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Neutral and Ionic Cycloruthenated 2-Phenylindoles as Cytotoxic Agents
Communication
pubs.acs.org/Organometallics
Neutral and Ionic Cycloruthenated 2‑Phenylindoles as Cytotoxic
Agents
Lluís Belsa,† Concepción López,*,† Asensio González,‡ Mercè Font-Bardıa,́ § Teresa Calvet,∥
Carmen Calvis,⊥ and Ramon Messeguer⊥
†
Departament de Quı ́mica Inorgànica, Facultat de Quı ́mica, Universitat de Barcelona, Martí i Franquès 1-11, E-08028 Barcelona,
Spain
‡
Laboratori de Quı ́mica Orgànica, Facultat de Farmàcia, Universitat de Barcelona, Pl. Pius XII s/n, E-08028 Barcelona, Spain
§
Unitat de Difracció de Raig-X, Centre Científic i Tecnològic de la Universitat de Barcelona, Solé i Sabarı ́s 1-3, E-08028 Barcelona,
Spain
∥
Departament de Crystal·lografı ́a, Mineralogia i Dipòsits Minerals, Facultat de Geologı ́a, Universitat de Barcelona, Martı ́ i Franquès
s/n, E-08028 Barcelona, Spain
⊥
Biomed Division, LEITAT Tecnological Center, Parc Científic de Barcelona, Edifici Hèlix, Baldiri Reixach 15-21, E-08028 Barcelona,
Spain
S Supporting Information
*
ABSTRACT: The synthesis and characterization of two families of
cyclometalated Ru(II) complexes with the new (Csp2,Nindole)− motif
formed by activation of the C−H bonds of 2-phenylindole ligands of the
general formula {(4′-R1-C6H4)-3-NOMe-5-R2-6-R3-(C6H2N)} are presented. The novel ruthenacycles show a remarkable cytotoxic activity in
MCF7 and MDA-MB231 breast cancer cell lines, which clearly exceeds
those of the trans and cis isomers of [PtCl2(L)(DMSO)] derived from the
same ligands and even that of cisplatin.
C
ancer is one of the main causes of death in developed
countries.1 The discovery of the cytotoxic properties of
cis-[PtCl2(NH3)2] (cisplatin) and its clinical use has marked the
origin of fast and increasing interest in the chemistry of
platinum(II).2−5 Unfortunately, cisplatin and other Pt-based
cytotoxic agents (i.e., carboplatin and oxaliplatin) display
limited activity against certain types of cancers, trigger drug
resistance, and provoke adverse effects (kidney toxicity, nausea,
and bone marrow disruption).5 Thus, the design of new
antitumoral drugs with activity greater than that of cisplatin and
lower adverse side effects is one of the main challenges of
current research. Organometallic compounds with potent
cytotoxic activities containing metallocenes, half-sandwiches,
or cyclometalated rings have been described.6
Ruthenium compounds have attracted intense research
interest as potential anticancer agents.7 Recently new classes
of neutral and cationic half-sandwich Ru(II)−arene compounds
were found to have promising anticancer activity.8 Representative examples of these organometallic compounds are RAPTAC and RM175 (Figure 1). Furthermore, cycloruthenated
complexes are scarce9 and show great promise for the design
of antitumoral drugs. RCD-11 (Figure 1) deserves special
attention, with reduced neurotoxicity and good antitumor
activity in vitro and in vivo using a wide panel of cell lines
(including some cisplatin-resistant ones).10
Some 2-phenylindole derivatives (1 and 2 in Figure 2)
exhibit interesting antitumoral activity.11,12 In addition, they are
© 2013 American Chemical Society
Figure 1. Main examples of highly cytotoxic organometallic
ruthenium(II) complexes used for both in vitro and in vivo studies.
valuable reagents in coordination and organometallic chemistry.13 Cyclopalladation of the 3-metoxyimino-2-phenylindoles
(3a,b in Figure 2) has been described.14 trans (4) and cis (5)
isomers of [Pt(L)Cl2(DMSO)] (L = 3a−c) have also been
prepared,15,16 and most of them showed cytotoxic activity (IC50
= 2 μM) greater than that of cisplatin in the MCF7 cell line.16
In view of the cytotoxic activity of the Pt(II) complexes 4a−c
and 5a−c and the increasing interest in ruthenacycles as
antitumoral agents, here we report two sets of cycloruthenated
complexes (neutral (6a−e) and ionic (7a−e)) with the
uncommon (Csp2,Nindole)− cyclometalation motif.
Compounds 6a−e were isolated by reaction of [Ru(η6-pcymene)Cl(μ-Cl)]2 with Ag[PF6] in acetone, followed by the
addtion of the corresponding ligand 3a−e (at 328 K for 24 h)
Received: September 21, 2013
Published: December 6, 2013
7264
dx.doi.org/10.1021/om400941b | Organometallics 2013, 32, 7264−7267
Organometallics
Communication
Figure 2. Relevant 2-phenylindole derivatives 1 and 2 with cytotoxic
activity, reported previously, and the 3-methoxyimino derivatives 3
used in this work.
Scheme 1. Preparation of Compounds 6 and 7
Figure 4. X-ray crystal structure of 6c·H2O. Hydrogen atoms have
been omitted for clarity. Selected bond lengths (in Å) and angles (in
deg): Ru(1)−N(1), 2.074(3); Ru(1)−C(11), 2.057(5); Ru(1)−Cl(1),
2.04858(11); N(1)−Ru(1)−C(11), 76.77(18); N(1)−Ru−Cl(1),
88.50(10); C(11)−Ru−Cl(1), 86.66(14).
a
heterocyclic ligands through the indole nitrogen and the C(11)
atom of the phenyl ring. It should be noted that compounds 6
and 7 are the first examples of ruthenacycles with the
(Cphenyl,Nindole)− motif.
An evaluation of the cytotoxic activity of the new products in
MCF7 and MDA-MB231 breast cancer cell lines (Table 1)
reveals that the Ru(II) complexes 6 and 7 are more active than
their free ligands, cisplatin, and even the trans and cis isomers of
[Pt(3)Cl2(DMSO)]16 (Figure 5). Moreover, most of them
showed IC50 < 2 μM and the ionic products are more effective
than their parent neutral derivatives.
a
Legend: (i) Ag[PF6] in acetone, removal of AgCl, treatment with the
corresponding ligand 3 and SiO2 column chromatography; (ii)
Ag[PF6] in MeCN.
and subsequent workup by SiO2 column chromatography
(Scheme 1(i)). Further treatment of 6 with Ag[PF6] in
acetonitrile produced the precipitation of AgCl and the ionic
products (7) (Scheme 1(ii). In all cases, characterization data
(Supporting Information) are consistent with the proposed
formulas. Moreover, the crystal structures of 6b·1/2CH2Cl2 and
6c·H2O (Figures 3 and 4)17 confirmed the binding of the
Table 1. Cytotoxic Activities of the Free Ligands 3a−e, the
Cycloruthenated Complexes 6a−e and 7a−e, and Cisplatin
on MCF7 and MDA-MB231 Breast Cancer Cell Lines
IC50 (μM)
R1
R2
R3
MCF7
MDA-MB231
a
Figure 3. X-ray crystal structure of 6b·1/2CH2Cl2. The molecule of
solvation and hydrogen atoms have been omitted for clarity. Selected
bond lengths (in Å) and angles (in deg): Ru(1)−C(11), 2.036(6);
Ru(1)−N(1), 2.067(9); Ru(1)−Cl(1), 2.049(1); N(1)−Ru−C(11),
78.5(3); Cl(1)−Ru(1)−C(11), 88.53(15).
a
7265
3a
3b
3c
3d
3e
H
Cl
H
F
F
6a
6b
6c
6d
6e
H
Cl
H
F
F
7a
7b
7c
7d
7e
H
Cl
H
F
F
Free Ligands
H
H
∼100
H
H
∼100
OMe
H
34 ± 15
OMe
H
∼100
OMe
OMe
∼100
Neutral Ru(II) Complexes
H
H
2.1 ± 0.4
H
H
1.1 ± 2.7
OMe
H
1.9 ± 0.2
OMe
H
5.4 ± 0.5
OMe
OMe
3.7 ± 0.4
Ionic Ru(II) Complexes
H
H
1.5 ± 0.2
H
H
0.66 ± 0.03
OMe
H
2.4 ± 0.3
OMe
H
0.91 ± 0.1
OMe
OMe
1.7 ± 0.2
Cisplatin
19 ± 4.5
80
∼100
∼100
12.4 ± 4.2
∼100
1.1 ± 0.44
0.45 ± 0.4
1.3 ± 0.23
3.5 ± 0.5
3.2 ± 0.3
1.4 ± 0.1
0.57 ± 0.03
1.9 ± 0.2
0.87 ± 0.04
1.5 ± 0.2
6.5 ± 2.4
Data for ligands 3a−c were reported previously.16
dx.doi.org/10.1021/om400941b | Organometallics 2013, 32, 7264−7267
Organometallics
Communication
drawing groups on any of the positions of the aromatic rings
and (b) their subsequent use as ligands to give both neutral and
ionic cycloruthenated complexes.
The new products 6a−e and 7a−e are also attractive in view
of their use in other relevant fields.19 Examples of the utility of
cycloruthenated compounds with [Csp2 (phenyl),N]− ligands as
precursors in synthesis, in catalytic processes, or as components
of dye sensitized solar cells (DSSC) have been recently
reported.18,19
In summary, in this contribution we have introduced the 2phenylindole skeleton as a novel type of cyclometalated ligand
for Ru(II) and proved that these products have a promising
future in the development of antitumoral drugs. The study of
their biological activity with a wider panel of cell lines and their
toxicity on normal cells and additional work in order to
elucidate their mechanism of action will be actively pursued in
the future. Complex 7b also appears to be an excellent
candidate for in vivo assays.
■
Figure 5. Comparative study of the cytotoxic activity (IC50 in μM) of
the Ru(II) complexes 6a−c and 7a−c, the trans (4a−c) and cis (5a−c)
isomers of [Pt(L)Cl2(DMSO)] (L = 3a−c), and cisplatin on MCF7
and MDA-MB231 breast cancer cell lines.
ASSOCIATED CONTENT
S Supporting Information
*
Text giving experimental procedures and characterization data
(elemental analyses, MS, melting (for 3d,e) or decomposition
(for 6 and 7) points, IR, UV−vis, and NMR), Figures S1 and
S2 (showing the variation of the 1H NMR spectrum of the
solution containing 7b and 9MeG with time and photographs
obtained from the electrophoretic studies, respectively), and
CIF files giving the crystal structures of 6b·1/2CH2Cl2 and 6c·
H2O. This material is available free of charge via the Internet at
http://pubs.acs.org.
Among all of the products tested 7b, and to a lesser extent
also 7d, are especially outstanding. They exhibited IC50 values
in the submicromolar level in the MCF7 and MDA-MB231 cell
lines (i.e., for 7b IC50 = 0.66 ± 0.03 and 0.57 ± 0.03 μM,
respectively). In order to get further information on the mode
of action of the Ru(II) complexes, additional experiments were
carried out.
First of all, we studied the effect produced by the presence of
9-methylguanine (9MeG) on a solution of 7b in a DMSO-d6/
D2O (1/4) mixture. As shown in Figure S1 (Supporting
Information), the 1H NMR spectrum of the freshly prepared
solution changed with time (t). After 20 h the spectrum showed
two sets of signals, one of them due to 7b and the other
suggesting the formation of a new species, 8b. The molar ratio
8b:7b increased with time. For t = 100 h, the NMR spectrum
suggested the presence of small amounts of 7b; this indicates
that the reaction is slow. The set of resonances attributed to 8b
showed a singlet at δ 8.69 ppm (consistent with the binding of
9MeG to the Ru(II) atom) and the typical pattern of the signals
of the p-cymene and metalated ligands. In view of these
findings, we tentatively postulate that 8b may arise from the
replacement of the MeCN ligand of 7b by 9MeG.
We also compared the effect induced by complex 7b on the
electrophoretic mobility of pBluescript SK+ plasmid DNA with
those of cisplatin and 9-aminoacridine (9-AA) (Figure S2,
Supporting Information). The results revealed that compound
7b did not produce any significant change in the DNA mobility,
for any of the assayed concentrations. The effect of 7b is
markedly different from that of cisplatin, but it resembles that
of 9-AA, which is a typical intercalator.
For comparison purposes, we also evaluated the activity of 7b
with the HCT116 colon cell line. Interestingly, it was more
potent (IC50 = 1.51 ± 0.07 μM) than cisplatin (24 ± 4 μM)
and even than RDC-11 (IC50 = 3 ± 2 μM).9 On this basis, the
new Ru(II) complexes with [Csp2(phenyl),N(indole)]−, and
especially 7b, are among the most active organometallic
cytotoxic agents reported so far.
The results summarized here are the first stages of further
studies centered on (a) the synthesis of a large variety of 2phenylindole derivatives with electron-donating and/or -with-
■
AUTHOR INFORMATION
Corresponding Author
*C.L.: e-mail, conchi.lopez@qi.ub.es; tel, (+34) 93-403-91-34;
fax, (+34) 93-490-77-25.
Notes
The authors declare no competing financial interest.
■
■
ACKNOWLEDGMENTS
This work was supported by the Ministerio de Ciencia e
Innovación of Spain (Grant No. CTQ2009-11501).
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