Synthesis of iridium and ruthenium complexes with (N,N), (N,O) and (O,O) coordinating bidentate ligands as potential anti-cancer agents

Article abstract of DOI:10.1039/c2dt32104a

Several Ru-arene and Ir-Cp* complexes have been prepared incorporating (N,N), (N,O) and (O,O) coordinating bidentate ligands and have been found to be active against both HT-29 and MCF-7 cell lines. By incorporating a biologically active ligand into a metal complex the anti-cancer activity is increased.

Full text of DOI:10.1039/c2dt32104a

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COMMUNICATION
Synthesis of iridium and ruthenium complexes with (N,N), (N,O) and (O,O)
coordinating bidentate ligands as potential anti-cancer agents†
Stephanie J. Lucas,a Rianne M. Lord,a Rachel L. Wilson,a Roger M. Phillips,b Visuvanathar Sridharana and
Patrick C. McGowan*a
Received 13th August 2012, Accepted 13th September 2012
DOI: 10.1039/c2dt32104a
Several Ru-arene and Ir–Cp* complexes have been prepared
incorporating (N,N), (N,O) and (O,O) coordinating bidentate
ligands and have been found to be active against both HT-29
and MCF-7 cell lines. By incorporating a biologically active
ligand into a metal complex the anti-cancer activity is
increased.
In recent years, organometallic complexes have shown promising
activity as anti-cancer agents.1–4 Design concepts for such
organometallic drugs, however, are still in their infancy. There
are few recently reported studies on the anti-cancer activity of
iridium complexes.5,6 Sadler et al. have recently reported the
organometallic half-sandwich Ir(III) complexes of general struc-
ture [(η5Cp‡)Ir(XY)Cl]0/+ where Cp‡ is either Cp* or a functio-
nalised Cp ligand.7 Their potency towards A2780 human
ovarian cancer cells increases with phenyl substitution on the
cyclopentadienyl ligand. We have previously shown that
ruthenium arene picolinamide complexes possess anti-cancer
activity.8,9 Iridium Cp* picolinamide complexes have been pre-
pared previously, but, to the best of our knowledge have not
been tested as anti-cancer agents.10
Scheme 1 Synthesis of the iridium Cp* halide picolinamide com-
plexes 1 and 2.
We aimed to explore the synthesis of Ru(II)/Ir(III) complexes
with the general structure [Ru(p-cymene)(XY)Cl]/[IrCp*(XY)-
Cl], where XY is a bidentate ligand which binds to the metal
through (N,N), (N,O) or (O,O) coordination, and their application
as anti-cancer agents. All complexes were prepared through
deprotonation of the bidentate ligand. Complexes 1 and 2 were
prepared by refluxing [IrCp*Cl2] with two equivalents of the
corresponding picolinamide and NH4PF6 in ethanol (Scheme 1).
The picolinamide ligands bind through the nitrogens, indi-
cated by the loss of the amide proton in the 1H NMR spectrum.
We have previously shown that picolinamide ligands can bind
as (N,O) donors in charged Ru(p-cymene) complexes however
Scheme 2 Synthesis of the iridium Cp* and ruthenium p-cymene
ketoiminate complexes 3 and 4.
aSchool of Chemistry, University of Leeds, Woodhouse Lane, Leeds, LS2
9JT, UK. E-mail: P.C.McGowan@leeds.ac.uk; Fax: +44 (0)113436565;
Tel: +44 (0)1133436404
they were shown to be inactive against a range of cell lines.9 We
were interested in preparing similar neutral complexes with
(N,O) coordinated ligands, such as ketoiminates.
Complexes 3 and 4 were‡ prepared by stirring either
[IrCp*Cl2]2 or [Ru(p-cymene)Cl2]2 with 3′-fluorophenyl-
3(phenylamino)-2-buten-1-one and triethylamine in dichloro-
methane (Scheme 2). Red single crystals of 3 were grown from a
dichloromethane/hexane solvent system and of 4 from a
bThe Institute of Cancer Therapeutics, University of Bradford, West
Yorkshire, BD7 1DP, UK. E-mail: R.M.Phillips@bradford.ac.uk;
Fax: +44 (0)1274233234; Tel: +44 (0)1274235367
†Electronic supplementary information (ESI) available: Experimental
procedures for compounds, cell line experimental and crystal structure
determination details. CCDC 890355, 890356 and 890357. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c2dt32104a
13800 | Dalton Trans., 2012, 41, 13800–13802
This journal is © The Royal Society of Chemistry 2012

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Scheme 3 Synthesis of the iridium Cp* 2-hydroxy-1,4-napthoquinone
complex 5.
Fig. 2 Molecular structure of 5. Hydrogen atoms are omitted for
clarity. Displacement ellipsoids are at the 50% probability level.
Table 1 IC50 values for complexes 1–5 along with cisplatin,
[IrCp*Cl2]2, [Ru(p-cymene)2Cl2]2 and 2-hydroxy-1,4-napthoquinone for
reference. Cultures 1 and 2 refer to different sets of MCF-7 cells, with
different IC50 values for cisplatin (— means not tested). The drugs were
incubated for 5 days
MCF-7 IC50/μM
HT-29 IC50
/
Compound
μM
Culture 1
Culture 2
Cisplatin
[IrCp*Cl2]2
[Ru(p-cymene)2Cl2]2
1
2.4 0.1
0.528 0.003
6.1 0.7
—
—
—
92
198
4
5
100
184
39
2
3
2
1
34.1 0.7
81
2
1
149
—
3
4
5
5.1 0.3
3.5 0.3
—
—
11.0 0.4
7.1 0.4
—
20
81
1
1
13.2 0.2
22
2-Hydroxy-1,4-
napthoquinone
1
—
oxygens were substituted with S or Se.14 Quinones exhibit bio-
logical properties, such as anti-microbacterial and anti-
tumour.15,16 The 1,4-naphthoquinone pharmacophore is known
to impart anti-cancer activity17 in a number of drugs, for
example streptonigrin18 and mitomycins.19 Another advantage is
that naphthoquinone will increase the hydrophobicity of the
metal complex and possibly allowing easier passive transport
into cells.
Fig. 1 (a), (b) Molecular structure of 3. Solvent omitted for clarity, (c)
(d) Molecular structure of 4. Hydrogen atoms are omitted for clarity.
Displacement ellipsoids are at the 50% probability level.
Complex 5 was prepared in the same manner as 3 and 4 but
with an excess of 2-hydroxy-1,4-napthoquinone and triethyl-
amine (Scheme 3).
Purple crystals of 5 were obtained by vapour diffusion from a
dichloromethane/pentane solvent system.‡ The X-ray structure of
5 can be seen in Fig. 2. As with 3 and 4 the complex adopts a
piano stool configuration. The ligand retains its planarity when
complexed which may allow intercalation of the quinone with
DNA.
methanolic solution. The molecular structures are shown in
Fig. 1, showing that the ketoiminate binds in an (N,O) fashion.
There are similarities in that they conform to the 3-legged piano
stool with Cp* and p-cymene rings respectively. There are differ-
ences in the ligand arrangement around the metal centre (shown
in Fig. 1(b) and (d)) and we were interested in investigating
these effects for the complexes’ cytotoxic capabilities.
The cytotoxic activity of the complexes 1–5 along with
cisplatin, [IrCp*Cl2]2, [Ru(p-cymene)2Cl2]2 and 2-hydroxy-1,4-
napthoquinone, were tested against HT-29 and MCF-7 cell lines
with the IC50 results shown in Table 1.
Compound 1 shows moderate activity against both HT-29 and
MCF-7 cell lines, with IC50 value of 34 μM and 39 μM respect-
ively. Compound 2 however, shows poor activity with an IC50 of
81 μM for HT-29 cell lines and 149 μM for MCF 7 cell lines.
Given the ease of synthesis and large potential for structure
activity relationships, we decided to investigate the possible
cooperative effects of biologically active organic compounds
which would bind to metals as (O,O) donors. The naphtho-
quinone ligand has been reported to form complexes with Sn,11
Co12 and Pt13 but to the best of our knowledge, not with iridium
or ruthenium. IrCp* benzoquinone complexes have been
previously reported but were found to be inactive unless the
This journal is © The Royal Society of Chemistry 2012
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the picolinamide ligand has a significant effect on cytotoxicity.
The ketoiminate complexes 3 and 4 have high activities, compar-
able with cisplatin, with IC50 values of 5.1 and 3.5 μM (2.4 μM
for cisplatin) for HT-29 cells, and 11.0 and 7.1 μM (6.1 μM for
cisplatin) for MCF-7 cells. The iridium napthoquinone complex
5 shows a cooperative effect, having higher activity than both
the napthoquinone ligand and metal source [IrCp*Cl2]2, most
noticeably for the HT-29 cells where complex 5 is four times as
active as the free ligand with IC50 values of 20 and 81 μM.
The anti cancer activity of complexes 1–5 correlates with the
type of bidentate ligand, where cytotoxicity of (N,O) > (O,O) >
(N,N).
In summary, we have prepared four iridium and one ruthenium
arene complexes with either (N,N), (N,O) or (O,O) coordinating
ligands The piano stool complexes were active against both
HT-29 and MCF 7 cell lines with the (N,O) complexes being the
most active showing comparable activity with cisplatin. By com-
plexing the 2-hydroxy-1,4-napthoquinone to iridium, a coopera-
tive effect can be seen whereby the resulting complex is more
active than both the ligand and starting dimer.
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Notes and references
‡The data for the crystal structures were collected by Stephanie Lucas. 3
and 4 were solved by Stephanie Lucas and Rianne Lord respectively. We
wish to acknowledge Dr Marc Little for helping to solve the crystal
structure of complex 5 and Technology Strategy Board for funding.
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13802 | Dalton Trans., 2012, 41, 13800–13802
This journal is © The Royal Society of Chemistry 2012