Ruthenium compounds as

anticancer agents
New ruthenium-based compounds with fewer and less severe side effects, could replace
longstanding platinum-based anticancer drugs
Simon Page

In short This observation led to cis-

diamminedichloroplatinum(II),
●● As clinical trials
commonly known as cisplatin, being
progress, ruthenium
compounds may
approved by the American Food and
provide a less toxic and Drugs Administration (FDA) for
more effective cancer therapy in 1978. It has since
alternative to become the most widely used
platinum therapies anticancer drug, with an estimated
●● Many different
70% of patients receiving the
ruthenium compounds compound as part of their treatment.
1

have been tested for

their anticancer Cisplatin
properties, without Cisplatin was heralded as a completely
enough investigation novel type of antitumour agent, and its
into their mode(s) of discovery enticed a veritable army of
action inorganic chemists to devise and test
other precious metal-based therapies.
Disappointingly however, fifty years
and countless clinical candidates later,
there have only been two more
worldwide drug approvals for
precious metal-containing anticancer
drugs: carboplatin and oxaliplatin –
both of which are direct analogues of
cisplatin (fig 1) – approved in 1993
and 2002 respectively.
The mode of action of these
platinum complexes is known: the
chloride or dicarboxylate ligands are
hydrolysed within the cell to
generate a bis-aqua species, which
binds irreversibly to DNA – usually
to two adjacent guanine bases –
shutterstock

(fig 2) and the cell, unable to

replicate, defaults to apoptosis (that
is, controlled cell death).

Platinum therapies Rosenberg used a platinum electrode From platinum to ruthenium

For half a century, the field of metal-
based anticancer drugs has been
dominated by the precious metal
platinum. The discovery of platinum’s
anticancer properties was made by
chance during an experiment in 1965,
conducted at Michigan State
University by Barnett Rosenberg.
to apply an electric field to a colony of
E. coli, which was observed to inhibit
their growth. A diligent investigation
into the cause of this effect concluded
that the platinum electrode was
breaking down to generate
platinum(II) species in situ, which was
stopping the cells from multiplying.
Whilst the chemotherapeutic success
of platinum is undeniable, it is by no
means the perfect drug. It is not
effective against many common types
of cancer, drug resistance is common
and it has a deplorable range of side
effects, which can include nerve
damage, hair loss and nausea.

26 | Education in Chemistry | January 2012 www.rsc.org/eic

 1 O
H2N Cl
H2N
Pt
H2N Cl H2N
To overcome these limitations,
some compounds based on ruthenium
have been developed and tested
against cancer cell lines. These
compounds tend to cause fewer (and
less severe) side effects compared to
platinum drugs.
Ruthenium’s properties are well
suited towards pharmacological
2
american chemical society
applications. It can access a range of
oxidation states (II, III and IV) under
physiologically relevant conditions.
Also, the energy barriers to
interconversion between these
oxidation states is relatively low,
allowing for ready oxidation state
changes when inside the cell. In spite
of this flexibility in oxidation state,
ruthenium complexes display
relatively slow ligand exchange rates in
water (fig 3) – its kinetics are on the
timescale of cellular reproduction
(mitosis), meaning that if a ruthenium
ion does bind to something in the cell,
it is likely to remain bound for the
remainder of that cell’s lifetime.
3 evaluation as anticancer drugs (as far
Simon Page/J ReedJick
www.rsc.org/eic
H concentration of molecular oxygen
O N
O O
Pt Pt
O O O
N These two factors taken in parallel
O H
Fig 1 Furthermore, ruthenium tends to
The chemical form octahedral complexes, which
structures of gives the chemist two more ligands to
cisplatin, exploit compared with platinum(II)
carboplatin and complexes, which adopt a square
oxaliplatin planar geometry. Ruthenium can also
form strong chemical bonds with a
range of different elements of varying
chemical ‘hardness’ and
Fig 2 electronegativities, meaning that
A crystal structure ruthenium can bind to a range of
showing cisplatin biomolecules, not just DNA.
(red) binding to
and ‘kinking’ DNA Why is ruthenium less toxic?
(grey)2 One hypothesis as to why ruthenium
compounds are less toxic in general
than platinum drugs is ‘Activation by
Reduction’. This theory is based on the
observation that ruthenium(III)
Fig 3 complexes are more inert than
The ligand exchange ruthenium(II), which can partially be
rates of platinum attributed to its higher effective
group metals are nuclear charge (Zeff ). Also, cancerous
considerably slower cells tend to have a more chemically
than those of other reducing environment than healthy
metals cells, owing to their lower
January 2012 | Education in Chemistry | 27
(due to their higher metabolic rate and
remoteness from the blood supply).
mean that compounds of ruthenium
can be administered in the (relatively
inert) III oxidation state, causing
minimal damage to healthy cells, but
being reduced to the (active) II
oxidation state in cancer cells.3
Recently, however, this theory has
come under considerable criticism
and even the question of how
ruthenium compounds enter cells has
been the subject of some literature
debate.
Can ruthenium impersonate
iron?
Ruthenium is a transition metal in
group 8 – the same chemical group as
iron. Iron, in spite of its potential
reactivity and biological toxicity, is a
key element without which most cells
cannot survive. In fact, nature has
developed considerable machinery to
sequester, transport and make use of
iron. The fact that iron and ruthenium
are in the same chemical group has
led to some chemists postulating that
it is capable of taking iron’s place in
some proteins, most notably in the
chaperone and uptake protein
transferrin.4 However, others remain
skeptical that the two metals are
similar enough to be interchangeable;
specifically, ruthenium binds tighter
and more slowly than iron and has a
preference for ‘softer’ ligands. Nature
has also developed extremely high
affinity iron binding sites (eg
transferrin holds iron with a binding
constant of 1023 M-1), and it has been
questioned whether ruthenium can
outcompete iron in these contexts.
Another suggestion is that ruthenium
can bind to other sites on transferrin,
and ‘piggy-back’ into the cell when
iron is taken into the cell (fig 4).5
Key molecules
Two ruthenium compounds are
currently undergoing clinical
as the author is aware): NAMI-A and
KP1019 (fig 5). A great deal of the
remaining literature can be
categorised as follows:
Coordination Compounds
In ‘classical’ coordination compounds,
the metal is surrounded by Lewis
bases with lone pairs. The compounds
KP1019 and NAMI-A fall into this
 4 Fig 6
Simon page/richard wheeler
category. Given that these compounds
have some ligands that can feasibly be
hydrolysed (eg chloride, DMSO), it is
thought that the actual ‘active’
molecules which reach the cancer cell
are unlikely to be the same as the
molecular structures shown (fig 5).
KP1019 and NAMI-A appear to be
quite similar structurally (both are
Ru(III)+ complexes with chloride and
heterocyclic ligands and a heterocyclic
counterion) yet they display
remarkably different types of
anticancer activity: KP1019 is active
against primary cancers (ie the main
tumour mass which forms first in a
patient), whereas NAMI-A is active
against secondary tumour cells (ie the
metastases which form after cells from
the primary tumour have moved to a
different organ, eg via the
bloodstream). Currently there are very
5 the above work is that here the
NH
N N
Cl Cl
NH
Cl
Ru
Cl
N Cl
H HN
O SH
28 | Education in Chemistry | January 2012
few treatment options for secondary
(metastatic) cancers, and the
prognosis for patients who develop
this form of the disease is much worse.
Organometallics
An organometallic complex is often
defined as a molecule with a distinct
metal-carbon bond. Although they
have a reputation as being unstable
compounds, better known for
spontaneous combustion than
therapeutic effects, some ruthenium
organometallics have displayed high
water- and air-stability and an
interesting spectrum of anticancer
activity.
Arguably the most successful
ruthenium organometallic anticancer
complexes have been the so-called
‘RAPTA’ complexes (fig 6). RAPTA
complexes are characterised by the
HN
Cl
Cl
Ru
Cl
N N
NH H to right) NAMI-A
6
An example of a
RAPTA complex
presence of a facially-coordinated
aromatic ring (which is relatively
hydrophobic) and a PTA
(1,3,5-triaza-7-phosphaadamantane)
ligand (which is highly water
soluble). Oddly, RAPTA complexes
display a similar spectrum of activity
to the coordination complex
NAMI-A, in spite of their apparent
differences in oxidation state, ligands,
charge and geometry.
Fig 4 Multinuclear
Ruthenium The ability of ruthenium species to
‘piggy-backing’ form multinuclear and
into cells on the supramolecular architectures has been
surface of the iron known for some time, but their
uptake protein application to medicinal chemistry has
transferrin. only been explored recently.
Some particularly interesting
strategies include ruthenium-
platinum mixed-metal compounds,6
ruthenium cluster complexes,7
ruthenium DNA intercalators8 and
supramolecular ‘Trojan Horses’, which
contain a cytotoxic payload that is
released upon entry to the cancer cell9
(fig 7).
Directed therapies
Recently, chemists have developed
compounds where a precious metal
is chemically linked to an ‘organic
directing molecule’ (ODM), which
has a known biological target – eg a
drug molecule. It has been
speculated that the organic molecule
can ‘lead’ the metal into the cell and
to a specific target. If the metal then
binds directly to the cellular target, it
could massively increase the potency
of the drug (fig 8). The main
difference between this strategy and
biological target of the molecule is
known, making this strategy a more
rational form of drug design.
Fig 5 Biological target of ruthenium
Chemical drugs
structures of (left A recent trend in medicinal chemistry
has been a trend away from high-
and KP1019, the throughput approaches to drug
first ruthenium discovery (ie those where vast
anticancer databases of molecules are screened
compounds to against a biological target) towards
enter clinical trials structure-based drug discovery (ie
www.rsc.org/eic
 7 high affinity for cancer targets, with
Ruthenium cluster complex
Ruthenium DNA intercalator
those where drug design is based on
specific structural information about a
biological target) which recent
research estimates can save around
50% of the cost associated with
discovering a drug.10 However, a major
limitation in the field is the lack of an
agreed biological target. Currently, the
two main theories are that ruthenium
compounds target DNA or (as yet
unknown) proteins. To date, a great
deal of research has been directed at
generating novel complexes for testing,
with relatively little rational design or
work aimed at elucidating the modes
of action of these complexes.
Future ruthenium drugs
In conclusion, ruthenium compounds
have shown highly promising
anticancer activity in cells, animals
and humans. To date, two compounds
are being evaluated in phase II clinical
trials. However, a major limitation in
ruthenium drug discovery is their
unknown mode of action. This leads
to three possible strategies for future
ruthenium drug design.
Chemists could continue the
current approach, without a clear
biological target for their compounds,
Simon page
but instead generating large numbers
of different compounds to screen
www.rsc.org/eic
Ruthenium-platinum mixed
metal complex
Supramolecular ‘Trojan Horse’
Fig 7 against different targets and cell lines.
Selected This approach could include
multinuclear structure-activity relationships (SARs)
ruthenium in order to determine how altering
anticancer different functional groups on the
complexes molecule affect its anticancer activity.
This strategy has the advantage of
simplicity, but it would be inefficient
and a lack of information about the
physiological target of the resultant
complexes could complicate
regulatory approval.
Alternatively, more research could
be directed at eliciting the mode of
Fig 8 action of existing ruthenium
An organic molecule compounds. Then, armed with
directs a metal (M) to detailed information about how
a Lewis Basic Amino ruthenium behaves in biological
Acid (B) near the media – what it prefers to bind to, how
active site of a it gets into cells etc – chemists can
target protein begin to design
ruthenium
8 drugs which
have a
January 2012 | Education in Chemistry | 29
far less severe side effects. This
strategy could be highly advantageous
if a target can be identified.
The final and most recent approach
to ruthenium drug design would be
the generation of further
ruthenium-ODM complexes, in which
an organic molecule binds to the
active site of an enzyme and the
attached ruthenium ion binds to a
nearby residue of the same protein.
The high-energy interaction set up
between the metal and the target
offers medicinal chemists a high-
energy mode of bonding which isn’t
available to ‘traditional’ organic
medicines. The advantage to this
approach is that the compound has a
known (or, at least, desired) biological
target against which enzymological
studies can be performed – such as
enzyme inhibition studies and protein
crystallography.
Of course, in reality, it is likely that
all three of these approaches will be
followed to a greater or lesser degree,
as more and more chemists enter the
newly emerging field of ruthenium
anticancer drugs. The continued
progress of ruthenium compounds in
clinical trials, and the frequent and
exciting reports of new ruthenium-
containing drug candidates in the
literature point towards a future where
medicinal chemists look beyond the
classical ‘biological’ elements of
carbon, hydrogen, nitrogen and
oxygen, and begin to consider the
potential of the less explored regions
of the periodic table to generate
powerful and effective drugs.
Simon Page is a PhD student in the Cancer
Research UK PhD Programme in Medicinal
Chemistry at the University of Cambridge
References
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