A Bis(dipyridophenazine)(2-(2-pyridyl)pyrimidine-4-carboxylic acid)ruthenium(II) Complex with Anticancer Action upon Photodeprotection

Article abstract of DOI:10.1002/anie.201309576

Improving the selectivity of anticancer drugs towards cancer cells is one of the main goals of drug optimization; the prodrug strategy has been one of the most promising. A light-triggered prodrug strategy is presented as an efficient approach for control

Full text of DOI:10.1002/anie.201309576

.
Angewandte
Communications
DOI: 10.1002/anie.201309576
Prodrugs
A Bis(dipyridophenazine)(2-(2-pyridyl)pyrimidine-4-carboxylic
acid)ruthenium(II) Complex with Anticancer Action upon
Photodeprotection**
Tanmaya Joshi,* Vanessa Pierroz, Cristina Mari, Lea Gemperle, Stefano Ferrari, and
Gilles Gasser*
Abstract: Improving the selectivity of anticancer drugs
towards cancer cells is one of the main goals of drug
optimization; the prodrug strategy has been one of the most
promising. A light-triggered prodrug strategy is presented as an
efficient approach for controlling cytotoxicity of the substitu-
tionally inert cytotoxic complex [Ru(dppz)2(CppH)](PF6)2
(C1; CppH = 2-(2-pyridyl)pyrimidine-4-carboxylic acid;
which have been found to not only act as potent kinase
inhibitors, but also as effective cytotoxic compounds.[2c,e,4] The
mechanism of action for cytotoxic RuII polypyridyl com-
pounds is believed to be a complex function of inherent
physicochemical and pharmacological properties. As interest
in substitutionally inert metal complexes as anti-cancer drug
candidates has only recently regained momentum,[3a,4a,b,d,5] in
most cases only limited information is available on their
precise mode of action and metabolic activity. Moreover,
a scarcity of structure–activity relationship (SAR) studies
focusing on these aspects also implies that biochemical
understanding on most of these systems is still pre-
mature.[4a–c,6]
Nonetheless, targeting the cytotoxic aspects of one such
coordinatively saturated and substitutionally inert RuII com-
plex, [Ru(dppz)2(CppH)]2+ (C1; Scheme 1), we have demon-
strated that this particular bis(dppz) complex exerts its
cytotoxic action by disrupting the mitochondrial function.[7]
Through correlations from the detailed SAR studies, we could
deduce that structural alterations in this lead prototype can
significantly diminish its cytotoxic potency.[8] Furthermore,
with no decomposition of the complex in human plasma, it
was concluded that the intact RuII complex is responsible for
the cytotoxic activity.[7]
dppz = dipyrido[3,2-a:2’,3’-c]phenazine).
Attachment
of
a
photolabile 3-(4,5-dimethoxy-2-nitrophenyl)-2-butyl
(DMNPB) ester (“photocaging”) makes the otherwise active
complex C1 innocuous to both cancerous (HeLa and U2OS)
and non-cancerous (MRC-5) cells. The cytotoxic action can be
successfully unleashed in living cells upon light illumination
(350 nm), reaching similar level of activity as the parent
cytotoxic compound C1. This is the first substitutionally inert
cytotoxic metal complex to be used as a light-triggered prodrug
candidate.
P
latinum- and ruthenium-based cytotoxic compounds are by
far the most explored metal-based anticancer agents.[1] For the
majority of such metal complexes, their anticancer activity
originates from the presence of a labile ligand and/or a redox-
active metal center.[2] (Organo)metallic complexes can, how-
ever, also exert anticancer activity in their inert intact form.[3]
The best examples are the substitutionally inert RuII scaffolds,
Taking the above findings into consideration, we explored
the potential of light-triggered prodrug strategy for tuning the
intracellular cytotoxic activity of the complex, while retaining
the structural integrity of the active parent complex. Such
molecules, which are rendered inactive through covalent
modification with a photocleavable moiety but can regain
biological activity upon light exposure, are commonly
referred to as “photocaged” compounds.[9] Light-activatable
pro-moieties allow the modulation of the release and activity
of a “photocaged” drug as a function of the wavelength,
duration, intensity, or location of illumination.[10] Whilst
photochemical control of activity (also referred to as “photo-
caging/uncaging”) has been widely explored with organic
drugs, application of this concept to metal coordination
complexes has been surprisingly limited.[9,11] Of note, metal
complexes were previously used in combination with light to
trigger biological activity.[3a,11,12] Specific to substitutionally
inert RuII complexes, photoactivation to date has primarily
revolved around the studies exploring their capacity to
undergo photoinduced ligand exchange/expulsion, DNA
binding, DNA cleavage, and cytotoxic effects.[3a,4a–c,13] To the
best of our knowledge, this work is the first example of a light-
triggered structurally inert metallo-prodrug candidate, with
[*] Dr. T. Joshi,[+] V. Pierroz,[+] C. Mari, L. Gemperle, Prof. Dr. G. Gasser
Department of Chemistry, University of Zurich
Winterthurerstrasse 190, 8057 Zurich (Switzerland)
E-mail: tanmaya.joshi3@uzh.ch
gilles.gasser@aci.uzh.ch
Homepage: http://www.gassergroup.com
V. Pierroz,[+] Priv.-Doz. Dr. S. Ferrari
Institute of Molecular Cancer Research, University of Zurich
(Switzerland)
[+] These authors contributed equally to this work.
[**] This work was supported by the Swiss National Science Foundation
(Professorship No. PP00P2_133568 to G.G.), the University of
Zurich (G.G. and S.F.), the Stiftung fꢀr Wissenschaftliche For-
schung of the University of Zurich (G.G. and S.F.), the Stiftung zur
Krebsbekꢁmpfung (S.F.), the Huggenberger–Bischoff Stiftung
(S.F.), and the University of Zurich Priority Program (S.F.). The
authors gratefully acknowledge the assistance and support of the
Center for Microscopy and Image Analysis of the University of
Zurich, and Dr. Jakob Heier from the Laboratory for Functional
Polymers, Empa, Swiss Federal Laboratories for Material Science
and Technology, for generous access to a near-IR fluorimeter.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201309576.
2960
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 2960 –2963

Angewandte
Chemie
UPLC-MS
Information,
(Supporting
Figure S2).
With time, gradual disap-
pearance, upon light irradi-
ation, of the peak corre-
sponding to C2 (tR =
2.6 min) was seen along
with appearance of the
peak for free C1 (tR =
2.3 min); the observed
spectral changes are in
agreement
with
the
expected photolytic reac-
tion. After 20 min of light
irradiation (5.16 JcmÀ2), an
almost quantitative amount
of C1 (ꢀ 92%) was photo-
released (Supporting Infor-
mation, Figure S3), as esti-
Scheme 1. Chemical structures of the active bis(dppz)RuII complex C1 and its photolabile protected version C2
(isolated as racemic mixtures of hexafluorophosphate salts). The DMNPB group is released upon irradiation
at 350 nm.[14] CppH=2-(2-pyridyl)pyrimidine-4-carboxylic acid; dppz=dipyrido[3,2-a:2’,3’-c]phenazine.
no “caged” variants of any substitutionally inert cytotoxic
metal complex been previously constructed.
For the proof-of-principle design of a light-activatable
RuII prodrug candidate, inspiration was drawn from the
recent structure–activity analysis on the lead prototype. The
results pointed towards the presence of the carboxylate
functionality on the pyrimidine ring as being essential for
cytotoxic activity of the complex, making it an ideal site for
attachment of a photocleavable moiety. 3-(4,5-Dimethoxy-2-
nitrophenyl)-2-butyl (DMNPB) ester was used as the photo-
cleavable moiety for derivatization of the carboxylic handle
(Scheme 1).[14] This ortho-nitrophenyl chromophore has pre-
viously been used for efficient photocontrolled release of l-
glutamate, a neurotransmitter, and for phototriggered cell
adhesion of “caged” RGD peptides, at near-UV wavelengths
(ca. 360 nm).[15] The synthesis of the aryl butyl esterified RuII
pro-moiety (C2) followed the route shown in the Supporting
Figure 1. Changes in absorption spectra of C2 (50 mm in PBS, pH 7.2)
as observed upon irradiation at 350 nm. Arrows indicate the direction
of change in absorbance with increasing periods of irradiation.
Information, Scheme S1. The identity of C2 was confirmed by
1H NMR spectroscopy and mass spectrometry, and its purity
was determined by elemental analysis (see the Supporting
Information for more details).
The hydrolytic stability of C2 was evaluated by monitor-
ing a sample of this compound in phosphate-buffered saline
(PBS) at 258C in the dark. Over a time period of 24 h, aliquots
were examined by HPLC for the release of C1; formation of
about 7% C1 was observed over the time of experiment.
Photolytic stability of C2 was also assessed prior to perform-
ing the cytotoxicity experiments. The complex solution in PBS
(pH 7.2) was irradiated with 350 nm UV-A radiation, and
changes in the UV/Vis absorption spectra were monitored
over time (Figure 1). Upon light irradiation, the metal-to-
ligand charge transfer (MLCT) band centered at 478 nm is
hypsochromically shifted to a broad MLCT band centered at
451 nm. With time, a clear isosbestic point at 467 nm is
observed along with increasing absorption intensity in the
250–400 nm region. As the photolytic reaction proceeds,
a shoulder at about 318 nm that is characteristic of the free
complex C1 also appears, reflecting its photorelease from C2.
Furthermore, removal of DMNPB from the prodrug candi-
date C2 to release C1 could also be easily confirmed by
mated from UPLC analysis (see the Supporting Information
for more details). The calculated quantum yield for the
photorelease of C1, as determined by comparison with 1-(2-
nitrophenyl)ethyl phosphate (F = 54%),[16] was found to be
3.8%, indicating a modest photolytic efficiency (Supporting
Information, Figure S4).
Having confirmed the light-triggered removal of DMNPB
from the prodrug candidate C2 to release C1, the cytotoxic
evaluations were performed on cervical cancer (HeLa), bone
cancer (U2OS), and non-cancerous lung fibroblast (MRC-5)
cell lines. Resazurin based fluorometric assay was employed
for the cytotoxicity assessment of the prodrug candidate in the
dark and upon 350 nm light irradiation (Table 1). Different
concentrations of prodrug candidate C2 administered for 4 h
in the dark to both HeLa and U2OS cells, followed by
incubation at 378C in fresh cell culture media for additional
48 h, were found to be non-toxic up to the highest complex
concentration (100 mm) examined in this study. Similar
cytotoxic response was also observed on MRC-5 cells upon
Angew. Chem. Int. Ed. 2014, 53, 2960 –2963
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
2961

.
Angewandte
Communications
Table 1: Cytotoxic activity data (IC50) for C1, C2, DMPNB (4), and cisplatin against human cervical carcinoma (HeLa), human osteosarcoma (U2OS),
and non-cancerous lung fibroblast (MRC-5) cell lines.
IC50 [mm]
HeLa
U2OS
MRC-5
48 h
(dark)
4 h
(dark)
4 h
48 h
(dark)
4 h
(dark)
4 h
48 h
(dark)
(+ UV-A)[a]
(+ UV-A)[a]
C2
C1
>100
17.0Æ0.8
5.9Æ1.7
>100
12.7Æ3.6
85.8Æ5.8
10.0Æ1.3[7]
>100
9.9Æ0.9
>100
17.2Æ3.8
13.5Æ2.1
>100
32.6Æ5.1
>100
85.3Æ0.2
15.1Æ2.2[7]
>100
8.5Æ0.9
16.0Æ0.1
30.5Æ1.1
13.5Æ2.5[7]
>100
DMPNB (4)
cisplatin
>100
>100
9.8Æ4.5
26.8Æ1.9
11.8Æ1.7[7]
[a] 10 min UV-A irradiation (350 nm, 2.58 JcmÀ2).
incubation with C2. Interestingly, even extending the treat-
ment up to 48 h for prodrug candidate C2 did not induce any
cytotoxicity towards U2OS cells up to the highest dosed
complex concentration (100 mm), also causing no significant
change in its cytotoxic action towards HeLa and MRC-5 cells
(IC50 ꢁ 85 mm). That prodrug candidate C2 shows a promising
lack of cytotoxicity toward both cells lines, in the dark, is in
stark contrast with the cytotoxic activity data obtained for the
active RuII complex, C1, for which the IC50 values against
HeLa, U2OS, and MRC-5 cell lines were determined to be
10.0 mm, 13.5 mm, and 15.1 mm, respectively. The parent
cytotoxic complex C1 losing its activity upon covalent
modification reflects similar findings previously reported by
us.[7,8] For example, the benzylic and ethyl ester derivatives of
C1 showed 3–4 times less activity on HeLa cells than the
parent complex.[8]
regains cytotoxic activity after light activation, it thus follows
that any cytotoxic effect introduced on light irradiation of C1
may have a role to play in the elevated cytotoxic potency of
the prodrug candidate C2. That the photoinduced toxicity of
C1 contributes to the observed light-triggered increase in
activity of C2 is supported by the fact that light irradiation at
350 nm of HeLa and U2OS cells dosed with C1 (4 h) further
led to up to about threefold increase in cytotoxicity compared
to those kept in the dark. Nevertheless, photolytic removal of
DMNPB from C1 still remains the critical first step in the case
of C2 regaining cytotoxicity upon photolysis. Thus, it is
conceivable that as the complex C1 is photoreleased from the
prodrug candidate C2, the overall enhancement in exerted
cytotoxicity in HeLa cells is a cumulative effect of the direct
cytotoxic activity of C1 and the activity, in part, potentially
originating as a result of a cascade of photolytic reactions
involving the RuN6 coordination sphere of complexes C1 and
C2.
Furthermore, the effect of light irradiation on the cellular
localization of the prodrug candidate C2 was also probed
qualitatively using confocal laser scanning microscopy
(CLSM; Supporting Information, Figure S7). CLSM studies
on HeLa cells treated with C2 in the dark revealed a non-
specific manner of localization (Supporting Information,
Figure S7a). Intense luminescence signals were observed
from the cytoplasmic regions as well as the cell nucleoli.
Furthermore, a distinct sharp signal marking the periphery of
the nuclear membrane was also observed, which persisted
even after co-staining of cellular DNA with DAPI (4’,6-
diamidino-2-phenylindole; Supporting Information, Fig-
ure S7c). For the cells exposed to light irradiation (350 nm),
a relatively less-intense luminescence was observed in cells
(Supporting Information, Figure S7b). Nevertheless, from the
respective overlay image with DAPI staining (Supporting
Information, Figure S7d), accumulation appeared to mainly
occur in cytoplasmic organelles, with weak visual signs of red
emission from the nucleus under the conditions used for the
confocal microscopy experiments. However, a possibility that
the polarity and water accessibility of bis(dppz)–RuII com-
plexes in the cellular microenvironment is reflected in the
decreased intensity of the emission signals, cannot be ruled
out. This highlights the uncertainty on precise cellular
accumulation of metal complexes as assessed by confocal
microscopy. However, in case of C1, we could previously show
that visually observed mitochondrial accumulation is highly
The effect of light irradiation on the cytotoxic action of
the prodrug candidate C2 was examined on HeLa and U2OS
cells. The cells were first incubated with C2 in the dark for 4 h,
before suspension in fresh cell culture media followed by
irradiation at 350 nm for 10 min (2.58 JcmÀ2) and incubation
for additional 48 h. As anticipated, light irradiation of HeLa
and U2OS cells exposed to prodrug C2 restored the cytotoxic
effect (Table 1). An IC50 value of ca. 17.0 mm was obtained
when cells were subjected to light exposure. Notably, the
cytotoxicity level re-attained by the pro-moiety C2 upon light
irradiation is in excellent agreement with the cytotoxic
response observed for C1, in the dark, toward HeLa cells
(IC50 = 16.0 mm) under similar conditions, with an almost
twofold increase in cytotoxicity against U2OS cells (Table 1).
Control light irradiation experiments performed on HeLa and
U2OS cells either in the absence of the complex or after
incubation with the photolabile group DMNPB showed no
toxic effect on the cells, ruling out their possible contributions
to the elevated cytotoxic effects observed upon light activa-
tion.
Tris(diimine)–RuII complexes can produce 1O2 upon light
1
irradiation and therefore induce O2-mediated DNA photo-
cleavage, and can also exert phototoxicity.[4b,c,13a,17] In our
case, the separately conducted measurements indeed con-
firmed the ability of C1 to produce singlet oxygen (see
Supporting Information) upon irradiation at 350 nm with the
determined quantum yield (F) of 0.81 and 0.06 in acetonitrile
and PBS (pH 7.2), respectively; the values indicating an
extremely efficient singlet oxygen production in lipophilic
environments. Given that the prodrug candidate C2 only
2962 www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 2960 –2963

Angewandte
Chemie
[6] a) M. J. Pisani, P. D. Fromm, Y. Mulyana, R. J. Clarke, H.
correlated to that determined using high-resolution contin-
uum source atomic absorption spectrometry (HR-CS AAS).[7]
In conclusion, we report on an efficient approach for
controlling cytotoxicity of a substitutionally inert cytotoxic
RuII complex. Attaching an appropriate photolabile moiety to
C1 makes the otherwise active complex innocuous to both
cancerous (HeLa and U2OS) and non-cancerous (MRC-5)
cells. Furthermore, the cytotoxic action of the pro-moiety C2
is controlled by light and can be regained upon illumination.
With light-induced (350 nm) liberation of C1 from the pro-
moiety, cytotoxic action of the prodrug on the cancer cells is
unleashed, reaching similar levels of cytotoxicity as for the
original complex in absence of light. Though still at the
prototype stage, this light-triggered prodrug strategy holds
tremendous potential for designing more sophisticated pro-
drug systems, where properties are tailored to produce
a controllable cytotoxic action in physiologically relevant
optical window. Efforts towards this end are currently under
investigation. It should be noted, however, that the UV-A
light dosage (2.58 JcmÀ2) used to induce cytotoxicity in C2 is
comparable to that frequently employed for other UV-A
activated metal complexes.[11,12d,18]
Kçrner, K. Heimann, J. G. Collins, F. R. Keene, ChemMedChem
2011, 6, 848 – 858; b) U. Schatzschneider, J. Niesel, I. Ott, R.
Gust, H. Alborzinia, S. Wçlfl, ChemMedChem 2008, 3, 1104 –
1109; c) T. Chen, Y. Liu, W.-J. Zheng, J. Liu, Y.-S. Wong, Inorg.
Chem. 2010, 49, 6366 – 6368; d) C. Qian, J.-Q. Wang, C.-L. Song,
L.-L. Wang, L.-N. Ji, H. Chao, Metallomics 2013, 5, 844 – 854.
[7] V. Pierroz, T. Joshi, A. Leonidova, C. Mari, J. Schur, I. Ott, L.
Spiccia, S. Ferrari, G. Gasser, J. Am. Chem. Soc. 2012, 134,
20376 – 20387.
[8] T. Joshi, V. Pierroz, S. Ferrari, G. Gasser, 2014, DOI: 10.1002/
cmdc.201400029.
[9] a) C. Brieke, F. Rohrbach, A. Gottschalk, G. Mayer, A. Heckel,
Angew. Chem. 2012, 124, 8572 – 8604; Angew. Chem. Int. Ed.
2012, 51, 8446 – 8476; b) G. Mayer, A. Heckel, Angew. Chem.
2006, 118, 5020 – 5042; Angew. Chem. Int. Ed. 2006, 45, 4900 –
4921.
[10] a) H.-M. Lee, D. R. Larson, D. S. Lawrence, ACS Chem. Biol.
2009, 4, 409 – 427; b) G. C. R. Ellis-Davies, Nat. Methods 2007, 4,
619 – 628.
[11] K. L. Ciesienski, K. J. Franz, Angew. Chem. 2011, 123, 840 – 850;
Angew. Chem. Int. Ed. 2011, 50, 814 – 824, and references
therein.
[12] a) D. P. Kennedy, C. Gwizdala, S. C. Burdette, Org. Lett. 2009,
11, 2587 – 2590; b) H. W. Mbatia, S. C. Burdette, Biochemistry
2012, 51, 7212 – 7224; c) A. A. Kumbhar, A. T. Franks, R. J.
Butcher, K. J. Franz, Chem. Commun. 2013, 49, 2460 – 2462;
Received: November 4, 2013
Revised: December 17, 2013
Published online: February 5, 2014
ˇ
d) F. S. Mackay, J. A. Woods, P. Heringovꢄ, J. Kaspꢄrkovꢄ, A. M.
Pizarro, S. A. Moggach, S. Parsons, V. Brabec, P. J. Sadler, Proc.
Natl. Acad. Sci. USA 2007, 104, 20743 – 20748; e) B. J. Heilman,
J. St. John, S. R. J. Oliver, P. K. Mascharak, J. Am. Chem. Soc.
2012, 134, 11573 – 11582; f) A. E. Pierri, A. Pallaoro, G. Wu, P. C.
Ford, J. Am. Chem. Soc. 2012, 134, 18197 – 18200; g) C. Spagnul,
R. Alberto, G. Gasser, S. Ferrari, V. Pierroz, A. Bergamo, T.
Gianferrara, E. Alessio, J. Inorg. Biochem. 2013, 122, 57 – 65.
[13] a) U. Schatzschneider, Eur. J. Inorg. Chem. 2010, 1451 – 1467;
b) X. Chen, F. Gao, W.-Y. Yang, Z.-X. Zhou, J.-Q. Lin, L.-N. Ji,
Chem. Biodiversity 2013, 10, 367 – 384; c) M. Frasconi, Z. Liu, J.
Lei, Y. Wu, E. Strekalova, D. Malin, M. W. Ambrogio, X. Chen,
Y. Y. Botros, V. L. Cryns, J.-P. Sauvage, J. F. Stoddart, J. Am.
Chem. Soc. 2013, 135, 11603 – 11613; d) E. Wachter, D. K.
Heidary, B. S. Howerton, S. Parkin, E. C. Glazer, Chem.
Commun. 2012, 48, 9649 – 9651.
Keywords: medicinal inorganic chemistry · photolysis ·
.
prodrugs · ruthenium · substitutionally inert complexes
[1] E. Alessio, Bioinorganic Medicinal Chemistry, Wiley-VCH,
Weinheim, 2011, and references therein.
[2] a) N. P. E. Barry, P. J. Sadler, Chem. Commun. 2013, 49, 5106 –
5131; b) I. Romero-Canelꢀn, P. J. Sadler, Inorg. Chem. 2013, 52,
12276 – 12291; c) G. Gasser, I. Ott, N. Metzler-Nolte, J. Med.
Chem. 2010, 53, 3 – 25, and references therein; d) N. Graf, S. J.
Lippard, Adv. Drug Delivery Rev. 2012, 64, 993 – 1004; e) T. W.
Hambley, Science 2007, 318, 1392 – 1393.
[3] a) D.-L. Ma, H.-Z. He, K.-H. Leung, D. S.-H. Chan, C.-H. Leung,
Angew. Chem. 2013, 125, 7820 – 7837; Angew. Chem. Int. Ed.
2013, 52, 7666 – 7682; b) D. Can, B. Spingler, P. Schmutz, F.
Mendes, P. Raposinho, C. Fernandes, F. Carta, A. Innocenti, I.
Santos, C. T. Supuran, R. Alberto, Angew. Chem. 2012, 124,
3410 – 3413; Angew. Chem. Int. Ed. 2012, 51, 3354 – 3357; c) I.
Neundorf, J. Hoyer, K. Splith, R. Rennert, H. W. Peindy Nꢁ-
Dongo, U. Schatzschneider, Chem. Commun. 2008, 5604 – 5606;
d) E. A. Hillard, A. Vessiꢂres, G. Jaouen in Medicinal Organo-
metallic Chemistry, Vol. 32 (Eds.: G. Jaouen, N. Metzler-Nolte),
Springer, Heidelberg, 2010, pp. 81 – 117; e) A. M. Pizarro, A.
Habtermariam, P. J. Sadler, in Medicinal Organometallic
Chemistry, Vol. 32 (Eds.: G. Jaouen, N. Metzler-Nolte), Springer,
Heidelberg, 2010, pp. 21 – 56, and references therein; f) F.
Giannini, J. Furrer, A.-F. Ibao, G. Sꢃss-Fink, B. Therrien, O.
[14] A. Specht, J.-S. Thomann, K. Alarcon, W. Wittayanan, D. Ogden,
T. Furuta, Y. Kurakawa, M. Goeldner, ChemBioChem 2006, 7,
1690 – 1695.
[15] a) S. Petersen, J. M. Alonso, A. Specht, P. Duodu, M. Goeldner,
A. del Campo, Angew. Chem. 2008, 120, 3236 – 3239; Angew.
Chem. Int. Ed. 2008, 47, 3192 – 3195; b) M. Wirkner, S. Weis, V.
San Miguel, M. ꢅlvarez, R. A. Gropeanu, M. Salierno, A.
Sartoris, R. E. Unger, C. J. Kirkpatrick, A. del Campo, Chem-
BioChem 2011, 12, 2623 – 2629.
[16] J. W. Walker, G. P. Reid, J. A. McCray, D. R. Trentham, J. Am.
Chem. Soc. 1988, 110, 7170 – 7177.
[17] a) O. J. Stacey, S. J. A. Pope, RSC Adv. 2013, 3, 25550 – 25564;
b) S. Swavey in Ruthenium: Properties, Production and Appli-
cations (Ed.: D. B. Watson), Nova Science, New York, 2011,
pp. 249 – 268.
ˇ
ˇ
ˇ
Zava, M. Baquie, P. Dyson, P. Stepnicka, J. Biol. Inorg. Chem.
[18] a) Y. Zhao, J. A. Woods, N. J. Farrer, K. S. Robinson, J.
Pracharova, J. Kasparkova, O. Novakova, H. Li, L. Salassa,
A. M. Pizarro, G. J. Clarkson, L. Song, V. Brabec, P. J. Sadler,
Chem. Eur. J. 2013, 19, 9578 – 9591; b) A. Leonidova, V. Pierroz,
R. Rubbiani, J. Heier, S. Ferrari, G. Gasser, Dalton Trans. 2014,
DOI: 10.1039/C3DT51817E.
2012, 17, 951 – 960.
[4] a) M. R. Gill, J. A. Thomas, Chem. Soc. Rev. 2012, 41, 3179 –
3192; b) N. L. Kilah, E. Meggers, Aust. J. Chem. 2012, 65, 1325 –
1332; c) L. Salassa, Eur. J. Inorg. Chem. 2011, 4931 – 4947; d) A.
Bergamo, G. Sava, Dalton Trans. 2011, 40, 7817 – 7823; e) E.
Meggers, Chem. Commun. 2009, 1001 – 1010.
[5] J. G. Vos, J. M. Kelly, Dalton Trans. 2006, 4869 – 4883.
Angew. Chem. Int. Ed. 2014, 53, 2960 –2963
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 2963