[Tris(pyrazolyl)methane]ruthenium complexes capable of inhibiting cancer cell growth

Article abstract of DOI:10.1002/ejic.200900766

The [tris(pyrazolyl)methane]ruthenium complexes [(K³-tpm) RuCl(solv)₂]PF₆ [tpm = tris(pyrazolyl)methane; solv = MeCN, dmso] and [(K³-tpm)RuCl(LL)]PF₆ [LL = K ²-dppe, K²-dppp, K

Full text of DOI:10.1002/ejic.200900766

SHORT COMMUNICATION
DOI: 10.1002/ejic.200900766
[Tris(pyrazolyl)methane]ruthenium Complexes Capable of Inhibiting Cancer
Cell Growth
Jesse M. Walker,[a] Alexis McEwan,[b] Roxanne Pycko,[b] Mary Lynn Tassotto,[b]
Christine Gottardo,[a] John Th’ng,[a,b,c] Ruiyao Wang,[d] and Gregory J. Spivak*[a]
Keywords: Ruthenium / Tris(pyrazolyl)methane / Half-sandwich complexes / Antiproliferative assays / Anticancer agents
The [tris(pyrazolyl)methane]ruthenium complexes [(κ3-tpm)
RuCl(solv)2]PF6 [tpm = tris(pyrazolyl)methane; solv = MeCN,
dmso] and [(κ3-tpm)RuCl(LL)]PF6 [LL = κ2-dppe, κ2-dppp, κ2-
dppb, (PMePh2)2] have been prepared, characterized and
screened in vitro for their antiproliferative properties against
the MCF-7 (breast) and HeLa (cervical) cancer cell lines by
using the MTT assay. Although the MeCN and dmso com-
plexes showed no activity under the conditions used, the
phosphane complexes exhibited remarkable cytotoxic be-
haviour.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
siderable attention. For example, (arylazopyridine)-,[6] (aryl-
iminopyridine)-[7] and (polypyridyl)ruthenium[8] complexes
have shown promise as anticancer agents. The ruthenium
drug candidates NAMI-A[9] (an antimetastatic agent) and
KP1019[10] are presently undergoing clinical evaluation. A
large number of other preclinical candidates have also dis-
played encouraging potential, in particular the piano-stool
ruthenium complexes independently studied by Dyson[11]
and Sadler[12] which contain, as a common group, a coordi-
nated face-capping arene ligand. We contemplated em-
ploying a ligand with similar facially coordinating proper-
ties, but that could also be easily modified, and thus allow
access to a wide range of candidates for screening. Indeed,
research emerging from the Alessio group has revealed that
the arene ligand is not a necessary feature for activity, and
that substituting the arene ligand for other face-capping li-
gands (e.g., 1,4,7-trithiacyclononane) might yield new
classes of piano-stool-type anticancer complexes.[13] The tris-
(pyrazolyl)methane (tpm) ligand[14] is a flexible polydent-
ate ligand that, in its κ3 form, is isoelectronic with the η6-
arene ligand. What is especially encouraging is that a
number of (tpm)metal complexes have already proven to
function as potent cytotoxic agents in vitro.[15] One particu-
lar advantage of the tpm ligand is that the basic scaffold is
readily modified, both on the pyrazole rings[14,16] and at the
bridgehead carbon atom,[17] so that the electronic, steric
and coordination properties can be tailored as desired. In
addition, simple modifications to the tpm ligand can impart
aqueous solubility on its complexes.[18] Included along with
the basic (tpm)ruthenium scaffold, we also chose to focus
initially on phosphanes as supporting ligands, since there
are extensive reports of (phosphane)metal complexes dis-
playing antitumour activities, particularly for the coinage
metals.[19]
Introduction
Platinum metal drugs continue to occupy a prominent
position in the arsenal of anticancer agents used in the
treatment of various malignancies. Following the approval
of the first-generation drug cisplatin in 1978, a number of
variants have emerged, with several receiving worldwide
(e.g., carboplatin and oxaliplatin) or at least limited (e.g.,
nedaplatin, lobaplatin and heptaplatin) approval as chemo-
therapeutic agents for clinical use.[1] Although there have
been some improvements in reducing the undesirable toxici-
ties often associated with these clinical drugs,[1b] it remains
unclear whether or not they are effective beyond the narrow
range of tumours against which cisplatin is already active.[2]
Furthermore, comparatively poor aqueous solubilities and
the development of tumour resistance towards these drugs
remain as current challenges in their clinical applications.[3]
The issues surrounding the platinum-based drugs con-
tinue to drive the intense search for new metal-based anti-
cancer compounds,[4] and ruthenium has played a promi-
nent role in this capacity.[5] Ruthenium complexes bearing
nitrogen-containing heterocyclic ligands have received con-
[a] Department of Chemistry, Lakehead University,
Thunder Bay, Ontario, P7B 5E1, Canada
Fax: +1-807-346-7775
E-mail: greg.spivak@lakeheadu.ca
[b] Regional Cancer Care, Thunder Bay Regional Health Sciences
Centre,
Thunder Bay, Ontario, P7B 6V4, Canada
[c] Medical Sciences Divisions, Northern Ontario School of Medi-
cine,
Thunder Bay, Ontario, P7B 5E1, Canada
[d] Department of Chemistry, Queen’s University,
Kingston, Ontario, K7L 3N6, Canada
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejic.200900766.
Eur. J. Inorg. Chem. 2009, 4629–4633
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4629

G. J. Spivak et al.
SHORT COMMUNICATION
Results and Discussion
Our initial efforts were directed towards establishing a
practical synthetic strategy which would allow access to our
target (tpm)ruthenium complexes, and also allow the auxil-
iary ligand environment to be varied easily. We reasoned
that this would eventually enable us to synthesize and
screen a wide variety of candidates for their antiproliferative
properties. A zinc reduction method[20] employing (tpm)-
RuCl3 as a precursor[21] has been reported; however, no ex-
perimental details were provided. We chose to experiment
with this approach, and eventually found it to be a relatively
simple and versatile method of preparing our target com-
plexes in reasonable yields. For example, reductions of
methanol suspensions of (tpm)RuCl3 with a slight excess of
zinc dust in the presence of excess MeCN or dmso, followed
by salt metathesis with (NH4)PF6, yielded the solvent com-
plexes [(κ3-tpm)RuCl(solv)2]PF6 [solv = MeCN (1), dmso
(2)] in good yields (Scheme 1). Structurally similar solvent
complexes {e.g., [(κ3-tpm)RuCl2(dmso)]} have been re-
ported previously, but were isolated from ethanol mixtures
of cis-[RuCl2(dmso)4] and tpm.[22] Originally we had hoped
the solvent ligands of 1 and 2 would be readily substituted
for our intended ligands. Indeed, the previously reported
synthesis of [(κ3-tpm)RuCl(κ2-dppe)]PF6 (3) {which can be
prepared through a lengthy, multi-step process beginning
with [RuCl2(COD)]n},[23] suggested our proposed target
complexes were accessible. Unfortunately, complex 1 proved
to be poorly labile, although the dmso ligands of 2 could
be replaced by phosphanes under forcing conditions (e.g.,
in refluxing 1,2-dichlorobenzene over 24 h). Alternatively,
and more conveniently, when the same zinc reduction pro-
cedure is applied, but instead in the presence of a phos-
phane, our target complexes [(κ3-tpm)RuCl(LL)]PF6 [LL =
κ2-dppe (3), κ2-dppp (4), κ2-dppb (5), (PMePh2)2 (6)] could
be isolated by using conventional workup procedures. The
phosphane complexes 3–6 are analogous to the complexes
[(κ3-tpm)RuCl(PPh3)2]X (X = Cl or BF4),[24] which are pre-
pared from RuCl2(PPh3)3 and tpm. In separate experiments,
we explored replacing the triphenylphosphane ligands of
these complexes as a possible alternate pathway to 3–6. Un-
fortunately, the triphenylphosphane ligands were observed
to be poorly labile, despite investigating a variety of experi-
mental conditions. Complexes 1–6 were only slightly soluble
in water, but dissolved more readily in organic solvents such
as chloroform, dichloromethane, acetone and dmso at the
concentrations examined (up to ca. 50 m).
Scheme 1. General synthetic strategy for preparing complexes 1–6.
phosphorus atoms [2.124(3) Å and 2.197(3) Å] compared to
the pyrazolyl ring trans to the chlorido ligand [2.095(3) Å],
thus illustrating the greater trans influence of the dppp li-
gand (vs. the chlorido ligand). The somewhat constrained
“bite” of the tpm ligand in 4 is exemplified by the N–Ru–
N bond angles [82.22(10), 82.67(10), 87.44(10)°], which are
smaller than the 90° expected for perfect octahedral geome-
try. The three methylene spacers allow the dppp ligand in 4
to adopt a P–Ru–P bond angle [93.58(3)°] close to the ideal
angle of 90°. Not surprisingly, by removing one of the
methylene links, as in [(κ3-tpm)RuCl(κ2-dppe)]PF6, leads to
a smaller bite angle;[23] the corresponding bis(triphenyl-
phosphane) complex [(κ3-tpm)RuCl(PPh3)2]Cl has a larger
P–Ru–P bond angle [103.9(1)°] than 4 as a consequence of
the steric bulk of the PPh3 ligands.[24]
The X-ray crystal structure of the dppp complex 4 (Fig-
ure 1) confirmed the general structure proposed for com-
plexes 1–6.[25] The ruthenium centre of 4 adopts an approxi-
mately octahedral geometry, with the tpm ligand occupying
a face of the octahedron, and the chelate phosphane and
chlorido ligands occupying the remaining positions. The
distances between the ruthenium atom and the metal-
bound pyrazolyl nitrogen atoms compare well with those
observed in the structure of [(κ3-tpm)RuCl(κ2-dppe)]PF6.[23]
Figure 1. ORTEP representation of the cation of complex 4. Se-
lected bond lengths [Å] and angles [°]: Ru(1)–N(6) 2.095(3), Ru(1)–
N(2) 2.124(3), Ru(1)–N(4) 2.197(3), Ru(1)–P(2) 2.3035(9), Ru(1)–
P(1) 2.3235(9), Ru(1)–Cl(1) 2.4056(8); N(2)–Ru(1)–N(4) 82.22(10),
N(6)–Ru(1)–N(4) 82.67(10), N(6)–Ru(1)–N(2) 87.44(10), N(2)–
Ru(1)–P(1) 174.43(8), N(4)–Ru(1)–P(2) 172.12(8), N(6)–Ru(1)–
Cl(1) 173.59(8), P(2)–Ru(1)–P(1) 93.58(3).
The complexes 1–6 were readily characterized by NMR
These same distances are also asymmetric, with longer dis- spectroscopy. Perhaps the most revealing of their structures,
tances observed for the pyrazolyl rings trans to the dppp the 1H NMR spectra show (along with the signal attributed
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[Tris(pyrazolyl)methane]ruthenium Complexes
to the unique bridgehead hydrogen atom) two sets of three ginal, suggesting the linkage between donor atoms is not
tpm resonances with intensities in the ratio of 2:1 corre- crucial here. Likewise, chelate ring size does not appear to
sponding to the three pyrazolyl ring hydrogen atoms in the influence activity dramatically.
3-, 4-, and 5-positions.[24] Thus, the Cs symmetry of these
It is not obvious at this stage why the phosphane com-
complexes requires the two pyrazolyl rings trans to the sol- plexes display such promising cytotoxic behaviour. The en-
vent ligands in 1 and 2, and trans to the phosphorus atoms hanced cytotoxicities we observed might possibly be related
in 3–6, to be equivalent, with the pyrazolyl ring trans to to an increase in lipophilic character (vs. 1 and 2), which
the chlorido ligand being unique. Each of the phosphane could facilitate cellular uptake. Organophosphanes can be
complexes shows a singlet in its respective 31P{1H} NMR cytotoxic, and some (phosphane)gold complexes are
spectrum at room temperature, also consistent with overall thought simply to function as a vehicle and transport the
Cs symmetry. We note that, given the ability of the dppb phosphane ligand to the cancer cells.[30] Although we have
ligand to bridge metal centres,[26] complex 5 could also not yet unequivocally ruled out this scenario, we see no
adopt the alternative structure {[(κ3-tpm)RuCl(µ-dppb)]- evidence of phosphane dissociation occurring in solution
PF6}2, yet still give NMR and microanalytical data consis- (31P NMR, [D6]dmso) even over several days. Metal chlo-
tent with a monomeric structure. Unfortunately, X-ray ride complexes in some cases can undergo chlorido ligand
quality crystals were not obtained.
substitution with a polar, coordinating solvent.[31] Again,
We next turned our attention towards screening com- the NMR spectra of complexes 3–6 in [D6]dmso (the protio
plexes 1–6 for their antiproliferative properties (Table 1). solvent was used in the growth inhibition assays; see the
For comparison, we also included in these studies an arene Supporting Information) remain unchanged at room tem-
analogue of complex 4, specifically [(η6-p-cymene)RuCl(κ2- perature up to 72 h, suggesting complexes 3–6 resist solvol-
dppp)]Cl,[27] as well as cisplatin.
ysis and remain intact in this coordinating solvent. Finally,
there is, as yet, no clear indication of the role of the tpm
ligand in the active complexes, especially since the phos-
phane variants show activities comparable to the arene
complex also examined as part of this investigation. We
note that the identity of the arene ligand in [(η6-arene)-
RuCl(LL)]+ (LL = chelate ligand) does influence the cyto-
toxicity of the complex.[32] This will also be the focus of
future studies.
Table 1. Growth inhibition of MCF-7 (breast) and HeLa (cervical)
cancer cells after 72 h of exposure to complexes 1–6, [(η6-p-
cymene)RuCl(κ2-dppp)]Cl and cisplatin.
Complex
IC50 []
MCF-7
HeLa
1
Ͼ50
Ͼ50
Ͼ50
Ͼ50
2
3
8.1Ϯ4.6
2.9Ϯ0.07
2.9Ϯ0.07
4.7Ϯ0.07
0.8Ϯ0.00
Ͼ18
4Ϯ0.00
6.9Ϯ1.31
5.8Ϯ0.35
7.4Ϯ0.21
1.4Ϯ0.07
12.4Ϯ0.85
4
5
Conclusions
6
[(η6-p-cymene)RuCl(κ2-dppp)]Cl
Cisplatin[a]
The (phosphane)(tpm)ruthenium complexes examined as
part of this preliminary study have displayed very promising
cytotoxic activity against the MCF-7 and HeLa cell lines.
At this point, the roles of the phosphane and tpm ligands
are unclear; however, we hope that our continued investiga-
tion of these and related complexes will provide more in-
sight into their function and activity.
[a] Supplied as a saline solution (see the Supporting Information).
MTT assays[28] were performed in vitro for each complex
by using the MCF-7 (breast) and HeLa (cervical) cancer
cell lines. The effects of 1–6, [(η6-p-cymene)RuCl(κ2-dppp)]-
Cl and cisplatin on the growth of these cell lines were evalu-
ated after 72 h. The solvent complexes 1 and 2 showed no
significant cytotoxicity under the conditions employed.
However, substituting the solvent ligands with phosphane
ligands impacts their activity dramatically, as complexes 3–
6 displayed exceptional cytotoxic behaviour, and were more
active than cisplatin, even on the MCF-7 breast cancer cells
which showed greater resistance towards cisplatin than the
Experimental Section
General: A sample synthetic procedure for one of the active com-
plexes (4) is provided here. All of the remaining experimental de-
tails are provided in the Supporting Information.
[(κ3-tpm)RuCl(κ2-dppp)][PF6] (4): A flask was charged with (tpm)-
cervical cancer HeLa cell line. The arene complex [(η6-p- RuCl3·1.5H2O (0.243 g, 0.541 mmol), dppp (0.224 g, 0.543 mmol)
cymene)RuCl(κ2-dppp)]Cl also displayed remarkable ac-
and Zn dust (0.055 g, 0.841 mmol). Next, MeOH (30 mL) was
added, and the solution was stirred at reflux for 25 h. After this
tivity. Perhaps these results are not unexpected since there
time, a dark green solid had deposited from a clear orange superna-
are other reports of (phosphane)ruthenium complexes exhi-
tant. The mixture was allowed to cool to room temperature before
biting marked cytotoxicity.[29] For example, the complexes
filtering through Celite into a flask containing NH4PF6 (0.088 g,
[CpRu(PP)L]OTf [PP = dppe, (PPh3)2; L = pyridazine,
0.540 mmol). The mixture was stirred at reflux for 1 h before the
volatiles were removed under reduced pressure. The green-yellow
1,3,5-triazine][29b] yielded IC50 values in the submicromolar
range against the LoVo human colon adenocarcinoma and
residue was redissolved in CH2Cl2 (20 mL) and filtered through
MiaPaCa pancreatic cancer cell lines. The differences in ac-
tivity between the complex with monophosphanes (6) and
Celite. The volatiles were removed from the orange-yellow filtrate
under reduced pressure to yield an orange-yellow solid. The solid
those with chelate phosphanes (3, 4, and 5) were only mar- was washed with H2O (30 mL) followed by diethyl ether (20 mL).
Eur. J. Inorg. Chem. 2009, 4629–4633
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4631

G. J. Spivak et al.
SHORT COMMUNICATION
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The solid was dried under reduced pressure. Yield 0.230 g (47%).
C37H36ClF6N6P3Ru·H2O (926.07): calcd. C 47.98, H 4.13, N 9.08;
found C 48.03, H 3.97, N 8.93. 1H NMR (499.9 MHz, 22᭺C,
CDCl3): δ = 9.11 (s, 1 H, Pz3CH), 8.30 (br. m, 2 H, H5 of Pz), 8.20
(br. m, 1 H, H5Ј of Pz), 7.74 (br. m, 4 H, Ph), 7.43 (m, 2 H, Ph),
7.34 (m, 4 H, Ph), 7.31 (m, 2 H, Ph), 7.10 (m, 4 H, Ph), 6.65 (br.
m, 2 H, H3 of Pz), 6.56 (br. m, 4 H, Ph), 6.12 (m, 2 H, H4 of Pz),
5.32 (m, 1 H, H4Ј of Pz), 5.08 (m, 1 H, H3Ј of Pz), 3.01 (m, 2 H,
CH2 of dppp), 2.93 (m, 1 H, CHH of dppp), 2.88 (m, 2 H, CH2 of
dppp), 2.38 (m, 1 H, CHH of dppp) ppm. 31P{1H} NMR
[9]
[10]
(202.3 MHz, CDCl3, 22᭺C): δ = 32.9 (s, dppp), –142.6 (sept, PF6 )
[11]
[12]
–
ppm.
Supporting Information (see footnote on the first page of this arti-
cle): Complete details on the synthesis of complexes 1–6, the X-ray
crystallographic study of 4,[33] and the MTT assays.
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Received: August 4, 2009
Published Online: October 1, 2009
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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