Cationic arene ruthenium(ii) complexes with chelating P-functionalized alkyl phenyl sulfide and sulfoxide ligands as potent anticancer agents

Article abstract of DOI:10.1039/c3dt33064h

The synthesis and characterization of cationic ruthenium(ii) complexes of the type [Ru(η⁶-p-cym)Cl{Ph₂P(CH₂) _nS(O)_xPh-κP,κS}][PF₆] (n = 1-3; x = 0, 1; p-cym = p-cymene) are presented. Furth

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Cationic arene ruthenium(II) complexes with chelating Pꢀfunctionalized
alkyl phenyl sulfide and sulfoxide ligands as potent anticancer agents
Gerd Ludwig,a Goran N. Kaluñerović,a,b Tobias Rüffer,c Martin Bette,a Marcus Korb,c Michael Block,a
Reinhard Paschke,b Heinrich Langc and Dirk Steinborn*a
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
phenyl sulfide, sulfoxide, and sulfone ligands (type VII, Fig. 1),
whereas some of them showed in vitro cytotoxicities comparable
to cisplatin.35 Type VII complexes with κP-coordinated ligands
50 with pendant sulfide and sulfoxide groups (1a–5a) were prepared
according to Scheme 1 starting from the dinuclear complex
[{Ru(η6ꢀpꢀcym)Cl2)}2] (reaction pathway a). Here, we report on
the synthesis and characterization of cationic ruthenium(II) comꢀ
plexes with bidentately coordinated (κP,κS) ωꢀdiphenylphosꢀ
55 phinoꢀfunctionalized alkyl phenyl sulfide and sulfoxide ligands
Ph2P(CH2)nS(O)xPh (x = 0, 1) as well as on their cytotoxic activiꢀ
ty, particularly on the influence of the spacer length (n = 1–3) on
it.
Synthesis and characterization of cationic ruthenium(II)
complexes of the type [Ru(η6ꢀpꢀcym)Cl{Ph2P(CH2)nS(O)xPhꢀ
κP,κS}][PF6] (n = 1–3; x = 0, 1; pꢀcym = pꢀcymene) are preꢀ
10 sented. Furthermore, their high biological potential even
against cisplatinꢀresistant tumor cell lines and structure–
activity relationships are discussed.
The discovery of the chemotherapeutic activity of cisplatin by
Barnett Rosenberg in 1965 was a milestone in the field of bioꢀ
15 inorganic chemistry.1,2 Cisplatin itself developed to be the "gold
standard" by which all anticancer drugs should be judged.3 Howꢀ
ever, drawbacks of cisplatin and other platinumꢀbased anticancer
agents are doseꢀdepending toxic side effects as well as the occaꢀ
sional occurrence of resistances against cancer cells.4–6 Thus, a
20 manifold of transition metal complexes were screened for their
cytotoxic activity, where some of them were able to enter clinical
trials.7–9 Major efforts were done in the field of rutheniumꢀbased
anticancer drugs, especially by the research groups of Sadler,
Dyson and Keppler,10–19 which may have not only a good cytoꢀ
25 toxic activity, but also an antimetastatic activity.20 Furthermore,
the ruthenium complexes hardly affect normal cells and, in some
cases, they can overcome the resistance of cancer cells against
various platinumꢀbased anticancer drugs.21–23 The most promiꢀ
nent ruthenium complexes in the field of anticancer research are
30 the octahedral ruthenium(III) complexes I and II (Fig. 1), which
have entered clinical trials.24–29 Unlike other anticancer drugs,
complex II is not very toxic toward cancer cells, but the main
effect that counts is the ability to stop the metastasis of the canꢀ
cer. It is assumed that ruthenium(III) complexes underwent in
35 vivo a reduction into the oxidation state +2,30,31 which can be
stabilized through πꢀbonded arene ligands.32 Thus, arene rutheniꢀ
um(II) complexes of type III (Fig. 1) showed both in vitro and in
vivo promising anticancer activity with in vitro IC50 values (IC50
= concentration of compound that inhibits 50% of cell growth) in
40 the range of 6–300 ꢁM against human cancer cell lines.32.33 So
far, only a few examples of cytotoxic active ruthenium(II) comꢀ
plexes with phosphorus ligands are known. Examples are comꢀ
plexes IV–VI,23,34 whereas complex IV exhibits nearly no cytoꢀ
toxicity but a promising antimetastatic activity.23 Recently, our
45 group has investigated neutral arene ruthenium(II) complexes
having κP-coordinated ωꢀdiphenylphosphinoꢀfunctionalized alkyl
Reactions of neutral ruthenium complexes 1a–3a bearing κP
60 coordinated ωꢀdiphenylphosphinoꢀfunctionalized alkyl phenyl
sulfide ligands Ph2P(CH2)nSPh (n = 1–3) with [NH4][PF6] resultꢀ
ed under chloride abstraction in the formation of cationic comꢀ
plexes
of
the
type
[Ru(η6ꢀpꢀcym)Cl{Ph2P(CH2)nSPhꢀ
κP,κS}][PF6] (1b–3b) having the ligands coordinated in a bidenꢀ
65 tate fashion (κP,κS), cf. Scheme 1 (path b).
Fig. 1 Examples of rutheniumꢀbased anticancer drugs.
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Scheme 1 Synthetic route to ruthenium(II) complexes bearing Ph2P(CH2)nS(O)xPhꢀκP,κS ligands (1b–5b).
When the neutral complexes 1a–3a were not isolated, i.e. followꢀ
ing a oneꢀpot reaction (path a + b), the cationic complexes 1b–3b
angles at the ruthenium(II) atoms are close to 90° (81.4(2)–
90.9(3)°), with the exception of complex 1b (S–Ru–P 70.6(4)°),
5
were obtained in good yields (67–83%) as yellow powders. Analꢀ 55 therefore the structures can be considered as slightly distorted
ogously, the neutral ruthenium complexes 4a and 5a with κP
coordinated ωꢀdiphenylphosphinoꢀfunctionalized alkyl phenyl
sulfoxide ligands Ph2P(CH2)nS(O)Ph (n = 2, 3) were found to
react with [NH4][PF6] following oneꢀpot procedure producing
octahedrons. The deviation of mentioned angle in 1b can be
likely attributed to the ring strain in the fourꢀmembered RuPCS
cycle. The bite angles of the chelating ligands P(CH2)nS(O)xPhꢀ
κP,κS are directly related to the chain length n. Thus, the bite
10 cationic complexes of the type [Ru(η6ꢀpꢀcym)Cl{Ph2P(CH2)nꢀ 60 angles range from 70.6(4)° for the ruthenium complex 1b with a
S(O)PhꢀκP,κS}][PF6] (4b, 5b; Scheme 1) in yields between 74
and 78% as yellow powders. All complexes are stable on air over
weeks and soluble in dimethylsulfoxide and in methylene chloꢀ
ride. The complexes 1b−5b were characterized by elemental
methylene spacer (n = 1) via 85.5(4)/81.4(2)° for complexes
2b/4b with an dimethylene spacer (n = 2) up to 88.1(3)/88.8(2)°
for complexes 3b/5b with a trimethylene spacer (n = 3). The fiveꢀ
membered RuPC2S ruthenacycles adopt an envelope (2b) and a
15 analyses, NMR spectroscopy (1H, 13C, 31P) and singleꢀcrystal Xꢀ 65 twist form (4b). The two sixꢀmembered RuPC3S ruthenacycles
ray structure analyses.
(3b, 5b) possess a chair conformation. For all complexes, the Ru–
Cl (2.381(1)–2.404(9) Å), Ru–P (2.312(7)–2.349(4) Å) as also
the Ru–S bond lengths (2.262(7)–2.390(1) Å) are in the expected
range (median Ru–Cl: 2.414 Å, lower/higher quartile:
Selected NMR spectroscopic parameters of complexes 1b−5b
are given in Table S1. Compared to the requisite neutral rutheniꢀ
um complexes 1a–5a having these ligands only κP coordinated
20 (Scheme 1), the formation of fourꢀ and fiveꢀmembered ruthenaꢀ 70 2.389/2.442 Å, n = 5542; median Ru–P: 2.332 Å, lower/higher
cycles results in highfield (by 31 ppm, 1b) and downfield shifts
(44/49 ppm, 2b, 4b), respectively, in 31P NMR spectra, whereas
the formation of sixꢀmembered ruthenacycles (3b, 5b) shifts the
phosphorus resonances only marginally (< 5 ppm).35 Furtherꢀ
quartile: 2.287/2.375 Å, n = 2520; median Ru–S: 2.299 Å, lowꢀ
er/higher quartile: 2.266/2.352 Å, n = 678; n – number of obserꢀ
vations). The Ru–P bonds are longer in complexes forming sixꢀ
membered ruthenacycles (2.348(9)/2.349(4) Å) compared to
25 more, the formation of the RuP(CH2)nS(O)x cycles goes along 75 those in complexes with fourꢀ and fiveꢀmembered cycles
with an increase of the 1JP,C coupling constants up to 10 Hz comꢀ
(2.312(7)–2.318(1) Å). The Ru–Ssulfinyl bonds (2.262(7)/2.285(4)
Å, 4b/5b) are significantly shorter than the Ru–Ssulfide bonds
(2.354(1)–2.390(1) Å, 1b–3b).
1
pared to the analogous neutral complexes.35 Thus, the JP,C couꢀ
plings of the cationic ruthenium(II) complexes 1b–5b are generꢀ
ally in the range of 30 Hz, with the exception of 1b (21.0 Hz)
30 forming a fourꢀmembered RuPCS cycle. All proton resonances of
the p-cymene ligand in complexes 1b−5b were found to be in a
narrow range (aromatic CH: 4.79−6.11 ppm; isopropyl CH/CH3;
1.97–2.57/0.01–1.12 ppm; methyl CH3: 1.23–2.07 ppm), largely
independent from the type of the S(O)x function.
35
Crystals of [Ru(η6ꢀpꢀcym)Cl{Ph2PCH2SPhꢀκP,κS}][PF6]ꢀ
ꢂCH2Cl2
(1bꢂCH2Cl2),
[Ru(η6ꢀpꢀcym)Cl{Ph2P(CH2)2SPhꢀ
κP,κS}][PF6]ꢂMe2CO (2bꢂMe2CO), [Ru(η6ꢀpꢀcym)Cl{Ph2Pꢀ
(CH2)3SPhꢀκP,κS}][PF6] (3b), [Ru(η6ꢀpꢀcym)Cl{Ph2P(CH2)2ꢀ
S(O)PhꢀκP,κS}][PF6]ꢂCH2Cl2 (4bꢂCH2Cl2) and [Ru(η6ꢀpꢀcyꢀ
40 m)Cl{Ph2P(CH2)3S(O)PhꢀκP,κS}][PF6] (5b) suitable for Xꢀray
diffraction analyses were obtained from methylene chloride/nꢀ
pentane or acetone solutions at room temperature. The comꢀ
pounds crystallized in discrete cations and anions. Between them
weak C–HꢂꢂꢂF interactions ranging from 2.897(4) Å (C12ꢂꢂꢂF3,
45 4bꢂCH2Cl2) to 3.224(7) Å (C42ꢂꢂꢂF41, 1bꢂCH2Cl2) were found.
The molecular structures of the cations are shown in Figures
2 and S1−S5 and selected structural parameters are given in the
respective figure captions.
All the five complexes have a half sandwich (“piano stool”)
50 structure, in which the coordination spheres of ruthenium(II) are
built up by a η6ꢀpꢀcymene, a chlorido as well as a P∩SꢀκP,κS
(1b–3b) and a P∩S(O)ꢀκP,κS (4b, 5b) ligand, respectively. The
80
Fig. 2 Molecular structure of the cation in crystals of [Ru(η6ꢀpꢀcym)ꢀ
Cl{Ph2P(CH2)3S(O)PhꢀκP,κS}][PF6], 5b.‡ The ellipsoids are shown
with a probability of 50%. H atoms have been omitted for clarity. Selectꢀ
ed structural parameters (distances in Å, angles in °): Ru–Cl 2.400(4),
85 Ru–P 2.349(4), Ru–S 2.285(4), Cl–Ru–P 83.4(2), Cl–Ru–S 89.4(2), S–
Ru–P 88.8(2), C29–S–C23 100.6(8).
2
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Table 1 IC50 valuesa (in ꢀM) of the ruthenium(II) complexes 1b−5b in comparison with cisplatin.
Compound
n/x
1/0
2/0
3/0
2/1
3/1
518A2
8505C
A253
MCFꢀ7
SW480
1b
2b
1.81 ± 0.11
1.70 ± 0.06
1.32 ± 0.10
1.74 ± 0.09
0.96 ± 0.12
1.52 ± 0.19
1.81 ± 0.11
1.70 ± 0.06
1.32 ± 0.10
1.53 ± 0.05
0.96 ± 0.12
5.02 ± 0.23
1.29 ± 0.09
0.93 ± 0.04
0.37 ± 0.06
2.15 ± 0.22
1.21 ± 0.03
0.81 ± 0.02
0.41 ± 0.11
0.26 ± 0.03
0.17 ± 0.01
0.39 ± 0.04
0.14 ± 0.01
2.03 ± 0.11
1.85 ± 0.02
1.73 ± 0.14
1.30 ± 0.05
1.72 ± 0.02
0.86 ± 0.04
3.24 ± 0.21
3b
4b
5b
cisplatin
a Mean values ± SD (standard deviation) from three experiments.
In vitro cytotoxicity studies of the cationic ruthenium(II) comꢀ
plexes 1b–5b were performed against 518A2 (melanoma), 8505C
4. A correlation between the spacer lengths –(CH2)n– (n = 1–3)
and cytotoxic activity (cell lines 518A2, 8505C, A253, MCFꢀ7,
5
(anaplastic thyroid tumor), A253 (head and neck tumor), MCFꢀ7 50 SW480) has been observed, namely, the longer the spacer the
(breast), and SW480 (colon) cell lines. The results, based on the
sulforhodamineꢀB (SRB) microculture colorimetric assay,36 are
shown in Table 1 in which, for comparison, the respective activiꢀ
higher the in vitro activity (cf. 1b < 2b < 3b and 4b < 5b). This
leads, for example, for the cell line A253 to a four times higher
activity of complex 3b having a trimethylene spacer (n = 3) comꢀ
pared to that of the respective complex 1b having only a methꢀ
10 ties of cisplatin are included. The complexes of the type [Ru(η6ꢀ
pꢀcym)Cl{Ph2P(CH2)nS(O)xPhꢀκP,κS}][PF6] (1b–5b; n = 1–3, x 55 ylene spacer (n = 1).
= 0, 1) show IC50 values in the same order of magnitude or, in
some cases, even lower than cisplatin. Especially, the novel catꢀ
ionic ruthenium(II) complexes are highly active against cisplatinꢀ
15 resistant tumor cell lines 8505C, MCFꢀ7 and SW480. The most
5. In vitro anticancer activity investigations revealed that the
most active ruthenium complex is compound 5b (n = 3, x = 1)
against the MCFꢀ7 cell line with an IC50 value of 0.1 ꢁM, thus,
active compound of this series is complex 5b with an IC50 value 60 being more than one order of magnitude more active than cisplaꢀ
of 0.1 ꢁM against MCFꢀ7 cell line (cisplatin: 2.0 ꢁM).
tin (IC50: 2.0 ꢁM).
Conclusions
Consequently, the cationic ruthenium(II) complexes presented
here revealed high biological potential, especially against cisplaꢀ
20 In this study, cationic ruthenium(II) complexes of the type
[Ru(η6ꢀpꢀcym)Cl{Ph2P(CH2)nS(O)xPhꢀκP,κS}][PF6] (1b–5b; n = 65 tinꢀresistant tumor cell lines 8505C, MCFꢀ7 and SW480. Furꢀ
1–3; x = 0, 1) were prepared by reactions of ωꢀdiphenylphosꢀ
phinoꢀfunctionalized alkyl phenyl sulfides and sulfoxides with
the dinuclear complex [{Ru(η6ꢀpꢀcym)Cl2)}2] and [NH4][PF6]
25 (Scheme 1). The constitution of all these complexes, especially
thermore, the correlation between the length of the spacer in the
ligands and the cytotoxicity of the complexes can be traced back
to an increasing hydrophobicity.
the κP,κS coordination of the ligands, was unequivocally conꢀ 70 Acknowledgment
firmed by NMR studies and by singleꢀcrystal Xꢀray diffraction
analyses, too. Investigations of the in vitro toxicity of these half
sandwich (“piano stool”) ruthenium(II) complexes against five
30 different cell lines have shown high cytotoxicities. The following
conclusions can be drawn:
G. L. gratefully acknowledges financial support from the Graduꢀ
ate Scholarship of the State SaxonyꢀAnhalt.
Notes and references
aInstitute of Chemistry, Martin Luther University Halle-Wittenberg, Kurt-
75 Mothes-Straße 2, D-06120 Halle, Germany.
1. Generally, in almost all cell lines, the cationic ruthenium comꢀ
plexes 1b–5b with the κP,κS coordinated ligands show higher in
35 vitro activities than the corresponding neutral ruthenium comꢀ
plexes [Ru(η6ꢀpꢀcym)Cl2{Ph2P(CH2)nS(O)xPhꢀκP}] (1a–5a)
bearing the same, but only κP coordinated ligands,35 cf. the valꢀ
ues given in Table 1 with those in Table S2. As an example, this
is demonstrated in Fig. S7 for the most active complex 5b.
40
E-mail: dirk.steinborn@chemie.uni-halle.de
bBiocenter, Martin Luther University Halle-Wittenberg, Weinbergweg 22,
D-06120 Halle, Germany.
cInstitute of Chemistry, Chemnitz University of Technology, Straße der
80 Nationen 62, D-09111 Chemnitz, Germany.
† Electronic Supplementary Information (ESI) available: Complete
experimental details, Tables and Figures of NMR spectroscopical data
and molecular structures of 1b–5b, crystallographic data for 1b–5b.
CCDC reference numbers 911007–911011. See DOI: 10.1039/b000000x/
85 ‡ Crystallographic data for 5b: C31H35ClF6OP2RuS, M = 768.11 g mol–1,
triclinic, P–1, a = 10.0603(2), b = 12.0758(3), c = 13.1404(3) Å, α =
83.783(2)º, β = 80.719(2)º, γ = 87.902(2)º, V = 1565.92(6) Å3, Z = 2, T =
110 K, ꢁ(MoKα) = 0.816 mm–1. Using 388 parameters, wR2 = 0.0491
(6126 unique reflections), R1 = 0.0207 (5707 reflections with I > 2σ(I)).
90
2. The ligands themselves show moderate or only very weak
cytotoxic activities (IC50: 6–153 ꢁM).35
3. The oxidation state of sulfur (–SPh vs. –S(O)Ph) in the ligands
45 does not have a significant influence on the IC50 values of the
cationic ruthenium complexes (cf. 2b/3b vs. 4b/5b).
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Graphical Abstract
Synthesis and characterization of cationic ruthenium(II) complexes of the type [Ru(η6ꢀpꢀ
cym)Cl{Ph2P(CH2)nS(O)xPhꢀκP,κS}][PF6] (n = 1–3; x = 0, 1) are presented. Furthermore,
their high biological potential even against cisplatinꢀresistant tumor cell lines and structure–
activity relationships are discussed.
Highlights
► Cationic ruthenium(II) complexes with Pꢀfunctionalized alkyl phenyl sulfide and sulfoxide
ligands of the type [Ru(η6ꢀpꢀcym)Cl{Ph2P(CH2)nS(O)xPhꢀκP,κS}][PF6] (n = 1–3; x = 0, 1) are
presented. ► These complexes proved to be potent inhibitors of cancer cell growth as active
as cisplatin. ► Structure–activity relationships are discussed.
Keywords
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Ruthenium(II) complexes
P,S ligands
Cytotoxic activity