. Chierotti, A. Girlando,
R. Gobetto, G. Lapadula, P. Pelagatti, A. Sironi and
M. Zecchini, CrystEngComm, 2011, 13, 4365–4375.
This journal is © The Royal Society of Chemistry 2014
Chemical Science
48 F. Y. Wang, A. Habtemariam, E. P. L. van der Geer,
R. Fernandez, M. Melchart, R. J. Deeth, R. Aird,
S. Guichard, F. P. A. Fabbiani, P. Lozano-Casal,
I. D. H. Oswald, D. I. Jodrell, S. Parsons and P. J. Sadler,
Proc. Natl. Acad. Sci. U. S. A., 2005, 102, 18269–18274.
49 Y. Fu, A. Habtemariam, A. M. Pizarro, S. H. van Rijt,
D. J. Healey, P. A. Cooper, S. D. Shnyder, G. J. Clarkson
and P. J. Sadler, J. Med. Chem., 2010, 53, 8192–8196.
50 N. Gligorijevic, S. Arandelovic, L. Filipovic, K. Jakovljevic,
R. Jankovic, S. Grguric-Sipka, I. Ivanovic, S. Radulovic and
Z. L. Tesic, J. Inorg. Biochem., 2012, 108, 53–61.
51 K. D. Camm, A. El-Sokkary, A. L. Gott, P. G. Stockley,
T. Belyaeva and P. C. McGowan, Dalton Trans., 2009,
10914–10925.
52 B. Hungerhoff, H. Sonnenschein and F. Theil, Angew. Chem.,
Int. Ed., 2001, 40, 2492–2494.
53 P. Beier and D. O'Hagan, Chem. Commun., 2002, 1680–
1681.
54 C. W. Song, Cancer Res., 1984, 44, 4721–4730.
55 F. K. Storm, W. H. Harrison, R. S. Elliott and D. L. Morton,
Cancer Res., 1979, 39, 2245–2251.
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