First-and second-generation heterometallic dendrimers containing ferrocenyl-ruthenium(II)-arene motifs: Synthesis, structure, electrochemistry, and preliminary cell proliferation studies

Article abstract of DOI:10.1021/om500809g

Four first- and second-generation heterometallic ferrocenyl derived p-cymene-Ru(II) metallodendrimers, of general formula [DAB-PPI{(κ⁶-p-cymene)Ru((C₇H₅NO)-²-N,O)PTA(5-ferrocenylvinyl)}_n][PF₆

Full text of DOI:10.1021/om500809g

Article
pubs.acs.org/Organometallics
First- and Second-Generation Heterometallic Dendrimers Containing
Ferrocenyl−Ruthenium(II)−Arene Motifs: Synthesis, Structure,
Electrochemistry, and Preliminary Cell Proliferation Studies
†
‡
†
§
‡
Preshendren Govender, Heidi Lemmerhirt, Alan T. Hutton, Bruno Therrien, Patrick J. Bednarski,
and Gregory S. Smith*
,
†
†
Department of Chemistry, University of Cape Town, Rondebosch 7701, Cape Town, South Africa
‡
Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Ernst-Moritz-Arndt University Greifswald, 17487
Greifswald, Germany
§
Institute of Chemistry, University of Neuchatel, 51 Ave de Bellevaux, CH-2000 Neuchatel, Switzerland
S Supporting Information
*
ABSTRACT: Four first- and second-generation heterometal-
lic ferrocenyl derived p-cymene-Ru(II) metallodendrimers, of
6
2
general formula [DAB-PPI{(η -p-cymene)Ru((C H NO)-κ -
7
5
6
N,O)PTA(5-ferrocenylvinyl)} ][PF ] and [DAB-PPI{(η -p-
cymene)Ru((C H N )-κ -N,N)Cl(5-ferrocenylvinyl)} ][PF ]
n
6 n
2
6
5
2
n
6 n
(
where n = 4 (G ), 8 (G ), DAB = 1,4-diaminobutane, PPI =
1 2
poly(propyleneimine), PTA
= 1,3,5-triaza-7-
phosphatricyclo[3.3.1.1]decane) have been synthesized. All
complexes have been characterized using analytical (i.e., HR-
ESI mass spectrometry, HPLC, elemental analysis, and cyclic
1
13
1
voltammetry) and spectroscopic (i.e., H and C{ H} NMR
and infrared) methods. Electrochemical studies reveal that the
N,O-p-cymene-Ru(II)-PTA complexes result in two irreversible redox processes (oxidation of the Fe(II) and Ru(II) centers),
while the N,N-p-cymene-Ru(II) complexes display one reversible wave (Fe(II)/Fe(III) couple). Heterometallic model complexes
have been prepared, and for one of the complexes, its molecular structure has been determined by single-crystal X-ray
crystallography. In vitro antiproliferation activity of the dendritic ligands and their complexes were evaluated against A2780 and
A2780cisR human ovarian cancer lines, the SISO human cervix cancer line, the LCLC-103H human lung cancer line, and the
5
5
637 human bladder cancer line. Nine of the twelve compounds slowed the growth of the ovarian cancer cell lines by more than
0% at equi-iron concentrations of 5 μM.
7
6
INTRODUCTION
agents. RAPTA compounds of general formula [(η -arene)-
R u ( P T A ) C l2 ] ( w h e r e P T A 1 , 3 , 5 - t r i a z a - 7 -
phosphatricyclo[3.3.1.1]decane) have been extensively stud-
■
1
=
After the discovery of platinum-based anticancer drugs,
ruthenium compounds were investigated as therapeutic agents,
as the platinum-based drugs are poorly selective and produce
several undesirable side effects. Ruthenium is less toxic than
platinum, with its biological activity attributed to its ability to
mimic the behavior of iron and bind to biomolecules, such as
8
9
ied, although most are not particularly cytotoxic. However, in
vivo they display promising activity against solid metastatic
2
1
0
11
tumors and exert a strong antiangiogenic effect.
Research into the introduction of a second metal in the
design of heterobimetallic complexes as potential anticancer
agents has flourished. One such metal is iron and, more
specifically, the iron-based organometallic complex ferrocene.
Ferrocene-based molecules have become very attractive in the
field of medicinal chemistry, with the activity of these
complexes attributed to their favorable electronic properties
and ease of functionalization. Furthermore, simple derivatives
3
human serum albumin and transferrin. Two inorganic Ru(III)
complexes, namely NAMI-A (H Im[trans-RuCl (DMSO)-
12
2
4
13
4
(
Him)] (Him = imidazole)) and KP1339 (H Na[trans-
2
5
RuCl (Hind) ] (Hind = indazole)), are currently progressing
4
2
14
through clinical trials, with the former active against solid
metastases, whereas KP1339 displays profound activity against
neuroendocrine tumors (NET). The activity of the Ru(III)
complexes is thought to be brought on by reduction in vivo to
the more reactive Ru(II) species. As a consequence, Ru(II)
complexes of general formula [(η -arene)Ru(X)(Y)(Z)], where
15
of ferrocene display good activity in vitro, with inhibition of
tumors observed in vivo. In the pursuit for new tamoxifen-like
drugs, Jaouen and co-workers synthesized ferrocifens from 1-
16
6
17
6
X and Y are bidentate chelating groups (NN, NO, OO, SO) or
two monodentate ligands and Z is a monodentate moiety, often
a leaving group, have been extensively studied as anticancer
Received: August 6, 2014
Published: September 17, 2014
©
2014 American Chemical Society
5535
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Scheme 1. Synthesis of N,O- and N,N-Ferrocenyl-Derived Precursors 1 and 2
26b,c
[
4-(2-dimethylaminoethoxy)]-1-(phenyl-2-ferrocenylbut-1-
metallodendrimers previously reported by us,
in an effort to
ene), which are highly active ferrocenyl derivatives of the purely
organic breast cancer drug tamoxifen. The increase in activity is
attributed to the dual action of the organic drug and the Fenton
improve the antitumor activity of these complexes.
RESULTS AND DISCUSSION
18
■
chemistry (i.e., formation of singlet oxygen) of the Fe center.
Synthesis of N,O- and N,N-Ferrocenyl-Derived Pre-
cursors. Synthesis of the ferrocenyl-derived precursors 1 and 2
required the preparation of vinylferrocene, via a Wittig
reaction, from ferrocenecarboxaldehyde. The ferrocenyl-derived
precursors (4E)-(4-ferrocenylvinyl)-2-hydroxybenzaldehyde
Moreover, the stability of ferrocene in aqueous and aerobic
media, the facility with which a large variety of derivatives may
be prepared, and its favorable electrochemical properties have
resulted in ferrocene becoming a promising molecule for
29
19
incorporation in biological applications.
In an effort to develop cytotoxic anticancer agents, ferrocene
(
1) and (5E)-(5-ferrocenylvinyl)-2-pyridinecarboxaldehyde
2
6
20
(2) were prepared via a Heck coupling reaction of vinyl-
derivatives have been coupled with gold,
silver,
1
2a
21
21
ferrocene and the appropriate aryl bromide (Scheme 1). The
palladium, rhodium, and iridium complexes in order to
achieve a synergistic effect between the two active metals. The
introduction of the second metal resulted in cytotoxicities (in
various cancer cell lines) comparable to that of the benchmark
drug cisplatin. However, there are only a handful of reports
where ruthenium and iron have been combined within the
30
method described by Reyes et al. was modified for the
preparation of 1 and 2. The Pd catalyst, triphenylphosphine,
triethylamine, vinylferrocene, and the appropriate aldehyde
were heated under reflux for 3 days in 1,4-dioxane, to afford 1
and 2 as purple solids in low yields (10−25%). 1 and 2 are
soluble in most organic solvents such as dichloromethane,
methanol, toluene, diethyl ether, and dimethyl sulfoxide.
22
same molecule and investigated for anticancer activity. The
majority of these derivatives display moderate activity in
comparison to cisplatin, while a heterobimetallic ruthenium
hexamethylbenzene phosphinoferrocene amino derivative dis-
plays activity in the low micromolar range (∼4 μM in A2780,
1
13
1
The H and C{ H} NMR spectra of 1 and 2 affirm the
coupling of the two starting materials. The characteristic singlet
for the presence of a highly deshielded proton on an aldehyde
functionality is observed for both 1 (Figure S1, Supporting
22a
human ovarian cancer cells), further providing motivation for
this study.
Information) and 2 (Figure S2, Supporting Information) at
1
∼
10 ppm. Three doublets of doublets (observed in the H
NMR spectrum of vinylferrocene) disappear, and two doublets
Following the successes of cisplatin and the trinuclear Pt-
23
based anticancer complex BBR3464, researchers have used
the polynuclear strategy by conjugating metallodrugs onto
dendritic scaffolds in an effort to improve the overall biological
(
∼6.7 and ∼7.1 ppm) appear and are assigned to the two
protons on the alkene moiety for both 1 and 2, suggesting C−
C bond formation. The two doublets have a coupling constant
of J ≈ 16 Hz each, suggesting that the alkene moieties of 1
and 2 adopt a trans conformation rather than a cis
2
4
activity. Furthermore, the multivalency of dendrimers may
lead to increased interactions between a dendrimer−drug
conjugate and a target bearing multiple receptors. There are
only a handful of metallodendrimers specifically developed to
3
HH
conformation, as typical coupling constants for a cis
3
31
conformation would be much lower ( J ≈ 9 Hz). A similar
HH
25
3
target cancerous cells. We have reported the synthesis of a
series of metallodendrimers containing half-sandwich organo-
coupling constant (i.e., J = 16 Hz) was reported by Yang et
HH
al., for the structurally similar compound (4E)-(4-
26
27
28
28
32
metallic ruthenium, osmium, iridium, and rhodium
ferrocenylvinyl)pyridne. A strong sharp stretching vibration
is observed in the infrared (IR) spectra at 1614 and 1575 cm−
for 1 and 2, respectively, and is assigned to the CC bond of
the alkene moiety. This observation further confirms successful
C−C bond formation via the Heck reaction. The HR-ESI mass
1
functionalities located on the periphery of a dendritic scaffold.
Herein, we report the synthesis of first- and second-
generation heterometallic ferrocenyl-derived N,O-p-cymene-
Ru(II)-PTA-salicylaldimine and N,N-p-cymene-Ru(II)-2-pyri-
dylimine metallodendrimers ([7][PF ] −[10][PF ] ). Further-
+
6
4
6 8
spectra of 1 and 2 give a base peak for [M + H] ions at m/z
more, in order to compare size dependence on the biological
333.0562 and 318.0580, respectively, consistent with the
proposed structures. Analytical HPLC traces were obtained
activity, heterometallic model complexes ([13][PF ] and
6
[
14][PF ]) were synthesized as models for the larger
for 1 and 2, with single peaks observed at t = 17 and 16 min,
6
R
metallodendrimers. The presence of heterometallic active
sites contained in biological metalloenzymes has led us to
explore the synthesis of heterometallic dendrimers by
incorporating a ferrocenyl group into the p-cymene-ruthenium
respectively, attesting to the purity of these compounds.
Synthesis of Ferrocenyl-Derived Dendritic Ligands.
The third step in the synthesis involved preparation of the two
ferrocenyl-derived N,O-salicylaldiminato dendritic ligands 3 and
5
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Scheme 2. Synthesis of N,O- and N,N-Ferrocenyl-Derived Dendritic Ligands 3−6
Scheme 3. Synthesis of Ferrocenyl-Derived Cationic N,O-p-cymene-Ru(II)-PTA and N,N-p-cymene-Ru(II) Metallodendrimers
[
7][PF ] −[10][PF ]
6
4
6 8
4
and the two ferrocenyl-derived N,N-pyridylimine dendritic
disappearance of the singlet at ∼10 ppm (aldehyde proton of 1
1
ligands 5 and 6. The dendritic ligands 3−6 were prepared via a
Schiff base condensation of 1 (for 3 and 4) or 2 (for 5 and 6)
with the amino groups of DAB-G -PPI-(NH ) (where DAB =
and 2) in the H NMR spectrum of 3−6 (Figures S3−S6,
Supporting Information), with an appearance of a broad singlet
at ∼8.2 ppm (for 3 and 4) and ∼8.4 ppm (for 5 and 6), which
is assigned to the proton of the newly formed imine bond.
Typically, the signals for the aliphatic protons on the dendritic
core and dendritic arms appear in the region between 1.4 and
3.7 ppm for 3−6. The carbonyl carbon singlet observed in the
1
2 4
1,4-diaminobutane and PPI = poly(propyleneimine), for 3 and
5) or of DAB-G -PPI-(NH ) (for 4 and 6) in dichloromethane
2
2 8
(
Scheme 2). The dendritic ligands 3−6 were isolated as orange
solids in moderate yields (50−65%). The dendritic ligands 3−6
are air and moisture stable, are soluble in a handful of solvents,
such as dichloromethane, chloroform, acetonitrile, and dimethyl
sulfoxide, and are insoluble in protic and nonpolar solvents.
1
3
1
C{ H} NMR spectrum of 1 and 2, at ∼195 and ∼193 ppm,
respectively, was not observed in the 13C{ H} NMR spectrum
1
of 3−6. This observation further confirms formation of the
1
13
1
13
1
The H and C{ H} NMR data of 3−6 display overlapping
and broadening of signals, similarly observed with other
poly(propyleneimine) dendrimers functionalized at the periph-
imine bond, as a singlet in the C{ H} NMR spectrum at
∼164 ppm (for 3 and 4) and at ∼162 ppm (for 5 and 6) is
observed and is assigned to the carbon of the imine bond. The
IR spectra of 3 and 4 display a strong broad stretching vibration
26b,33
ery with inorganic and organic moieties.
There is a
5
537
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Scheme 4. Synthesis of N,O- and N,N-Ferrocenyl-Derived Monomeric Ligands 11 and 12
−
1
at ∼1610 cm , which is assigned to both the CN and CC
to the aromatic protons. The signals for the protons on the
PTA ligand (4.1−4.6 ppm) overlap with the broad signals
assigned to the protons on the ferrocenyl functionality and the
diastereotopic protons (as a result of the stereogenicity induced
by the ruthenium ion) on the aliphatic carbon adjacent to the
imine nitrogen. Furthermore, the signals for the PTA ligand
display the typical splitting pattern for an AB spin system and
correlate well with splitting patterns observed with other PTA
bonds of the imine and alkene moieties, respectively. However,
and 6 display two bands of medium intensity, at ∼1580 and
1640 cm , and these are assigned to the alkene and imine
5
∼
−1
bonds, respectively. Following extensive drying of 3−6,
satisfactory elemental analysis data was not obtained, as the
percentages obtained were outside acceptable limits and are
ascribed to possible solvent inclusions. The inclusion of small
molecules has been observed with purely organic dendrimers,
as the free rotation of the dendritic arms allows for folding onto
one another, in turn trapping small molecules. Thus, the
inclusion of dichloromethane resulted in C, H, and N
percentages for 3−6 to fall within acceptable limits. HR-ESI
mass spectrometry was used to confirm the proposed structures
of 3−6, with all complexes exhibiting a base peak
corresponding to a charged complex.
34
31
1
complexes in the literature. The P{ H} NMR spectra of
[
7][PF ] and [8][PF ] display a singlet at ∼−32 ppm,
6
4
6 8
33
suggesting a single phosphine species and further attesting to
the purity of these complexes.
On the other hand, chirality induced by coordination to the
ruthenium ion results in the appearance of two broad multiplets
1
(
[
4.4−4.8 ppm) in the H NMR spectrum of metallodendrimers
9][PF ] (Figure S9, Supporting Information) and [10][PF ]
6
4
6
8
Synthesis of Ferrocenyl-Derived Heterometallic Met-
allodendrimers. The metallodendrimers [7][PF ] −[10]-
PF ] were synthesized by reacting the appropriate first- or
(
Figure S10, Supporting Information), which are assigned to
6
4
the diastereotopic protons on the dendritic arms. These broad
multiplets overlap with the two broad doublets assigned to the
protons on the substituted ferrocenyl functionality, while the
protons on the unsubstituted ferrocenyl functionality appear as
a singlet at 4.2 ppm.
[
6 8
second-generation dendritic ligand (3−6) with the ruthenium
6
dimer [Ru(η -p-cymene)Cl ] in an ethanol/dichloromethane
2
2
(
50/50% v/v) mixture at room temperature (Scheme 3). The
water-soluble PTA ligand was added to displace the chlorido
ligand, in turn generating a cationic species. Metallodendrimers
−10 were isolated as hexafluorophosphate salts, via a
metathesis reaction with NaPF , to afford orange solids
13
1
The C{ H} NMR data for metallodendrimers [7][PF ]
6
4
and [8][PF ] display two singlets for the carbon atoms of the
6
8
7
PTA ligand in the range 51−72 ppm, confirming coordination
to the ruthenium ion and displacement of the chlorido ligand.
Upon coordination of the ligand to the ruthenium ion, IR data
of [7][PF ] −[10][PF ] display a distinct shift in the C
6
(
[7][PF ] and [8][PF ] ) or dark purple solids ([9][PF ]
6 4 6 8 6 4
and [10][PF ] ), in good yields (72−85%). Compounds
6
8
6
4
6 8
[
7][PF ] −[10][PF ] are nonhygroscopic, air- and moisture-
6
4
6 8
−1
C
(
and CN
stretching vibrations from ∼1613 cm
alkene
imine
stable solids, can be stored over extended periods, and are
soluble in dimethyl sulfoxide, acetone, and dimethylformamide
−
1
for 3 and 4) to ∼1590 cm (for [7][PF ] and [8][PF ] )
6
4
6 8
and a similar shift to lower wavenumbers of the CN
imine
and partially soluble in acetonitrile.
A comparison of the H NMR spectra of [7][PF ] −
10][PF ] to those of the corresponding dendritic ligands
1
stretching vibration for metallodendrimers [9][PF ] and
6 4
6
4
−1
−1
[
10][PF ] , from ∼1640 cm (for 5 and 6) to ∼1625 cm ,
6
8
[
6 8
is observed. The inclusion of dichloromethane resulted in C, H,
reveals chelation of the dendritic ligand to the ruthenium ion,
which is confirmed by a slight downfield shift in the imine
signal from ∼8.0 ppm (for 3 and 4) and ∼8.3 ppm (for 5 and
and N percentages for [7][PF ] −[10][PF ] to fall within
6 4
6 8
acceptable limits. In addition, HR-ESI mass spectrometry for
the first-generation metallodendrimers [7][PF ] and [9][PF ]
6
) to ∼8.1 ppm (for [7][PF ] (Figure S7, Supporting
6 4
6 4
6
4
exhibit a base peak corresponding to 6+ and 5+ charged ions,
respectively. However, the second-generation derivatives [8]-
Information) and [8][PF ] (Figure S8, Supporting Informa-
6
8
tion)) and ∼8.9 ppm (for [9][PF ] (Figure S9, Supporting
Information) and [10][PF ] (Figure S10, Supporting In-
6
4
[
PF ] and [10][PF ] depict a multicharged ion complex and a
6 8 6 8
6
8
molecular ion peak in the mass spectrum, respectively.
Synthesis of Ferrocenyl-Derived Monomeric Ligands
and Ferrocenyl-Derived Heterometallic Model Com-
plexes. The monomeric ferrocenyl-derived ligands 11 and
12 were synthesized in a similar manner to their dendritic
derivatives 3−6, by reaction of n-propylamine with 1 and 2
(Scheme 4), via a Schiff base condensation reaction. Following
purification over a small pad of silica, the new monomeric
ligands 11 and 12 were isolated as orange-red solids in 56% and
71% yields, respectively.
formation)) respectively. Coordination of the dendritic ligand
to the ruthenium ion in [7][PF ] −[10][PF ] results in a loss
6
4
6 8
of 2-fold symmetry of the p-cymene moiety. This results in the
methyl protons of the isopropyl group exhibiting two broad
multiplets in the range 1.1−1.3 ppm (for [7][PF ] −[10]-
6
4
[
PF ] ), with a broad multiplet observed at ∼2.6 ppm assigned
6
8
to the single proton on the isopropyl group.
1
The H NMR spectra of [7][PF ] (Figure S7, Supporting
6
4
Information) and [8][PF ] (Figure S8, Supporting Informa-
6
8
tion) show signals in the range 5.5−7.2 ppm and are assigned
5
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Scheme 5. Synthesis of Ferrocenyl-Derived Cationic N,O-Ru(II)-p-cymene-PTA and N,N-p-cymene-Ru(II) Heterometallic
Model Complexes [13][PF ] and [14][PF ]
6
6
In order to compare size dependence on the biological
activity, the heterometallic model complexes [13][PF ] and
6
[
14][PF ] of the ferrocenyl-derived ruthenium-p-cymene
6
metallodendrimers were prepared. Two equivalents of the
monomeric ligand 11 or 12 was reacted with 1 equiv of the
6
ruthenium arene dimer [Ru(η -p-cymene)Cl ] by stirring at
2
2
room temperature in ethanol/dichloromethane (50/50% v/v)
Scheme 5), in the presence of triethylamine (for the
(
preparation of [13][PF ]). PTA was added to the reaction
6
mixture containing the N,O-salicylaldiminato ligand 11, which
displaced the chlorido ligand and generated a cationic complex.
Figure 1. ORTEP representation of 1, with thermal ellipsoids at the
50% probability level. Selected bond lengths (Å) and angles (deg):
O1−C1 1.227(3), O2−C3 1.360(3), C8−C9 1.339(3); O1−C1−C2
124.5(3), O2−C3−C2 121.1(2), C5−C8−C9 126.3(2).
The new heterometallic model complexes [13][PF ] and
6
[
14][PF ] were isolated as orange and dark purple hexa-
6
fluorophosphate salts, respectively, and have solubilities in polar
solvents similar to those of their dendritic counterparts
[
7][PF ] −[10][PF ] . The synthesis and purity of the
6
4
6 8
monomeric ligands 11 and 12 and heterometallic model
complexes [13][PF ] and [14][PF ] were confirmed by
6
6
1
spectroscopic ( H (Figures S11− S14, Supporting Information)
and 13C{ H} NMR and infrared spectroscopy) and analytical
techniques (HPLC, elemental analysis, and mass spectrome-
try).
1
X-ray Crystallography. The trans conformation of the
alkene moiety was also confirmed from a single-crystal X-ray
structure analysis of 1 (Figure 1). In the solid state, the
hydroxybenzaldehyde group was found to be coplanar with the
cyclopentadienyl unit, thus suggesting an optimal electronic
delocalization in 1 with a C5−C8−C9−C10 torsion angle of
−
179.1(2)°. Crystallographic details of 1 are summarized in
Table S1 (Supporting Information).
The molecular structure of the mononuclear complex
[
13][PF ] was also elucidated by a single-crystal X-ray
+
6
Figure 2. ORTEP representation of [13] , with thermal ellipsoids at
diffraction analysis. Crystals were grown by slow evaporation
the 50% probability level. The water molecule and the PF anion have
6
of a solution of [13][PF ] in acetone and crystallized in the
been omitted for clarity. Selected bond lengths (Å) and angles (deg):
Ru1−N1 2.097(5), Ru1−O1 2.068(4), Ru1−P1 2.305(2), O1−C6
1.324(7), C11−C12 1.331(11); P1−Ru1−O1 80.5(1), P1−Ru1−N1
6
monoclinic space group P2 /c. An ORTEP drawing of
1
[
13][PF ]·H O is shown in Figure 2, together with selected
6 2
+
8
6.9(1), O1−Ru1−N1 87.5(2).
geometrical parameters. In [13] , the ferrocenyl unit adopts an
eclipsed conformation and the trans conformation of the vinylic
5
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+
Table 1. Redox Potentials (V vs Ag/Ag ) of Metallodendrimers [7][PF ] −[10][PF ] , [13][PF ], [14][PF ], and ferrocene
6
4
6 8
6
6
a
(
Fc)
Fe(II)/Fe(III)
Ru(II)/Ru(III)
b
c
d
complex
Epa
Epc
ΔEp
E1/2
ΔE1/2
i /i
pa pc
Epa
[
[
[
[
[
[
7][PF6]4
8][PF6]8
9][PF6]4
10][PF6]8
13][PF6]
14][PF6]
0.16
0.17
0.23
0.22
0.18
0.23
0.17
n.o.
n.o.
0.15
0.15
n.o.
0.16
0.07
0.98
0.98
n.o.
n.o.
0.97
n.o.
0.08
0.07
0.19
0.19
0.07
0.07
1.14
1.46
0.07
0.10
0.20
0.12
0.08
0
0.98
0.99
Fc
a
−1
b
−1
Measured in CH CN at a scan rate of 100 mV s ([7][PF ] , [8][PF ] , and [13][PF ]) or 50 mV s ([9][PF ] , [10][PF ] , and [14][PF ])
3
6
4
6
8
6
6
4
6
8
6
+
+
and referenced to Ag/Ag . n.o. = not observed. ΔE = E − E , where E and Epc are the anodic and cathodic peak potentials vs Ag/Ag ,
respectively. E1 = (Epa + E )/2. ΔE = E1/2(Fc compound) − E (Fc).
p
pa
pc
pa
c
d
/2
pc
1/2
1/2
carbon−carbon double bond is further confirmed, the C8−
C11−C12−C13 torsion angle being 177.1(7)°. The ruthenium
atom is coordinated to the nitrogen and the oxygen atoms of
the Schiff base ligand as well as to the phosphorus atom of the
6
PTA ligand and an η -p-cymene ligand, thus leading to a typical
chiral-at-metal pseudotetrahedral or “piano-stool” complex. The
crystallographic details of [13][PF ]·H O are summarized in
6
2
Table S1 (Supporting Information).
+
In [13] the average distance between the ruthenium and
6
carbon atoms of the η -p-cymene ring is 2.23 Å, comparable to
those in structurally similar ruthenium-p-cymene complexes
2
6b
+
reported in the literature.
(
The Ru−P distance in [13]
2.305(2) Å) is comparable to that observed in analogous
35
ruthenium-arene-PTA compounds. In the crystal structure,
the cyclopentadienyl group attached to the vinyl moiety (plane
defined by C13−C17) and the phenol group (plane defined by
C5−C10) are not coplanar; an angle of 15.5° is found between
these two planes. The presence of water molecules in the
Figure 3. Cyclic voltammogram of [7][PF ] showing a partial (top)
6
4
crystal packing of [13][PF ] generates a series of hydrogen
bonds. The water molecule interacts with the PF6 group (O···
F distance 3.017(8) Å with an O−H···F angle of 151.7°) and a
nitrogen atom of the PTA ligand (O···N distance 2.866(9) Å
with an O−H···N angle of 154.3°).
and a full scan (bottom), as recorded in acetonitrile (scan rate 100 mV
6
−
−1
+
s ). The potential scale is referenced to Ag/Ag (see the Experimental
Section). The scan started at −0.40 V.
Electrochemistry. The different σ-donating and π-accept-
ing capacities of the dendritic ligands 3−6 influence the
oxidation potentials of the Ru(II) centers upon complexation.
Furthermore, these potentials provide insight into the
fundamental character of the ligands in the complexes. Previous
reports suggest that ligands which favor oxidation of the
ferrocenyl moiety can produce reactive oxygen species, which
have the ability to disrupt lipid membranes and in turn
36
influence the antitumor activity of the complexes. Hence, to
investigate such possible correlations in the current systems and
to provide further characterization of the complexes, the
metallodendrimers [7][PF ] −[10][PF ] and model com-
6
4
6 8
plexes [13][PF ] and [14][PF ] were studied by cyclic
6
6
voltammetry at a Pt-disk working electrode in acetonitrile,
containing [n-Bu N][ClO ] as the background electrolyte, a
4
4
+
platinum-wire auxiliary electrode, and a Ag/Ag reference
electrode. A comparison of the relevant electrochemical data is
given in Table 1.
Figure 4. Cyclic voltammogram of [9][PF ] showing a full scan, as
6 4
−1
recorded in acetonitrile (scan rate 50 mV s ). The potential scale is
+
referenced to Ag/Ag (see the Experimental Section). The partial
voltammogram is shifted by +2 μA to avoid overlap. The scan started
at −0.50 V.
The free ferrocene standard exhibits a one-electron reversible
+
wave with E1 = 0.12 V for the Fc/Fc couple relative to the
/2
+
Ag/Ag reference electrode. First- and second-generation
metallodendrimers display similar voltammetric behaviors in
acetonitrile, and hence representative cyclic voltammograms are
shown in Figures 3 and 4 for the first-generation N,O-p-
cymene-ruthenium-PTA metallodendrimer [7][PF ] and N,N-
6
4
p-cymene-ruthenium metallodendrimer [9][PF ] , respectively.
6
4
5
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Table 2. Relative Growth (in T/Ccorr (%); See Eq 1) of Cells Treated with the Ferrocenyl-Derived Ligands and Their
a
Heterometallic Complexes in Comparison to Untreated Controls
b
T/Ccorr at 5 μM Fe (%)
c
d
d
d
d
d
compd
metal
Fe
n
A2780
A2780-cisR
SISO
LCLC-103H
5637
3
4
5
6
1
1
4
8
42.3 ± 34.2
21.1 ± 15.3
31.3 ± 28.4
23.0 ± 18.7
7.8 ± 10.1
26.0 ± 19.4
−2.3 ± 5.6
5.5 ± 12.6
86.1 ± 26.3
107.6 ± 97.8
70.3 ± 16.0
12.0 ± 9.6
37.3 ± 19.5
36.8 ± 21.7
29.4 ± 16.5
30.8 ± 21.5
18.6 ± 4.7
24.9 ± 20.6
−4.3 ± 1.5
−1.8 ± 4.2
59.9 ± 12.7
42.5 ± 13.1
54.6 ± 5.8
25.5 ± 8.9
50.7 ± 18.3
37.2 ± 22.3
67.9 ± 18.6
71.8 ± 16.7
5.0 ± 4.4
64.8 ± 20.8
73.0 ± 64.4
95.3 ± 61.9
90.4 ± 13.9
105.2 ± 51.4
100.2 ± 5.4
22.9 ± 11.6
66.5 ± 34.2
58.5 ± 28.7
75.8 ± 38.3
84.6 ± 37.7
31.9 ± 10.4
78.8 ± 38.3
103.7 ± 10.1
103.1 ± 28.9
42.5 ± 14.1
64.8 ± 20.0
19.8 ± 9.5
41.5 ± 15.4
41.6 ± 16.6
27.6 ± 8.2
38.1 ± 15.8
57.6 ± 26.4
67.6 ± 33.8
10.8 ± 13.4
Fe
Fe
4
Fe
8
1
Fe
1
2
Fe
1
[
[
[
[
[
[
7][PF6]4
8][PF6]8
9][PF6]4
10][PF6]8
13][PF6]
14][PF6]
Fe−Ru
Fe−Ru
Fe−Ru
Fe−Ru
Fe−Ru
Fe−Ru
8
16
8
e
e
16
2
40.7
54.4
102.5 ± 16.5
84.2 ± 29.9
34.2 ± 20.5
12.6 ± 10.9
2
a
Compounds were tested against five human cancer cell lines after 96 h exposure to compound at 5 μM Fe, relative to untreated control.
b
c
d
Concentrations normalized to the mole equivalents of Fe in each complex. n = Number of metals present in the complex. Average of three or
e
more independent experiments ± standard deviation. Average of two determinations.
The redox potentials of [7][PF6]4 and [8][PF ] were
Ru oxidation more difficult. As expected, the ferrocene/
ferrocenium redox potentials of [9][PF ] and [10][PF ] are
nearly identical (Table 1). In comparison to free ferrocene
6 8
−1
measured at a scan rate of 100 mV s , and ferrocene was
used as the internal standard. Both [7][PF6]4 (Figure 3,
bottom) and [8][PF6]8 (Figure S15, bottom (Supporting
Information)) exhibit similar voltammograms with two
irreversible oxidation waves in the positive region. The
ferrocenyl oxidation wave (Fe(II) → Fe(III)) appears at Epa
6
4
6 8
(E1/2 = 0.12 V), the ferrocenyl moiety of [9][PF ] and
6 4
[10][PF ] is more difficult to oxidize (E = 0.19 V), and this
6
8
1/2
is attributed to the electron-withdrawing effects of the alkene
moiety, the ruthenium center, and the overall positive charge of
the complexes. This was similarly demonstrated for mono-
substituted ferrocenyl-derived complexes containing electron-
=
0.16 and 0.17 V for [7][PF ] and [8][PF ] , respectively. A
6 4 6 8
second redox event for the oxidation of the ruthenium center
Ru(II) → Ru(III)) appears at 0.98 V for both [7][PF ] and
40
(
withdrawing groups bonded to the ferrocene ring. As
6
4
[
8][PF6]8 and is electrochemically irreversible, suggesting
expected, both [13][PF ] (Figure S17, Supporting Informa-
6
3
7,38
thermodynamic instability of the oxidation products.
On
tion) and [14][PF ] (Figure S18, Supporting Information)
6
an oxidative scan with the switching potential set just after the
first oxidation wave, a reversible one-electron ferrocene/
ferrocenium redox wave is observed for both [7][PF ] (Figure
exhibit similar cyclic voltammograms and wave potentials in
comparison to their dendritic counterparts [7][PF ] −[10]-
6
4
[PF ] .
6
4
6 8
3
, top) and [8][PF6]8 (Figure S15, top (Supporting
Inhibition of Cancer Cell Proliferation. Preliminary in
vitro cell proliferation studies of the ligands (3−6, 11, and 12)
and their complexes ([7][PF ] −[10][PF ] , [13][PF ], and
Information)). Unlike other ruthenium−iron heterometallic
systems,
22a,c,38a,39
where an irreversible wave for the ruthenium
6
4
6 8
6
center and a reversible wave for the ferrocenyl moiety are
common, here this is not observed. Instead, the oxidation of the
Ru center inhibits the reversibility of the Fc/Fc+ couple.
However, the electrochemical studies performed on the
reported heterometallic systems found in the literature were
performed using different conditions (i.e., background electro-
lyte, reaction solvent, and/or the compound counterion), and
these affect the redox processes compared. In the present study,
the electrochemical data suggest that oxidation of the
ruthenium center influences and prevents reduction of the
ferrocenium species, resulting in the two irreversible redox
processes observed for [7][PF ] and [8][PF ] .
[14][PF ]) were evaluated against A2780 and A2780cisR
6
human ovarian cancer lines, the SISO human cervix cancer line,
the LCLC-103H human lung cancer line, and the 5637 human
bladder cancer line (Table 2). We used a microtiter plate assay
41
based on the staining of cells with crystal violet. Cells were
grown for 24 h following plating and then treated continuously
for 96 h with the test compound. To express cell growth, the
T/Ccorr method was used (see eq 1 in the Experimental
Section): a T/Ccorr value of 100% indicates the same growth
rate as the untreated controls over 96 h, a positive T/Ccorr
between 100 and 0% indicates slower cell growth relative to
untreated controls, a T/Ccorr value of 0 indicates no cell growth
over 96, and a negative T/Ccorr value indicates cytotoxicity, i.e.,
fewer cells after 96 h than at the time of treatment.
6
4
6 8
The redox potentials of [9][PF ] and [10][PF ] were
6
4
6 8
−1
measured at a scan rate of 50 mV s . Due to the partial
solubility of [9][PF ] and [10][PF ] in acetonitrile, a slower
scan rate was chosen, as faster scan rates did not produce
smooth cyclic voltammograms. The cyclic voltammograms for
The cell proliferation studies of the ferrocenyl-derived
compounds were initially performed at an equi-iron concen-
tration of 20 and 10 μM; however, many of the compounds
displayed very potent antiproliferative activity, and so no
structure−activity relationships were observed. After the iron
concentration for all compounds was lowered to 5 μM, both
the ferrocenyl-derived ligands (3−6, 11, and 12) and
ferrocenyl-derived p-cymene-ruthenium complexes ([7][PF ] ,
6
4
6 8
[
9][PF ] (Figure 4) and [10][PF ] (Figure S16, Supporting
6 4 6 8
Information) exhibit one reversible wave (current ratios (ipa/
i ) are close to unity) in the positive region and is assigned to
pc
2
2c,39c
the Fe(II)/Fe(III) couple.
However, there was no
oxidation of Ru(II) observed and this is attributed to the
electron-withdrawing nature of the chlorido ligand, which
lowers the electron density at the ruthenium center, making the
6
4
[8][PF ] , and [14][PF ]) slowed the growth of both the
6
8
6
A2780 and A2780cisR cell lines by more than 50% (Figure S19,
5
541
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Article
Supporting Information), with the A2780 cell line being the
most sensitive and showing no cross resistance to cisplatin. On
the other hand, metallodendrimers [9][PF ] and [10][PF ]
6 8
complexes display one reversible wave (Fe(II)/Fe(III) couple)
in the positive region. Single-crystal X-ray diffraction was
utilized to further confirm the proposed structures and illustrate
the mode of coordination, through N,O- and N,N-donor atoms.
Preliminary biological studies performed on the ferrocenyl-
derived ligands and ferrocenyl-derived p-cymene-ruthenium
complexes indicate that 9 of 12 compounds at equi-iron
concentrations of 5 μM slowed the growth of both the A2780
and A2780cisR human cancer cell lines by more than 50% (i.e.,
IC50 < 5 μM). The complexes displayed no cross resistance to
cisplatin. In three additional human cancer cell lines the activity
was mostly reduced relative to that for the ovarian cancer lines.
The first- and second-generation ferrocenyl-derived N,O-p-
cymene-ruthenium-PTA metallodendrimers are the most active
of the series.
6
4
and complex [13][PF ] were generally unable to inhibit cell
6
growth of the ovarian lines by more than 50% at a 5 μM iron
concentration (Table 2). The 5637 bladder cancer line was also
quite sensitive to the antiproliferative effects of the tested
compounds, while both the SISO and LCLC-103H lines were
generally more resistant. Thus, the compounds possess a degree
of selectivity for certain cancer cell lines, with a particularly
strong activity in ovarian cancer. This selectivity should be
characterized further in more ovarian cancer cell lines.
The relatively large error bars obtained for some of the
ferrocenyl-derived complexes were attributed to the poor water
solubility of the compounds in the culture medium, with
precipitation sometimes observed at higher concentrations.
Nevertheless, the ferrocenyl-derived N,O and N,N ligands (3−6
and 12) display moderate activity in all cell lines, with the
monomeric ferrocenyl-derived N,O-salicylaldiminato ligand 11
displaying good activity (Figure S19, Supporting Information).
However, there is no correlation between the size of the
dendritic ligand and the activity observed. More specifically, it
seems that the first- and second-generation ferrocenyl-derived
N,O-p-cymene-ruthenium-PTA metallodendrimers [7][PF6]4
and [8][PF ] are the most active of the heterometallic series
EXPERIMENTAL SECTION
■
General Procedures. All reactions were performed under an inert
atmosphere using a dual vacuum/nitrogen line and standard Schlenk-
line techniques unless stated otherwise. All reaction solvents were
dried by heating under reflux and under an inert atmosphere, over the
appropriate drying agent, and all samples were dried under vacuum. 4-
Bromo-2-hydroxybenzaldehyde, 5-bromo-2-pyridinecarboxaldehyde,
triphenylphosphine, palladium acetate, triethylamine, DAB-G -PPI-
1
(
NH ) , sodium hexafluorophosphate, and n-propylamine were
2 4
6
8
purchased from Sigma-Aldrich; DAB-G -PPI-(NH ) was purchased
2
2 8
(
Figure S19). There is an increase in activity observed when
from SyMO-Chem and used without further purification. Ruthenium-
(III) trichloride trihydrate was obtained as a generous donation from
Johnson Matthey/Anglo-American Platinum Limited. Deuterated
moving from the heterometallic model complex [13][PF ] to
6
the higher generation dendritic derivatives [7][PF6] and
4
43a
[
8][PF ] . Furthermore, introduction of the ruthenium-arene
solvents were purchased from Sigma-Aldrich. Vinylferrocene and
6
8
6
43b
moiety does improve the activity in at least two of the
[Ru(η -p-cymene)Cl ]
were prepared according to literature
2
2
metallodendrimers ([7][PF ] and [8][PF ] ) and may be
procedures. Infrared (IR) spectra were measured as pure solids on a
PerkinElmer Spectrum 100 FT-IR spectrometer equipped with a
SMART iTR ATR unit. Intensity of stretching vibrations are marked
as strong (s), medium (m), and weak (w). Melting points (mps) were
6
4
6 8
attributed to possible transmembrane interactions and
increased bioavailability brought on by the ferrocene moiety,
1
7a,19,42
similarly observed with ferrocifens.
A similar trend was
determined using a Bu
̈
chi B-540 instrument. Nuclear magnetic
observed by Auzias et al., where ferrocenyl-derived ruthenium-
arene complexes displayed improved in vitro antitumor activity
against A2780 human ovarian cancer cells in comparison to
resonance (NMR) spectra were recorded on a Varian Unity XR400
1
13
1
31
1
spectrometer ( H, 399.95 MHz; C{ H}: 100.58 MHz; P{ H}:
1
1
61.90 MHz) or Varian Mercury XR300 spectrometer ( H: 300.08
22b
13
1
31
1
their ferrocenyl-derived ligands. However, the improvement
in activity is not observed for the ferrocenyl-derived N,N-p-
cymene-ruthenium metallodendrimers [9][PF6]4 and [10]-
MHz; C{ H}, 75.46 MHz; P{ H}, 121.47 MHz) or Bruker Biospin
1
13
1
GmbH spectrometer ( H, 400.22 MHz; C{ H}, 100.65 MHz;
31
1
P{ H}, 162.00 MHz) at ambient temperature. Chemical shifts δ in
[
PF ] (Figure S19). It cannot be ruled out that the quite
ppm indicate a downfield shift relative to tetramethylsilane (TMS) and
6 8
44
were referenced relative to the signal of the solvent. Coupling
constants J are given in Hz. Individual peaks are marked as singlet (s),
doublet (d), doublet of doublets (dd), triplet (t), or multiplet (m).
High-resolution electrospray ionization-mass spectrometry (HR-ESI-
MS) was carried out on a Waters Synapt mass spectrometer. Data
were recorded in positive ion mode. HPLC analysis was performed on
a Dionex Ultimate 3000 instrument equipped with a ReproSil 100
column (C18 5 μm, 4.6 or 10 mm diameter, 250 mm length) using a
different redox potential of the ruthenium unit in [7][PF ] and
6
4
[
8][PF ] relative to [9][PF ] and [10][PF ] is responsible,
6 8 6 4 6 8
at least in part, for the decrease in cytotoxicity. However, one of
the next steps in the biological evaluation of the heterometallic
ferrocenyl-derived ruthenium-arene metallodendrimers is to
determine the IC50 values of the most active compounds.
Hence, a direct comparison cannot be made between these
heterometallic ferrocenyl-derived ruthenium-arene metalloden-
drimers mentioned and the homometallic ruthenium-arene
linear gradient of 5−90% MeOH/H O containing 0.1% TFA as the
2
−1
eluent over 40 min at a flow rate of 0.6 mL min for analytical
chromatography, respectively. Elemental analysis (C, H, N) was
carried out using a Thermo Flash 1112 Series CHNS-O Analyzer. For
certain metallodendrimers, the analyses are outside acceptable limits
and are ascribed to the encapsulation of solvent molecules and/or
other inorganic salts by the dendritic compounds. The preparation of
compounds 1−6 and 11−14 is given in the Supporting Information.
Synthesis of Ferrocenyl-Derived Cationic N,O-p-cymene-
Ru(II)-PTA Metallodendrimers [7][PF ] and [8][PF ] . Triethyl-
26b,c
metallodendrimers reported;
going.
these experiments are on-
CONCLUSION
■
Heterometallic N,O- and N,N-ferrocenyl-derived ruthenium-
arene metallodendrimers have been successfully synthesized.
All complexes were characterized using an array of spectro-
scopic and analytical techniques, which confirmed formation of
the desired compounds. Their heterometallic model complexes
were prepared and characterized. Electrochemical studies were
performed, revealing that the N,O-p-cymene-Ru(II)-PTA
complexes result in two irreversible redox processes (oxidation
of the Fe(II) and Ru(II) centers), while the N,N-Ru(II)-arene
6
4
6 8
amine (0.017 mL, 0.122 mmol for [7][PF ] ; 0.039 mL, 0.279 mmol
6
4
for [8][PF ] ) was added dropwise to a stirred solution of 3 (0.473 g,
6
8
0
.0301 mmol for [7][PF ] ) or 4 (0.114 g, 0.0347 mmol for
6 4
[
8][PF ] ) in a EtOH/DCM (50/50, 60 mL) solution. The resulting
6 8
orange solution was stirred at room temperature for 0.5 h. Next,
6
[Ru(η -p-cymene)Cl ] (0.0377 g, 0.0616 mmol for [7][PF ] ; 0.0860
2
2
6 4
g, 0.140 mmol for [8][PF ] ) was added to the reaction mixture. The
6
8
5
542
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reaction mixture was stirred overnight at room temperature, and then
under reduced pressure, which resulted in the precipitation of a dark
the reaction mixture was filtered and PTA (0.0191 g, 0.122 mmol for
purple solid. The solid was isolated by filtration, washed with cold
[
7][PF ] ; 0.0438 g, 0.279 mmol for [8][PF ] ) was added to the
EtOH followed by Et O, and dried in vacuo.
6
4
6
8
2
6
2
filtrate. The solution was stirred at room temperature for 6 h and
filtered. A solution of NaPF (0.0205 g, 0.122 mmol for [7][PF ] ;
0
the filtrate at 0 °C and stirred for 1 h. The DCM was removed from
the reaction mixture under reduced pressure, which resulted in the
precipitation of an orange solid. The solid was isolated by filtration,
[DAB-G -PPI-{(η -p-cymene)Ru((C H N )-κ N,N)Cl(5-
1
6
5
2
ferrocenylvinyl)}
][PF ] ([9][PF ] ). Dark-purple solid. Yield: 0.0983 g,
6 4 6 4
1
6
6 4
4
−
.0495 g, 0.279 mmol for [8][PF ] ) in EtOH (5 mL) was added to
84.7%. IR (ATR): ν (cm ) 1586 (s, alkene, CC), 1623 (s, pyridyl
6
8
1
and imine, CN). H NMR ((CD
) CO): δ (ppm) 1.09 (br m, 24H,
3 2
CH(CH
NCH CH
12H, CH3 p‑cymene), 2.62 (br m, 4H, CH(CH
8H, NCH CH CH branch), 4.19 (s, 20H, Cp-CHunsubst ring), 4.43−4.78
(overlapping m, 24H, NCH CH CH N
)
2 p‑cymene), 1.30 (br m, 4H, NCH
CH2 core), 2.00 (br m, 8H,
CH2 core), 2.32 (br d,
2 p‑cymene), 3.26 (br m,
3
2
CH
N
branch), 2.24 (br m, 4H, NCH
2
2
2
2
washed with cold EtOH followed by Et O, and dried in vacuo.
)
3
2
6
2
[
DAB-G -PPI-{(η -p-cymene)Ru((C H NO)-κ N,O)PTA(5-
2
2
N
2
1
7
5
ferrocenylvinyl)} ][PF ] ([7][PF ] ). Orange solid. Yield: 0.0807 g,
7
N). H NMR ((CD ) CO): δ (ppm) 1.13 and 1.27 (br m, 24H,
CH(CH3)2 p‑cymene), 1.66 (br m, 4H, NCH CH2 core), 2.00 (m, 8H,
NCH CH CH Nbranch), 2.09 (br s, 12H, CH3 p‑cymene), 2.16−2.26
(
m, 4H, CH(CH3)2 p‑cymene), 3.96 (br m, 8H, NCH CH CH Nbranch),
, 2 × Cp-CH), 6.00 and
branch
4
6 4
6 4
2
2
2
−1
2.2%. IR (ATR): ν (cm ) 1590 (br s, alkene, CC and imine, C
6.30 (m, 16H, Arp‑cymene), 6.97 and 7.56 (m, 8H, CHalkene), 8.10 (m,
1
4H, Pyr), 8.39 (m, 4H, Pyr), 8.88 (br s, 4H, CHimine), 9.52 (br s, 4H,
3
2
1
3
1
Pyr). C{ H} NMR ((CD
)
CO): δ (ppm) 18.6, 21.5, 22.0
); 68.0, 69.1,
2
3
2
(CH3 p‑cymene); 24.5, 25.0, 51.2, 51.8, 52.7, 64.1 (CH
2
2
2
2
overlapping m, 12H, NCH CH
, NCH CH CH N ), 2.63 (br
70.6 (Cp-CH); 69.5 (Cp-CHunsubst ring); 81.4 (CCp); 31.1, 83.9, 85.2,
85.6, 87.5 (CHp‑cymene); 104.9, 105.3 (Cp‑cymene); 119.1, 137.3
(CHalkene); 129.1, 133.4, 153.7 (CHPyr); 139.3, 151.5 (CPyr); 168.1
2
2 core
2
2
2
branch
2
2
2
4
.13 (br s, 20H, Cp-CHunsubst ring), 4.22−4.55 (overlapping m, 64H,
PTA, 2 × Cp-CH), 5.58 (br d, 4H, Arp‑cymene), 5.83 (br d, 4H,
Ar ), 6.24 (br d, 4H, Arp‑cymene), 6.40 (br d, 4H, Arp‑cymene), 6.66
(CHimine). Anal. Found for C128H N10Cl F24Fe P Ru ·4.5DCM
148 4 4 4 4
(3558.1648): C, 44.45; H, 4.68; N, 3.84. Calcd: C, 44.73; H, 4.45;
N, 3.94. MS (HR-ESI-TOF, m/z): 649.1115 [M + H] (where M =
p‑cymene
3
5+
(
d, J = 16.2 Hztrans, 4H, CHalkene), 6.78 (br d, 4H, Ar), 6.85 (br s, 4H,
3
Ar), 7.07 (d, J = 16.0 Hztrans, 4H, CHalkene), 7.17 (m, 4H, Ar), 8.08 (br
s, 4H, CHimine). C{ H} NMR ((CD ) CO): δ (ppm) 17.9, 20.9, 21.5
(
(
(
1
(
−
C
[9][PF
[DAB-G
ferrocenylvinyl)} ][PF ] ([10][PF ] ). Dark purple solid. Yield: 0.0985
]
6
4
− 4PF
2
). Mp: 236 °C (decomposes without melting).
6
6 2
13
1
-PPI-{(η -p-cymene)Ru((C
H N )-κ N,N)Cl(5-
6 5 2
3
2
CH3 p‑cymene); 25.0, 53.9, 65.5, 68.3 (CH ); 51.1, 51.2, 72.4, 72.5
8
6 8
6 8
2
−
1
g, 72.9%. IR (ATR): ν (cm ) 1588 (s, alkene, CC), 1625 (s,
CH2 PTA); 67.1, 67.3, 69.4 (Cp-CH); 69.1 (Cp-CHunsubst ring); 83.2
CCp); 30.7, 82.9, 87.5, 88.8, 91.7 (CHp‑cymene); 97.5, 119.9 (Cp‑cymene);
1
pyridyl and imine, CN). H NMR ((CD ) CO): δ (ppm) 1.06 and
3
2
1
.11 (br m, 48H, CH(CH )
), 1.28 (br m, 4H, NCH CH
),
2 core
12.9, 119.3, 135.4 (CH ); 118.5, 145.0, 164.5 (C ); 125.4, 130.4
3
2 p‑cymene
2
Ar
Ar
31
1
1
.86−2.30 (overlapping m, 48H, NCH CH CH Nfirst branch,
CHalkene); 165.6 (CHimine). P{ H} NMR ((CD ) CO): δ (ppm)
2
2
2
3
2
1
NCH CH CH N
, CH
), 2.54−3.23 (overlapping m,
32.7 (s, PTA), −144.1 (sep, J = 709.7 Hz, PF ). Anal. Found for
2
2
2
second branch
3 p‑cymene
6
4
4 H , N C H C H 2
,
N C H C H C H N
,
,
H
N F Fe O P Ru ·3DCM (3973.589): C, 48.27; H, 5.76; N,
2
c o r e
f i r s t b r a n c h
CH(CH3)2 p‑cymene), 4.19 (br s, 40H, Cp-CH
2
2
2
f i r s t b r a n c h
1
56 196 18 24
4
4
8
4
NCH CH CH N
,
NCH CH CH N
6
6
(
.44. Calcd: C, 48.06; H, 5.12; N, 6.35. MS (HR-ESI-TOF, m/z):
2
2
2
2
2
2
s e c o n d b r a n c h
), 4.43−4.71
27.7885 [M + 2H]6 (where M = [7][PF ] − 4PF ). Mp: 166 °C
+
unsubst ring
6
4
6
(
overlapping m, 48H, NCH CH CH Nsecond branch, 2 × Cp-CH), 5.90
decomposes without melting).
2 2 2
6
2
and 6.21 (m, 32H, Arp‑cymene), 6.98 and 7.55 (m, 16H, CHalkene), 8.06
[
DAB-G -PPI-{(η -p-cymene)Ru((C H NO)-κ N,O)PTA(5-
2
7
5
ferrocenylvinyl)} ][PF ] ([8][PF ] ). Orange solid. Yield: 0.2013 g,
7
N). H NMR ((CD ) CO): δ (ppm) 1.12 and 1.26 (br d, 48H,
(m, 8H, Pyr), 8.34 (m, 8H, Pyr), 8.73 (br s, 8H, CHimine), 9.50 (br s,
8
6 8
6 8
−1
13
1
6.6%. IR (ATR): ν (cm ) 1590 (br s, alkene, CC and imine, C
8H, Pyr). C{ H} NMR ((CD
3
)
2
CO): δ (ppm) 18.5, 21.4, 22.0
); 68.1, 70.6 (Cp-CH);
1
(CH3 p‑cymene); 26.7, 50.8, 51.4, 51.7, 64.9 (CH
3
2
2
CH(CH3)2 p‑cymene), 1.81−3.25 (overlapping m, 64H, NCH CH2 core,
69.5 (Cp-CH unsubst. ring); 81.5 (C Cp); 31.1, 84.3, 85.2, 85.3, 87.4 (CH
p‑cymene); 103.9, 105.4 (Cp‑cymene); 119.0, 137.1 (CHalkene); 128.6, 133.4,
151.7 (CHPyr); 139.1, 151.7 (CPyr); 166.8 (CHimine). Anal. Found for
C264H312N Cl F Fe P Ru ·9DCM (7256.558): C, 45.41; H, 4.11; N,
2
NCH CH
, NCH CH CH N
, NCH CH CH Nfirst branch,
2
2 core
2
2
2
first branch
2
2
2
NCH CH CH N
,
NCH CH CH N
,
2
2
2
f i r s t b r a n c h
2
2
2
s e c o n d b r a n c h
NCH CH CH Nsecond branch), 2.20 (s, 24H, CH3 p‑cymene), 2.60 (br m,
2
2
2
22
8
48
8
8
8
8
H, CH(CH3)2 p‑ cymene), 3.89 and 4.00 (br m, 16H,
4.37. Calcd: C, 45.19; H, 4.58; N, 4.25. MS (HR-ESI-TOF, m/z):
667.4059 [M]8 (where M = [10][PF ] − 8PF ). Mp: 203−204 °C.
+
NCH CH CH Nsecond branch), 4.13 (br s, 40H, Cp-CHunsubst ring),
2
2
2
6
8
6
4
.13−4.61 (overlapping m, 128H, PTA, 2 × Cp-CH), 5.52 (m, 8H,
Electrochemical Studies. Electrochemical studies were not
performed on the ferrocenyl-derived precursors 1 and 2 and ligands
3−6, 11, and 12, as the focus of this study was on the ferrocenyl-
Ar ), 5.82 (m, 8H, Ar ), 6.19 (m, 8H, Ar ), 6.38 (m,
p‑cymene
p‑cymene
p‑cymene
8
8
H, Arp‑cymene), 6.65 (br d, 8H, CHalkene), 6.71 (m, 8H, Ar), 6.84 (br s,
H, Ar), 7.05 (br d, 8H, CHalkene), 7.22 (m, 8H, Ar), 8.13 (br s, 8H,
derived p-cymene-ruthenium complexes [7][PF
]
−[10][PF
]. Cyclic voltammetric studies were performed at
6
] , [13]-
6
4
6 8
13
1
CHimine). C{ H} NMR ((CD ) CO): δ (ppm) 18.0, 21.0, 21.4
[PF ], and [14][PF
6
3
2
(
CH3 p‑cymene); 23.5, 43.2, 59.2, 68.2 (CH ); 51.1, 51.2, 72.5 (CH2 PTA);
ambient temperature using a Bioanalytical Systems Inc. BAS 100W
Electrochemical Analyzer with a one-compartment, three-electrode
2
6
8
1
7.1, 67.4, 69.5 (Cp-CH); 69.2 (Cp-CHunsubst ring); 83.0 (C ); 30.7,
Cp
2.9, 87.6, 88.8, 91.8 (CHp‑cymene); 97.2, 120.0 (Cp‑cymene); 112.9, 119.2,
35.5 (CH ); 118.6, 145.0, 164.5 (C ); 125.5, 130.4 (CHalkene); 165.7
system comprising of a Pt-disk working electrode, a platinum-wire
+
auxiliary electrode, and a Ag/Ag reference electrode (0.01 M AgNO
Ar
Ar
3
31
1
(
−
C
CHimine). P{ H} NMR ((CD ) CO): δ (ppm) −31.5 (s, PTA),
and 0.1 M [n-Bu
electrochemical potentials (given in Table 1) are with reference to this
electrode. Measurements were made on anhydrous CH CN solutions,
which were 2 mM in sample and contained 0.1 M [n-Bu N][ClO ] as
4 4 3
N][ClO ] in anhydrous CH CN). The reported
3
2
1
144.0 (sep,
J = 711.5 Hz, PF ). Anal. Found for
6
320H414N F Fe O P Ru ·9DCM (8348.252): C, 47.29; H, 6.60;
3
38
48
8
8
16
8
N, 6.46. Calcd: C, 47.33; H, 5.22; N, 6.38. MS (HR-ESI-TOF, m/z):
2
4
4
47.1670 [M + 18H]2 (where M = [8][PF ] − 8PF ). Mp: 285 °C
6+
the background electrolyte. (Caution! Perchlorate salts of metal
complexes are potentially explosive and the samples should be handled
with care.) Scan rates were optimized in an effort to obtain smoother
voltammograms. Unless otherwise stated, the scan rate used was 100
6
8
6
(
decomposes without melting).
Synthesis of Ferrocenyl-Derived Cationic N,N-p-cymene-
6
Ru(II) Metallodendrimers [9][PF ] and [10][PF ] . [Ru(η -p-
6
4
6 8
−1
cymene)Cl ] (0.0906 g, 0.148 mmol for [9][PF ] ; 0.0516 g, 0.0843
mV s . Under these conditions the ferrocene/ferrocenium couple,
2
2
6 4
mmol for [10][PF ] ) was added to a stirred orange-red solution of 5
which was used as a reference, had E1/2 = +0.12 V and ΔE = 0.10 V.
6
8
p
(
0.0553 g, 0.0365 mmol for [9][PF ] ) or 6 (0.0659 g, 0.0208 mmol
All solutions were purged with argon, and voltammograms were
recorded under a blanket of argon. The platinum working electrode
was polished between runs.
6
4
for [10][PF ] ) in a EtOH/DCM (50/50, 60 mL) solution. The dark
6
8
purple reaction mixture was stirred overnight at room temperature,
and then the reaction mixture was filtered. A solution of NaPF6
X-ray Crystallography. Crystals of 1 and the heterometallic
(
0.0249 g, 0.148 mmol for [9][PF ] ; 0.0281 g, 0.168 mmol for
mononuclear complex [13][PF ] were mounted on a STOE Image
6
4
6
[
10][PF ] ) in EtOH (5 mL) was added to the filtrate at 0 °C and
Plate Diffraction system equipped with a ϕ circle goniometer, using
Mo Kα graphite monochromated radiation (λ 0.71073 Å) with ϕ
6
8
stirred for 1 h. The DCM was removed from the reaction mixture
5
543
dx.doi.org/10.1021/om500809g | Organometallics 2014, 33, 5535−5545

Organometallics
Article
range 0−200°. The structures were solved by direct methods using the
program SHELXS-97, while the refinement and all further calculations
they are gratefully acknowledged. We also thank members of
COST Action CM1105 for useful discussions.
45
were carried out using SHELXL-97. The H atoms were included in
calculated positions and treated as riding atoms using the SHELXL
default parameters. The non-H atoms were refined anisotropically,
REFERENCES
■
2
using weighted least squares on F . Crystallographic details are
(
(
1) Gordon, M.; Hollander, S. J. Med. Chem. 1993, 24, 209−265.
2) Wheate, N. J.; Walker, S.; Craig, G. E.; Oun, R. Dalton Trans.
summarized in Table S1 (Supporting Information). Figures 1 and 2
46
were drawn with ORTEP.
2
(
010, 39, 8097−8340.
3) Pongratz, M.; Schluga, P.; Jakupec, M. A.; Arion, V. B.; Hartinger,
C. G.; Allmaier, G.; Keppler, B. K. J. Anal. At. Spectrom. 2004, 19, 46−
1.
4) Bergamo, A.; Sava, G. Dalton Trans. 2007, 13, 1267−1272.
5) (a) Dickson, N. R.; Jones, S. F.; Burris, H. A. J. Clin. Oncol. 2011,
9, (suppl.; abstract 2607). (b) Heffeter, P.; Atil, B.; Kryeziu, K.;
Cell Proliferation Assay. Testing was done with cells growing in
9
6-well microtiter plates at 37 °C with 5% CO /air. Shortly before
2
confluency, cells were trypsinized and a single-cell suspension was
prepared. Cells were then plated out at a density of 250−2000 cells/
well in 100 μL medium, depending on the cell line. Plates were
returned to the incubator and cells allowed to attach and begin
growing for 24 h before adding test substances. On the next day, one
untreated plate for each cell line was removed, fixed with
glutaraldehyde, and stored in the refrigerator; this plate served later
5
(
(
2
Groza, D.; Koellensperger, G.; Korner, W.; Jungwirth, U.; Mohr, T.;
Keppler, B. K.; Berger, W. Eur. J. Cancer 2013, 49, 3366−3375.
(6) Clarke, M. J.; Zhu, F. C.; Frasca, D. R. Chem. Rev. 1999, 99,
as the control (T ). All test substances were dissolved in DMF to a
c,0
2
(
511−2533.
7) (a) Noffke, A. L.; Habtemariam, A.; Pizarro, A. M.; Sadler, P. J.
Chem. Commun. 2012, 48, 5219−5246. (b) Suss-Fink, G. Dalton Trans.
010, 39, 1673−1688. (c) Nazarov, A. A.; Hartinger, C. G.; Dyson, P.
concentration of Fe of 5.0 mM, as calculated from the molecular
formula. Next, these solutions were diluted 500-fold into culture
medium to give twice the target concentration. Then, 100 μL of
medium containing the test substance was added to each well, which
already contained 100 μL of medium. The final solvent concentration
̈
2
J. J. Organomet. Chem. 2014, 751, 251−260. (d) Bratsos, I.;
Gianferrara, T.; Alessio, E.; Hartinger, C. G.; Jakupec, M. A.;
Keppler, B. K., In Bioinorganic Medicinal Chemistry, Alessio, E., Ed.;
Wiley-VCH: Weinheim, Germany, 2011; pp 151−174. (e) Liu, H.-K.;
Sadler, P. J. Acc. Chem. Res. 2011, 44, 349−359. (f) Jakupec, M. A.;
Galanski, M.; Arion, V. B.; Hartinger, C. G.; Keppler, B. K. Dalton
Trans. 2008, 183−194.
(
i.e., DMF) in each well was 0.1%. After 96 h incubation with
substance, the culture medium was discarded and replaced with 100
μL/well of a 1% glutaraldehyde−buffer solution for 20 min to fix the
cells. The fixing solution was discarded, and the cells were stored
under 100 μL/well of PBS at 4 °C until staining. Before the cell mass
was stained with crystal violet, the PBS medium was removed. Cell
staining was done for 30 min with 100 μL/well of a 0.02% solution of
crystal violet dissolved in PBS buffer solution. After the excess dye was
discarded and the cells washed for 15 min in clear water, the cell-
bound dye was redissolved in 100 μL/well 70% ethanol/water and the
optical densities of the wells were measured at λ 570 nm with a
microtiter plate reader. Cell proliferation (T/Ccorr) was calculated by
the equation
(8) (a) Casini, A.; Hartinger, C. G.; Nazarov, A. A.; Dyson, P. J.
Organometallic Antitumour Agents with Alternative Modes of Action;
Springer: Berlin, 2010; Top. Organomet. Chem. Vol. 32. (b) Ang, W.
H.; Casini, A.; Sava, G.; Dyson, P. J. J. Organomet. Chem. 2011, 696,
9
(
89−998.
9) Scolaro, C.; Bergamo, A.; Brescacin, L.; Delfino, R.; Cocchietto,
M.; Laureneczy, G.; Geldbach, T. J.; Sava, G.; Dyson, P. J. J. Med.
Chem. 2005, 48, 4161−4171.
O.D. − O.D.
T
c,0
c,0
(10) Chatterjee, S.; Kundu, S.; Bhattacharyya, A.; Hartinger, C. G.;
Dyson, P. J. J. Biol. Inorg. Chem. 2008, 13, 1149−1155.
T/Ccorr (%) =
× 100
O.D. − O.D.
c
(1)
(11) Nowak-Sliwinska, P.; van Beijnum, J. R.; Casini, A.; Nazarov, A.
where OD is the mean optical density of the treated cells, OD the
mean optical density of the controls, and ODc,0 the mean optical
density at the time drug was added (Tc,0).
̀
A.; Wagnieres, G.; van den Bergh, H.; Dyson, P. J.; Griffioen, A. W. J.
T
c
Med. Chem. 2011, 54, 3895−3902.
(12) (a) Lease, N.; Vasilevski, V.; Carreira, M.; de Almeida, A.;
Sanau, M.; Hirva, P.; Casini, A.; Contel, M. J. Med. Chem. 2013, 56,
5806−5818. (b) Donzello, M. P.; Viola, E.; Ercolani, C.; Fu, Z.; Futur,
D.; Kadish, K. M. Inorg. Chem. 2012, 51, 12548−12559. (c) Gonzalez-
Pantoja, J. F.; Stem, M.; Jarzecki, A. A.; Royo, E.; Robles-Escajeda, E.;
Varela-Ramirez, A.; Aguilera, R. J.; Contel, M. Inorg. Chem. 2011, 50,
ASSOCIATED CONTENT
Supporting Information
Text, figures, a table, and CIF files giving details of syntheses
■
*
S
and characterization data, NMR spectra, cyclic voltammograms,
1
1099−11110. (d) Pelletier, F.; Comte, V.; Massard, A.; Wenzel, M.;
a plot of T/Ccorr, and crystal data for 1 and [13][PF ]·H O.
6
2
Toulot, S.; Richard, P.; Picquet, M.; Le Gendre, P.; Zava, O.; Edafe, F.;
This material is available free of charge via the Internet at
Casini, A.; Dyson, P. J. J. Med. Chem. 2010, 53, 6923−6933.
http://pubs.acs.org. CCDC 1011457 (1) and 1011458 ([13]-
(e) Wenzel, M.; Bertrand, B.; Eymin, M. J.; Comte, V.; Harvey, J. A.;
[
PF ]·H O) also contain supplementary crystallographic data
Richard, P.; Groessl, M.; Zava, O.; Amrouche, H.; Harvey, P. D.; Le
Grande, P.; Picquet, M.; Casini, A. Inorg. Chem. 2011, 50, 9472−9480.
(13) Heinze, K.; Lang, H. Organometallics 2013, 32, 5623−5625.
6
2
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
(14) (a) van Staveren, D. R.; Metzler-Nolte, N. Chem. Rev. 2004, 104,
5
931−5985. (b) Fouda, M. F. R.; Abd-Elzaher, M. M.; Abdelsamaia, R.
A.; Labib, A. A. Appl. Organomet. Chem. 2006, 21, 613−625. (c) Braga,
AUTHOR INFORMATION
Corresponding Author
G.S.S.: e-mail, gregory.smith@uct.ac.za; fax, +27-21-650 5195.
■
*
S. S.; Silva, A. M. S. Organometallics 2013, 32, 5626−5639.
(
̀ ́
15) (a) Pigeon, P.; Top, S.; Vessieres, A.; Huche, M.; Hillard, E. A.;
Salmon, E.; Jaouen, G. J. Med. Chem. 2005, 48, 2814−2821.
(b) Vessieres, A.; Top, S.; Beck, W.; Hillard, E. A.; Jaouen, G. Dalton
Trans. 2006, 4, 529−541.
16) (a) Popova, L. V.; Babin, V. N.; Belousov, Y. A.; Nekrasov, Y. S.;
Snegueva, A. E.; Borodina, N. P.; Shaposhnikova, G. M.; Bychenko, O.
B.; Raevskii, P. M. Appl. Organomet. Chem. 1993, 7, 85−94. (b) Kopf-
Maier, P.; Kopf, H.; Neuse, E. W. J. Cancer Res. Clin. 1984, 108, 336−
40.
(17) (a) Nguyen, A.; Vessieres, A.; Hillard, E. A.; Top, S.; Pigeon, P.;
Jaouen, G. Chimia 2007, 61, 716−724. (b) Top, S.; Vessieres, A.;
Notes
̀
The authors declare no competing financial interest.
(
ACKNOWLEDGMENTS
■
̈
Financial support from the University of Cape Town and the
National Research Foundation (NRF) of South Africa and a
generous donation of ruthenium trichloride trihydrate from the
Anglo-American Platinum Limited Corporation/Johnson Mat-
̈
3
̀
̀
5
544
dx.doi.org/10.1021/om500809g | Organometallics 2014, 33, 5535−5545

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Article
̌
̈
̌ ̌
(38) (a) Tauchman, J.; Therrien, B.; Suss-Fink, G.; Stepnicka, P.
Cabestaing, C.; Laios, I.; Leclereq, G.; Provot, C.; Jaouen, G. J.
Organomet. Chem. 2001, 637−639, 500−506.
Organometallics 2012, 31, 3985−3994. (b) Mai, J.-F.; Yamamoto, Y. J.
Organomet. Chem. 1998, 560, 223−232.
(
18) (a) Hillard, E. A.; Vessier
D.; Huche,
references therein. (b) Wardman, P.; Candeias, L. P. Radiat. Res. 1996,
̀
es, A.; Le Bideau, F.; Plazul, D.; Spera,
̌
̌ ̌
(39) (a) Stepnicka, P.; Gyepes, R. Organometallics 1997, 16, 5089−
́
M.; Jaouen, G. Chem. Med. Chem. 2006, 1, 551−559 and
5
095. (b) Sixt, T.; Sieger, M.; Krafft, M. J.; Bubrin, D.; Fiedler, J.;
Kaim, W. Organometallics 2010, 29, 5511−5516. (c) Therrien, B.;
1
(
(
45, 523−531.
̌
Vieille-Petit, L.; Jeanneret-Gris, J.; Step
Organomet. Chem. 2004, 689, 2456−2463.
40) Lopez, C.; Bosque, R.; Perez, S.; Roig, A.; Molins, E.; Solans, X.;
Font-Bardia, M. J. Organomet. Chem. 2006, 691, 475−484.
41) Bracht, K.; Boubakari; Gruner, R.; Bednarski, P. J. Anticancer
Drugs 2006, 17, 41−51.
42) Hillard, E. A.; Pigeon, P.; Vessier
Dalton Trans. 2007, 5073−5081.
43) (a) Bennett, M. A.; Smith, A. K. J. Chem. Soc., Dalton Trans.
974, 2, 233−241. (b) Sonoda, A.; Moritani, I.; Saraie, T.; Wada, T.
Tetrahedron Lett. 1969, 2943−2946.
44) Fulmer, G. R.; Miller, A. J. M.; Sherden, N. H.; Gottlieb, H. E.;
̌ ̌
̈
nicka, P.; Suss-Fink, G. J.
19) Ornelas, C. New J. Chem. 2011, 35, 1973−1985.
20) Goitia, H.; Nieto, Y.; Villacampa, D.; Kasper, C.; Laguna, A.;
(
Gimeno, C. Organometallics 2013, 32, 6069−6078.
(
21) Rajput, J.; Moss, J. R.; Hutton, A. T.; Hendricks, D. T.; Arendse,
(
C. E.; Imrie, C. J. Organomet. Chem. 2004, 689, 1553−1568.
̌
(
22) (a) Tauchman, J.; Su
̈
ss-Fink, G.; Step
̌
nick
̌
a, P.; Zava, O.; Dyson,
(
̀
es, A.; Amatore, C.; Jaouen, G.
P. J. J. Organomet. Chem. 2013, 723, 233−238. (b) Auzias, M.;
Gueniat, J.; Therrien, B.; Suss-Fink, G.; Renfrew, A. K.; Dyson, P. J. J.
Organomet. Chem. 2009, 694, 855−861. (c) Auzias, M.; Therrien, B.;
̈
(
1
̌
̈
̌ ̌
ss-Fink, G.; Stepnicka, P.; Ang, W. H.; Dyson, P. J. Inorg. Chem.
Su
008, 47, 578−583.
23) Billecke, C.; Finniss, S.; Tahash, L.; Miller, C.; Mikkelsen, T.;
Farrell, N. P.; Bogler, O. Neuro-Oncology 2006, 8, 215−226.
24) (a) Astruc, D.; Boisselier, E.; Ornelas, C. Chem. Rev. 2010, 110,
2
(
(
Nudelman, A.; Stoltz, B. M.; Bercaw, J. E.; Goldberg, K. I.
Organometallics 2010, 29, 2176−2179.
(
(
(
45) Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, A64, 112−122.
46) Farrugia, L. J. Appl. Crystallogr. 1997, 30, 565.
1
6
857−1959. (b) Newkome, G. R.; Shreiner, C. Chem. Rev. 2010, 110,
338−6442. (c) Newkome, G. R.; He, E.; Moorefield, C. N. Chem.
Rev. 1999, 99, 1689−1746. (d) Seek-Ho, H.; Shreiner, C. D.;
Moorefield, C. N.; Newkome, G. R. New J. Chem. 2007, 31, 1192−
1217. (e) Angurell, I.; Rossell, O.; Seco, M. Inorg. Chim. Acta 2014,
4
(
09, 2−11.
25) (a) Govender, P.; Therrien, B.; Smith, G. S. Eur. J. Inorg. Chem.
2
012, 2853−2862. (b) El Kazzouli, S.; El Brahmi, N.; Mignani, S.;
Bousmina, M.; Zablocka, M.; Majoral, J.-P. Curr. Med. Chem. 2012, 19,
995−5010.
26) (a) Govender, P.; Antonels, N. C.; Mattsson, J.; Renfrew, A. K.;
Dyson, P. J.; Moss, J. R.; Therrien, B.; Smith, G. S. J. Organomet. Chem.
009, 694, 3470−3476. (b) Govender, P.; Renfrew, A. K.; Clavel, C.
M.; Dyson, P. J.; Therrien, B.; Smith, G. S. Dalton Trans. 2011, 40,
158−1167. (c) Govender, P.; Sudding, L. C.; Clavel, C. M.; Dyson, P.
J.; Therrien, B.; Smith, G. S. Dalton Trans. 2013, 42, 1267−1277.
27) Govender, P.; Edafe, F.; Makhubela, B. C. E.; Dyson, P. J.;
Therrien, B.; Smith, G. S. Inorg. Chim. Acta 2014, 409, 112−120.
28) Payne, R.; Govender, P.; Therrien, B.; Clavel, C. M.; Dyson, P.
J.; Smith, G. S. J. Organomet. Chem. 2013, 729, 20−27.
29) (a) Liu, W.-Y.; Xu, Q.-H.; Ma, Y.-X.; Liang, Y.-M.; Dong, N.-L.;
4
(
2
1
(
(
(
Guan, D.-P. J. Organomet. Chem. 2001, 625, 128−131. (b) Gallei, M.;
Klein, R.; Rehahn, M. Macromolecules 2010, 43, 1844−1854.
(
30) Reyes, M. I.; Vazquez Garcia, R. A.; Klimova, T.; Klimova, E.;
Ortiz-Frade, L.; Martinez Garcia, M. Inorg. Chim. Acta 2008, 361,
597−1605.
31) Williams, D. H.; Fleming, I. In Spectroscopic Methods in Organic
Chemistry; McGraw-Hill: United Kingdom, 1989; Table 3.27.
32) Yang, Y.-F.; Chen, Y.; Xie, T.; Liang, Y.-M. Synth. Commun.
002, 32, 2627−2631.
33) Jansen, J. F. G. A.; de Brabander-van den Berg, E. M. E.; Meijer,
E. W. Science 1994, 266, 1226−1269.
34) (a) Smolenski, P.; Pruchnik, F. P.; Ciunik, Z.; Lis, T. Inorg.
1
(
(
2
(
(
Chem. 2003, 42, 3318−3322. (b) Pruchnik, F. P.; Smolenski, P.;
Galdecka, E.; Galdecki, Z. New J. Chem. 1998, 22, 1395−1398.
(
35) (a) Renfrew, A. K.; Phillips, A. D.; Tapavicza, E.; Scopelliti, R.;
Rothlisberger, U.; Dyson, P. J. Organometallics 2009, 28, 5061−5071.
b) Ang, W. H.; Daldini, E.; Scolaro, C.; Scopelliti, R.; Juillerat-
Jeanneret, L.; Dyson, P. J. Inorg. Chem. 2006, 45, 9006−9013.
36) (a) Chavian, N.; Vezin, H.; Dive, D.; Touati, N.; Paul, J. F.;
(
(
Buisine, E.; Biot, C. Mol. Pharmaceutics 2008, 5, 710−716. (b) Dubar,
F.; Bohic, S.; Slomianny, C.; Morin, J. C.; Thomas, P.; Kalamou, H.;
Guerardel, Y.; Cloetens, P.; Khalife, J.; Biot, C. Chem. Commun. 2012,
4
8, 910−912. (c) Biot, C.; Castro, W.; Botte, C. Y.; Navarro, M.
Dalton Trans. 2012, 41, 6335−6349.
37) Matsinha, L. C.; Malatji, P.; Hutton, A. T.; Venter, G. A.;
Mapolie, S. F.; Smith, G. S. Eur. J. Inorg. Chem. 2013, 4318−4326.
(
5
545
dx.doi.org/10.1021/om500809g | Organometallics 2014, 33, 5535−5545