Heterobimetallic Ru(μ-dppm)Fe and homobimetallic Ru(μ-dppm)Ru complexes as potential anti-cancer agents

Article abstract of DOI:10.1016/j.jorganchem.2019.120934

Two heterobimetallic μ-dppm bridged Fe,Ru complexes, [(η⁶-Arene)RuCl₂(μ-dppm)Fe(CO)I(η⁵-C₅H₅)] (Ar = C₆H₆ (1) and p-cymene (2), dppm = 1,1-bis(diphenylphosphino)methane) were obt

Full text of DOI:10.1016/j.jorganchem.2019.120934

Journal Pre-proof
Heterobimetallic Ru(μ-dppm)Fe and homobimetallic Ru(μ-dppm)Ru complexes as
potential anti-cancer agents
Brian Herry, Lucinda K. Batchelor, Basile Roufosse, Dario Romano, Judith
Baumgartner, Marina Borzova, Tim Reifenstahl, Thomas Collins, Amal Benamrane,
Jordana Weggelaar, Marie C. Correia, Paul J. Dyson, Burgert Blom
PII:
S0022-328X(19)30377-8
DOI:
https://doi.org/10.1016/j.jorganchem.2019.120934
JOM 120934
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 22 August 2019
Revised Date: 9 September 2019
Accepted Date: 10 September 2019
Please cite this article as: B. Herry, L.K. Batchelor, B. Roufosse, D. Romano, J. Baumgartner, M.
Borzova, T. Reifenstahl, T. Collins, A. Benamrane, J. Weggelaar, M.C. Correia, P.J. Dyson, B.
Blom, Heterobimetallic Ru(μ-dppm)Fe and homobimetallic Ru(μ-dppm)Ru complexes as potential
anti-cancer agents, Journal of Organometallic Chemistry (2019), doi: https://doi.org/10.1016/
j.jorganchem.2019.120934.
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Heterobimetallic Ru(µ-dppm)Fe and Homobimetallic Ru(µ-
dppm)Ru Complexes as Potential Anti-cancer Agents
Brian Herry,a Lucinda K. Batchelor,e Basile Roufosse,a Dario Romano,b,c Judith Baumgartner,d Marina
Borzova,a Tim Reifenstahl,a Thomas Collins,a Amal Benamrane,a Jordana Weggelaar,a Marie C. Correia,a
e
∗
Paul J. Dyson, Burgert Blom,a,
aMaastricht Science Programme, Faculty of Science and Engineering, Maastricht University, Kapoenstraat 2, PO Box
616, 6200 MD, Maastricht, The Netherlands
bDepartment of Biobased Materials, Faculty of Science and Engineering, Maastricht University, Brightlands Chemelot
Campus, Urmonderbaan 22, Geleen, 6167 RD, The Netherlands
cAachen-Maastricht Institute for Biobased Materials, Brightlands Chemelot Campus, Urmonderbaan 22, Geleen, 6167
RD, The Netherlands
dInstitut für Anorganische Chemie, Technische Universität Graz, Stremayrgasse 9, A-8010 Graz, Austria
e Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH1015 Lausanne,
Switzerland
Abstract
Two heterobimetallic µ-dppm bridged Fe,Ru complexes, [(η6-Arene)RuCl2(µ-dppm)Fe(CO)I(η5-C5H5)] (Ar
= C6H6 (1) and p-cymene (2), dppm = 1,1-bis(diphenylphosphino)methane were obtained in a facile
reaction between [Fe(η5-C5H5)I(CO)(κ1-dppm)] (5) and the corresponding [(η6-Arene)RuCl2]2 complexes
by dimer cleavage, mediated by the pendant -PPh2 in 5. The homodinuclear Ru,Ru complex, [(η6-
C6H6)RuCl2(µ-dppm)RuCl2(η6-C6H6)] (3), was also isolated in a straightforward fashion upon reaction of
[(η6-C6H6)RuCl2(κ1-dppm)] (4) with [(η6-C6H6)RuCl2]2. All complexes were fully characterized by
multinuclear (1H, 13C{1H}, 31P{1H}) NMR, UV-Vis, IR spectroscopy and HRMS (ESI), and additionally
complex 3 was characterized by single crystal X-ray diffraction. Density functional theory (DFT)
calculations (Level of theory B3LYP, basis set for H, C, P, O, N and Cl is 6-31+G(d,p) and for Ru,Fe
DGDZVP) of 1, 2 and 3 are also reported. Complexes 1 and 2 feature HOMOs and LUMOs delocalized
over the iron-centered terminus of the bimetallic complexes. The cytotoxicity of 1 – 5 were evaluated on
A2780 and A2780cisR (Human ovarian carcinoma) cell lines and the HEK293 (Human embryonic kidney)
cell line. The complexes containing iron are more cytotoxic than cisplatin in the A2780 cells and
significantly more active in the A2780cisR cell line and exhibit some selectivity towards the cancer cells.
The dinuclear Ru,Ru complex 3 and the mononuclear complex 4 exhibit moderate activity on A2780 and
A2780cisR cells also with some cancer cell selectivity. This study hence reveals the potential of Fe,Ru
complexes as potent cytotoxic agents.
Keywords: Bioorganometallic chemistry, Heterobimetallic complexes, Homobimetallic
complexes, Metal-based drugs, Cytotoxicity studies.
∗Corresponding author. ∗∗Corresponding author. Email addresses: burgert.blom@maastrichtuniversity.nl (Burgert Blom)

1. Introduction
Chemotherapies based on the metal containing compounds is one of the most widely used ways to
treat cancer and platinum-based drugs are extensively used in this regard. Historically, the most
prominent of these platinum drugs is cisplatin, [1] which binds to the purine base pairs of DNA,
causing DNA damage and subsequently inducing apoptosis [2]. Disadvantages of cisplatin include
intrinsic and acquired resistance along with toxicity leading to severe side-effects [3]. Other
platinum-containing anticancer drugs such as carboplatin, oxaliplatin, nedaplatin and heptaplatin
(Chart 1) have been developed that, to varying extents, overcome these disadvantages. Carboplatin
and cisplatin remain extensively used drugs to treat cancer due to their extensive spectrum of
activity. Oxaliplatin and nedaplatin are also approved for clinical treatment of certain cancers and
heptaplatin is undergoing clinical trials [4].
O
O
O
H2
N
H2
N
O
O
O
O
O
O
H3N
H3N
O
O
Pt
Pt
Pt
N
N
H2
H2
O
O
O
a
b
c
O
C O
NH3
NH3
Cl
Cl
NH3
NH3
Pt
Pt
d
H2C O
e
Chart 1. Structures of several platins: a. Carboplatin, b. Oxaliplatin, c. Heptaplatin, d. Cisplatin, e.
Nedaplatin.
Substituting platinum by other transition metals is an alternative approach to overcome the
limitations of platinum-based drugs [ 5 ]. Ruthenium complexes show substantial promise as
antineoplastic agents and can potentially reduce severe side effects due to their higher selectivity
towards cancer cells [6]. Ruthenium complexes have the potential to bind to a wide variety of
biomolecules including DNA and histone proteins [ 7 ]. Studies also suggest that ruthenium
complexes (in particular Ru(III) have the propensity to bind (or associate) to transferrin, and
consequently might be a mechanism by which Ru complexes gain access to cells [8]. This notion
2

punctuates past and even recent literature, [9] but has also been questioned [10].
A classic example of a promising Ru-based anticancer agent is RAPTA-C (Chart 2) [11]. RAPTA-
C, when combined with other drugs, shows a reduction in tumour growth of up to 80% without
serious side effects [12]. Other notable examples of promising ruthenium-based agents are NAMI-A
and KP1019 [13, 14].
Chart 2. Cytotoxic ruthenium based complexes: a. NAMI-A, b. KP1019, c. RAPTA-C
Another strategy is to incorporate two metal centres, exploiting their distinct biological and
pharmacological features into one well-defined molecular complex. The interactions of two distinct
metal centres may result in a synergic influence on cytotoxicity compared to their monometallic
counterparts [15]. In this regard, systems bearing Ru and Au centers bridged by a dppm ligand,
(Chart 3) have been reported and the bimetallic complexes are more active than their monometallic
precursors [5i].
Cl
Ru
S
Cl
P
N
Cl
Au
Ru
Au
Cl
P
P
Cl
S
P
Ph2 Ph2
Ph2 Ph2
Chart 3. Heterobimetallic Ru,Au complexes showing promising anti-cancer activity [5i]
3

Inspired by these findings we decided to target heterobimetallic Fe,Ru complexes and elucidate
their in vitro cytotoxicity. Since some piano-stool Cp (η5-C5H5) iron complexes are cytotoxic in
their own right, [16] we hypothesized that a possible synergistic effect might also be found on
combination with RAPTA-like complexes, as with the earlier reported Ru,Au complexes (see
above). Surprisingly, heterobimetallic µ-phosphane Fe,Ru complexes are somewhat rare [17] and,
to the best of our knowledge, their anti-cancer properties have not been investigated. Herein, we
report on the facile entry to two related Fe,Ru complexes, [(η6-Arene)RuCl2(µ-dppm)Fe(CO)I(η5-
C5H5)] (Arene = C6H6 (1) or p-cymene (2), dppm = 1,1-bis(diphenylphosphino)methane and
compare their cytotoxicity to a related homodinuclear Ru,Ru complex [(η6-C6H6)RuCl2(µ-
dppm)RuCl2(η6-C6H6)] (3) as well as the mononuclear complexes [(η6-C6H6)RuCl2(κ1-dppm)] (4),
[Fe(η5-C5H5)I(CO)(κ1-dppm)] (5).
2. Results and discussion
2.1 Synthesis and characterisation
Complexes 1 and 2 were prepared by reacting [Fe(η5-C5H5)I(CO)(κ1-dppm)] (5), reported in 1972
by Haines and du Preez [18] with [(η6-C6H6)RuCl2]2 and [(η6-p-cymene)RuCl2]2, respectively, in a
2:1 ratio in dichloromethane. The reactions were monitored by TLC tracing the consumption of the
green complex 5 (typically within ca. 1 h) and the complexes were isolated as dark brown solids in
good to excellent yield (Scheme 1).
4

Scheme 1. Synthesis of heterobimetallic Fe,Ru complexes 1 and 2.
31
Complexes 1 and 2 exhibit two sets of doublet resonance signals in their respective P{1H} NMR
spectra indicative of coordination to two distinct metal centres with the high field shifted resonance
corresponding to Ru-P coordination, and the lower field shifted doublet resonance signal
2
2
corresponding to Fe-P coordination (1: 63.8 (d, JPP = 45.0 Hz, Fe-PPh2), 24.5 (d, JPP = 44.5 Hz,
1
2
2
Ru-PPh2; 2: 63.2 (d, JPP = 44.1 Hz, Fe-PPh2), 24.1 (d, JPP = 43.9 Hz, Ru-PPh2). The H NMR
spectra of 1 and 2 exhibit some line broadening for both complexes which might be due to the
presence of trace amounts of paramagnetic impurities, or paramagnetic cross-over at the Fe(II)
1
centre [19]. Nevertheless, a full assignment of their H NMR spectra was possible for both
complexes. In particular, for 1, singlets corresponding to the metal bound η5-C5H5 (δ = 4.04 ppm)
and η6-C6H6 (δ = 4.70 ppm) ligands are observed as broad singlets. In complex 2 the resonances for
the η6-p-cymene are observed as a series of complex multiplets while the η5-C5H5 ligand affords a
singlet (δ = 4.00 ppm). In both complexes the methylene bridge between the two P atoms of the
dppm ligand exhibit two distinct sets of broad multiplets, corresponding to diastereotopic CHAHB
atoms. The IR spectra of 1 and 2 contain a characteristic ν(CO) stretching vibration at 1937 cm-1
compared to the iron precursor 5 at 1944 cm-1. In both complexes a weak signal in the electron
impact mass spectrum (EI-MS) could be detected corresponding to the mass of the complex at the
corresponding m/z, and the [M+Na]+ ion was detected in the high resolution electrospray ionization
mass spectrum (ESI-MS) for both complexes further confirming their constitution.
The synthesis of the homodinculear Ru,Ru dimer 3 was achieved via reaction of [RuCl2(η6-
C6H6)(κ1-dppm)] (4) [20] with [(η6-C6H6)RuCl2]2 in a 2:1 ratio to selectively afford 3 in high yield
(Scheme 2). The p-cymene analogue of 3 i.e. [(RuCl2(η6-p-cymene))2(ꢀ-dppm)] (3-cym) has been
reported previously [21].
Scheme 2. Synthesis of the symmetrical homobimetallic Ru,Ru complex 3.
We attempted to prepare the asymmetric complex [RuCl2(η6-C6H6)(µ-dppm)RuCl2(η6-p-cymene)]
(i.e. with different arenes on each metal centre) by reacting 4 with the dimer [(η6-p-cymene)RuCl2]2
5

(2:1 ratio), or the other way around, i.e. reacting [RuCl2(η6-p-cymene)(κ1-dppm)] (4-cym) [22] with
[(η6-C6H6)RuCl2]2. In both cases, the desired asymmetric complex was not obtained, instead 1:1
31
mixtures of the symmetrical dimer complexes 3 and 3-cym were observed, on the basis of P and
1H NMR spectroscopy and ESI-MS. This result can possibly be understood by considering dppm
decomplexation equilibria from 4 (or 4-cym) affording free dppm, which then reacts with the dimer
[(η6-Arene)RuCl2]2 rapidly affording the distribution of products observed. The desired asymmetric
complexes might form in situ but subsequently rearrange to their symmetrical counterparts [23].
1
Complex 3 features a singlet in the 31P{1H} NMR spectrum at δ = 22.6 ppm. The H NMR
spectrum (in CDCl3) shows the characteristic singlet resonance signal for the η6 coordinated
benzene at δ= 5.31 ppm and the methylene protons in the µ-dppm bridge as a triplet (due to P,H
coupling) centered at δ = 4.7 ppm. The structure of 3 was corroborated by HRMS which showed the
adduct [M+Na]+: m/z = 906.8844 (expt.) Found: 906.8842. We obtained crystals, suitable for single
crystal X-ray diffraction analysis of 3 by slow evaporation of a concentrated dichloromethane
solution of the complex. The solid-state structure of 3 is show in in Figure 1. At both Ru centres in
the benzene rings are coordinated in an η6-fashion since the Ru-C bonds lengths are comparable to
each other within narrow limits (in Ru1 this ranges from 2.179(5) Å – 2.232(5) Å). The metal
centres in both cases may be described as having distorted octahedral geometries, with the benzene
rings occupying three coordination sites, and the other sites being occupied by two chlorido ligands
and the P atom of the µ-dppm. The bond angles around the Ru centres are close to 90º in
accordance with this geometry. Note that viewing the structure down the Ru-Ru axis reveals a
staggered configuration of the two metal bound arene ring systems. The phenyl rings in the µ-dppm
seem to exhibit quasi-parallel planes of phosphorous bound phenyl rings, possibly due to π-
π stacking.
6

Figure 1. ORTEP representation of the solid-state structure of 3 determined by X-ray diffraction. Thermal
ellipsoids are set at the 30 % probability level. All H atoms omitted for clarity. Selected bond lengths [Å]:
Ru(1)-C(5) 2.179(5), Ru(1)-C(3) 2.182(5), Ru(1)-C(6) 2.188(5), Ru(1)-C(1) 2.196(5), Ru(1)-C(2) 2.196(5),
Ru(1)-C(4) 2.232(5), Ru(1)-P(1) 2.3543(12), Ru(1)-Cl(4) 2.4024(12), Ru(1)-Cl(3) 2.4088(12), Ru(2)-C(23)
2.154(4), Ru(2)-C(21) 2.174(5), Ru(2)-C(19) 2.180(5), Ru(2)-C(24) 2.190(5), Ru(2)-C(22) 2.209(5), Ru(2)-
C(20) 2.253(5), Ru(2)-P(2) 2.3442(12), Ru(2)-Cl(2) 2.4116(11), Ru(2)-Cl(1) 2.4132(11). Selected bond
angles [º]: P(1)-Ru(1)-Cl(4) 87.17(4), P(1)-Ru(1)-Cl(3) 87.49(4), Cl(4)-Ru(1)-Cl(3) 86.50(5), P(2)-Ru(2)-
Cl(2) 86.98(4), P(2)-Ru(2)-Cl(1) 84.62(4), Cl(2)-Ru(2)-Cl(1) 90.43(4).
2.2 Density Functional Theory Calculations
In order to probe the electronic structure of 1, 2 and 3, we undertook density functional theory
(DFT) investigations (Level of theory B3LYP, basis set for H, C, P, O, N and Cl is 6-31+G(d,p) and
for Ru,Fe DGDZVP). We decided to focus our attention on the location of the frontier orbitals to
gain insights into the reactivity of the complexes in vitro. Since we were unable to obtain an X-ray
structure of complex 1 and 2, we also relied on the optimized structures for structural information
(see Figure 2).
7

Figure 2. Optimized structures of 1 (left) and 2 (right). (Blue = Fe, Purple = I, Orange = P, Cyan = Ru, Red
= O, Green = Cl, Grey = C, White = H).
Both complexes exhibit a syn configuration of the Fe,Ru moieties, akin to that of Ru,Ru dimer 3
(see above). Indeed, the optimized geometries of 1 and 2 are strikingly similar to those obtained by
X-Ray diffraction analysis of 3.
8

1.12
-2.76
1.14
-2.76
Figure 3. Boundary surface representations of HOMO (left) and LUMO (right) for complexes 1 (top) and 2
(bottom) and relative energies (HOMO bottom and LUMO top in eV). (Purple = I, Orange = P, Cyan = Ru,
Red = O, Green = Cl, Grey = C, White = H).
The HOMOs and LUMOs of 1 and 2 (Figure 3) are similar and both are located on the same group
of atoms, indicating that change from benzene to p-cymene has little effect. In particular, the
HOMOs are mainly located on the group of Fe-CO axis and extend over the iodine atoms. The
LUMOs are localised on the iron atom and involves mainly one phenyl group on the coordinated
phosphine ligand, with some delocalization over the Cp ring. For both 1 and 2, the energy values for
the HOMO and LUMO are essentially the same. The locality of both frontier orbitals on the iron
moiety indicates that reactivity of 1 and 2 would be initiated there, rather than at the ruthenium
center. The calculated HOMO-LUMO gap for complex 1 is 3.88 eV which corresponds to a
calculated λmax absorption value of 319 nm. This compared fairly well with the experimental value
9

of 365 nm. Similarly, complex 2 features a HOMO-LUMO separation of 3.9 eV, corresponding to a
calculated λmax absorption value of 318 nm which also compares well with the experimental value
of 357 nm. The differences arise from the fact that the calculations were carried out in the absence
of solvation.
For comparison, the location of the frontier orbitals (HOMO and LUMO) for the homobimetallic
complex 3 is shown in Figure 4.
1.01
-3.10
Figure 4. Boundary surface representations of HOMO (left) and LUMO (right) for 3 and relative energies
(HOMO bottom and LUMO top in eV). (Cyan = Ru, Red = O, Green = Cl, Grey = C, White = H).
The shapes of the frontier orbitals for 3 are similar to 1 and 2. However, the HOMO and the LUMO
involve both ruthenium atoms in the complexes, in contrast 1 and 2. Notably, the optimized
structure obtained by DFT of 3 is in excellent agreement with the experimentally determined X-ray
structure and the metrical parameters are comparable.
2.3 In vitro cytotoxicity investigations
The cytotoxicity of complexes 1-5 was evaluated on Human Ovarian Carcinoma cell lines (A2780
and A2780cisR, the latter with acquired resistance to cisplatin) and non-tumorigenic Human
Embryonic Kidney Cells (HEK293) together with cisplatin and RAPTA-C as a positive (0−100
ꢀM) and negative (200 ꢀM) controls, respectively (see Table 1). Remarkably, complex 5 reported in
1972, has escaped cytotoxic investigations and was included in the study for comparison.
10

Complex
A2780
A2780cisR
HEK293
2.2
1.4
30
±
0.1
0.1
2
1.5
1.2
±
±
0.1
0.1
1
2.2
2.6
34
±
0.1
1
1
±
±
2
±
16
±
±
±
2
3
16
±
1.2
0.1
0.3
13.8
1.5
±
0.8
0.1
0.5
18
1.6
0.9
1.1
4
2.1
2.3
±
±
4.5
7.6
±
5
±
17.6
±
±
cisplatin
RAPTA-C
<200
<200
<200
Table 1. IC50 values (µM) of 1-5, cisplatin and RAPTA-C after 72 h drug exposure. Values are represented
as the mean ±SD of two or more independent experiments.
The cytotoxicity studies reveals that the iron containing complexes (1, 2 and 5) are considerably
more cytotoxic than the mononuclear ruthenium complex (4) or its dinuclear counterpart (3). The
iron containing complexes exhibit similar activities on both the A2780 and A2780cisR cell lines
with 2 being more cytotoxic than cisplatin on the A2780 cell line. The iron containing complexes
(1, 2 and 5) overcome resistance in the A2780cisR cell line, i.e. they exhibit similar cytotoxicities in
both the A2780 and A2780cisR cell lines, in the range 1.2 – 2.2 µM, with 2 and 5 also displaying a
modest degree of cancer cell selectivity in that about twice the concentration is required to afford an
IC50 value in the HEK293 cells. Interestingly, the homodinuclear complex 3 is less cytotoxic than
its mononuclear counterpart 4 in the A2780 and HEK293 cell lines. The marked decrease in
cytotoxicity of complex 3 vs 4 is possibly due to retarded uptake in the cell, and can potentially be
explained by the size of complex 3 which might encounter difficulties crossing the cell membrane.
It is indeed instructive to compare this result with the enhanced cytotoxicity of the heterobimetallic
dinuclear complex 2 where the trend goes in the opposite direction and having iron instead of
ruthenium present in the complex boosts cytotoxicity. Overall this shows that having iron vs
ruthenium present in the dinculear complexes enhances cytotoxicity.
11

3. Conclusions
Facile synthetic entry to heterobimetallic Fe,Ru complexes (1 and 2) and a homodinuclear Ru,Ru
complex (3) have been reported. DFT calculations reveal, as expected, localization of the HOMO
and LUMOs on the iron centred part of the heterobimetallic complexes. The in vitro cytotoxicity of
the bimetallic complexes towards tumorigenic A2780 and A2780cisR cells has also been reported
compared to non-tumorigenic HEK293 cells and, notably, the heterobimetallic Fe,Ru complexes are
highly cytotoxicity, overcoming cisplatin resistance with some selectivity towards cancer cells.
These results indicate, for the first time, the potential of heterobimetallic Fe,Ru phosphane bridged
complexes as potential anti-cancer agents. The mechanism of action in vitro requires further
investigation. Further work is underway in our laboratory to explore other heterobimetallic systems
and similar cooperative effects, and will be reported in subsequent communications.
4. Experimental
4.1 General Considerations
All reactions were conducted under a nitrogen atmosphere at room temperature using standard
Schlenk line and glove-box techniques unless otherwise stated. Reagents were obtained from
commercial sources and used as received. Dimethylsulfoxide D6 (99,80%, D) was purchased from
VWR Chemicals. Toluene (anhydrous, 99,8%), Dicarbonylcyclopentadienyliodoiron (II) (97%),
1,1-bis(diphenylphosphino)methane (97%), η6-benzene-ruthenium(II)chloride dimer, (η6-p-
cymene)-ruthenium(II) chloride dimer and silica gel (technical grade, 60 Å pore size, 70-230 mesh,
63-200 ꢀm) were purchased from Sigma-Aldrich. n-hexane (AR grade), toluene (HPLC), and
dichloromethane (stab. Amylene) were purchased from Biosolve Chimie SARL. Neutral TLC Silica
60 F254 sheets were used for thin layer chromatography and the aforementioned silica gel was used
for column chromatography. [RuCl2(η6-C6H6)(κ1-dppm)] (4) and [CpFe(CO)I(κ1-dppm)] (5), 3-cym
and 4-cym were prepared according to a literature procedures (see SI). All solvents, with the
exception of toluene, were dried on a short plug of alumina oxide column and were purged with
Nitrogen gas. A SMP10 (Stuart equipment) was used to measure melting points. A GCMS-
QP2010Ultra (Shimadzu) was used to acquire mass spectra using electron impact (EI) mass
spectrometry by direct injection. The software used for data interpretation was GCMS Real Time
12

Analysis (Admin). A 300 MHz Ultrashield™ Magnet System (Bruker) was used for NMR
1
13
experiments at ambient temperature. Chemical shifts for H and C NMR were measured relative
to tetramethylsilane (TMS). For 31P NMR, the chemical shifts were measured relative to phosphoric
acid (85%), using Topspin 3.5pl7 software. A MIRacle 10 (single reflection ATR accessory,
Shimadzu) was used to acquire FTIR spectra (Happ-Genzel apodisation, 64 scans, resolution 2)
with the software IR solution. A UV-188 spectrophotometer (Shimadzu), and quartz suprasil
precision cells (type 100-QS, 10 mm light path; Hellma Analytics) were used to obtain UV-Vis
spectra. High resolution Electron Ionisation Spray (ESI) mass spectra were recorded using an
Orbitrap LTQ XL of Thermo Scientific mass spectrometer at the Technische Universitaet Berlin.
Raw data was evaluated and processed using the X-calibur computer program. In all cases the
isotope distribution pattern of the signal was checked against theory. All values reported related to
the line of highest intensity in the isotope pattern.
4.2 Cytotoxicity tests
Human ovarian carcinoma (A2780 and A2780cisR) cell lines were obtained from the European
Collection of Cell Cultures. The human embryonic kidney (HEK-293) cell line was obtained from
ATCC (Sigma, Buchs, Switzerland). Penicillin streptomycin, RPMI 1640 GlutaMAX (where RPMI
= Roswell Park Memorial Institute), and DMEM GlutaMAX media (where DMEM = Dulbecco’s
modified Eagle medium) were obtained from Life Technologies, and fetal bovine serum (FBS) was
obtained from Sigma. The cells were cultured in RPMI 1640 GlutaMAX (A2780 and A2780cisR)
and DMEM GlutaMAX (HEK-293) media containing 10% heat-inactivated FBS and 1% penicillin
streptomycin at 37 °C and CO2 (5%). The A2780cisR cell line was routinely treated with cisplatin
(2 ꢀM) in the media to maintain cisplatin resistance. The cytotoxicity was determined using the 3-
(4,5-dimethyl 2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay [24]. Cells were
seeded in flat-bottomed 96-well plates as a suspension in a prepared medium (100 ꢀL aliquots and
approximately 4300 cells/well) and preincubated for 24 h. Stock solutions of compounds were
prepared in DMSO and were diluted in medium. The solutions were sequentially diluted to give a
final DMSO concentration of 0.5% and a final compound concentration range (0−200 ꢀM).
Cisplatin and RAPTA-C were tested as a positive (0−100 ꢀM) and negative (200 ꢀM) controls
respectively. The compounds were added to the preincubated 96-well plates in 100 ꢀL aliquots, and
the plates were incubated for a further 72 h. MTT (20 ꢀL, 5 mg/mL in Dulbecco’s phosphate
buffered saline) was added to the cells, and the plates were incubated for a further 4 h. The culture
13

medium was aspirated and the purple formazan crystals, formed by the mitochondrial
dehydrogenase activity of vital cells, were dissolved in DMSO (100 ꢀL/well). The absorbance of
the resulting solutions, directly proportional to the number of surviving cells, was quantified at 590
nm using a SpectroMax M5e multimode microplate reader (using SoftMax Pro software, version
6.2.2). The percentage of surviving cells was calculated from the absorbance of wells corresponding
to the untreated control cells. The reported IC50 values are based on the means from two
independent experiments, each comprising four tests per concentration level.
4.3 X-ray structure determination
For X-ray structure analysis of complex 3 the crystals were mounted onto the tip of glass fibers,
and data collection was performed with a BRUKER-AXS SMART APEX CCD diffractometer
using graphite-monochromated Mo Kα radiation (0.71073 Å). The data were reduced to F2 and
0
corrected for absorption effects with SAINT [25] and SADABS [26, 27] respectively. Structures
were solved by direct methods and refined by full-matrix least-squares method (SHELXL97 and
SHELX2013) [28]. All non-hydrogen atoms were refined with anisotropic displacement parameters.
Hydrogen atoms were placed in calculated positions to correspond to standard bond lengths and
angles. All diagrams were drawn with 30 % probability thermal ellipsoids and all hydrogen atoms
were omitted for clarity.
4.4 Synthesis of [(η6-C6H6)RuCl2(µ-dppm)Fe(CO)I(η5-C5H5)] (1)
0.094 g (0.14 mmol) of [CpFe(CO)(κ1-dppm)I] and 0.037 mg (0.074 mmol) of [Ru(η6-C6H6)Cl2]2
were dissolved in 26 mL of dried dichloromethane, and stirred for 1 h. The progress of the reaction
was monitored by thin layer chromatography in 60:40 mixture of dichloromethane and n-hexane
every 10 minutes. TLC showed complete consumption of starting material after 40 minutes of
reaction. The solvent was removed in vacuo to isolate the solid and was washed with dried n-
hexane (3 x 2 mL). After decanting the washings, the solid was dried in vacuo at room temperature.
Air stable. 0.106 g (0.116 mmol). Dark brown solid (78.5%). Melting point 207˚C + dec. 1H NMR
(CDCl3, 298.2 K): δ 7.64 - 7.52 (8H, br m, C-H, dppm), 7.40 - 7.37 (4H, br m, C-H, dppm), 7.16 -
7.06 (8H, br m, C-H, dppm), 5.24 (6H, s, η6-C6H6), 4.32 (5H, s, η5-C5H5), 3.58 (1H, br m, HA,
B
1
13
PCH2P), 3.48 (1H, br m, H , PCH2P). C { H} NMR (CDCl3, 298.2 K): δ 134.5 - 133.8 (br m,
dppm), 132.5 (br s, dppm), 131.9 (br s, dppm), 131.1 - 129.9 (br m, dppm), 127.7 (br m, dppm),
88.6 (s, η6-C6H6), 82.5 (s, η5-C5H5), (PCH2P and FeCO not visible despite high concentrations and
31
2
very high scan rate ca. 5 k scans). P {1H} NMR (CDCl3, 298.2 K): δ 63.8 (d, JPP = 45.0 Hz, Fe-
14

PPh2), 24.5 (d, 2JPP = 44.5 Hz, Ru-PPh2). 1H NMR (C6D6, 298.2 K): δ 7.79 (8H, br m, C-H, dppm),
6.88 (12H, br m, C-H, dppm), 5.18 (1H, m, HA, PCH2P), 5.02 (1H, m, HB, PCH2P), 4.70 (6H, s, η6-
5
31
2
C6H6), 4.04 (5H, s, η -C5H5). P {1H} NMR (C6D6, 298.2 K): δ 64.0 (d, JPP = 45.0 Hz, Fe-PPh2),
2
25.4 (d, JPP = 44.7 Hz, Ru-PPh2). FTIR: 3663 (vw), 2963 (br, m), 2922 (br, m), 1937 (s, C≡O
streching), 1670 (vw), 1585 (vw), 1572 (vw), 1483 (m), 1433 (s), 1315 (vw), 1260 (s), 1186 (vw),
1157 (vw), 1090 (br, vs), 1016 (br, vs), 862 (vw), 797 (vs), 731 (s), 692 (vs), 623 (w), 608 (m), 565
(br, m). UV-Vis: (nm)/dichloromethane λmax = 365.0. EIMS (70 eV) m/z 910.50 (< 0.1%, M+),
384.15 (2.76%, (Ph)2P(CH2)P(Ph)2), 400.20 (36.45%, O=P(Ph)2(CH2)P(Ph)2), 416.20 (0.59%,
O=P(Ph)2(CH2)(Ph)2P=O), 551.15 (18.93%, [Ru(η6-C6H6)Cl2]2), 678.05 (18.85%, CpFe(CO)(κ1-
dppm)I + H2O adduct). TGA (Weight % decrease): 108.74˚C - 113.21˚C (2.372%), 187.97˚C -
188.78˚C (2.893%), 268.22˚C - 273.80˚C (6.203%), 351.10˚C - 401.31˚C (43.81%). ESI-MS, m/z
Calcd. For [M+Na]+ 932.8719. Found 932.8698.
4.5 Synthesis of Synthesis of [(η6-p-cymene)RuCl2(µ-dppm)Fe(CO)I(η5-C5H5)] (2)
0.1502 g (0.227 mmol) of [CpFe(CO)(κ1-dppm)I] and 0.0722 g (0.118 mmol) of [Ru(η6-p-
MeC6H4Pri)Cl2]2 were dissolved in 10 mL of dried dichloromethane, and stirred for 30 min. The
reaction was followed by TLC, which showed complete consumption of the starting material after
30 minutes. The solvent was removed in vacuo to isolate a brown solid and was washed with n-
hexane (3 x 2 mL). After decanting the washings, the solid was dried under vacuum at room
temperature. Air stable. 0.2151 g (0.223 mmol). Dark Brown solid (94.3%). Melting point 238˚C +
3,5
6
1
dec. H NMR (CDCl3, 298.2 K): δ 8.10 - 7.05 (20H, m, C-H, dppm), 5.08 (2H, m, C -H, η -p-
cymene), 4.97 (2H, m, C2,6-H, η6-p-cymene), 4.23 (5H, br s, η5-C5H5), 2.86 (1H, m, 2JHP = 22.0 Hz,
PCH2P, HB), 2.48 (1H, m, 2JHP = 18.3 Hz, PCH2P, HA), 1.72 (6H, d, 2JHH = 6.1 Hz, CH(CH3)2), 1.18
(3H, br s, CH3), (CH(CH3)2 not visible). 13C {1H} NMR (CDCl3, 298.2 K): δ 133.7 (br t, 2JPC = 6.5
2
Hz, dppm), 131.7 - 131.0 (br m, dppm), 129.4 - 128.8 (m, dppm), 126.7 (d, JPC = 8.8 Hz, dppm),
2
2
126.3 (br t, JPC = 10.6 Hz, dppm), 83.9 (d, JPC = 7.1 Hz, η6-p-cymene) (other signals expected
from coordinated ring not visible), 81.5 (s, η5-C5H5), 29.2 (s, CH(CH3)2), 28.7 (m, PCH2P), 21.4 (s,
6
31
CH(CH3)2), 20.6 (s, CCH3, η -p-cymene), (FeCO not visible). P {1H} NMR (CDCl3, 298.2 K): δ
2
2
1
63.2 (d, JPP = 44.1 Hz, Fe-PPh2), 24.1 (d, JPP = 43.9 Hz, Ru-PPh2). H NMR (C6D6, 298.2 K): δ
2
7.81 (8H, br m, C-H, dppm), 6.87 (12H, br m, 13H, C-H, dppm), 5.14 (1H, br m, JHP = 6.81 Hz,
HA, PCH2P), 4.97 (1H, br m, 2JHP = 5.3 Hz, HB, PCH2P), 4.88 (2H, br s, C3,5-H, η6-p-cymene), 4.76
(1H, br s, C2-H, η6-p-cymene), 4.41 (1H, br s, C6-H, η6-p-cymene), 4.00 (5H, s, η5-C5H5), 2.67 (1H,
2
3
31
sept, JHH = 5.34 Hz, CH(CH3)2), 1.85 (3H, s, CH3), 0.92 (6H, br t, JHH = 7.5 Hz, CH(CH3)2). P
15

{1H} NMR (C6D6, 298.2 K): δ 63.4 (d, 2JPP = 43.6 Hz, Fe-PPh2), 25.1 (d, 2JPP = 43.8 Hz, Ru-PPh2).
FTIR: 3051 (w), 2959 (w), 1937 (br s, C≡O streching), 1483 (w), 1433 (m), 1375 (w), 1319 (w),
1263 (w), 1182 (br w), 1159 (w), 1096 (m), 1057 (w), 1028 (w), 999 (w), 839 (w), 822 (w), 797
(w), 731 (br, s), 692 (s), 623 (w), 608 (br w), 554 (br w). UV-Vis: (nm)/dichloromethane λmax
=
357.1. EIMS (70 eV) m/z 966.10 (< 0.1%, M+), 119.15 (100.0%, η6-C6H5Pri - H+), 134.15 (30.64%,
η6-p-MeC6H4Pri), 350.0 (3.22%, Ru(η6-p-MeC6H4Pri)Cl2), 384.20 (2.55%, (Ph)2P(CH2)P(Ph)2),
400.20 (14.88%, O=P(Ph)2(CH2)P(Ph)2), 678.10 (5.39%, CpFe(CO)(κ1-dppm)I with H2O adduct).
ESI-MS, m/z Calcd. For [M+Na]+ 988.9345. Found 988.9324.
4.6 Synthesis of [RuCl2(η6-C6H6)]2(
ꢀ-dppm)] (3)
223 mg (0.367 mmol) of 1 was stirred with 88 mg (0.099 mmol) of [RuCl(ꢀ-Cl)(η6-C6H6)]2 in
DCM for 2.5h under reflux. The solvent was removed in vacuo to isolate a solid, which was then
washed with diethyl ether (3 x 10 mL). After disposing of the washings; the solid was dried at room
temperature. Air stable. 246 mg (0.278 mmol) of brown solid (70.2 %). Melting point 180ºC + dec.
1H NMR (CDCl3, 298 K): δ 7.54 (4H, m, C4–H, dppm), 7.33-7.25 (8H, m, C3,5 or 2,6–H, dppm), 7.18-
2
13
7.10 (8H, m, C2,6 or 3,5–H, dppm), 5.31 (12H, s, η6-C6H6), 4.70 (2H, t, JPH = 8.55 Hz, PCH2P). C
2
{1H} NMR (CDCl3, 298 K): δ 133.7 (t, JPC = 4.1 Hz, C2,6-dppm), 130.7 (s, C4 -dppm), 130.1 (d,
3
1
1JPC = 23.1 Hz, C1-dppm), 127.7 (t, JPC = 5 Hz, C3,5-dppm), 88.6 (s, η6-C6H6), 25.7 (t, JPC = 9.9
Hz, PCH2P). 31P {1H} NMR (CDCl3, 298K): δ 22.6 (s, Ru-PPh2). FTIR (cm-1): 1482 (m), 1433 (vs),
1263 (m), 1096 (s), 1028 (vw), 1000 (w), 732 (s), 692 (s), 608 (m), 594 (w), 585 (m), 567 (w), 561
(w), 557 (vw), 554 (w), 548 (w), 542 (w), 539 (vw), 533 (w), 530 (m), 522 (w), 506 (m), 503 (m).
UV–vis: (nm)/dichloromethane: λ 372.0. ESI-MS (THF), m/z: calcd for [C37H34Ru2P2Cl4+Na]+:
906.8844. Found: 906.8842.
4.7 Density Functional Theory Calculations
DFT calculations were performed to model the complexes 1, 2 and 3. Guassian09 software package
was used. For all the calculations, the level of theory used for all calculations is B3LYP with the
basis set 6-31+G(d,p) for H, C, O, P, I and Cl atoms; while for Ru and Fe atoms DGDZVP basis set
was used. Geometry optimizations were calculated without any constrains. All the optimized
geometries show not imaginary frequency. Energies were calculated on the optimized structures
[29].
16

Acknowledgements
We would like to thank the Maastricht Science Programme (MSP) and Maastricht University
(Faculty of Science and Engineering) for financial support of this research. BB thanks numerous
students who did some preliminary work in this area as part of a research project within the MSP.
JB thanks the Austrian Fonds zur Förderung der wissenschaftlichen Forschung (FWF) via the
project P-30955. Dr. Maria Schlangen-Ahl (TU Berlin) is thanked for recording HRMS of all
complexes.
Associated Content
The supporting information is available free of charge. Supporting Information is available with
experimental details, NMR, IR and ESI-MS spectra, X-ray crystallographic details of 3 and
Cartesian coordinates for the complexes studied by DFT methods.
Accession codes
CCDC 1936145 contain the supplementary crystallographic data for this paper. This data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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(b) Morais, T. S.; Valente, A.; Tomaz, A. I.; Marques, F.; Garcia, M. H., Future Medicinal Chemistry 2016,
8 (5), 527.
(c) Poh, H. T.; Ho, P. C.; Fan, W. Y., RSC Advances 2016, 6 (23), 18814.
(d) Florindo, P. R.; Pereira, D. M.; Borralho, P. M.; Rodrigues, C. M. P.; Piedade, M. F. M.; Fernandes, A.
C., Journal of Medicinal Chemistry 2015, 58 (10), 4339.
(e) Gonçalves, A. C.; Morais, T. S.; Robalo, M. P.; Marques, F.; Avecilla, F.; Matos, C. P.; Santos, I.;
Tomaz, A. I.; Garcia, M. H., Journal of Inorganic Biochemistry 2013, 129, 1.
[17] A search for bimetallic Fe,Ru complexes bridged with R2P(CH2)nPR2 (n = 1, 2, 3) yielded surpisingly
few results. See: (a) Nawar, N.; Smith, A. K., Journal of Organometallic Chemistry 1995, 493 (1), 239.
(b) Dolby, P. A.; Harding, M. M.; Newar, N.; Smith, A. K., Journal of the Chemical Society, Dalton
Transactions 1992, 2939.
(c) Venäläinen, T.; Iiskola, E.; Pursiainen, J.; Pakkanen, T. A.; Pakkanen, T. T., Journal of Molecular
Catalysis 1986, 34 (3), 293.
(d) Coleman, A. W.; Jones, D. F.; Dixneuf, P. H.; Brisson, C.; Bonnet, J. J.; Lavigne, G., Inorganic
Chemistry 1984, 23 (7), 952.
[18] (a) Haines, R.J.; du Preez, A. L., Inorganic Chemistry 1972, 11, 330.
(b) Serra, D.; Correia, M. C.; McElwee-White, L., Organometallics 2011, 30 (21), 5568.
(c) Serra, D.; Abboud, K. A.; Hilliard, C. R.; McElwee-White, L., Organometallics 2007, 26 (13), 308.
6
4
2
[19] High-spin-Low-Spin equilibria are rather common for Fe(II) complexes (t2g vs t2g eg for octahedral
configured species) which leads to line broadening which can be reduced at lower temperatures. As an
example of this, see the behavior of complex [Fe(depe)2Cl2] (depe = 1,1-bis(diethylphosphino)ethane
21

B.Blom, PhD dissertation, University of Bonn, 2011.
[20] (a) Zelonka, R. A.; Baird, M. C. Canadian Journal of Chemistry 1972, 50 (18), 3063.
(b) Zelonka, R. A.; Baird, M. C., Journal of Organometallic Chemistry 1972, 44 (2), 383.
[21] (a) Coleman, A. W.; Zhang, H.; Bott, S. G.; Atwood, J. L.; Dixneuf, P. H., Journal of Coordination
Chemistry 1987, 16 (1), 9.
(b) Estevan, F.; Lahuerta, P.; Latorre, J.; Sanchez, A.; Sieiro, C., Polyhedron 1987, 6 (3), 473.
(c) Coleman, A. W.; Jones, D. F.; Dixneuf, P. H.; Brisson, C.; Bonnet, J. J.; Lavigne, G., Inorganic
Chemistry 1984, 23 (7), 952.
[22] (a) Chaplin, A. B.; Fellay, C.; Laurenczy, G.; Dyson, P. J., Organometallics 2007, 26 (3), 586.
(b) Gupta, D. K.; Sahay, A. N.; Pandey, D. S.; Jha, N. K.; Sharma, P.; Espinosa, G.; Cabrera, A.; Puerta, M.
C.; Valerga, P., Journal of Organometallic Chemistry 1998, 568 (1), 13.
(c) Coleman, A. W.; Zhang, H.; Bott, S. G.; Atwood, J. L.; Dixneuf, P. H., Journal of Coordination
Chemistry 1987, 16 (1), 9.
[23] Interestingly, in our hands, the reactions of 4 and 4-cym with cisplatin in an attempt to prepare the
heterobimetallic Ru,Pt complexes of the type [(η6-Arene)Cl2Ru(µ-dppm)PtCl2(NH3)] (Arene = C6H6 or p-
cymene) by NH3 substitution at the Pt(II) centre also afforded a mixture of 3 and [PtCl2(κ2-dppm)] or 3-cym
31
and [PtCl2(k2-dppm)] respectively, confirmed on the basis of P and 1H NMR spectroscopy and comparison
to authentic samples.
[24] Mosmann, T, Journal of Immunological Methods 1983, 65, 55.
[25] SAINT+ Version 6.45, Bruker Analytical X-Ray Systems. Inc., Madison, Wisconsin, USA 2003.
[26] Sheldrick G.M., SADABS v. 2.10. Bruker AXS Inc., Madison, Wisconsin, USA 2003.
[27] Blessing R. H., Acta Crystallographica Section A 1995, 51 (1), 33.
[28] (a) Sheldrick G. M., Acta Crystallographica Section C: Structural Chemistry 2015, 71 (1), 3.
(b) Sheldrick G .M., Acta Crystallographica Section A: Foundations of Crystallography 2008, 64 (1), 112.
[29] Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani,
G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.;
Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;
Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.;
Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.;
Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi,
M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C. J.; Ochterski, W.; Martin,
R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels,
A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.Gaussian 09, revision D.01; Gaussian,
Inc.: Wallingford, CT, 2009
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Highlights
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Facile entry to homo and heterobimetallic Ru,Ru and Fe,Ru complexes
In vitro cytotoxicity Investigations on A2780 and A2780cisR cell lines
Enhanced cytotoxicity observed in iron containing complexes
DFT investigations reveal HOMO and LUMO over the iron terminus of Fe,Ru complexes
X-ray structure of Ru,Ru complex