Thiolato-bridged arene-ruthenium complexes: Synthesis, molecular structure, reactivity, and anticancer activity of the dinuclear complexes [(arene) 2Ru2(SR)2Cl2]

Article abstract of DOI:10.1002/ejic.201101057

Treatment of an arene-ruthenium dichloride dimer with thiols RSH to lead to cationic trithiolato complexes of the type [(arene)₂Ru ₂(SR)₃]⁺ was shown to proceed through the neutral thiolato complexes [(arene)₂Ru₂(SR) ₂Cl₂], which have been isolated and characterized for arene = p-MeC₆H₄iPr and R = CH₂Ph (1), CH ₂CH₂Ph (2), CH₂C₆H₄-p-tBu (3), and C₆H₁₁ (4). The single-crystal X-ray structure analysis of the p-tert-butylbenzyl derivative 3 reveals that the two ruthenium atoms are bridged by the two thiolato ligands without a metal-metal bond. The neutral dithiolato complexes[(arene)₂Ru₂(SR) ₂Cl₂] (1-3) are intermediates in the formation of the cationic trithiolato complexes [(arene)₂Ru₂(SR) ₃]⁺ (5-7). Of the new [(arene)₂Ru ₂(SR)₂Cl₂] complexes, derivative 2 is highly cytotoxic against human ovarian cancer cells, with IC₅₀ values of 0.20 μM for the A2780 cell line and 0.31 for the cisplatin-resistant cell line A2780cisR. Treatment of p-cymene-ruthenium dichloride dimer with aliphatic thiols to give cationic trithiolato-diruthenium complexes was shown to proceed through the intermediacy of the corresponding neutral dithiolato complexes.

Full text of DOI:10.1002/ejic.201101057

FULL PAPER
DOI: 10.1002/ejic.201101057
Thiolato-Bridged Arene–Ruthenium Complexes: Synthesis, Molecular
Structure, Reactivity, and Anticancer Activity of the Dinuclear Complexes
[(arene)2Ru2(SR)2Cl2]
Anne-Flore Ibao,[a] Michaël Gras,[a] Bruno Therrien,[a] Georg Süss-Fink,*[a] Olivier Zava,[b]
and Paul J. Dyson[b]
Dedicated to Dr. Hubert Le Bozec on the occasion of his 60th birthday
Keywords: Ruthenium / Arene ligands / Thiolato bridges / Cytotoxicity
Treatment of an arene–ruthenium dichloride dimer with thi-
ols RSH to lead to cationic trithiolato complexes of the type
nium atoms are bridged by the two thiolato ligands without
metal–metal bond. The neutral dithiolato complexes
a
[(arene)2Ru2(SR)3]+ was shown to proceed through the neu- [(arene)2Ru2(SR)2Cl2] (1–3) are intermediates in the forma-
tral thiolato complexes [(arene)2Ru2(SR)2Cl2], which have
been isolated and characterized for arene = p-MeC6H4iPr
and R = CH2Ph (1), CH2CH2Ph (2), CH2C6H4-p-tBu (3), and
C6H11 (4). The single-crystal X-ray structure analysis of the
p-tert-butylbenzyl derivative 3 reveals that the two ruthe-
tion of the cationic trithiolato complexes [(arene)2Ru2(SR)3]+
(5–7). Of the new [(arene)2Ru2(SR)2Cl2] complexes, deriva-
tive 2 is highly cytotoxic against human ovarian cancer cells,
with IC50 values of 0.20 μM for the A2780 cell line and 0.31
for the cisplatin-resistant cell line A2780cisR.
highly cytotoxic toward human ovarian cancer cells.[9] They
are in fact among the most active ruthenium anticancer
compounds.[10]
Introduction
The chemistry of arene–ruthenium complexes has been
extensively studied,[1] ever since G. Winkhaus and H. Singer
reported in 1967 the synthesis of [(C6H6)2Ru2Cl4], which
was at first considered to be a polymer[2] but later shown
to be a dimer.[3,4] Thus, the dimeric arene–ruthenium di-
chloride complexes were found to react with thiols to give
cationic trithiolato complexes of the type [(arene)2Ru2-
(SR)3]+, the first examples being the hexamethylbenzene de-
rivative [(C6Me6)2Ru(SC6H5)3]+ reported by H. T. Schacht
et al.[5] and the p-cymene derivative [(p-MeC6H4iPr)2Ru-
(SC6H5)3]+ reported by K. Mashima et al.,[6] both of which
contain three thiophenolato bridges. We completed this
series in 2003 with the p-bromothiophenolato derivative [(p-
MeC6H4iPr)2Ru2(SC6H4-p-Br)3]+,[7] the p-methylthiophen-
olato and p-hydroxythiophenolato derivatives [(arene)2-
Ru2(SC6H4-p-X)3]+ (arene = C6H6, p-MeC6H4iPr, C6Me6;
X = CH3, OH),[8] as well as the 2-hydroxyethanethiolato
derivatives [(arene)2Ru2(SCH2CH2OH)3]+ (arene = C6H6,
p-MeC6H4iPr, C6Me6).[8] We also found that the chloride
salts of the trithiolato complexes [(arene)2Ru2(SR)3]+ are
With the exception of the 2-hydroxyethanethiolato com-
plexes [(arene)2Ru2(SCH2CH2OH)3]+ (arene = C6H6, p-Me-
C6H4iPr, C6Me6),[8] all these trithiolato complexes contain
aromatic substituents at the sulfur atom. We therefore set
out to synthesize [(arene)2Ru2(SR3)]+ complexes with ali-
phatic substituents R. When we treated [(p-MeC6H4iPr)2-
Ru2Cl4] with p-tBuC6H4CH2SH under the usual conditions
in ethanol heated at reflux, we observed the formation of
two complexes that were difficult to separate. One of them
was the expected trithiolato complex [(p-MeC6H4iPr)2Ru2-
(SCH2C6H4-p-tBu)]+, the other one turned out to be the
dithiolato complex [(p-MeC6H4iPr)2Ru2(SCH2C6H4-p-
tBu)2Cl2]. However, it was possible to direct the synthesis
by choosing the reaction conditions to give exclusively
either the cationic trithiolato complex or the neutral dithiol-
ato complex. The new dithiolato complex is an organic de-
rivative of the dihydrosulfido complex [(p-MeC6H4iPr)2-
Ru2(SH)2Cl2] reported by M. Hidai and co-workers as a
product of the reaction of the p-cymene dichloride dimer
with hydrogen sulfide.[11]
[a] Institut de Chimie, Université de Neuchâtel
Avenue de Bellevaux 51, 2000 Neuchâtel, Switzerland
Fax: +41-32-7182511
In this paper, we report the synthesis, characterization,
molecular structure, and the anticancer activity of the neu-
tral dithiolato complexes of the type [(arene)2Ru2(SR)2Cl2],
which are supposed to be intermediates in the synthesis of
the cationic trithiolato complexes [(arene)2Ru2(SR)3]+.
E-mail: georg.suess-fink@unine.ch
[b] Institut des Sciences et Ingénierie Chimiques, Ecole
Polytechnique Fédérale de Lausanne (EPFL),
1015 Lausanne, Switzerland
Eur. J. Inorg. Chem. 2012, 1531–1535
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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G. Süss-Fink et al.
FULL PAPER
Results and Discussion
Synthesis of the Neutral Dithiolato Complexes 1–4
The p-cymene–ruthenium dichloride dimer reacts in cold
ethanol (0 °C) with phenylmethanethiol, 2-phenylethane-
thiol, and (4-tert-butylphenyl)methanethiol (2 equiv.) to
give the neutral dithiolato complexes [(p-MeC6H4iPr)2Ru2-
(SCH2Ph)2Cl2] (1), [(p-MeC6H4iPr)2Ru2(SCH2CH2Ph)2Cl2]
(2), and [(p-MeC6H4iPr)2Ru2(SCH2C6H4-p-tBu)2Cl2] (3). In
the case of the bulky cyclohexylthiol, the reaction is carried
out in refluxing ethanol to yield the cyclohexylthiolato
derivative [(p-MeC6H4iPr)2Ru2(SC6H11)2Cl2] (4) (see
Scheme 1). The air-stable orange to red compounds were
isolated by precipitation with diethyl ether. The spectro-
scopic and analytical data are given in the Experimental
Section.
Figure 1. Molecular structure of 3 at 50% probability level ellip-
soids. Selected bond lengths [Å] and angles [°]: Ru1–S1 2.384(2),
Ru1–S1i 2.395(3), Ru1–Cl1 2.424(2), Ru1–Ru1i 3.674(2); S1–Ru1–
S1i 79.51(9), S1–Ru1–Cl1 81.16(8), S1i–Ru1–Cl1 90.19(9), Ru1–S1–
i
Ru1i 100.49(9). Symmetry operator: 1 – x, –y, 1 – z.
Molecular Structure of 3
Suitable crystals for X-ray analysis were obtained for the
Conversion into the Cationic Trithiolato Complexes 5–7
(4-tert-butylphenyl)methanethiolato derivative
3
by
recrystallization from a chloroform/diethyl ether mixture.
The neutral dithiolato complexes 1–3 react in ethanol
The molecular structure, shown in Figure 1, can be de- heated at reflux with an excess amount of the correspond-
scribed in terms of two p-cymene–ruthenium units held to- ing thiol to give the cationic trithiolato complexes [(p-Me-
gether by two μ2-bridging thiolato units. Selected bond C6H4iPr)2Ru2(SCH2Ph)3]+
(5),
[(p-MeC6H4iPr)2Ru2-
lengths and angles are listed in Figure 1. In accordance with (SCH2CH2Ph)3]+ (6), and [(p-MeC6H4iPr)2Ru2(SCH2C6H4-
the electron count, there is no metal–metal bond; the dis- p-tBu)3]+ (7), which were purified by column chromatog-
tance between two ruthenium atoms is 3.674(2) Å, which is, raphy and isolated as the chloride salts (Scheme 2). The
however, slightly shorter than the Ru···Ru distances in the compounds [5]Cl, [6]Cl, and [7]Cl were obtained as air-
halido-bridged
complexes
[(p-MeC6H4iPr)2Ru2Br4] stable orange to red crystalline solids, which were charac-
[3.854(1) Å],[12] [(p-MeC6H4iPr)2Ru2I4] [3.854(1) Å],[12] and terized by 1H and 13C NMR spectroscopy, mass spectrome-
[(C6H6)2Ru2Cl4] [4.07 Å].[13] The geometrical parameters of try, and elemental analysis.
3 are comparable to those of the halido-bridged complexes,
The complexes 5–7 are also accessible by treating the p-
but the Ru–S–Ru angles [100.49(9)°] are somewhat wider cymene dichloride dimer with the corresponding thiol in
than the corresponding Ru–Cl–Ru [98.22°],[13] Ru–Br–Ru ethanol heated at reflux; however, the direct reaction takes
[97.01(3)°],[13] and Ru–I–Ru [96.96(2)°] angles.[12]
about 1 week and gives only poor yields (24–35%). This
In contrast to these dinuclear arene–ruthenium(II) com- observation is consistent with the assumption that the neu-
plexes, which show a long Ru···Ru distance, the short Ru– tral dithiolato complexes 1–3 are intermediates in the for-
Ru distances in the analogous pentamethylcyclopen- mation of the cationic trithiolato complexes 5–7. Complex
tadienyl–ruthenium(III) complexes [(C5Me5)2Ru2(SMe)2- 4 does not react further in ethanol heated at reflux, presum-
Cl2] (syn isomer 2.883 Å, anti isomer 2.889 Å),[14] [(C5Me5)2- ably due to steric reasons.
Ru2(SPh)2Cl2] (syn isomer 2.881 Å, anti isomer 2.902 Å),[14]
In a similar fashion, the pentamethylcyclopentadienyl–
and [(C5Me5)2Ru2(SEt)2Cl2] (2.850 Å)[15] could be interpre- ruthenium(III) complex [(C5Me5)2Ru2Cl4] was found to re-
ted as a consequence of metal–metal bonding.
act with aromatic thiols to give the cationic trithiolato com-
Scheme 1. Synthesis of 1–4.
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Inorg. Chem. 2012, 1531–1535

Thiolato-Bridged Arene–Ruthenium Complexes
Scheme 2. Synthesis of 5–7.
plexes [(C5Me5)2Ru2(SR)3]+, whereas aliphatic thiols gave IC50 values in the submicromolar range even for the cispla-
neutral dithiolato complexes of the type [(C5Me5)2Ru2- tin-resistant cell line A2780cisR.
(SR)2Cl2]. However, conversion of the dithiolato complexes
A comparison of the neutral complexes 1–3 with their
into the corresponding trithiolato with an excess amount of cationic analogues 5–7 shows that the [(arene)2Ru2-
the thiol was not observed for these ruthenium(III) com- (SR)3]+ cations are more active than the corresponding neu-
plexes.[16,17]
tral precursors [(arene)2Ru2(SR)2Cl2]. This may be due to a
better uptake of charged complexes by living cells.[18] As far
as the mode of action is concerned, we have shown recently
that the substitution-inert and stable complex [(p-MeC6H4-
iPr)2Ru2(SC6H4-p-Me)3]+ efficiently catalyzes the oxidation
of glutathione in water,[19] which may account for the cyto-
toxicity of these complexes.
Biological Activity
The antiproliferative activity of the dithiolato complexes
1–4 as well as of the trithiolato complexes 5–7 was evalu-
ated against the human ovarian A2780 cancer cell line and
its cisplatin-resistant derivative A2780cisR by using the
MTT [MTT = 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-
tetrazolium bromide] assay, which measures mitochondrial
dehydrogenase activity as an indication of cell viability. The
IC50 values of the complexes, which correspond to inhibi-
tion of cancer-cell growth at the 50% level, are reported in
Table 1 together with those of cisplatin.
Conclusion
A new series of neutral dithiolato–diruthenium com-
plexes has been prepared by the treatment of [(p-MeC6H4-
iPr)2Ru2Cl4] with aliphatic thiols. These dithiolato com-
plexes [(p-MeC6H4iPr)2Ru2(SR)2Cl2] were shown to react
further to give the cationic trithiolato complexes [(p-Me-
C6H4iPr)2Ru2(SR)3]+ with the exception of the cyclohexyl
derivative, which remains as [(p-MeC6H4iPr)2Ru2(SC6H11)2-
Cl2], presumably for steric reasons. All compounds are
highly cytotoxic toward human ovarian cancer cells.
Table 1. Cytotoxicities of cisplatin, 1–4, and [5–7]Cl towards A2780
and A2780cisR human ovarian cancer cells.
Compound
IC50 [μm] A2780
IC50 [μm] A2780cisR
1
2
3
4
2.94Ϯ0.6
0.20Ϯ0.05
Ͼ5
0.46Ϯ0.04
0.12Ϯ0.04
0.17Ϯ0.04
1.70Ϯ0.2
4.20Ϯ0.5
3.60Ϯ0.8
0.31Ϯ0.08
Ͼ5
0.67Ϯ0.08
0.11Ϯ0.03
0.12Ϯ0.02
3.40Ϯ0.7
15.2Ϯ2.3
Experimental Section
[5]Cl
[6]Cl
[7]Cl
cisplatin
General: The starting material [(p-MeC6H4iPr)2Ru2Cl4] was pre-
pared according to published methods.[20] All other reagents were
commercially available and were used without further purification.
NMR spectra were recorded with a Bruker 400 MHz spectrometer.
Electrospray mass spectra were obtained in positive- or negative-
ion mode with an LCQ Finnigan mass spectrometer. Microanalyses
were carried out by the Mikroelementaranalytisches Laboratorium,
ETH Zürich (Switzerland).
The neutral dithiolato complexes 1–3 are cytotoxic
towards the cancer cell lines A2780 and A2780cisR, but the
IC50 values are always higher than those of the correspond-
ing cationic trithiolato complexes 5–7 (Table 1). The sub-
stituent R has a strong influence on the cytotoxicity of the
complexes. For the dithiolato complexes, the presence of
two methylene groups in the aliphatic chain seems to be
beneficial. Thus, the IC50 values of 2.94 and 3.60 μm for 1
(with R = CH2Ph) decrease to 0.20 and 0.31 μm for 2 (with
R = CH2CH2Ph). This is in line with the submicromolar
IC50 values obtained for the cyclohexyl derivative 4 (0.46
and 0.67 μm). However, the tert-butyl group in the terminal
position of the substituent (R = CH2C6H4-p-tBu) in 3 has
an opposite effect, which, to a lesser extent, is also exhibited
by the corresponding cationic trithiolato complex 7. The
Synthesis of 1–3: [(p-MeC6H4iPr)2Ru2Cl4] (100 mg, 0.16 mmol) was
dissolved in technical-grade EtOH (10 mL). When the compound
had completely dissolved, the solution was cooled to 0 °C. After
addition of the corresponding thiol RSH (0.32 mmol; R = CH2Ph:
38 μL, R = CH2CH2Ph: 43 μL, R = CH2C6H4-p-tBu: 60 μL), the
solution was stirred at 0 °C for 2 h. Then the volume was reduced
to 2 mL and diethyl ether (30 mL) added, which caused precipi-
tation of the product. After cooling of the mixture to –18 °C for
24 h, the product was isolated by decantation using a cannula. The
yellow to red product was washed with diethyl ether (2 times with
40 mL) and dried under vacuum.
Data for 1: Yield: 110 mg (86%). C34H42Cl2Ru2S2 (787.87): calcd.
cytotoxicities of 2, 4, [5]Cl, and [6]Cl are remarkable, with C 51.83, H 5.37; found C 51.54, H 5.42. ESI MS (MeOH +
Eur. J. Inorg. Chem. 2012, 1531–1535
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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G. Süss-Fink et al.
FULL PAPER
CH2Cl2): m/z = 753.40 [M – Cl]+. H NMR (400 MHz, CDCl3): δ
ppm. 13C{1H} NMR (100 MHz, CDCl3): δ = 139.7, 129.3, 128.8,
1
= 7.44 (m, 10 H, CH2C6H5), 4.96 (m, 8 H, H–Ar), 4.19 (d, 2J = 128.1, 108.3, 100.4, 83.6, 83.5, 83.3, 81.9, 40.8, 31.5, 24.0, 23.6,
11.4 Hz, 2 H, SCH2), 3.31 (d, 2J = 11.4 Hz, 2 H, SCH2), 2.86 [sept,
3J = 6.8 Hz, 2 H, (CH3)2CH], 1.88 (s, 6 H, CH3), 1.21 [m, 12 H,
(CH3)2CH] ppm. 13C{1H} NMR (100 MHz, CDCl3): δ = 142.0,
130.6, 130.0, 129.3, 106.0, 100.0, 84.3, 83.2, 46.2, 32.2, 22.5,
18.0 ppm.
18.4 ppm.
Data for [6]Cl: Yield: 30 mg (78%). C44H55ClRu2S3·CH2Cl2·EtOH
(1049.12): calcd. C 53.83, H 6.06; found C 54.38, H 6.39. ESI MS
(MeOH): m/z = 883.20 [M + H]+. H NMR (400 MHz, CDCl3): δ
1
3
= 7.34 (m, 15 H, CH2CH2C6H5), 5.16 (m, 8 H, H–Ar), 3.03 (t, J
= 7.6 Hz, 6 H, SCH2CH2), 2.71 (t, 3J = 7.6 Hz, 6 H, CH2CH2),
Data for 2: Yield: 70 mg (53%). C36H46Cl2Ru2S2 (815.93): calcd. C
52.99, H 5.68; found C 52.77, H 5.71. ESI MS (MeOH + acetone):
m/z = 781.10 [M – Cl]+. 1H NMR (400 MHz, CDCl3): δ = 7.29 (m,
10 H, CH2CH2C6H5), 5.08 (m, 8 H, H–Ar), 3.15 (m, 4 H,
SCH2CH2), 2.92 [sept, 3J = 6.8 Hz, 2 H, (CH3)2CH], 2.26 (m, 4 H,
SCH2CH2), 2.17 (s, 6 H, CH3), 1.24 [m, 12 H, (CH3)2CH] ppm.
13C{1H} NMR (100 MHz, CDCl3): δ = 141.5, 128.9, 128.5, 126.14,
106.5, 96.5, 85.3, 85.1, 83.5, 80.8, 38.0, 35.4, 30.2, 23.0, 21.0,
18.9 ppm.
3
2.42 [sept, J = 6.8 Hz, 2 H, (CH3)2CH], 1.73 (s, 6 H, CH3), 1.19
[m, 12 H, (CH3)2CH] ppm. 13C{1H} NMR (100 MHz, CDCl3): δ
= 139.8, 128.8, 126.9, 125.9, 106.8, 101.0, 83.7, 83.6, 83.6, 83.4,
41.4, 38.8, 31.4, 23.8, 22.6, 18.3 ppm.
Data for [7]Cl: Yield: 75 mg (82%). C53H73ClRu2S3·0.25CH2Cl2
(1065.25): calcd. C 60.04, H 6.96; found C 59.94, H 7.18. MS
(MeOH): m/z = 1009.40 [M]+. 1H NMR (400 MHz, CDCl3): δ =
7.45 [s, 12 H, CH2C6H4C(CH3)3], 5.13 (d, 3J = 6.0 Hz, 2 H, H–
3
3
Ar), 5.07 (d, J = 6.0 Hz, 2 H, H–Ar), 4.80 (d, J = 6.0 Hz, 2 H,
Data for 3: Yield: 100 mg (69%). C42H58Cl2Ru2S2·CH2Cl2 (984.10):
calcd. C 52.43, H 6.14; found C 51.88, H 6.16. ESI MS (MeOH +
CH2Cl2): m/z = 865.30 [M – Cl]+. 1H NMR (400 MHz, CDCl3): δ =
7.49 [d, 3J = 8.0 Hz, 4 H, CH2C6H4C(CH3)3], 7.32 [d, 3J = 8.0 Hz, 4
H, CH2C6H4C(CH3)3], 4.97 (m, 8 H, H–Ar), 4.11 (d, 2J = 11.4 Hz,
2 H, CH2), 3.32 (d, 2J = 11.4 Hz, 2 H, CH2), 2.82 [sept, 3J = 6.8 Hz,
3
H–Ar), 4.61 (d, J = 6.0 Hz, 2 H, H–Ar), 3.50 (s, 6 H, CH2), 2.04
3
[sept, J = 6.8 Hz, 2 H, (CH3)2CH], 1.72 (s, 6 H, CH3), 1.35 [s, 18
3
3
H, C(CH3)3], 1.03 [d, J = 6.8 Hz, 6 H, (CH3)2CH], 0.97 [d, J =
6.8 Hz, 6 H, (CH3)2CH] ppm. 13C{1H} NMR (100 MHz, CDCl3):
δ = 151.6, 136.6, 129.1, 125.6, 108.1, 100.7, 83.4, 83.3, 82.8, 81.9,
40.4, 34.8, 31.5, 31.5, 31.3, 29.7, 23.6, 22.9, 18.5 ppm.
2
H, (CH3)2CH], 1.89 (s, 6 H, CH3), 1.38 [s, 18 H,
CH2C6H4C(CH3)3], 1.16 [m, 12 H, (CH3)2CH] ppm. 13C{1H}
NMR (100 MHz, CDCl3): δ = 150.0, 137.8, 130.2, 124.5, 105.7,
97.2, 83.4, 83.3, 82.8, 81.9, 36.5, 34.6, 31.5, 31.5, 31.5, 29.9, 23.3,
23.3, 18.7 ppm.
Single-Crystal X-ray Structure Analysis of 3
X-ray Data for [(p-MeC6H4iPr)2Ru2(SCH2C6H4-p-tBu)2Cl2] (3):
C42H58Cl2Ru2S2, Mr = 900.04, triclinic, space group P1 (no. 2), cell
¯
parameters a = 8.7997(18) Å, b = 9.3427(18) Å, c = 13.300(2) Å, α
= 96.285(14)°, β = 99.419(15)°, γ = 102.542(16)°, V = 1041.0(3) Å3,
T = 173(2) K, Z = 1, Dcalcd. = 1.430 gcm–3, λ(Mo-Kα) = 0.71073 Å,
5540 reflections measured, 2577 unique (Rint = 0.1440), which were
used in all calculations. The crystal was mounted on a Stoe image
plate diffraction system equipped with a φ circle goniometer, and
Mo-Kα graphite-monochromated radiation (λ = 0.71073 Å) was
used with a φ range of 0–200°. The structure was solved by direct
methods with the program SHELXS-97, whereas the refinement
and all further calculations were carried out by using SHELXL-
97.[21] The hydrogen atoms were included in calculated positions
and treated as riding atoms by using the SHELXL default param-
eters. The non-hydrogen atoms were refined anisotropically by
using weighted full-matrix least squares on F2. R1 = 0.0765
[IϾ2σ(I)] and wR2 = 0.1810, GoF = 1.134; max./min. residual den-
sity 1.069/–0.743 eÅ–3. Figure 1 was drawn with ORTEP.[22]
CCDC-846981 (3) contains the supplementary crystallo-
graphic data 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.
Synthesis of 4: Cyclohexanethiol (0.32 mmol, 38 mg) dissolved in
EtOH (5 mL) was added to a solution of [(p-MeC6H4iPr)2Ru2Cl4]
(100 mg, 0.16 mmol) in technical-grade ethanol (50 mL). Then the
solution was heated to reflux for 18 h, cooled to room temperature,
and filtered through Celite. After evaporation of the solvent, the
residue was purified by column chromatography on silica gel by
using dichloromethane/ethanol (5:1) as eluent. The product was
isolated as an orange powder and dried under vacuum.
Data for 4: Yield: 75 mg (61%). C32H50Cl2Ru2S2 (771.86): calcd. C
49.79, H 6.53; found C 49.76, H 6.55. ESI MS (MeOH + CH2Cl2):
m/z = 736.30 [M – Cl]+. 1H NMR (400 MHz, CDCl3): δ = 5.70 (d,
3
3J = 8.0 Hz, 4 H, H–Ar), 5.58 (d, J = 8.0 Hz, 4 H, H–Ar), 3.20
(m, 2 H, C6H11), 2.55 [sept, 3J = 8.0 Hz, 2 H, (CH3)2CH], 2.42 (m,
4 H, C6H11), 2.05 (s, 6 H, CH3), 1.99 (m, 8 H, C6H11), 1.59 (m, 8
3
H, C6H11), 1.23 [d, J = 8.0 Hz, 12 H, (CH3)2CH] ppm. 13C{1H}
NMR (100 MHz, CDCl3): δ = 82.3, 82.2, 82.7, 39.2, 37.1, 33.0,
31.9, 31.7, 31.1, 29.6, 29.4, 27.3, 25.8, 24.1, 22.8, 22.6, 22.4, 18.4,
18.1, 14.2 ppm.
Synthesis of 5–7: The corresponding thiol (6 equiv.; R = CH2Ph:
36 μL, R = CH2CH2Ph: 33 μL, R = CH2C6H4-p-tBu: 99 μL) was
added to a solution of the neutral dithiolato complexes (1 equiv.;
1: 40 mg, 2: 34 mg, 3: 80 mg) in technical-grade ethanol (50 mL).
Then the solution was heated to reflux for 12 h. After evaporation
of the solvent, the residue was purified by column chromatography
on silica gel by using dichloromethane/ethanol (9:1) as eluent. The
yellow to brown product was isolated and dried under vacuum.
Cell Culture and Inhibition of Cell Growth: Human A2780 and
A2780cisR ovarian carcinoma cells were obtained from the Euro-
pean Centre of Cell Cultures (ECACC, Salisbury, UK) and main-
tained in culture as described by the provider. The cells were rou-
tinely grown in RPM1 1640 medium with GlutaMAX that con-
tained fetal calf serum (FCS) (5%) and antibiotic (penicillin and
streptomycin) at 37 °C and CO2 (5%). For the evaluation of
growth-inhibition tests, the cells were seeded in 96-well plates
(25ϫ103 cells per well) and grown in complete medium for 24 h.
The compounds were dissolved in DMSO and added to the re-
quired concentration to the cell culture for 72 h incubation. Solu-
tions of compounds were applied by diluting a fresh stock solution
of the corresponding compound in aqueous RPM1 medium with
Data for [5]Cl: Yield: 25 mg (56%). C41H49ClRu2S3 (875.63): calcd.
C 56.24, H 5.64; found C 55.64, H 5.85. ESI MS (MeOH): m/z =
1
841.20 [M + H]+. H NMR (400 MHz, CDCl3): δ = 7.55 (m, 6 H,
CH2C6H5), 7.41 (m, 9 H, CH2C6H5), 5.17 (d, 3J = 6.0 Hz, 2 H, H–
3
3
Ar), 5.05 (d, J = 6.0 Hz, 2 H, H–Ar), 4.75 (d, J = 6.0 Hz, 2 H,
3
H–Ar), 4.69 (d, J = 6.0 Hz, 2 H, H–Ar), 3.51 (s, 6 H, CH2), 2.07 GlutaMAX (20 mm). Following drug exposure, MTT was added to
[sept, J = 6.8 Hz, 2 H, (CH3)2CH], 1.90 (s, 6 H, CH3), 1.07 [d, J cells at a final concentration of 0.25 mgmL–1 and incubated for 2 h.
3
3
3
= 6.8 Hz, 6 H, (CH3)2CH], 1.02 [d, J = 6.8 Hz, 6 H, (CH3)2CH]
Then the culture medium was aspirated and the violet formazan
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Eur. J. Inorg. Chem. 2012, 1531–1535

Thiolato-Bridged Arene–Ruthenium Complexes
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(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
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Acknowledgments
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Published Online: December 16, 2011
Eur. J. Inorg. Chem. 2012, 1531–1535
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjic.org
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