Thiophenolato-bridged dinuclear arene ruthenium complexes: A new family of highly cytotoxic anticancer agents

Article abstract of DOI:10.1039/c0dt00887g

New cationic diruthenium complexes of the type [(arene)₂Ru ₂(SPh)₃]⁺, arene being C₆H ₆, p-ⁱPrC₆H₄Me, C₆Me ₆, C₆H₅R, where R = (CH₂) _nOC(O)C₆H₄-p-O(CH₂) ₆CH₃ or (CH₂)_nOC(O)CHCHC ₆H₄-p-OCH₃ and n = 2 or 4, are obtained from the reaction of the corresponding precursor [(arene)RuCl₂] ₂ and thiophenol and isolated as their chloride salts. The complexes have been fully characterised by spectroscopic methods and the solid state structure of [(C₆H₆)₂Ru₂(SPh) ₃]⁺, crystallised as the hexafluorophosphate salt, has been established by single crystal X-ray diffraction. The complexes are highly cytotoxic against human ovarian cancer cells (cell lines A2780 and A2780cisR), with the IC₅₀ values being in the submicromolar range. In comparison the analogous trishydroxythiophenolato compounds [(arene)₂Ru ₂(S-p-C₆H₄OH)₃]Cl (IC₅₀ values around 100 μM) are much less cytotoxic. Thus, it would appear that the increased antiproliferative effect of the arene ruthenium complexes is due to the presence of the phenyl or toluyl substituents at the three thiolato bridges. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/c0dt00887g

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Thiophenolato-bridged dinuclear arene ruthenium complexes: a new family of
highly cytotoxic anticancer agents†
Michae¨l Gras,a Bruno Therrien,a Georg Su¨ss-Fink,*a Olivier Zavab and Paul J. Dysonb
Received 21st July 2010, Accepted 11th August 2010
DOI: 10.1039/c0dt00887g
New cationic diruthenium complexes of the type [(arene)2Ru2(SPh)3]+, arene being C6H6, p-iPrC6H4Me,
C6Me6, C6H5R, where R = (CH2)nOC(O)C6H4-p-O(CH2)6CH3 or (CH2)nOC(O)CH CHC6H4-p-OCH3
and n = 2 or 4, are obtained from the reaction of the corresponding precursor [(arene)RuCl2]2 and
thiophenol and isolated as their chloride salts. The complexes have been fully characterised by
spectroscopic methods and the solid state structure of [(C6H6)2Ru2(SPh)3]+, crystallised as the
hexafluorophosphate salt, has been established by single crystal X-ray diffraction. The complexes are
highly cytotoxic against human ovarian cancer cells (cell lines A2780 and A2780cisR), with the IC50
values being in the submicromolar range. In comparison the analogous trishydroxythiophenolato
compounds [(arene)2Ru2(S-p-C6H4OH)3]Cl (IC50 values around 100 mM) are much less cytotoxic. Thus,
it would appear that the increased antiproliferative effect of the arene ruthenium complexes is due to
the presence of the phenyl or toluyl substituents at the three thiolato bridges.
colon (SW480) cancer cell lines. A pronounced influence of the
spacer length and cytotoxicity was found (A2780 IC50 25 mM for
n = 3, 30 mM for n = 6, 1.5 mM for n = 12, SW480 IC50 62 mM for
1. Introduction
Water-soluble arene ruthenium complexes such as the
prototype (p-iPrC6H4Me)Ru(P-pta)Cl2 (pta
= 1,3,5-triaza-
n = 3, 26 mM for n = 6, 0.3 mM for n = 12), with the cytotoxicity
7-phosphatricyclo[3.3.1.1]decane) (termed RAPTA-C)1 and
lipophilic compounds such as the benchmark [(C6H5Ph)Ru(N,N-
en)Cl]+ (en = 1,2-ethylenediamine)2 have antitumoral or an-
timetastatic properties in vitro and in vivo. The anticancer potential
of these types of compounds has been explained by their dual
character, with the hydrogen bonding capacity of the pta or
en ligands counterbalanced by the lipophilicity of the arene
ligand,3 while the mechanism of cytotoxic action is thought to
involve hydrolysis of the Ru–Cl bond followed by reaction with
the biomolecular target or targets.4 The underlying design of
arene ruthenium anticancer agents and the current understand-
ing of their mode of action is summarised in several review
articles.5–9
being correlated with lipophilicity and water solubility.12,13
A
detailed structure–activity relationship was established based on
water/octanol partition and hydrolytic stability, showing that only
the most lipophilic (long) chain (n = 12) is highly active, due to
the ability of the compound to cross-link with biomolecules.14
This is in agreement with the cytotoxicities we observed
for dinuclear ferrocenyl pyridine arene ruthenium complexes
[(arene)RuCl2]2(NC5H4OOCC5H4FeC5H4COOC5H4N), arene be-
ing p-iPrC6H4Me (Fig. 1) or C6Me6.15
Dinuclear arene ruthenium complexes containing 2,3-bis(2-
pyridyl)pyrazine (bpp) as
a doubly chelating ligand in
the N,N:N,N-bridge have been synthesised and studied for
photoactivation by Sadler in view of their potential in
photodynamic therapy. The benzene and indane deriva-
tives [{(C6H6)RuCl}2(N,N:N,N-bpp)]2+ and [{(C9H10)RuCl}2-
(N,N:N,N-bpp)]2+ (Fig. 1) readily undergo arene loss upon
UV irradiation whereas the p-cymene and hexamethylbenzene
derivatives do not. The indane derivative undergoes aquation in
the dark, and UV or visible light leads to a dissociation of the
indane ligand and to the formation of strong diruthenium DNA
adducts.16
Based on our earlier work on dinuclear arene ruthenium
complexes of the type [(arene)2Ru2(SX)3]+ (arene = C6H6, p-
iPrC6H4Me or C6Me6 and X = p-C6H4-OH, p-C6H4Br, p-C6H4-
3¢-C4H3S, p-C6H4–C6H5, p-C6H4-(m-C6H4C6H5), p-C6H4C10H7,
C6H4-p-CH3 or C2H4-OH),17–21 we now report on the synthesis
of new trithiophenolato-bridged dinuclear arene ruthenium com-
plexes [(arene)2Ru2(SPh)3]+, which in the form of their chloride
salts proved to be highly active against human ovarian cancer
cell lines, with the cytotoxicity being in the submicromolar
range.
While most cytotoxicity studies with arene ruthenium com-
pounds have been concerned with mononuclear complexes,
the question of applying the multinuclearity concept to arene
ruthenium complexes was recently raised,10 in the light of
an increased cytotoxicity of trinuclear arene ruthenium clus-
ter cations.11 This is indeed confirmed by recent findings
with highly active dinuclear arene ruthenium complexes: the
dinuclear arene ruthenium complexes (p-iPrC6H4Me)Ru(O,O-
C6H5O2N(CH2)nNC6H5O2-O,O)Ru(p-iPrC6H4Me) containing a
pyridone-derived linker (Fig. 1) reported by Hartinger show
relevant cytotoxic effects against human ovarian (A2780) and
aInstitut de Chimie, Universite´ de Neuchaˆtel, Case postale 158, CH-2009,
Neuchaˆtel, Switzerland; Fax: +41 (0) 32 718 25 11; Tel: +41 (0) 32 718
24 00
bInstitut des Sciences et Inge´nierie Chimiques, Ecole Polytechnique Fe´de´rale
de Lausanne (EPFL), CH1015, Lausanne, Switzerland
† CCDC reference number 771826. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/c0dt00887g
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Fig. 1 Cytotoxic dinuclear arene ruthenium complexes.
Scheme 1 Synthesis of the diene precursors 1–4.
6, (CH2)2OC(O)CH CHC6H4-p-OCH3: 7, (CH2)4OC(O)-
CH CHC6H4-p-OCH3: 8), are accessible from the reaction
of the corresponding dienes 1, 2, 3 and 4 with ruthenium(III)
chloride hydrate in refluxing acetone/water (5 : 1), see Scheme 2.
Complexes 5–8 are air-stable brown to orange crystalline solids
(see Experimental for spectroscopic and analytical data), which
are soluble in dichloromethane and chloroform.
2. Results and discussion
Synthesis and characterisation of the diene precursors 1–4
The compounds 2-(cyclohexa-1,4-dienyl)ethanol and 4-
(cyclohexa-1,4-dienyl)butanol, accessible by Birch reduction
of the corresponding benzene derivatives,22,23 react in the presence
of 4-(dimethylamino)pyridine, N,N¢-dicyclohexylcarbodiimide
and 4-pyrrolidinopyridine as coupling reagents, with 4-
(heptyloxy)benzoic acid to give the functionalised dienes 1 and
2, using conditions similar to those reported previously.24 The
coupling with 4-methoxycinnamic acid under the same conditions
yields to the functionalised dienes 3 and 4 (Scheme 1). The new
compounds, obtained as colorless oils, were characterised by
NMR spectroscopy, mass spectrometry and elemental analysis
(see Experimental).
Synthesis and characterisation of the functionalised arene
ruthenium thiophenolato complexes 9–12
The arene ruthenium chloro intermediates 5–8 react with thiophe-
nol in refluxing ethanol to give the dinuclear arene ruthenium thio-
phenolato complexes [(arene)2Ru2(SPh)3]+, arene being C6H5R
(R = (CH2)2OC(O)C6H4-p-O(CH2)6CH3: 9, (CH2)4OC(O)C6H4-
p-O(CH2)6CH3: 10, (CH2)2OC(O)CH CHC6H4-p-OCH3: 11,
(CH2)4OC(O)CH CHC6H4-p-OCH3: 12), according to Scheme
3.
The chloride salts of 9–12 are obtained as air-stable or-
ange to red crystalline solids which are soluble in methanol,
dichloromethane and chloroform. The 1H NMR spectra
Synthesis and characterisation of the functionalised arene
ruthenium chloro intermediates 5–8
The complexes [(C6H5R)RuCl2]2 (where R = (CH2)2OC(O)-
C6H4-p-O(CH2)6CH3: 5, (CH2)4OC(O)C6H4-p-O(CH2)6CH3:
10306 | Dalton Trans., 2010, 39, 10305–10313
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Scheme 2 Synthesis of the functionalised arene ruthenium chloro intermediates 5–8.
Scheme 3 Synthesis of the functionalised arene ruthenium thiophenolato complexes 9–12.
of the dinuclear arene ruthenium thiophenolato complexes
Synthesis and characterisation of the functionalised arene
ruthenium hydroxythiophenolato complexes 13–16
[(arene)2Ru2(SPh)3]+ 9–12 in CDCl3 give rise to two signals for
the three equivalent thiophenolato groups (9: 7.37 m, 7.88 d ppm;
10: 7.36 m, 7.92 d ppm; 11: 7.42 m, 7.88 d ppm; 12: 7.41 m,
7.85 d ppm), and to the characteristic arene ligand signals (see
Experimental for further details). The ESI mass spectra of 9–12
contain molecular ion peaks at m/z 1211, 1267, 1095 and 1151,
respectively.
Since the anticancer activity of arene ruthenium complexes
depends to some extent on their lipophilic and on their hydrophilic
properties,1,2,12,13 the thiolato bridges in the [(arene)2Ru2(SPh)3]+
complexes were modified by the introduction of a p-hydroxy
function onto the phenyl substituent to increase water
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Scheme 4 Synthesis of the functionalised arene ruthenium hydroxythiophenolato complexes 13–16.
solubility. This was achieved by reacting the [(arene)RuCl2]2
Synthesis and characterisation of the unfunctionalised arene
ruthenium thiophenolato complexes 17–19
intermediates 5–8 with p-hydroxythiophenol in a similar fashion
to the method outlined above, to afford the dinuclear arene
ruthenium complexes [(C6H5R)2Ru2(S-p-C6H4OH)3]+ (where
R = (CH2)2–O–C(O)–C6H4-p-O(CH2)6CH3: 13, (CH2)4–O–C(O)–
C6H4-p-O(CH2)6CH3: 14, (CH2)2–O–C(O)–CH CH–C6H4-p-
OCH3: 15, (CH2)4–O–C(O)–CH CH–C6H4-p-OCH3: 16), see
Scheme 4.
In order to study the influence of the lipophilic chains in the
arene ligands on the biological activity, we also synthesised
the unfunctionalised cation [(C6H6)2Ru2(SPh)3]+ (17) that was
prepared from the reaction of thiophenol with [(C6H6)RuCl2]2 in
refluxing ethanol (Scheme 5).
The known p-cymene and hexamethylbenzene analogs [(p-
iPrC6H4Me)2Ru2(SPh)3]+ (18),25 [(C6Me6)2Ru2(SPh)3]+ (19)26 (Fig.
2) and [(p-iPrC6H4Me)2Ru2(S-p-C6H4Me)3]+ (20)18 (Fig. 2) were
also synthesised according to this method which gives much
better yields than the reported procedures. All the complexes were
isolated as the chloride salts.
Compound [17]Cl, an air-stable yellow solid soluble in
water and in organic solvents, gives rise to two signals
for the three equivalent thiophenolato groups (7.37 m and
7.83 d ppm) and to a singlet for the two equivalent benzene
The chloride salts of 13–16, which are soluble in
dichloromethane, chloroform and in other polar organic solvents,
are obtained as air-stable yellow to orange crystalline solids. The
1H NMR spectra of 13–16 in CDCl3 provide the two signals of
the three equivalent hydroxythiophenolato groups (13: 7.01 d,
7.63 d ppm; 14: 6.93 d, 7.52 d ppm; 15: 6.90 d, 7.62 d ppm;
16: 6.82 d, 7.47 d ppm), and the characteristic arene ligand
signals (see Experimental). In the ESI mass spectra, the molecular
peaks of 13–16 are observed at m/z 1259, 1315, 1143 and 1199,
respectively.
Scheme 5 Synthesis of the unfunctionalised diruthenium complex 17.
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◦
˚
Table 1 Selected bond lengths (A) and angles ( ) for cation 17
Table 2 IC50 values of complexes 9–20 towards A2780 and A2780cisR
human ovarian cancer cells
Molecule A
Molecule B
Compound
IC50/mM A2780
IC50/mM A2780cisR
Interatomic distances
Ru–S
2.3764(12)
2.3858(12)
2.4014(12)
2.4019(13)
2.4112(12)
2.4239(12)
1.793(5)
1.795(5)
1.798(5)
1.704
2.3823(13)
2.3828(13)
2.3866(14)
2.3961(13)
2.4043(13)
2.4119(14)
1.792(5)
1.795(5)
1.796(6)
1.695
[9]Cl
2.2
4.9
2.7
5.6
[10]Cl
[11]Cl
[12]Cl
[13]Cl
[14]Cl
[15]Cl
[16]Cl
[17]Cl
[18]Cl
[19]Cl
[20]Cl
0.82
0.49
127
130
113
13.6
0.38
0.24
0.4
1.36
0.56
132
126
104
27.2
0.48
0.25
1.2
S–Cph
Ru-centroid
1.705
1.698
0.13
0.08
Angles
Ru–S–Ru
88.17(4)
88.48(4)
89.67(4)
88.58(4)
88.67(4)
88.96(4)
Fig. 2 Diruthenium complexes 19 (left) and 20 (right).
ligands (5.44 ppm) in the 1H NMR spectrum (in CDCl3).
The ESI mass spectrum shows the molecular peak at m/z
686.94. The spectroscopic data for the analogues [18]Cl, [19]Cl
and [20]Cl are in excellent agreement with those reported
previously.25,26,18
Fig. 3 Molecular structure of cation 17, thermal ellipsoids are drawn at
50% probability level and hydrogen atoms are omitted for clarity.
and the third phenyl group is tilted to the left whereas the tilts are
opposite in molecule B.
The molecular structure of 17 was established by single-crystal
-
X-ray diffraction analysis of the PF6 salt. The unit cell contains
two independent cations (molecules A and B), the bond distances
and angles being similar. An ORTEP drawing with the atom
labelling scheme for molecule A of cation 17 is shown in Fig. 3 and
selected bond lengths and angles are given in Table 1. The structure
contains a trigonal bipyramidal Ru2S3 framework, in which each
ruthenium atom adopts a pseudo-octahedral geometry due to the
three sulfur atoms and the benzene ligand that formally occupies
three coordination sites.
3. Biological activity towards human ovarian cancer
cells
The antiproliferative activity of complexes 9–20 was evaluated
against the human ovarian A2780 cancer cell line and its cisplatin-
resistant derivative A2780cisR using the MTT assay, which
measures mitochondrial dehydrogenase activity as an indication of
cell viability. The IC50 values of 9–20, corresponding to inhibition
of cancer cell growth at the 50% level, are listed in Table 2.
The complexes tested show a broad range of cytotoxicities,
depending on both the thiophenyl and arene substituents, but with
comparable effects on both the cisplatin sensitive and resistant cell
lines. More precisely, two general tendencies can be appreciated
from the data. First, the arene ruthenium thiophenato complexes
(9 to 12) are systematically more cytotoxic than their hydroxyl-
thiophenato analogues (13 to 16). Second, the arene moiety has
an effect, as shown by the diversity of toxicities observed for
compounds 9, 10, 17, 18, 19 and 20, although the IC50 values
obtained cannot be precisely correlated to the lipophilicity or the
The Ru–S bond distances in the cation 17 range from 2.3764(12)
˚
to 2.4239(12) A and the Ru–S–Ru angles range from 88.17(4)
to 89.67(4)◦, similar to those found in the known p-cymene and
hexamethylbenzene derivatives [(p-iPrC6H4Me)2Ru2(SPh)3]+ (18)25
and [(C6Me6)2Ru2(SPh)3]+ (19),26 but slightly longer than in a
thiopyrone complex.27 In accordance with the electron count, the
˚
Ru–Ru distances (3.3576(5) and 3.3481(6) A) are clearly outside of
the range for a metal-metal single bond (2.28–2.95 A).24 The three
˚
phenyl groups are not in the plane formed by the three sulfur
atoms. The difference between the two independent molecules
resides in the relative tilt of the phenyl groups with respect to
this plane; in molecule A two phenyl groups are tilted to the right
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size of the substituents. It is worth noting that the sub-micromolar
cytotoxicities observed for some of these compounds place
them amongst the most cytotoxic arene ruthenium compounds
reported, even based on the fact that two ruthenium centers are
present.
The stability of the most active complex [(p-iPrC6H4Me)2Ru2(S-
p-C6H4Me)3]+ (20) was assessed using 1H NMR spectroscopy
over 12 h at 37 ◦C in DMSO-d6, in D2O/DMSO-d6 (95 : 5),
and in DMSO-d6 in the presence of two drops of RPMI 1640
medium with GlutaMAXTM containing 5% foetal calf serum
and penicillin and streptomycin antibiotics to mimic pseudo-
physiological conditions. The 1H NMR signals of 20 did not
change at all during 12 h period which indicates that it is stable
under these conditions.
In conclusion, a series of highly cytotoxic cationic diruthenium
complexes of general formula [(arene)2Ru2(SPh)3]+ have been pre-
pared. The high in vitro anticancer activity of these complexes must
be ascribed, at least in part, to the presence of the thiophenolato
groups. Further work is required to delineate the mode of action
of these compounds and to develop further derivatives in order to
understand the role of the bridging thiophenolato ligands.
CH2–O–(CO)–Ar), 2.69 (s, 4H, CH2diene), 3.99 (t, 2H, –O–CH2–
(CH2)5–CH3), 4.38 (t, 2H, C6H7–CH2–CH2–O–(CO)–Ar), 5.55 (s,
3
1H, CHdiene), 5.71 (t, 2H, CHdiene), 6.89 (d, J = 6.8 Hz, 2H,
3
1
H–Ar), 7.98 ppm (d, J = 6.8 Hz, 2H, H–Ar). 13C{ H} NMR
(100 MHz, CDCl3): 14.18, 22.70, 26.05, 26.88, 29.13, 29.22, 29.26,
31.86, 35.42, 36.73, 60.66, 63.08, 65.23, 68.28, 114.09, 120.98,
124.17, 126.61, 131.64, 138.15, 163.07, 166.38 ppm. Mass (ESI,
m/z): 365.18 [M+Na+]. Anal Calc. for (%): C22H30O3 : C, 77.16;
H, 8.83. Found: C, 77.25; H, 8.69.
2. Colorless oil, yield: 1.16 g, 95%. 1H NMR (400 MHz,
CDCl3): 0.91 (t, 3H, –CH3), 1.33 (m, 10H, –CH2–(CH2)4–CH3,
C6H7–CH2–CH2–CH2–CH2–O–(CO)–Ar), 1.79 (m, 4H, C6H7–
CH2–CH2–CH2–CH2–O–(CO)–Ar, –O–CH2–CH2–(CH2)4–CH3),
2.05 (t, 2H, C6H7–CH2–(CH2)3–O–(CO)–Ar), 2.62 (m, 2H,
CH2diene), 2.70 (m, 2H, CH2diene), 4.01 (t, 2H, –O–CH2–(CH2)5–
CH3), 4.31 (t, 2H, C6H7–(CH2)3–CH2–O–(CO)–Ar), 5.46 (s, 1H,
CHdiene), 5.72 (t, 2H, CHdiene), 6.91 (d, 3J = 6.8 Hz, 2H, H–Ar),
1
8.00 ppm (d, 3J = 6.8 Hz, 2H, H–Ar). 13C{ H} NMR (100 MHz,
CDCl3): 14.10, 22.62, 25.26, 25.98, 26.78, 27.87, 28.46, 28.88,
29.06, 29.15, 31.79, 37.05, 64.61, 68.21, 114.05, 118.73, 124.30,
124.32, 125.84, 128.36, 131.53, 134.53, 162.93, 166.48 ppm. Mass
(ESI, m/z): 393.10 [M+Na+]. Anal Calc. for (%): C24H34O3 : C,
77.80; H, 9.25. Found: C, 77.91; H, 9.39.
4. Experimental
3. Colorless oil, yield: 1.02 g, 89%. 1H NMR (400 MHz,
CDCl3): 2.37 (t, 2H, C6H7–CH2–CH2–O–(CO)–CH CH–), 2.69
(m, 4H, CH2diene), 3.82 (s, 3H, –O–CH3), 4.29 (t, 2H, C6H7–
CH2–CH2–O–(CO)–CH CH–), 5.53 (s, 1H, CHdiene), 5.71 (t,
General comments
All reagents were purchased either from Aldrich or Fluka and
used as received. The dimers [(arene)2RuCl2]2
28
were prepared
3
according to literature methods. Reactions were carried out under
nitrogen. NMR spectra were recorded on a Bruker AMX 400
spectrometer using the residual protonated solvent as internal
standard. Micro-analyses were performed by the Laboratory of
Pharmaceutical Chemistry, University of Geneva (Switzerland)
or by Mikroelementaranalytisches Laboratorium, ETH Zu¨rich
(Switzerland). Electrospray ionisation mass spectra were obtained
in positive-ion mode with an LCQ Finnigan mass spectrometer or
performed at the Department of Chemistry of the University of
Fribourg (Switzerland).
2H, CHdiene), 6.30 (d, J = 16 Hz, 1H, –CH CH–), 6.91 (d,
3
2H, H–Ar), 7.47 (d, 2H, H–Ar), 7.64 ppm (d, J = 16 Hz, 1H,
1
–CH CH–). 13C{ H} NMR (100 MHz, CDCl3): 26.85, 36.64,
55.42, 62.78, 64.93, 114.38, 115.83, 120.88, 124.21, 126.61, 129.11,
129.76, 129.81, 144.43, 161.44, 161.48, 167.27, 167.34 ppm. Mass
(ESI, m/z): 307.20 [M+Na+]. Anal Calc. for (%): C18H20O3 : C,
77.03; H, 7.09. Found: C, 77.26; H, 7.15.
1
4. Colorless oil, yield: 870 mg, 84%. H NMR (400 MHz,
CDCl3): 1.54 (m, 2H, C6H7–CH2–CH2–(CH2)2–O–(CO)–
CH CH–), 1.71 (m, 2H, C6H7–(CH2)2–CH2–CH2–O–(CO)–
CH CH–), 2.03 (t, 2H, C6H7–CH2–(CH2)3–O–(CO)–CH
CH–), 2.61 (m, 2H, CH2diene), 2.69 (m, 2H, CH2diene), 3.84
(s, 3H, –O–CH3), 4.21 (t, 2H, C6H7–(CH2)3–CH2–O–(CO)–
CH CH–), 5.45 (m, 1H, CHdiene), 5.72 (m, 2H, CHdiene),
6.32 (d, 3J = 16 Hz, 1H, –CH CH–), 6.91 (d, 2H, H–Ar),
7.49 (d, 2H, H–Ar), 7.65 ppm (d, 3J = 16 Hz, 1H, –CH
Preparation of the diene precursors 1–4
To a Schlenk tube, the corresponding acid (5.2 mmol, 1.24 g for
1; 4.3 mmol, 1.01 g for 2; 5.2 mmol, 934 mg for 3; 4.3 mmol,
761 mg for 4), in the presence of the coupling reagents 4-
(dimethylamino)pyridine (4 mmol, 492 mg for 1 and 3; 3.3 mmol,
401 mg for 2 and 4), N,N¢-dicyclohexylcarbodiimide (8 mmol,
1.66 g for 1 and 3; 6.6 mmol, 1.36 g for 2 and 4) and 4-
pyrrolidinopyridine (4 mmol, 597 mg for 1 and 3; 3.3 mmol, 497 mg
for 2 and 4) were dissolved in CH2Cl2 (100 mL). After the addition
of a solution of the diene (4 mmol, 500 mg for 1 and 3; 3.3 mmol,
500 mg for 2 and 4) in CH2Cl2 (10 mL), the reaction was stirred
at 20 ◦C during 18 h. Then resulting mixture was filtered through
Celite and the solvent was removed under reduced pressure. The
resulting oil was purified by column chromatography (silica gel,
CH2Cl2–EtOH 4.8 : 0.2); compounds 1–4 were isolated as colorless
oils and dried in vacuo.
1
CH–). 13C{ H} NMR (100 MHz, CDCl3): 23.68, 26.78, 28.22,
28.88, 37.04, 53.45, 55.37, 64.39, 114.33, 115.75, 118.71, 124.32,
125.84, 127.23, 128.43, 129.71, 134.54, 144.27, 161.37, 167.42 ppm.
Mass (ESI, m/z): 335.07 [M+Na+]. Anal Calc. for (%): C20H24O3 :
C, 76.89; H, 7.74. Found: C, 76.95; H, 7.62.
Preparation of the arene ruthenium chloro intermediates 5–8
To a solution of RuCl3·nH2O (0.8 mmol, 209 mg for 5 and 7;
0.6 mmol, 155 mg for 6 and 8) in degassed acetone/water 5 : 1
(100 mL) a solution of the corresponding diene (4 mmol, 1.37 g
for 5, 1.14 g for 7; 3 mmol, 1.10 g for 6, 937 mg for 8) in degassed
acetone/water 5 : 1 (10 mL) was added and the mixture was
refluxed for 18 h. The solvent was removed under reduced pressure,
and the residue was dissolved in dichloromethane (5 mL). Then
1. Colorless oil, yield: 1.15 g, 84%. 1H NMR (400 MHz,
CDCl3): 0.91 (t, 3H, –CH3), 1.44 (m, 8H, –CH2–(CH2)4–CH3),
1.80 (q, 2H, –O–CH2–CH2–(CH2)4–CH3), 2.42 (t, 2H, C6H7–CH2–
10310 | Dalton Trans., 2010, 39, 10305–10313
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the product was precipitated by addition of diethyl ether (50 mL),
isolated by filtration and dried in vacuo.
mixture was refluxed in EtOH for 18 h. After cooling to 20 ◦C, the
solvent was removed under reduced pressure. The mixture was
purified by column chromatography (silica gel, CH2Cl2–EtOH
5 : 1), and the compounds [9–12]Cl were isolated as air-stable
orange to red crystalline solids and dried in vacuo.
1
5. Orange solid, yield: 380 mg, 93%. H NMR (400 MHz,
CDCl3): 0.83 (t, 6H, –CH3), 1.37 (m, 16H, –CH2–(CH2)4–CH3),
1.79 (q, 4H, –O–CH2–CH2–(CH2)4–CH3), 3.04 (t, 4H, C6H5–CH2–
CH2–O–(CO)–Ar), 3.98 (t, 4H, –O–CH2–(CH2)5–CH3), 4.54 (t,
4H, C6H5–CH2–CH2–O–(CO)–Ar), 5.50 (d, 4H, CHarene), 5.66 (m,
6H, CHarene), 6.86 (d, 3J = 6.8 Hz, 4H, H–Ar), 7.86 ppm (d, 3J =
[9]Cl. Red solid, yield: 174 mg, 93%. 1H NMR (400 MHz,
CDCl3): 0.88 (t, 6H, –CH3), 1.30 (m, 16H, –CH2–(CH2)4–CH3),
1.78 (q, 4H, –O–CH2–CH2–(CH2)4–CH3), 2.12 (m, 4H, C6H5–
CH2–CH2–O–(CO)–Ar), 2.36 (m, 4H, C6H5–CH2–CH2–O–(CO)–
Ar), 3.98 (t, 4H, –O–CH2–(CH2)5–CH3), 4.13 (m, 4H, C6H5–CH2–
CH2–O–(CO)–Ar), 5.62 (m, 4H, C6H5–CH2–CH2–O–(CO)–Ar),
5.13 (d, 2H, CHarene), 5.38 (m, 4H, CHarene), 5.62 (m, 4H, CHarene),
6.86 (d, 3J = 9.2 Hz, 4H, H–Ar), 7.37 (m, 9H, H–Ar), 7.78
1
6.8 Hz, 4H, H–Ar). 13C{ H} NMR (100 MHz, CDCl3): 14.19,
22.46, 22.72, 26.06, 29.13, 29.21, 31.87, 33.70, 34.25, 62.91, 68.40,
80.48, 81.37, 84.22, 97.68, 114.35, 121.73, 131.67, 163.38, 165.95
ppm. Mass (ESI, m/z): 977.20 [M-2Cl-+Na+]. Anal Calc. for (%):
C44H56Cl4O3Ru2 : C, 51.56; H, 5.51. Found: C, 51.50; H, 5.34.
3
1
(d, J = 9.2 Hz, 4H, H–Ar), 7.88 ppm (d, 6H, H–Ar). 13C{ H}
NMR (100 MHz, CDCl3): 14.20, 22.71, 26.05, 29.13, 29.20, 31.87,
32.18, 63.01, 68.45, 85.57, 86.03, 86.08, 86.35, 87.56, 99.80, 114.38,
121.58, 128.63, 129.59, 131.64, 132.23, 138.55, 163.42, 165.81
ppm. Mass (ESI, m/z): 1211.26 [M+H+]. Anal Calc. for (%):
C62H71ClO6Ru2S3 : C, 59.76; H, 5.74. Found: C, 59.81; H, 5.80.
1
6. Orange solid, yield: 290 mg, 90%. H NMR (400 MHz,
CDCl3): 0.87 (t, 6H, –CH3), 1.37 (m, 16H, –CH2–(CH2)4–
CH3), 1.75 (m, 12H, C6H5–CH2–CH2–CH2–CH2–O–(CO)–Ar, –
O–CH2–CH2–(CH2)4–CH3), 2.60 (t, 4H, C6H5–CH2–(CH2)3–O–
(CO)–Ar), 3.97 (t, 4H, –O–CH2–(CH2)5–CH3), 4.26 (t, 4H, C6H5–
(CH2)3–CH2–O–(CO)–Ar), 5.38 (d, 4H, CHarene), 5.60 (m, 6H,
1
[10]Cl. Red solid, yield: 169 mg, 91%. H NMR (400 MHz,
3
3
CDCl3): 0.88 (t, 6H, –CH3), 1.30 (m, 16H, –CH2–(CH2)4–
CH3), 1.55 (m, 12H, C6H5–CH2–CH2–CH2–CH2–O–(CO)–Ar, –
O–CH2–CH2–(CH2)4–CH3), 1.80 (t, 4H, C6H5–CH2–(CH2)3–O–
(CO)–Ar), 3.99 (t, 4H, –O–CH2–(CH2)5–CH3), 4.11 (t, 4H, C6H5–
(CH2)3–CH2–O–(CO)–Ar), 4.97 (d, 2H, CHarene), 5.27 (m, 4H,
CHarene), 5.59 (m, 4H, CHarene), 6.88 (d, 3J = 8 Hz, 4H, H–Ar), 7.36
(m, 9H, H–Ar), 7.84 (d, 3J = 8 Hz, 4H, H–Ar), 7.92 ppm (d, 6H, H–
CHarene), 6.87 (d, J = 8.8 Hz, 4H, H–Ar), 7.92 ppm (d, J =
8.8 Hz, 4H, H–Ar). 13C{ H} NMR (100 MHz, CDCl3): 14.15,
1
22.65, 26.00, 26.35, 28.56, 29.08, 29.17, 31.81, 33.25, 64.00, 68.29,
79.86, 80.46, 84.22, 100.99, 114.16, 122.38, 131.62, 163.06, 166.37
ppm. Mass (ESI, m/z): 1033.20 [M-2Cl-+Na+]. Anal Calc. for
(%): C48H64Cl4O6Ru2 : C, 53.33; H, 5.97. Found: C, 53.51; H, 5.94.
1
1
Ar). 13C{ H} NMR (100 MHz, CDCl3): 14.19, 22.71, 26.06, 26.20,
7. Brown solid, yield: 216 mg, 72%. H NMR (400 MHz,
CDCl3): 2.85 (t, 4H, C6H5–CH2–CH2–O–(CO)–CH CH–),
3.67 (s, 6H, –O–CH3), 4.35 (t, 4H, C6H5–CH2–CH2–O–(CO)–
CH CH), 5.59 (d, 4H, CHarene), 5.77 (m, 6H, CHarene), 6.10 (d,
3J = 16 Hz, 2H, –CH CH–), 6.74 (d, 4H, H–Ar), 7.31 (d, 4H,
28.42, 29.14, 29.23, 31.87, 32.09, 63.76, 68.41, 85.40, 86.28, 86.34,
103.70, 114.24, 122.36, 128.48, 129.47, 131.66, 132.24, 138.87,
163.20, 166.44 ppm. Mass (ESI, m/z): 1267.32 [M+H+]. Anal
Calc. for (%): C66H79ClO6Ru2S3 : C, 60.88; H, 6.12. Found: C,
60.81; H, 5.98.
1
H–Ar), 7.44 ppm (d, 3J = 16 Hz, 2H, –CH CH–). 13C{ H} NMR
[11]Cl. Orange solid, yield: 148 mg, 87%. 1H NMR (400 MHz,
CDCl3): 2.76 (t, 4H, C6H5–CH2–CH2–O–(CO)–CH CH–),
3.83 (s, 6H, –O–CH3), 4.06 (t, 4H, C6H5–CH2–CH2–O–(CO)–
CH CH–), 5.12 (d, 2H, CHarene), 5.36 (m, 4H, CHarene), 5.61 (m,
4H, CHarene), 6.14 (d, 3J = 16 Hz, 2H, –CH CH–), 6.89 (d, 4H,
(100 MHz, CDCl3): 35.60, 55.12, 62.10, 84.34, 86.65, 88.48, 103.57,
114.10, 114.33, 126.45, 129.43, 144.93, 157.74, 161.30, 166.42,
172.13 ppm. Mass (ESI, m/z): 861.13 [M-2Cl-+Na+]. Anal Calc.
for (%): C36H36Cl4O2Ru2 : C, 47.59; H, 3.99. Found: C, 47.71; H,
4.06.
3
H–Ar), 7.42 (m, 13H, H–Ar), 7.53 (d, J = 16 Hz, 2H, –CH
1
8. Brown solid, yield: 252 mg, 82%. H NMR (400 MHz,
1
CH–), 7.88 ppm (d, 6H, H–Ar). 13C{ H} NMR (100 MHz,
CDCl3): 1.73 (m, 8H, C6H5–CH2–CH2–CH2–CH2–O–(CO)–
CH CH–), 2.61 (t, 4H, C6H5–CH2–(CH2)3–O–(CO)–CH CH),
3.83 (s, 6H, –O–CH3), 4.19 (t, 4H, C6H5–(CH2)3–CH2–O–(CO)–
CH CH–), 5.39 (d, 4H, CHarene), 5.60 (m, 6H, CHarene), 6.28 (d,
3J = 16 Hz, 2H, –CH CH–), 6.90 (d, 4H, H–Ar), 7.48 (d, 4H,
CDCl3): 32.12, 55.57, 62.73, 85.53, 86.07, 86.13, 86.37, 87.56,
99.84, 114.54, 114.61, 126.88, 128.63, 129.61, 130.06, 132.26,
138.60, 145.47, 161.79, 166.79 ppm. Mass (ESI, m/z): 1095.09
[M+H+]. Anal Calc. for (%): C54H51ClO6Ru2S3 : C, 57.41; H, 4.55.
Found: C, 57.52; H, 4.47.
1
H–Ar), 7.62 ppm (d, 3J = 16 Hz, 2H, –CH CH–). 13C{ H} NMR
[12]Cl. Orange solid, yield: 152 mg, 86%. 1H NMR
(400 MHz, CDCl3): 1.83 (m, 8H, C6H5–CH2–CH2–
(100 MHz, CDCl3): 26.41, 28.58, 33.31, 55.52, 63.85, 79.93, 80.56,
84.28, 101.08, 114.47, 115.58, 127.26, 129.91, 144.69, 161.56,
167.40 ppm. Mass (ESI, m/z): 917.07 [M-2Cl-+Na+]. Anal Calc.
for (%): C40H44Cl4O2Ru2 : C, 49.80; H, 4.60. Found: C, 49.87; H,
4.66.
CH2–CH2–O–(CO)–CH CH–),
CH2–(CH2)3–O–(CO)–CH CH–),
2.01
3.82
(m,
(s,
4H,
6H,
C6H5–
–O–
CH3), 4.02 (t, 4H, C6H5–(CH2)3–CH2–O–(CO)–CH
CH–), 4.97 (d, 2H, CHarene), 5.26 (m, 4H, CHarene), 5.59 (m,
6H, CHarene), 6.25 (d, 3J = 16 Hz, 2H, –CH CH–), 6.89 (d,
Preparation of the arene ruthenium thiophenolato complexes 9–12
3
4H, H–Ar), 7.41 (m, 13H, H–Ar), 7.60 (d, J = 16 Hz, 2H, –
1
The dinuclear dichloro complex [(arene)2RuCl2]2 (0.15 mmol,
150 mg for 9, 162 mg for 10, 136 mg for 11, 144 mg for 12)
was refluxed in technical grade EtOH (50 mL). As soon as
the starting material was completely dissolved, a solution of
thiophenol (0.9 mmol, 99 mg, 92 mL) in technical grade EtOH
(5 mL) was added dropwise to the hot solution. The resulting
CH CH–), 7.85 ppm (d, 6H, H–Ar),. 13C{ H} NMR (100 MHz,
CDCl3): 15.29, 26.05, 28.26, 31.97, 55.30, 55.45, 63.42, 65.86,
84.71, 85.28, 86.18, 86.21, 103.62, 113.91, 114.41, 115.32, 127.01,
128.39, 129.24, 129.27, 132.15, 138.78, 144.65, 161.53, 167.27
ppm. Mass (ESI, m/z): 1151.15 [M+H+]. Anal Calc. for (%):
C58H59ClO6Ru2S3 : C, 58.74; H, 5.01. Found: C, 58.82; H, 4.85.
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Dalton Trans., 2010, 39, 10305–10313 | 10311
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Preparation of the arene ruthenium thiophenolato complexes 13–16
CH–), 6.77 (d, 4H, H–Ar), 6.82 (d, 6H, H–Ar), 7.34 (d, 4H, H–Ar),
3
7.47 (d, 6H, H–Ar), 7.52 ppm (d, J = 16 Hz, 2H, –CH CH–).
1
13C{ H} NMR (100 MHz, CDCl3): 15.26, 26.12, 28.12, 31.92,
The dinuclear dichloro complex [(arene)2RuCl2]2 (0.05 mmol,
50 mg for 13, 54 mg for 14, 45 mg for 15, 48 mg for 16)
was refluxed in technical grade EtOH (50 mL). As soon as
the starting material was completely dissolved, a solution of p-
hydroxythiophenol (0.3 mmol, 38 mg) in technical grade EtOH
(5 mL) was added dropwise to the hot solution. The resulting
mixture was refluxed in EtOH for 18 h. After cooling to 20 ◦C, the
solvent was removed under reduced pressure. The mixture was
purified by column chromatography (silica gel, CH2Cl2–EtOH
5 : 1) and [13–16]Cl were isolated as air-stable yellow to orange
crystalline solids and dried in vacuo.
55.27, 63.32, 77.37, 83.40, 84.51, 84.84, 85.98, 114.23, 115.17,
116.44, 129.61, 132.84, 144.43, 158.32, 161.32, 167.03 ppm. Mass
(ESI, m/z): 1199.14 [M+H+]. Anal Calc. for (%): C58H59ClO9Ru2S3
: C, 56.46; H, 4.82. Found: C, 56.51; H, 4.85.
Preparation of the arene ruthenium thiophenolato complexes 17–19
The dinuclear dichloro complex [(arene)2RuCl2]2 (0.20 mmol,
100 mg for 17; 122 mg for 18; 133 mg for 19) was refluxed in
technical grade EtOH (50 mL). As soon as the starting material
was dissolved, a solution of thiophenol (1.2 mmol, 132 mg, 123 mL)
in technical grade EtOH (5 mL) was added dropwise to the hot
solution. The resulting mixture was refluxed in EtOH for 18 h.
After cooling to 20 ◦C, the solvent was removed under reduced
pressure. The mixture was purified by column chromatography
(silica gel, CH2Cl2–EtOH 5 : 1) and [17–19]Cl were isolated as air-
stable yellow to red crystalline solids and dried in vacuo.
1
[13]Cl. Orange solid, yield: 52 mg, 82%. H NMR (400 MHz,
CDCl3): 0.83 (t, 6H, –CH3), 1.35 (m, 16H, –CH2–(CH2)4–CH3),
1.71 (q, 4H, –O–CH2–CH2–(CH2)4–CH3), 2.30 (m, 8H, C6H5–
CH2–CH2–O–(CO)–Ar, C6H5–CH2–CH2–O–(CO)–Ar), 3.92 (t,
4H, –O–CH2–(CH2)5–CH3), 4.19 (m, 4H, C6H5–CH2–CH2–O–
(CO)–Ar), 5.05 (d, 2H, CHarene), 5.17 (m, 2H, CHarene), 5.25 (m,
2H, CHarene), 5.38 (m, 4H, CHarene), 6.82 (d, 4H, H–Ar), 7.01
(d, 6H, H–Ar), 7.63 (d, 6H, H–Ar), 7.74 ppm (d, 4H, H–Ar).
[17]Cl. Yellow solid, yield: 129 mg, 88%. 1H NMR (400 MHz,
CDCl3): 5.44 (s, 12H, H–Ar), 7.37 (m, 9H, H–Ar), 7.83 ppm (d,
1
13C{ H} NMR (100 MHz, CDCl3): 14.17, 22.67, 26.01, 29.17,
1
6H, H–Ar). 13C{ H} NMR (100 MHz, CDCl3): 86.55, 128.32,
29.79, 31.82, 32.28, 63.47, 68.44, 84.60, 85.93, 85.97, 86.54, 100.01,
114.41, 116.95, 121.46, 127.46, 131.64, 133.25, 158.29, 163.40,
166.12 ppm. Mass (ESI, m/z): 1259.23 [M+H+]. Anal Calc. for
(%): C62H71ClO9Ru2S3 : C, 57.55; H, 5.53. Found: C, 57.68; H,
5.59.
129.61, 132.05, 139.22 ppm. Mass (ESI, m/z): 686.94 [M+H+].
Anal Calc. for (%): C30H27ClRu2S3 : C, 49.95; H, 3.77. Found: C,
49.85; H, 3.70.
[18]Cl. Orange solid, yield: 155 mg, 93%. 1H NMR (400 MHz,
CDCl3): 0.78 (d, 3J = 8 Hz, 12H, (CH3)2CH), 1.57 (s, 6H, CH3),
1
[14]Cl. Orange solid, yield: 60 mg, 89%. H NMR (400 MHz,
3
3
1.86 (sept, J = 7.2 Hz, 2H, (CH3)2CH), 5.05 (d, J = 8 Hz, 2H,
H–Ar), 5.08 (d, 3J = 8 Hz, 2H, H–Ar), 5.19 (d, 2H, H–Ar), 5.36
(d, 2H, H–Ar), 7.34 (m, 9H, H–Ar), 7.84 ppm (d, 6H, H–Ar).
CDCl3): 0.83 (t, 6H, –CH3), 1.37 (m, 16H, –CH2–(CH2)4–
CH3), 1.52 (m, 12H, C6H5–CH2–CH2–CH2–CH2–O–(CO)–Ar, –
O–CH2–CH2–(CH2)4–CH3), 1.95 (t, 4H, C6H5–CH2–(CH2)3–O–
(CO)–Ar), 3.94 (t, 4H, –O–CH2–(CH2)5–CH3), 4.12 (t, 4H, C6H5–
(CH2)3–CH2–O–(CO)–Ar), 4.85 (d, 2H, CHarene), 5.04 (m, 4H,
CHarene), 5.29 (m, 4H, CHarene), 6.83 (d, 4H, H–Ar), 6.93 (d, 6H,
1
13C{ H} NMR (100 MHz, CDCl3): 17.71, 21.95, 22.53, 30.58,
83.65, 84.76, 85.03, 85.37, 99.97, 107.39, 128.45, 129.19, 132.57,
137.81 ppm. Mass (ESI, m/z): 799.07 [M+H+]. Anal Calc. for (%):
C38H43ClRu2S3 : C, 54.76; H, 5.20. Found: C, 54.69; H, 5.32.
1
H–Ar), 7.52 (d, 6H, H–Ar), 7.87 ppm (d, 4H, H–Ar). 13C{ H}
1
[19]Cl. Red solid, yield: 162 mg, 91%. H NMR (400 MHz,
NMR (100 MHz, CDCl3): 14.09, 22.57, 25.92, 26.43, 28.30, 29.00,
29.08, 31.72, 32.13, 63.81, 68.25, 83.57, 84.70, 86.05, 86.10, 103.81,
114.09, 116.74, 122.19, 127.20, 131.55, 132.93, 158.53, 163.03,
166.36 ppm. Mass (ESI, m/z): 1315.30 [M+H+]. Anal Calc. for
(%): C66H79ClO9Ru2S3 : C, 58.71; H, 5.90. Found: C, 58.83; H,
5.84.
CDCl3): 2.02 (s, 36H, CH3), 7.36 (m, 9H, H–Ar), 7.87 ppm (d, 6H,
1
H–Ar). 13C{ H} NMR (100 MHz, CDCl3): 14.99, 97.82, 128.42,
129.53, 132.15, 138.32 ppm. Mass (ESI, m/z): 855.13 [M+H+].
Anal Calc. for (%): C42H51ClRu2S3 : C, 56.70; H, 5.78. Found: C,
56.65; H, 5.70.
1
[15]Cl. Yellow solid, yield: 49 mg, 83%. H NMR (400 MHz,
Cell culture and inhibition of cell growth
CDCl3): 2.29 (m, 4H, C6H5–CH2–CH2–O–(CO)–CH CH–),
3.79 (s, 6H, –O–CH3), 4.09 (t, 4H, C6H5–CH2–CH2–O–(CO)–
CH CH–), 5.02 (d, 2H, CHarene), 5.21 (m, 4H, CHarene), 5.40
Human A2780 and A2780cisR ovarian carcinoma cells were
obtained from the European Centre of Cell Cultures (ECACC,
Salisbury, UK) and maintained in culture as described by the
provider. The cells were routinely grown in RPMI 1640 medium
with GlutaMAXTM containing 5% foetal calf serum (FCS) and
antibiotics (penicillin and streptomycin) at 37 ◦C and 5% CO2.
For the evaluation of growth inhibition tests, the cells were seeded
in 96-well plates (25 ¥ 103 cells per well) and grown for 24
h in complete medium. Complexes were dissolved in DMSO
and added to the required concentration to the cell culture for
72 h incubation. Solutions of the compounds were applied by
diluting a freshly prepared stock solution of the correspond-
ing compound in aqueous RPMI medium with GlutaMAXTM
(20 mM). Following drug exposure, 3-(4,5-dimethylthiazol-2-yl)-
2,5-diphenyltetrazolium bromide (MTT) was added to the cells
at a final concentration of 0.25 mg mL-1 and incubated for 2 h,
3
(m, 4H, CHarene), 6.13 (d, J = 16 Hz, 2H, –CH CH–), 6.90
3
(d, 6H, H–Ar), 7.42 (m, 8H, H–Ar), 7.48 (d, J = 16 Hz, 2H, –
1
CH CH–), 7.62 ppm (d, 6H, H–Ar). 13C{ H} NMR (100 MHz,
CDCl3): 32.13, 55.47, 63.03, 85.81, 85.95, 96.06, 86.46, 99.86,
114.46, 116.65, 126.77, 127.52, 129.25, 130.03, 133.23, 145.58,
158.11, 161.73, 167.13 ppm. Mass (ESI, m/z): 1143.09 [M+H+].
Anal Calc. for (%): C54H51ClO9Ru2S3 : C, 55.07; H, 4.36. Found:
C, 55.16; H, 4.44.
[16]Cl. Yellow solid, yield: 54 mg, 88%. 1H NMR
(400 MHz, CDCl3): 1.43 (m, 8H, C6H5–CH2–CH2–CH2–CH2–
O–(CO)–CH CH–), 1.89 (m, 4H, C6H5–CH2–(CH2)3–O–(CO)–
CH CH–), 3.71 (s, 6H, –O–CH3), 3.96 (t, 4H, C6H5–(CH2)3–
CH2–O–(CO)–CH CH–), 4.78 (d, 2H, CHarene), 4.98 (m, 4H,
3
CHarene), 5.24 (m, 6H, CHarene), 6.15 (d, J = 16 Hz, 2H, –CH
10312 | Dalton Trans., 2010, 39, 10305–10313
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
Table 3 Crystallographic and structure refinement parameters for
[17]PF6
References
1 C. S. Allardyce, P. J. Dyson, D. J. Ellis and S. L. Heath, Chem. Commun.,
2001, 1396.
[17]PF6
2 R. E. Morris, R. E. Aird, P. d. S. Murdoch, H. Chen, J. Cummings,
N. D. Hughes, S. Pearsons, A. Parkin, G. Boyd, D. I. Jodrell and P. J.
Sadler, J. Med. Chem., 2001, 44, 3616.
Chemical formula
Formula weight
Crystal system
C30H27F6PRu2S3
830.81
3 P. J. Dyson, Chimia, 2007, 61, 698.
Monoclinic
C 2/c (no. 15)
Yellow block
0.23 ¥ 0.18 ¥ 0.15
39.0178(15)
10.4836(3)
30.5653(13)
106.929(3)
11960.9(8)
16
173(2)
1.845
1.332
1.50 < q < 29.28
16075
11044
0.1253
4 (a) S. J. Dougan and P. J. Sadler, Chimia, 2007, 61, 704; (b) C. Scolaro,
A. B. Chaplin, C. G. Hartinger, A. Bergamo, M. Cocchietto, B. K.
Keppler, G. Sava and P. J. Dyson, Dalton Trans., 2007, 5065.
5 W. H. Ang and P. J. Dyson, Eur. J. Inorg. Chem., 2006, 4003.
6 C. G. Hartinger and P. J. Dyson, Chem. Soc. Rev., 2009, 38, 391.
7 M. Melchart, P. J. Sadler, in G. Jaouen, (editor), Bioorganometallics,
Wiley-VCH, Weinheim, 2006, p. 39.
Space group
Crystal colour and shape
Crystal size
˚
a/A
˚
b/A
˚
c/A
b (◦)
3
˚
8 L. Ronconi and P. J. Sadler, Coord. Chem. Rev., 2007, 251, 1633.
9 G. Su¨ss-Fink, Dalton Trans., 2010, 39, 1673.
10 P. J. Dyson, Nature, 2009, 458, 389.
11 B. Therrien, W. H. Ang, F. Che´rioux, L. Vieille-Petit, L. Juillerat-
Jeanneret, G. Su¨ss-Fink and P. J. Dyson, J. Cluster Sci., 2007, 18,
741.
12 M.-G. Mendoza-Ferri, C. G. Hartinger, R. E. Eichinger, N. Stolyarova,
K. Severin, M. A. Jakupec, A. A. Nazarov and B. K. Keppler,
Organometallics, 2008, 27, 2405.
V/A
Z
T/K
Dc/g cm-3
m/mm-1
Scan range (◦)
Unique reflections
Observed refls [I > 2s(I)]
Rint
13 M.-G. Mendoza-Ferri, C. G. Hartinger, A. A. Nazarov, W. Kandioller,
K. Severin and B. K. Keppler, Appl. Organomet. Chem., 2008, 22, 326.
14 (a) M.-G. Mendoza-Ferri, C. G. Hartinger, M. A. Mendoza, M.
Groessl, A. E. Egger, R. E. Eichinger, J. B. Mangrum, N. P. Farell,
M. Maruska, P. J. Bednarski, F. Klein, M. A. Jakupec, A. A. Nazarov,
K. Severin and B. K. Keppler, J. Med. Chem., 2009, 52, 916; (b) O.
Nova´kova´, A. A. Nazarov, C. G. Hartinger, B. K. Keppler and V.
Brabec, Biochem. Pharmacol., 2009, 77, 364.
Final R indices [I > 2s(I)]*
R indices (all data)
Goodness-of-fit
0.0688, wR2 0.0812
0.1153, wR2 0.0892
1.116
-3
˚
Max, Min Dr/e (A )
1.149, – 1.232
Structures were refined on F0 : wR2 = [R[w (F0 - Fc )2]/Rw (F0 )2]1/2
,
2
2
2
2
2
2
2
where w-1 = [R(F0 ) + (aP)2 + bP] and P = [max(F0 , 0) + 2Fc ]/3
ˇ
15 M. Auzias, B. Therrien, G. Su¨ss-Fink, P. Steˇpnicˇka, W. H. Ang and P.
then the culture medium was aspirated and the violet formazan
(artificial chromogenic precipitate of the reduction of tetrazolium
salts by dehydrogenases and reductases) dissolved in DMSO. The
optical density of each well (96-well plates) was quantified three
times in triplicates at 540 nm using a multiwall plate reader (iEMS
Reader MF, Labsystems, US), and the percentage of surviving
cells was calculated from the ratio of absorbance of treated to
untreated cells. The IC50 values for the inhibition of cell growth
were determined by fitting the plot of the logarithmic percentage of
surviving cells against the logarithm of drug concentration using
a linear regression function. The median value and the median
absolute deviation were obtained from the ExcelTM software
(MicrosoftTM) and those values are reported in Table 2.
J. Dyson, Inorg. Chem., 2008, 47, 578.
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S. Parsons, L. D. H. Oswald, V. Brabec and P. J. Sadler, Inorg. Chem.,
2007, 46, 5059.
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Single-crystal X-ray structure analysis
A crystal of [17]PF6, prepared by diffusion of a dichloromethane
solution of [17]Cl in the presence of KPF6 into a diethyl ether layer,
was mounted on a Stoe Image Plate Diffraction system equipped
with a f circle goniometer, using Mo-Ka graphite◦monochromated
27 W. Kandioller, C. G. Hartinger, A. A. Nazarov, M. L. Kuznetsov,
R. John, C. Bartel, M. A. Jakupec, V. B. Arion and B. K. Keppler,
Organometallics, 2009, 28, 4249.
˚
radiation (l = 0.71073 A) with f range 0–200 . The structure
was solved by direct methods using the program SHELXS-97,
while the refinement and all further calculations were carried out
using SHELXL-97.29 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, using
weighted full-matrix least-square on F2. Crystallographic details
are summarised in Table 3. Fig. 2 was drawn with ORTEP.30
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