New Class of Half-Sandwich Ruthenium(II) Arene Complexes Bearing the Water-Soluble CAP Ligand as an in Vitro Anticancer Agent

Article abstract of DOI:10.1021/acs.inorgchem.7b00915

Ruthenium(II) arene complexes of 1,4,7-triaza-9-phosphatricyclo[5.3.2.1]tridecane (CAP) were obtained. Cytotoxicity studies against cancer cell lines reveal higher activity than the corresponding PTA analogues and, in comparison to the effects on noncancerous cells, the complexes are endowed with a reasonable degree of cancer cell selectivity.

Full text of DOI:10.1021/acs.inorgchem.7b00915

Communication
pubs.acs.org/IC
New Class of Half-Sandwich Ruthenium(II) Arene Complexes Bearing
the Water-Soluble CAP Ligand as an in Vitro Anticancer Agent
Antonella Guerriero,† Werner Oberhauser,† Tina Riedel,‡ Maurizio Peruzzini,† Paul J. Dyson,*,‡
and Luca Gonsalvi*,†
†Istituto di Chimica dei Composti Organometallici, Consiglio Nazionale delle Ricerche, Via Madonna del Piano 10, 50019 Sesto
Fiorentino, Firenze, Italy
‡Institut des Sciences et Ingen
ierie Chimiques, Ecole Polytechnique Federale Lausanne, CH-1015 Lausanne, Switzerland
́ ́ ́
S
* Supporting Information
catalysts for hydrogenation reactions.26−33 Recently, the new
ligand 1,4,7-triaza-9-phosphatricyclo[5.3.2.1]tridecane (CAP,
1) was reported (Scheme 1).34
ABSTRACT: Ruthenium(II) arene complexes of 1,4,7-
triaza-9-phosphatricyclo[5.3.2.1]tridecane (CAP) were
obtained. Cytotoxicity studies against cancer cell lines
reveal higher activity than the corresponding PTA
analogues and, in comparison to the effects on non-
cancerous cells, the complexes are endowed with a
reasonable degree of cancer cell selectivity.
Scheme 1. Modified Synthesis of Ligand 1
ince the discovery of cisplatin in 1965,1,2 interest in the
S
application of coordination complexes to treat cancer and
other diseases has continually increased.3 In particular, when
resistance to cisplatin developed,4,5 certain classes of ruthenium
complexes were found to be active,6 including ruthenium(III)
coordination complexes7−9 and half-sandwich ruthenium(II)
arene organometallic derivatives.10−14 RAPTA-type compounds
(Chart 1) were identified as promising anticancer agents,15,16
CAP has a tris(homoadamantane) cage similar to PTA and
was obtained by Mannich-type condensation of 1,4,7-
triazacyclononane (TACN) and tris(hydroxymethyl)phosphine
(THP).35,36 CAP has a higher cage flexibility due to the
presence of two CH2 spacers between the N atoms. Electron
density distribution analysis showed that the P and N atoms of
CAP exhibit comparable electron donicity, bringing about
different reactivities of CAP and PTA toward protonation at N
sites and alkylation at N and P atoms.37−39 In the search for
new RAPTA-type compounds with potential anticancer activity,
we decided to explore the coordination properties of CAP to
ruthenium(II) arene moieties. The obtained complexes were
evaluated in vitro against human ovarian (A2780 and A2780cis)
cancer and human embryonic kidney (HEK) cell lines, and the
preliminary results of these studies are presented here.
Chart 1. Prototypical RAPTA-Type (R = H, Me, Me6) and
RAPTA-C Structures
The synthesis of 1 was slightly modified compared to that in
the literature. As for PTA,40 the air-stable and commercially
available tetrakis(hydroxymethyl)phosphonium chloride
(THPC; 80% aqueous solution) was first treated with a
NaOH solution (1.6 M), producing in situ THP [P-
(CH2OH)3], which was reacted without isolation with an
aqueous solution of TACN at room temperature (Scheme 1).
After extraction of the aqueous phase with CHCl3 and
recrystallization of the crude product from hot ethanol
(EtOH), 1 was obtained as a white crystalline solid in high
purity. Also in our case, formation of the unidentified
amorphous solid originally observed could not be avoided.34
Our procedure has the advantage of using the less expensive
and easier-to-handle THPC instead of air-sensitive THP and a
with their water solubility being given by the cage-like 1,3,5-
triaza-7-phosphaadamantane (PTA) ligand, binding the metal
in a κ1-P fashion.17−19 Several studies evaluating the antitumor
activity of RAPTA-C revealed strong antiangiogenic and
antimetastatic activities,20,21 together with a good efficacy in
inhibiting tumor growth even at moderate doses,22 low general
toxicity, and tolerance to low pH,23,24 suitable for investigation
as an orally administered drug. For this class of compounds, the
reactivity and stability, uptake into cancer cells, target
recognition, and overall cytotoxicity and cancer cell selectivity
were found to heavily depend on the choice of phosphine.
Indeed, modification of the PTA ligand often led to increased
cytotoxicity, but at the same time caused the cancer cell
selectivity to be lost.25
We have been interested in the application of Ru-PTA
complexes not only as antitumor agents but also as selective
Received: April 14, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.inorgchem.7b00915
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Inorganic Chemistry
Communication
facile workup consisting of a simple extraction and recrystalliza-
tion.
The complex κ1-P-[(η6-p-cymene)RuCl(MeCN)(CAP)]PF6
(4) was obtained from 2 by chloride abstraction with TlPF6 and
ligand substitution with CH3CN (Scheme 2). The 31P{1H}
NMR spectrum of 4 exhibits a singlet at 48.17 ppm
corresponding to the P atom in the CAP ligand and a septet
The RAPTA-C analogue κ1-P-[(η6-p-cymene)RuCl2(CAP)]
(2, RACAP-C) was obtained by reacting [(η6-p-cymene)-
RuCl2]2 with 2 equiv of CAP in CH2Cl2 at room temperature,
−
at −144.27 ppm (JPF = 707.8 Hz) corresponding to the PF6
ion (IR peak at 839.16 cm−1). The presence of coordinated
acetonitrile in 4 was confirmed by the singlet at 2.52 ppm in the
1H NMR spectrum and by the two singlets at 128.55 and 3.91
ppm in the 13C{1H} NMR spectrum, with the the former
Scheme 2. Syntheses of RACAP-Type Complexes 2−4
attributed to CN and the latter to CH3CN.42 The H NMR
1
spectrum of 4 showed two well-distinguished doublets centered
3
at 1.26 and 1.25 ppm ( JHH = 6.8 Hz) for the arene CH3
isopropyl groups upon loss of symmetry in the piano-stool
geometry. The solubilities of 2−4 in water were determined at
20 °C. Complex 2 was found to be much less water-soluble
than RAPTA-C, with S(H2O)20 °C = 0.86 versus 10 g/L. The
ionic complexes 3 and 4 were slightly more soluble than 2, with
values of 1.2 and 1.1 g/L, respectively.
The thermal stability of 2 in D2O was determined by
variable-temperature NMR experiments. No changes were
observed in the corresponding 31P{1H} NMR spectra (singlet
at 57.48 ppm) in the temperature range 25−60 °C for a total of
30 h of experiment.
affording 2 in 87% yield after purification (Scheme 2). The
31P{1H} NMR spectrum of 2 in CDCl3 shows a singlet at 52.83
ppm, a rather different chemical shift than RAPTA-C (−36.63
ppm)19 and in line with the gold(I) CAP derivative [(CAP-
H2)3Au]7+ (50.99 ppm).34 The substantial 31P{1H} NMR
downfield shift is not unexpected because of the different P-
donor properties of 1.37 In the corresponding 1H NMR
spectrum, the cage protons of coordinated CAP give a multiplet
in the range 3.07−2.92 ppm for N(CH2)2N and a doublet
centered at 3.70 ppm (2JHP = 7.2 Hz) due to PCH2N. This
The stabilities of complexes 2−4 under pseudopharmaco-
logical conditions were also determined in aqueous NaCl/D2O
(100 mM) at 37 °C for 72 h, monitoring every 24 h by 1H and
31P{1H} NMR (see the Supporting Information). Complex 2
was stable under these conditions; i.e., the NMR spectra
remained unchanged after 72 h, showing a 31P{1H} NMR
singlet at 57.31 ppm. Complex 3 showed after 7 h the presence
of singlets at 56.77 ppm (ca. 47% by integration), due to the
original complex, and at 57.31 ppm (ca. 30%), due to the
formation of 2 upon CAP-Cl− exchange. Two less intense
singlets were also observed at 58.46 ppm (10%) and 54.44 ppm
(13%). After 48 h, the 3:2 ratio reached ca. 1:1, and it was
maintained until the end of the experiment. Similarly, complex
4, characterized by a 31P{1H} NMR singlet at 54.30 ppm,
immediately underwent MeCN−Cl− exchange to form complex
2 (ca. 60%). The ratio between 2 and 4 remained constant
during the following 72 h (Figures S16−S21 in the Supporting
Information).
Suitable crystals for single-crystal X-ray diffraction of 2 and 3
were obtained from the slow diffusion of dry EtOH in a CH2Cl2
solution of each complex. The molecular structure of 2 (Figure
1) consists of a RuII center coordinated by a η6-p-cymene unit,
two Cl atoms, and a κ1-P CAP ligand. The CAP ligand does not
experience significant changes of the [333] conformation
observed in the free ligand.43 Accordingly, the intramolecular
P···N (dPN) and N···N (dNN) distances of CAP in 2 range from
2.824 to 2.808 Å and from 3.028 to 3.064 Å, respectively
(comparable to that found for uncoordinated CAP, i.e., an
average dPN of 2.886 Å and an average dNN of 3.1132 Å).37 The
Ru−P bond length in 2 is significantly longer compared to that
observed in the analogous PTA structure [i.e., 2.3180(5) vs
2.296(2) and 2.298(2) Å].19 The same applies to the Ru−C(p-
cymene) bond lengths [i.e., 2.198(2) and 2.275(2) Å in 2
versus 2.179(9) and 2.210(10) Å in the PTA analogue].19
The replacement of one Cl− in 2 by a CAP ligand, to give the
monocationic ruthenium species 3 (Figure 2), leads to an
elongation of the Ru−P [i.e., 2.3180(5) Å (2) vs 2.3254(7) and
2.3353(7) Å (3·2MeOH·H2O)] and Ru−C(p-cymene) [i.e.,
1.709 Å (2) vs 1.768 Å (3·2MeOH·H2O)] bonds compared to
1
assignment was verified by H{31P} NMR spectroscopy, with
the doublet turning into a singlet upon P decoupling. The
aromatic protons of the p-cymene ring give a broad singlet at
5.48 ppm, similar to the signal at 5.46 ppm reported for [(η6-p-
cymene)RuCl2(PTA)].19 In the 13C{1H} NMR spectrum of 2,
the η6-coordinated arene ring affords two doublets for the
2
aromatic CH C atoms at 88.55 and 83.97 ppm with JCP = 2.5
and 3.4 Hz, respectively. The proposed structure of 2 was also
confirmed by electrospray ionization mass spectrometry (ESI-
MS), with a peak envelope centered at m/z 470.2
corresponding to the cation [(η6-p-cymene)RuCl(CAP)]+,
i.e., the expected [M − Cl]+ ion.
The ruthenium(II) complex κ1-P-[(η6-p-cymene)RuCl-
(CAP)2]PF6 (3) was obtained in ca. 77% yield by reacting 2
with 1 equiv of CAP and a stoichiometric amount of TlPF6
(Scheme 2). The 31P{1H} NMR spectrum of 3 in acetone-d6
contains a singlet at 51.60 ppm, corresponding to the two
equivalent phosphines and a septet at −144.26 ppm (JPF
=
−
707.5 Hz) attributable to the PF6 counterion (confirmed by
1
the IR peak at 841.95 cm−1, KBr). In the H NMR spectrum,
two doublets at 6.55 and 6.26 ppm (JHH = 6.4 Hz)
corresponding to the aromatic protons of the arene ligand
were observed, and the protons of PCH2N give two sets of
multiplets in the range 3.85−3.67 ppm, which afford a defined
1
AB system (JHAHB= 16.0 Hz) in the H{31P} NMR spectrum
(see the Supporting Information). In line with the data
obtained for the PTA analogue,41 the ESI-MS spectrum of 3
contains a peak at m/z 669.3 consistent with the ion [(η6-p-
cymene)RuCl(CAP)2]+ and a peak of lower relative intensity at
m/z 470.2 corresponding to [(η6-p-cymene)RuCl(CAP)]+, due
to the loss of one phosphine ligand.
B
DOI: 10.1021/acs.inorgchem.7b00915
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Communication
Table 1. Cytotoxicity (IC50, μM, 72 h) of 1−4 to A2780 and
A2780cisR Cancer Cells and Non-cancerous HEK293 Cells
compound
A2780
>200
A2780cisR
>200
HEK293
>200
1
2
55.3 18.6
48.1 2.2
65.2 18.0
108 10
99.2 15.9
70.6 3.1
270
102 26
80.7 12.4
3
4
163 46
>1000
a
RAPTA-C
230
a
Values taken for comparison from ref 45.
induced a dose- and cell-dependent decrease in the cell viability,
with 1 exerting only minor cytotoxic effects (not reaching the
IC50 value in the tested concentration range). The similar IC50
values of the complexes are likely due to the same species
formed by 3 and 4 in aqueous solution after ligand exchange
reactions leading to 2. Compared to RAPTA-C, the compounds
are considerably more cytotoxic toward all cell lines. However,
only complex 4 shows essentially equal cytotoxicity toward
both the A2780 and A2780cisR cells. In comparison to
complexes with other PTA-type ligands, complexes 2−4
maintain their cancer cell selectivity by a 2-fold stronger
growth inhibition effect on A2780 cancer cells compared to
noncancerous HEK293 cells. Usually modification of the PTA
ligand has often led to more cytotoxic complexes but at the
same time reduces the cancer cell selectivity.30,44
Figure 1. Molecular structure of 2. Thermal ellipsoids are presented at
a 30% probability level, and H atoms are omitted for clarity. Selected
bond distances (Å) and angles (deg): Ru−Cl1 = 2.4184(5), Ru−Cl2 =
2.4205(5), Ru−P = 2.3180(5), Ru−centroid (C1−C6) = 1.709; Cl1−
Ru−Cl2 = 87.601(19), Cl1−Ru−P = 86.937 (19), Cl2−Ru−P =
83.775(18).
In conclusion, novel ruthenium(II) arene half-sandwich
complexes bearing the cage-type CAP were prepared and
characterized. Compared to RAPTA-C, the direct CAP
analogue 2 is more cytotoxic to cancer cells and exhibits a
reasonable degree of cancer cell selectivity. Other PTA-type
ligands previously studied have not maintained the desirable
cancer cell selectivity exhibited by the CAP derivatives.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.inorg-
chem.7b00915.
■
Figure 2. Molecular structure of 3·2MeOH·H2O. Thermal ellipsoids
are presented at a 30% probability level, and H atoms, counteranions,
and solvent molecules are omitted for clarity. Selected bond distances
(Å) and angles (deg): Ru−Cl = 2.4026(7), Ru−P1 = 2.3254(7), Ru−
P2 = 2.3353(7), Ru−centroid (C1−C6) = 1.768; Cl−Ru−P1 =
83.59(2), Cl−Ru−P2 = 87.90(3), P1−Ru−P2 = 93.37(3).
S
General methods and materials, synthetic procedures,
NMR and MS spectra, tables for X-ray crystal structure
determination, stability tests, and details of in vitro
cytotoxicity tests (PDF)
X-ray crystallographic data in CIF format (CIF)
X-ray crystallographic data in CIF format (CIF)
2, whereas the Ru−Cl bond shortens from 2.4205(5) Å (2) to
2.4026(7) Å (3·2MeOH·H2O). The overall conformation of
the coordinated CAP is essentially identical with that found in
2. The significantly different Ru−P bond lengths found for 2
and 3·2MeOH·H2O correlate with the slightly higher positive
31P coordination shift found for 2 in solution [i.e., 52.83 ppm,
dRuP= 2.3180(5) Å for 2, vs 51.60 ppm, dRuP = 2.3254(7) and
2.3353(7) Å for 3·2MeOH·H2O]. The stronger Ru−p-cymene
interaction in 2 compared to 3, observed in the solid state, is
thus maintained in solution. Accordingly, the aromatic 1H
NMR signals assigned to p-cymene in 2 are shifted upfield
compared to 3. In addition, the 13C{1H} NMR signals of the
aromatic C atoms of p-cymene in 2 have small 2JCP values of 2.5
and 3.4 Hz, whereas in 3, only 13C{1H} NMR singlets are
observed.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: paul.dyson@epfl.ch (P.J.D.).
*E-mail: l.gonsalvi@iccom.cnr.it (L.G.).
■
ORCID
Luca Gonsalvi: 0000-0002-5996-6307
Author Contributions
All authors have given approval to the final version of the
manuscript.
Notes
The authors declare no competing financial interest.
Compounds 1−4 were tested for their cytotoxicity to human
ovarian A2780 carcinoma cells and the A2780cisR variant with
acquired resistance to cisplatin as well as against noncancerous
HEK293 cells, using MTT assay (Table 1). All complexes
ACKNOWLEDGMENTS
We thank Laure D. Pittet for help with the cytotoxicity assays.
■
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