Neutral and ionic cycloruthenated 2-phenylindoles as cytotoxic agents

Article abstract of DOI:10.1021/om400941b

The synthesis and characterization of two families of cyclometalated Ru(II) complexes with the new (Csp²,N_indole)^- motif formed by activation of the C-H bonds of 2-phenylindole ligands of the general formula {(4′-R¹-C₆H₄)-3-NOMe-5-R ²-6-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.

Full text of DOI:10.1021/om400941b

Communication
pubs.acs.org/Organometallics
Neutral and Ionic Cycloruthenated 2‑Phenylindoles as Cytotoxic
Agents
†
,†
‡
§
∥
́
Lluís Belsa, Concepcion Lopez,* Asensio Gonzalez, Merce Font-Bardıa, Teresa Calvet,
́
́
́
̀
Carmen Calvis,⊥ and Ramon Messeguer⊥
†
́
́
Departament de Quımica Inorgan
̀
ica, Facultat de Quımica, Universitat de Barcelona, Martí i Franques
̀
1-11, E-08028 Barcelona,
Spain
‡
́
Laboratori de Quımica Organ
̀
ica, Facultat de Farmac
̀
ia, Universitat de Barcelona, Pl. Pius XII s/n, E-08028 Barcelona, Spain
§Unitat de Difraccio
́
de Raig-X, Centre Científic i Tecnolog
̀
ic de la Universitat de Barcelona, Sole
́
i Sabarıs 1-3, E-08028 Barcelona,
́
Spain
∥
́
́
́
Departament de Crystal·lografıa, Mineralogia i Diposits Minerals, Facultat de Geologıa, Universitat de Barcelona, Martı i Franques
̀
̀
s/n, E-08028 Barcelona, Spain
⊥Biomed Division, LEITAT Tecnological Center, Parc Científic de Barcelona, Edifici Hel
Spain
̀
ix, Baldiri Reixach 15-21, E-08028 Barcelona,
S
* Supporting Information
ABSTRACT: The synthesis and characterization of two families of
−
2
cyclometalated Ru(II) complexes with the new (Csp ,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 pre-
sented. 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.
ancer is one of the main causes of death in developed
1
Ccountries. 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
Figure 1. Main examples of highly cytotoxic organometallic
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 Representa-
tive examples of these organometallic compounds are RAPTA-
C 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
ruthenium(II) complexes used for both in vitro and in vivo studies.
valuable reagents in coordination and organometallic chem-
istry.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 (Csp ,Nindole)− cyclometalation motif.
2
Compounds 6a−e were isolated by reaction of [Ru(η6-p-
cymene)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)
Some 2-phenylindole derivatives (1 and 2 in Figure 2)
Received: September 21, 2013
Published: December 6, 2013
exhibit interesting antitumoral activity.11,12 In addition, they are
© 2013 American Chemical Society
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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.
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
Scheme 1. Preparation of Compounds 6 and 7
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
Free Ligands
3a
3b
3c
3d
3e
H
Cl
H
F
H
H
∼100
∼100
34 15
80
H
H
∼100
∼100
12.4 4.2
∼100
OMe
OMe
OMe
H
H
∼100
∼100
F
OMe
Neutral Ru(II) Complexes
6a
6b
6c
6d
6e
H
Cl
H
F
H
H
2.1 0.4
1.1 2.7
1.9 0.2
5.4 0.5
3.7 0.4
1.1 0.44
0.45 0.4
1.3 0.23
3.5 0.5
3.2 0.3
H
H
OMe
OMe
OMe
H
H
F
OMe
Ionic Ru(II) Complexes
7a
7b
7c
7d
7e
H
Cl
H
F
H
H
1.5 0.2
1.4 0.1
H
H
0.66 0.03
2.4 0.3
0.91 0.1
1.7 0.2
0.57 0.03
1.9 0.2
OMe
OMe
OMe
H
H
0.87 0.04
1.5 0.2
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).
F
OMe
Cisplatin
19 4.5
6.5 2.4
Data for ligands 3a−c were reported previously.16
a
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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
−
2
cycloruthenated compounds with [Csp (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 2-
phenylindole 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
* Supporting Information
■
S
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
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
1
S2 (showing the variation of the H 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.
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
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.
■
1
Information), the H 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.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the Ministerio de Ciencia e
■
Innovacion
́
of Spain (Grant No. CTQ2009-11501).
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̅
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