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Current Medicinal Chemistry, 2010, 17, 2729-2745 2729
0929-8673/10 $55.00+.00 © 2010 Bentham Science Publishers Ltd.
Organometallic Complexes: New Tools for Chemotherapy
N. Chavain*
,1
and C. Biot
#,2
1
Catholic University Leuven, Faculty of Pharmaceutical Sciences, Rega Institute, Laboratory of Medicinal Chemistry,
Minderbroedersstraat 10, 3000 Leuven, Belgium, natascha.chavain@rega.kuleuven.be
2
Université de Lille1, Unité de Catalyse et Chimie du Solide - UMR CNRS 8181, ENSCL, Bâtiment C7, B.P. 90108,
59652 Villeneuve d’Ascq Cedex, France
Abstract: The importance of organometallics can be noticed by their presence in all life organisms. The most known
natural organometallic molecule is vitamin B12, a porphyrin containing a cobalt atom, useful for several enzymatic trans-
formations. Based on the remarkable properties of this class of compounds, a new area of medicinal research was devel-
oped. Gérard Jaouen was the first to introduce the term of “bioorganometallic chemistry” in 1985 although the first or-
ganometallic therapeutical was Salvarsan®, discovered by Paul Ehrlich (Nobel Prize in Medicine in 1908). Bioor-
ganometallic chemistry consists of the synthesis and the study of organometallic complexes, complexes with at least one
metal-carbon bond, in a biological and medicinal interest. This field of research was accentuated by the discovery of the
ferrocene in 1951 by Pauson and Kealy, confirmed in 1952 by Wilkinson (Nobel Prize in 1973). Today, bioorganometallic
chemistry includes 5 main domains: (1) organometallic therapeuticals, (2) toxicology and environment, (3) molecular rec-
ognition in aqueous phases, (4) enzymes, proteins and peptides, (5) bioanalysis and pharmaceutical sensors. In this re-
view, we focused on organometallic therapeuticals. The exceptional properties of organometallics are first described and
then, an overview on the main organometallic complexes used for drug design is presented. This review gives an idea how
organometallics can be used for the rational design of new drugs.
Keywords: Bioorganometallic chemistry, chemotherapy, organometallic complexes, metallocenes.
INTRODUCTION
The first organometallic complexes developed by Paul
Ehrlich and used in experimental chemotherapy were Salvar-
san® and then neo-salvarsan, compounds with a direct As-C
bond. This chemistry was devoted to fight syphilis and
played a key role in the emergence of chemotherapy. Never-
theless, antibiotics (including penicillin) were preferred dur-
ing the Second World War. Between 1960 and 1970, the
discovery of cisplatin (an antitumor agent) by Rosenberg
gave again an impulse to metallodrugs as transition metals
and coordination chemistry. During this same time period,
new types of metal-carbon bonds were discovered, for ex-
ample those of metallocenes, metal carbonyls or metal car-
benes. Organometallic complexes were thought to be unsta-
ble in aqueous media and not adapted for a biological sys-
tem. In 1985 Gérard Jaouen defined the term of
« bioorganometallic chemistry » as the synthesis and study
of organometallic species of biological and medical interest.
Three previous reviews approched the bioorganometallic
chemistry field [1-3]. This review presents the different
therapeutical applications of bioorganometallic compounds.
ORGANOMETALLIC COMPLEXES
Organometallic complexes are metal complexes formed
between organic groups and metal atoms. They can be di-
vided into two general classes: (1) complexes containing
metal-carbon ! bonds and (2) "-bonded metal complexes of
*Address correspondence to this author at the Catholic University Leuven,
Faculty of Pharmaceutical Sciences, Rega Institute, Laboratory of Medicinal
Chemistry, Minderbroedersstraat 10, 3000 Leuven, Belgium; Tel: +32 16
337381; Fax: +32 16 337340;
E-mail: natascha.chavain@rega.kuleuven.be
#
Present address: Université de Lille 1, Unité de Glycobiologie Structurale
et Fonctionnelle, CNRS UMR 8576, IFR 147, 59650 Villeneuve d’Ascq
cedex, France.
unsaturated hydrocarbons. The main organometallic com-
plexes are shown in Fig. (1). Organometallic compounds
constitute a very large group of substances that have played a
major role in the development of chemistry. They are used to
a large extent as catalysts and since 1985, in medicinal
chemistry [4].
General Features
Organometallic complexes have similar properties to
those of metal complexes because they are a subgroup of the
metal complexes. The best known features of metal com-
plexes are (1) their variety of coordination numbers and
geometries, (2) their predictable ligand exchange reactions
and (3) all the characteristic properties of metals [5]. All
these features are very interesting for the design of new
pharmacophores that are not accessible by purely organic
synthesis. First, the higher coordination numbers of the tran-
sition metals, in comparison with carbon, give the opportu-
nity to obtain a high structural diversity of metallic com-
pounds [6]. Indeed, for example, an octahedral center with
six different substituents can form 30 stereoisomers com-
pared to only 2 for an asymmetric tetragonal carbon [7]. It
gives although more possibilities to organize the substituents
in the 3D space and so, to orient the ligands into the receptor
pockets. This high structural diversity is widely used by
Meggers in his work on ruthenium complexes as kinase in-
hibitors [8, 9]. Secondly, the possibility to predict the ligand
exchange reactions makes metal complexes good candidates
for combinatorial synthesis and high-throughput screening.
Finally, the metal complexes are interesting for their particu-
lar metal properties, such as adjustable ligand exchange ki-
netics, catalytic properties, redox activities, Lewis acidities,
easy access to radical species, magnetic properties, spectro-
scopic properties and radioactivity. These characteristic
properties of metals allow the generation of tailored func-
tions.
2730 Current Medicinal Chemistry, 2010 Vol. 17, No. 25 Chavain and Biot
Metallocenes
Metallocenes are a particular class of organometallic
complexes. A transition metal in its oxidation II state is asso-
ciated with two cyclopentadienyl anions, which models the
complex into a sandwich structure. Metallocene can adopt
the sandwich structure with a number of valence electrons
varying between 15 and 20. The more we go away from the
18 electrons structure, the less stable the metallocene gets.
This confers to metallocenes redox properties because they
can exist in different oxidation states. Cyclic voltametry is
often used to characterize the different redox states. For fer-
rocene, the one-electron oxidation or reduction is reversible
and takes place without structural variation. Ferricinium salts
formed by oxidation of ferrocene are stable but sensitive in
solution. Ferricinium salts are known to have antitumoral
activities. The oxidation state of the iron Fe
3+
might be re-
sponsible for the toxic effect [10, 11]. The redox properties
might also be used to label peptides or enzymes which be-
come then more electroactives [12].
Another important property is the water-octanol partition,
log P
oct
, used as an indicator of solute lipophilicity [13].
With a predicted value of 3.54, ferrocene is rather strongly
lipophilic [14]. It is more lipophilic than benzene and has a
log P
oct
value in the same order as aromatic compounds with
two rings, such as biphenyl and naphthalene
(Table 1). This
high lipophilicity property of ferrocene might increase the
bioavailability and also the membrane penetration of the
drug.
METALLOCENE PHARMACEUTICALS
Anticancer Titanocenes
Several examples show that titanium-based molecules
have significant potential against solid tumors. The first anti-
cancer titanocenes were designed from cisplatin, a platinum
based drug used to treat various types of cancers.
Cisplatin (Fig. (2)) was first synthesized by Peyronne in
1844 but the tumor suppressing properties of this inorganic
complex were discovered only more than 120 years later by
Rosenberg in 1969 [15, 16]. Cisplatin binds to DNA and
inhibits its replication. Because of the development of cellu-
lar resistance to platinum, the toxic side effects of cisplatin
(due to accumulation of platinum in the cells) and its limited
activity against certain cancers (in particular testicle cancer
[15]), the researchers tried to find new anticancer molecules.
Use of organometallic chemistry seemed to be a good alter-
native.
Transition from inorganic to organometallic chemistry
was fast and decisive. Towards the end of the 1970s, Köpf
and Köpf-Maier investigated the in vitro antitumor activity
of several early transition metal cyclopentadienyl complexes.
From these studies titanocene dichloride (Fig. (2)), which
has a similar structure to cisplatin, was the most potential
[17]. It was the first organometallic anticancer molecule. It
has medium antiproliferative activity in vitro but shows
promising results in vivo [18, 19]. Its mechanism of action is
actually unknown but the compound was found to bind more
M C N M
R
R
R
M
R R
R
RR
M C
O
cyanides alkyles aryles carbonyles
C C
R R
RR
M
C C RR
M
M C
R
R
C
C
C
R
R
R
R
R
M
M C R
alkenes alkynes
carbenes allyles
carbynes
C
C
C
C
R
R
R
R
R
R
M
RR
R
R
R
R R
R R
R R
dienes
cyclopentadienyles arenes
M
M
H
Fig. (1). Main organometallic complexes.
Table 1. Comparisons of Lipophilicity of Ferrocene with Other Compounds
Compound Log P
oct
Biphenyl 4.01
Ferrocene 3.54
Naphthalene 3.30
Benzene 2.13
Cyclopentadiene 1.89
Butanone 0.29
Dimethylformamide -1.01
Organometallic Complexes Current Medicinal Chemistry, 2010 Vol. 17, No. 25 2731
weakly to DNA bases [20]. One study shows that titanocene
dichloride is hydrolyzed in water and even loses the cy-
clopentadienyl rings under physiological conditions. The
organometallic species seems simply to act as a precursor to
Ti(IV) ions. The solvated Ti(IV) ion can bind then to the iron
transport protein transferrin (Tf) [21], that might serve as a
potential drug transport and delivery system [22]. In this way
the Ti(IV) ion (and potentially other metal-based drugs)
could be selectively delivered to cancer cells. Titanocene
dichloride entered clinical trials in 1993 and its industrial
development continued until phase II [23]. In these studies,
improvements over other therapies were not observed and
the trials were finally abandoned for more standard therapies.
These last years, the molecular structure of the class of ti-
tanocene dichloride compounds was changed to increase
their stability under physiological conditions. A novel ap-
proach to obtain new titanocene antitumoral drugs start from
fulvenes [24-35] and other precursors [34-38]. This strategy
gives a direct access to highly substituted titanocenes via
reductive dimerisation, carbolithiation or hydrodolithiation
of the fulvene followed by transmetallation in the last two
cases.
Ansa-titanocenes (Fig. (2)), which have a chelating cy-
clopentadienyl ligand system less prone to hydrolysis, have
been synthesized and evaluated for anticancer activity. They
were particularly active towards renal cell cancer line LLC-
PK [39] and exhibit in vitro anticancer activity at lower con-
centrations than titanocene dichloride.
Benzyl-substituted titanocenes were also developed to
avoid stereocenters. They showed also a better activity than
the precursor molecule against LLC-PK cancer cells.
Methoxyphenyl titanocene derivative (titanocene Y, Fig. (2))
was found as lead structure. The in vitro and ex vivo experi-
ments showed that prostate, cervix, and renal cell cancers are
prime targets for these novel classes of titanocenes [30, 40,
41]. These results were supported by mechanistic studies
investigating the effect of these titanocenes on apoptosis and
the apoptotic pathway in prostate cancer cells [42].
Titanocene C (Fig. (2)), a dimethylamino-functionalised
titanocene, exhibits also a better activity against the LLC-PK
cell line than titanocene dichloride (more than 360 times
more active) [43]. This might explain partly the failed Phase
II clinical trials against renal cell carcinoma of titanocene
dichloride. A series of titanocene C derivatives was designed
and synthesized to improve the cytotoxicity of titanocene C
by adding extra dimethylamino groups using the well-
established Mannich reaction [44-46].
Once passed through
the cell membrane, a mono- or dication might be formed by
hydrolysis of one or two of the chlorine groups, which could
be stabilized by coordination of the extra NMe
2
donor groups
to the titanium centre (Scheme 1) [47]. This probably finally
increases the number of titanocene-DNA interactions leading
to cell death at a lower concentration [48].
In order to overcome the instability problem, an oxali-
titanocene Y derivative was synthesized (Fig. (2)). In this
molecule, the two chlorine ligands were replaced by a chelat-
Pt
H
3
N
H
3
N
Cl
Cl
cisplatin
Ti
Cl
Cl
titanocene dichloride
Ti
Cl
Cl
X
X
Ti
Cl
Cl
O
CH
3
O
CH
3
ansa-titanocenes
titanocene Y
Ti
Cl
Cl
titanocene C
N
N
H
3
C
N
H
3
C
CH
3
H
CH
3
N
CH
3
H
3
C
H
Ti
O
CH
3
O
CH
3
O
O
O
O
oxali-titanocene Y
Fig. (2). Chemical structures of cisplatin and different titanocene derivatives.
Ti
Cl
Cl
R
R
NMe
2
H
NMe
2
H
-Cl
Ti
Cl
R
R
NMe
2
H
NMe
2
H
-Cl
Ti
R
R
NMe
2
H
NMe
2
H
2
Scheme 1. Coordination of the extra basic amine to the titanium centre.
2732 Current Medicinal Chemistry, 2010 Vol. 17, No. 25 Chavain and Biot
ing oxalate ligand. This concept was proven useful for plati-
num drugs [49]. It increases the stability, reduces side-effects
and extends the range of treatable tumors. Indeed, the chelat-
ing oxalate ligand is more stable towards hydrolysis than the
two chlorine ligands in the precursor molecule. However, the
water solubility of the complex is not reduced significantly
[50]. Initial in vitro screening of this new stable titanocene
derivative is very promising [51].
Anticancer Ferrocenes
As decribed before, ferrocene is not cytotoxic but its de-
rivatives, including ferricinium species, are cytotoxic. Fer-
rocene derivatives are able to produce reactive oxygen spe-
cies (ROS), which can damage DNA and other biomolecules
[52-54].
The mechanism of action of anticancer ferrocenes is
mainly based on this property.
The anticancer properties of ferrocenyl molecules first
gained attention in the 1970s [55-57] and growth with the
discovery of the antiproliferative properties of ferricinium
salts in 1984 [58, 59]. This effect is only observed at high
concentrations (10
-4
M) and ferrocene itself showedno effect.
From this observation, it was proposed that ferrocenyl com-
pounds could be oxidized in vivo, and both, ferricinium and
ferrocene, could be responsible for the cytotoxic effects [60].
As a result, ferrocene was incorporated into a large number
of molecules such as water soluble polymers [61-64], DNA
intercalator [65], phosphino compounds [66-69], and other
biomolecules [70-73].
Diferrocenyl compounds [74] and a
variety of other small ferrocenyl molecules [75-79] have also
been investigated for anticancer activity.
However, the most important class of ferrocene antican-
cer drugs is designed from estrogen targeting motifs, which
are selectively active against hormone dependent tumors
such as breast cancer. Estrogens are responsible for the
growth of certain tumors due to an interaction with the alpha
form of the estrogen receptor (ER!, implicated in 66% of
breast cancers). The growth can be inhibited by treatment
with antiestrogens, termed SERMs, such as tamoxifen (Fig.
(3)) [80, 81]. The real active form of tamoxifen is its metabo-
lite hydroxytamoxifen, which is administered as tamoxifen
for bioavailability reasons. The antiproliferative action of
hydroxytamoxifen is due to a competitive binding to the
ERs. The estradio-mediated DNA transcription is then re-
pressed in the tumoral tissues [82]. Unfortunately, the tumor
cells can change under the therapy and the expression of the
ER! can decrease so that tamoxifen is not effective any-
more. The discovery of alternative molecules seems to be
very important.
Ferrocene derivatives of tamoxifen, called ferrocifens
(Fig. (3)), were developed [83-86]. They show dual anti-
estrogenic and cytotoxic effects, while tamoxifen is only
antiestrogenic.
The "-phenyl ring of tamoxifen has been sub-
stituted by a ferrocenyl moiety, due to its aromatic character.
Such structural modifications lead to more lipophilic com-
pounds. The molecules can cross cell membranes more eas-
ily. Moreover, the ferrocenyl moiety gives a stronger cyto-
toxic effect because of its redox properties. The extended #-
system might also play an important role in the mode of ac-
tion of these complexes [87]. In order to confirm this obser-
vation, a series of ferrocifenyl analogues with hydroxyl- and
methoxy-benzene groups in different positions were pre-
pared. From this study, the cytotoxic effect was indeed corre-
lated to the ability of the compounds to transfer an electron
(Scheme 2), due to the conjugation of the ferrocenyl group
with the phenol [88]. Electrochemical experiments strongly
suggest that the toxic agent in the cell takes the form of an
oxidized quinone methide, the formation of which is facili-
tated by the redox properties of ferrocene.
The quinone me-
thide can undergo Michael addition of known intracellular
nucleophiles such as glutathione (GSH), leading to redox
imbalance and death of the cancer cell [89-91].
The studies
indicate that this mechanism seems not to work in healthy
tissue or reducing tissue at low concentration, suggesting
selectivity.
In order to further evaluate the proposed mechanism of
action, a series of ferrocifen analogues based on ruthenocene
were synthesized [92]. These compounds showed a very high
affinity to the estrogen receptor, ER!, but in contrast to the
ferrocifens, the ruthenium analogues behaved as antiestro-
gens with activity against the hormone-dependent human
breast adenocarcinoma MCF7 cells, but not against hor-
mone-independent cell lines [92]. Compared to the reversible
oxidation of the iron centre (FeII - FeIII) in the ferrocifens,
the ruthenocene analogues undergo an irreversible oxidation
(RuII - RuIII) which may be attributed to their differences in
biological action [88].
The use of organometallic steroids (derived from testos-
terone and dihydrotestosterone) [93] or non-steroidal antian-
drogens (derived from nilutamide, Fig. (4)) [94] to target
prostate cancer cells has given more mixed results. The de-
CH
3
O
N
CH
3
N
O
CH
3
H
3
C
HO
H
3
C
H
3
C
n
Fe
R
HO
HO
Fe
tamoxifen
ferrocifens ferrociphenols
Fig. (3). Chemical structures of tamoxifen, ferrocifens and ferrociphenols.
Organometallic Complexes Current Medicinal Chemistry, 2010 Vol. 17, No. 25 2733
rivative shown in Fig. (5) has an excellent IC
50
value against
AR- prostate cancer cells, but the depicted organic analogue
was shown to be as toxic. However, the addition of ferrocene
to the testosterone and dihydrotestosterone has produced
cytotoxic molecules with low IC
50
values. This strong anti-
proliferative effect is probably due to a structural effect
linked to the aromatic character of the ferrocene rather than
to its organometallic feature. In addition, it seems to be con-
nected to a cytotoxic effect rather than an antihormonal one.
These results open the way towards a new family of mole-
cules that are active against both hormone-dependent and
hormone-independent prostate cancer cells.
Ferrocenyl Antimalarials
In the mid-1990s, mainly inspired by the pioneering
works of Gérard Jaouen’s team [1, 2], a drug research pro-
gram was launched for discovering new antimalarial agents.
The bioorganometallic strategy was applied to several anti-
malarial drugs currently in use, which are chloroquine (CQ),
mepacrine (MQ), mefloquine (MF), quinine (QN) and artem-
isinine (ART) [95, 99]. Rapidly, a drug-candidate emerged
from a first screening of 50 ferrocenic compounds and ferro-
quine (FQ, SR97193, Fig. (5)) was selected. FQ results from
the incorporation of a ferrocene core in the lateral side chain
of CQ between the two amine atoms.
FQ is highly active against CQ-resistant P. falciparum
laboratory clones [100] and against P. falciparum isolated
from infected patients [101-106]. The in vitro and in vivo
activities of FQ were sufficient potent to meet candidate
nomination requirements.
As structural modifications of FQ were thought to im-
prove its antimalarial activity, a number of derivatives were
prepared and tested (Fig. (6)).
Secondary amines (Fig. (6), compounds (a)), possess in
vitro antimalarial activity comparable to that of FQ. Tertiary
amines, showed a strong antimalarial activity, especially
against the CQ-resistant Dd2 and W2 strains [107]. These
compounds were 2 to 10-fold more active than CQ, and as at
least active as FQ. All these compounds exhibited better in-
hibitory activity against the Dd2 strain than CQ itself [108].
So, it could be concluded that the in vitro antimalarial activ-
ity was not disturbed by slight modifications in the lateral
basic side chain.
CH
3
H
3
CO
HO
Fe
CH
3
H
3
CO
HO
Fe
- 1 e
-
CH
3
H
3
CO
O
Fe
- 1 H
CH
3
H
3
CO
O
Fe
- 1 e
-
- 1 H
CH
3
H
3
CO
O
Fe
Scheme 2. Prostulated mechanism of action of hydroxyferrociphens and ferrociphenols.
NC
F
3
C
N
NH
O
O
NC
CF
3
Fe
O
2
N
F
3
C
N
NH
O
O
CH
3
H
3
C
nilutamide
Fig. (4). Chemical structure of nilutamide and a ferrocenyl non-steroidal antiandrogen.
2734 Current Medicinal Chemistry, 2010 Vol. 17, No. 25 Chavain and Biot
FQ derivatives (Fig. (6), compounds (b)) closely mimick-
ing the antimalarial drug hydroxychloroquine (HCQ) have
been prepared [109]. Introduction of a hydroxyl group pro-
vided the expected reduction of cytotoxic effects compared
to FQ. These metallocenic compounds inhibited in vitro
growth of P. falciparum far better than CQ. The best results
were obtained when the amino sidechain R was an ethyl
group. The high potent antimalarial activity of this com-
pound was confirmed on Cambodian field isolates. This de-
rivative showed an activity similar to that of FQ. As ex-
pected, their IC
50
values were highly correlated (r
2
= 0.7129).
So, this derivative and FQ should have a similar mode of
action and/or uptake by the parasite. Moreover, this new
class of bioorganometallics exerts antiviral effects with some
selectivity towards SARS-CoV infection. These new drugs
(Fig. (6), compounds (c)) may offer an interesting alternative
for Asia where SARS originated and malaria has remained
endemic.
Hybrids of thiosemicarbazones (TSC) and FQ (Fig. (6),
compounds (c)) were also prepared [110]. These compounds
were supposed to combine the metal chelating properties of
TSC and the properties of FQ on CQ-resistant P. falciparum.
A covalent binding between both active fragments was real-
ized by merging the amino groups. In order to compare the
contribution of each fragment, analogues without the fer-
rocene core and analogues without the 4-aminoquinoline
moiety were also synthesized. Chimeras of TSC and FQ
were found to be the most active compounds against P. fal-
ciparum strains. Nevertheless, the corresponding purely or-
ganic derivatives showed comparable potency. Contrary to
previous results, introduction of the ferrocene moiety did not
increase antimalarial activity. Here again, no significant dif-
ference in the activity of ferrocenyl compounds was noted
between CQ-susceptible and CQ-resistant parasites.
Based on the prodrug concept, the FQ moiety was used
as a template for the design of new antimalarial ferrocenic
dual molecules (Fig. (6), compounds (d) and (e)) [111].
These bioorganometallics combine the core portions of two
structurally distinct moieties via an appropriate linker. As
side chain modification of FQ did not greatly affect its anti-
malarial activity, a FQ derivative was linked to a Glutathion
Reductase (GR) inhibitor (Fig. (6), compounds (d)) or GSH
depletor (Fig. (6), compounds (e)), previously demonstrated
to lower the GR activity or the GSH content in the cells, re-
NCl
HN
N
CH
3
CH
3
CH
3
chloroquine
NCl
HN
Fe
N
CH
3
CH
3
ferroquine
Fig. (5). Chemical structures of chloroquine and ferroquine.
Fe
NCl
HN
N
R
1
R
2
Fe
NCl
HN
N
R
OH
N
H
S
N
H
N CH
3
X
Y
Fe
NCl
HN
X
H
3
C
N
R
O
O
O
N
R
O
Y
Fe
NCl
HN
Fe
NCl
HN
(a)
(b)
(c)
(d)
(e)
Fig. (6). Chemical structures of second generation of ferrocene chloroquine conjugates.
Organometallic Complexes Current Medicinal Chemistry, 2010 Vol. 17, No. 25 2735
spectively. The results showed no enhancement of the anti-
malarial activity of the dual molecules but evidence a unique
mode of action of ferroquine and ferrocenyl analogues, dis-
tinct of those of chloroquine and non ferrocenic 4-
aminoquinoline analogues.
The bioorganometallic modification has been applied to
several classes of known antimalarials (arylaminoalcools,
artemisinin derivatives, naphthoquinones) and to other sub-
stances (such as sugars) without significant gain in activity.
For a full review about antimalarial metallocenes, see the
review published in Current Medicinal Chemistry – Anti-
Infective Agents in 2004.
More recently, ferrocene ciprofloxacin conjugates were
obtained by a double strategy: esterification of ciprofloxacin
(prodrug approach) and insertion of a ferrocene core in the
molecule (Fig. (7)) [112]. New achiral compounds (Fig. (7))
were found to be 10- to 100-fold more active than ciproflox-
acin against P. falciparum CQ-susceptible and CQ-resistant
strains. These derivatives killed parasites more rapidly than
ciprofloxacin did. Nevertheless, it was found that the esteri-
fication provided the main progress in antimalarial activity,
when the presence of the ferrocene enabled a complementary
effect.
Ferrocenyl Antibacterials
Due to the increased and fast development of resistance
to antibiotics, it seemed necessary to find new classes of
drugs with new mechanisms of action. Bioorganometallic
chemistry also found its place in this domain. Several fer-
rocenyl antibacterials and antimicrobials were designed and
synthesized. Some examples are described above.
Unsymmetrical 1,1’-disubstituted ferrocenes with antimi-
crobial properties were synthesized by condensation reac-
tions of 1,1’-diacetylferrocene with different heteroaromatic
amines, tetrazoles and tirazoles [113]. The biological proper-
ties of these antimicrobial compounds were evaluated and it
was shown that these molecules chelate with Co(II), Cu(II),
Ni(II) and Zn(II) metal ions. A screening of these ferrocenyl
amines against pathogenic bacterial strains has been done.
Unfortunately, they showed only moderate activity as anti-
bacterials in vitro.
Since many heterocyclic compounds exhibit different
biological activities, ferrocenyl heterocycles should be of a
particular interest for the discovery of new drugs. The pyra-
zole motif makes up the core structure of numerous biologi-
cally active compounds. Some pyrazole derivatives have
affinity for the human CFR-1 receptor [114] and exhibit
among other antibacterial activity [115-119].
Recently, the condensation of a ferrocenyl pyrazole de-
rivative with different amines lead to new ferrocenyl imines
and amines (after sodium borohydride reduction) (Scheme 3)
[120-123]. The synthesized compounds have been tested for
their in vitro antimicrobial activity against 11 bacteria and 3
fungal/yeast strains. They have shown a wide range of activi-
ties, from completely inactive to highly active compounds
[123].
Such a nonselective and strong activity promises a
possible use in the combat against antibiotic-resistant strains
of microorganisms as demonstrated for FQ against CQ-
resistant strains.
The unique properties of ferrocene were also used to
modify the pharmacodynamic profile of antimicrobial pep-
tides and to reinforce their biological specificity. Indeed,
antimicrobial peptides are presents in all living beings. They
are almost cationic and bind to the negatively charged mem-
brane of bacterial cells and thus, modify the membrane prop-
erties (increase of permeability, leak of metabolites and fi-
nally cell death). Because of the sensitivity towards proteoly-
sis and very expensive production of the natural antimicro-
bial peptides, organometallic functions were associated to
shorten synthetic peptide sequences using biphasic synthesis
(Fig. (8)) [124, 125]. As the mechanism governing the bio-
N
O
N
HN
COOHF
ciprofloxacin
N
O
OEt
O
F
N
N
Fe
N
O
OEt
O
F
Fe
N
HN
Fig. (7). Chemical structures of ciprofloxacin and ferrocenyl derivatives.
Fe
N
N
CHO
H
2
NR
Fe
N
N
N
R
Fe
N
N
H
N
R
NaBH
4
Scheme 3. Synthesis of ferrocenyl imines and amines.
2736 Current Medicinal Chemistry, 2010 Vol. 17, No. 25 Chavain and Biot
logical specificity of these organometallic peptides is still
unknown, it was nevertheless observed that this mechanism
depends on the the N-terminal amino acid of the peptide,
where the metallic complex is added. According to the na-
ture of this acid, the peptide becomes selective to either
Gram (-) or Gram (+) bacteria [125]. Indeed, ferrocenyl pep-
tide (1) (Fig. (8)) shows a very good activity against Gram
(+) Straphylococcus aureus (CI
50
= 7.1 !M) while ferrocenyl
peptide (2) (Fig. (8)) is very active towards Gram (-) Es-
cherichia coli (CI
50
= 16 !M).
Dopaminergic Receptors Ligands
The action of dopamine, one of the main neurotransmit-
ters, is due to its connection to its post-synaptic receptor.
Today, seven types of dopaminergic receptors are counted.
Because of the large structural variety of heteroarenes, spe-
cific ligands of the dopaminergic receptor D3 [126, 127] and
selective modulators of the dopaminergic receptor D4 were
developed [128, 129]. New ferrocenyl carboxamides have
shown a good affinity for these receptors and also, for sero-
toninergic receptors from the central nervous system. These
metallocenes were described as “fancy bioisosteres” (Fig.
(9)) [130]. The bioisosteric replacement, an effective strategy
commonly used for drug discovery, allows improving the
pharmacodynamic properties and the pharmacokinetics of
active molecules [131]. The steric hinderance of the fer-
rocenyl derivatives seems to have no influence on the bind-
ing of the carboxamides to the protein G-coupled receptors.
These bioisosteres seem to be interesting to treat neuropa-
thologicals as schizophrenia, L-dopa dyskinesia, attention
deficit, hyperactivity disorder, psychostimulants abuses and
sexual dysfunctions.
HALF-SANDWICH COMPOUNDS
As written above, development of cellular resistance to
platinum, toxic side effects of cisplatin and limited activity
to certain cancers led the researchers to new anticancer
molecules. The success of KP1019 and NAMI-A (Fig. (10)),
two coordination complexes based on ruthenium, guided the
investigators to consider ruthenium-based half-sandwiches
for the design of new anticancer drugs [132, 133]. These two
molecules are actually in clinical phase I trials [134]. NAMI-
A was retained for its antimetastatic activity and its low tox-
icity in vivo [135, 136].
Compared to platinum-based drugs,
ruthenium drugs are generally less toxic. Moreover, they are
active in tumors which platinum drugs can not treat.
N
NH
Ru
N
HN
Cl
Cl
Cl
Cl
N
HN
H
KP1019
NH
N
Ru
DMSO
Cl
Cl
Cl
Cl
NAMI-A
Fig. (10). Chemical structures of KP1019 and NAMI-A.
Fe
H
N
O
N
H
O
H
N
O
N
H
O
O
H
N
O
NH
2
NH
HN
NH
2
NH
HN
NH
2
N
H
N
H
N
H
Fe
H
N
O
N
H
O
H
N
O
N
H
O
O
H
N
O
NH
2
HN
HN
NH
NH
2
HN
NH
NH
2
HN
NH
NH
2
HN
ferrocenyl peptide 1
ferrocenyl peptide 2
Fig. (8). Chemical structure of two antibacterial ferrocenyl peptides.
M
H
N
O
R
1
R
2
1: M = Fe, R
1
= OCH
3
, R
2
= H
2: M = Fe, R
1
= Cl, R
2
= Cl
HO
OH
NH
2
dopamine
Fig. (9). Chemical structures of dopamine and ferrocenyl dopaminergic receptors ligands.
Organometallic Complexes Current Medicinal Chemistry, 2010 Vol. 17, No. 25 2737
The most widely studied organoruthenium compounds
are the piano-stool complexes (ruthenium-arene and ruthe-
nium-cyclopentadienyl half-sandwich compounds). This
class of compounds was discovered following the coordina-
tion of a Ru(II)-benzene dichloride complex to metronida-
zole, a well known anticancer agent (Fig. (11)). The or-
ganometallic compound was found to be more active than
the organic parent [137].
Ru
Cl
Cl
N
N
OH
NO
2
Fig. (11). Chemical structure of the ruthenium-benzene-
metronidazole complex.
Water-soluble Ru(II)-arene-PTA complexes (RAPTA)
were also designed and synthesized. The PTA ligand (1,3,5-
triaza-7-phosphoadamantane) is amphiphilic and permits
both a good oral administration of the drug and its ability to
cross cell membranes and hence enter cancer cells. Most of
the RAPTA compounds, like NAMI-A, are only weakly ac-
tive or inactive in vitro but show a remarkable selective ef-
fects on metastasis in vivo. In order to improve their activity,
a variety of functional groups have been attached to the
arene ring of the RAPTA compounds (Fig. (12)) [138]. The
chloro ligands have also been replaced by chelating dicar-
boxylato and other ligands to improve the uptake of the
compounds into the tumor [139, 140].
Other Ru(II)-arene compounds with monodentate ligands
(like dmso or ethylenediamine) or imidazole have also been
studied (Fig. (13)) [141]. Like NAMI-A and RAPTA com-
pounds, they may be selective towards metastasis but this
hypothesis has to be confirmed. These compounds seem to
target DNA in the same way as cisplatin but the monofunc-
tional adducts are formed preferentially with guanine.
Ru(II) and Os(II) complexes were also bound to carbo-
hydrate moieties [142, 143]. These new complexes exploit
the biochemical and metabolic functions used for sugars in
living organisms for transport and accumulation. Carbohy-
drates are able to coordinate metal centers because they pos-
sess a manifold of donors. Moreover, they have some addi-
tional advantages over other ligands: biocompatibility, non-
toxicity, enantiomeric purity, water solubility, and well-
explored chemistry. The sugar-linked Ru(II) and Os(II)
complexes (Fig. (14)) show good anticancer activity, affinity
towards albumin and transferrin and form a monoadduct
with 9-ethylguanine. The complexes are shown to undergo
aquation of the first halido ligand in aqueous solution, fol-
lowed by hydrolysis of a P-O bond of the phosphite ligand,
and finally formation of dinuclear species.
As for ferrocene, the redox activity of Ru(II) arene com-
plexes with diamine ligands was explored for their use in
anticancer therapy. These compounds show good activity
towards cancer cells including a lack of cross-resistance with
adriamycin [144]. A loss of cytotoxic activity was observed
upon oxidation of the amine ligand to an imine.
As for all classes of pharmaceuticals, multidrug resis-
tance to anticancer molecules appeared. One of the key pro-
teins involved in multidrug resistance is P-glycoprotein
(Pgp). A large number of Pgp inhibitors are known and
modification of phenoxazine with imidazole ligands results
into highly active compounds [145]. These compounds can
be accumulated rapidly in the cell nucleus what leads to cell
death via DNA synthesis inhibition. Another important en-
zyme responsible for multidrug resistance is glutathione S-
transferase (GST). This enzyme catalyses a Michael addition
reaction of GSH with any toxin in the cell. Ethacrynic acid is
Ru
Cl
Cl
P
Ar
N
N
N
RAPTA
N
N
H
2
P N
N
N
RAPTA-NH
2
Cl
Ru
O
P N
N
N
oxaliRAPTA-C
OO
O
Fig. (12). Chemical structures of RAPTA and some derivatives.
Ru
Cl
Cl
DMSO
Ru-cymene-dmso
Ru
Cl
Cl
N
Ru-cymene-imidazole
N
R
Ru
Cl
H
2
N
NH
2
Ru-arene-en
Ar
Fig. (13). Chemical structures of Ru(II)-arene complexes.
2738 Current Medicinal Chemistry, 2010 Vol. 17, No. 25 Chavain and Biot
the most effective GST inhibitor. It has been used in combi-
nation with ciplatin. Due to different accumulation rates of
these two molecules, the two entities were combined in a
single molecule (Fig. (15)) [146]. These molecules exhibit
significant cytotoxic activity comparable or superior to cis-
platin or other ruthenium agents.
Other organometallics have been prepared in which the
metal acts more as a scaffold and probably does not actively
participate in the activity. A series of ruthenocenyl
staurosporine derivatives have been designed and synthe-
sized (Fig. (16)).
Ru
N
OC
N
N
H
O
O
HO
N
N
N
H
O
O
CH
3
O
NH
CH
3
H
3
C
Fig. (16). Chemical structures of staurosporine and its ruthenocenyl
derivative.
Staurosporine is a protein kinase Pim-1 inhibitor which
prevents the binding of ATP to the kinase. Pim-1 is an
overexpressed protein kinase in prostate cancer cells and the
treatment works by blocking its hormone-independent acti-
vation of the androgen receptor [147]. Because of the com-
plex three-dimensional structure of protein kinase inhibitors,
their synthesis is often difficult. The use of organometallic
ruthenium moieties can give the desired specific spatial con-
formation to the molecule. The indolocarbazole alkaloid
scaffold was replaced by metal complexes (Fig. (16)). These
analogues show a good affinity in the nanomolar range,
twice as active as the organic inhibitors [148-150].
Fig. (17)
shows one of these compounds bound to the ATP-binding
site of the protein kinase Pim-1 [151].
Following this strategy, ATP ruthenium-based inhibitors
for different protein kinases were discovered, either by com-
binatorial chemistry or by rational design [152]. Paullones
constitute another class of kinase inhibitors, which inhibit
cyclin-dependent kinase (CDK) and glycogen synthase
kinase-3 (GSK-3). Because of their low water solubility,
their use is limited. Ruthenium and osmium arene derivatives
have been prepared (Fig. (18)). They seem to have ideal
pharmacological properties and show high activity in vitro
[153].
The complex EA1 and derivatives have also been demon-
strated to display promising anticancer activities in several
cancer cell lines and in a melanoma spheroid model [154].
This complex inhibits the GSK-3! enzyme. Further investi-
gations are in progress to study their potential efficacy in an
animal model.
Metallacyclic analogues with potent in vitro anticancer
activity were also reported [155]. The most active arene
complex of this series (Fig. (19)) was found to be as active as
cisplatin in most of the tested cell lines. These molecules
were able to interfere with many parts of the regulatory
pathways that control the cell growth cycle. This new class is
promising in the treatment of tumors which are generally
difficult to treat by common chemotherapy.
Recent work on Os(II) and Ru(II) compounds of the type
[(arene)Os(YZ)X] has shown that their aqueous reactivity,
stability and cancer cell cytotoxicity are highly dependent on
the nature of the chelating ligand YZ [156, 157]. A series of
this type of compounds was synthesized. X-ray crystal struc-
tures show typical “piano-stool” geometry with intermolecu-
lar "-" stacking. Some complexes are as active as cisplatin
and even overcome cisplatin resistance.
M
Y
P
X
X
O
O
O
O
O
O
R
R = C(CH
3
)
2
; C
6
H
10
; C
2
Cl
3
M = Ru; Os
X = Cl, C
2
O
4
Y = CH
3
C(CH
3
)
2
; C
2
H
5
OH; OC
2
H
5
OH;
CH
2
NH
3
Cl; CH
2
NHCOC
14
H
9
; C
2
H
5
NHCOC
14
H
9
Fig. (14). Chemical structures of sugar-linked Ru(II) and Os(II) complexes.
Ru
N
N
Cl
Cl
Ru
N
N
Cl
Cl
N
H
O
OCl
Cl
O
Fig. (15). Chemical structures of the phenoxazine analogue and the ethacrynic acid derivative.
Organometallic Complexes Current Medicinal Chemistry, 2010 Vol. 17, No. 25 2739
Fig. (17). Crystal structure of Pim-1 with the ruthenocenyl staurosporine derivative in the ATP binding site.
Ru
N
Cl
N
HO
H
3
C
HO
N
HN
Br
Fig. (18). Chemical structure of the Ru-cymene-paullone complex.
Ru
Me
2
N
PhMe
2
P
Fig. (19). Chemical structure of ruthenacycle.
The attachment of maltol as ligand to Ru(II)-arene moie-
ties gave compounds which are not active in vitro. However,
switching from maltol or other pyrones to pyridinone and
thiopyrone ligands resulted in mono- and dinuclear com-
pounds with high in vitro anticancer activity (Fig. (20))
[158]. These results show another example of the importance
of the ligand in anticancer ruthenium-based molecules.
PRECIOUS METAL DRUGS
Gold Complexes
Gold complexes have been evaluated for many different
pharmaceutical purposes, especially cancer and arthritis.
Auranofin is the most prominent example of a gold drug and
is in widespread clinical use as an antiarthritic compound.
Several gold(III) and organogold(III) compounds were iden-
tified as potential antitumor agents. They shown a significant
structural variety and very encouraging in vitro pharmacol-
ogical properties [159].
M
Y
R
1
O
N
O
N
O
O
M
Y
R
1
Ru
Y
R
1
O
O
X
R
R
n
R = H, CH
3
, C
2
H
5
X = O, S
M = Ru, Os
Y = Cl, Br, I, H
2
O, 5'-GMP, amino acids
n = 2, 3, 4, 6, 8, 12, 14
Fig. (20). Chemical structures of Ru-arene- pyridinone and thiopy-
rone complexes.
2740 Current Medicinal Chemistry, 2010 Vol. 17, No. 25 Chavain and Biot
The interest in antitumor metallodrugs started with the
discovery of the anticancer properties of cisplatin in the
1960s [160]. The main idea was to find other metal-based
compounds with important antitumor effects but with lower
systemic toxicity [161, 162].
Because of its isoelectronic and
isostructural with Pt(II) complexes, Au(III) seems to be an
excellent metal candidate. The problem was that the gold
analogues were less stable (kinetically more labile, light sen-
sitive, reducible to metallic gold) than the corresponding
platinum compounds [159]. Moreover an important systemic
toxicity of these gold compounds was found. Au(III) was
abandoned until the 1990s, when new gold complexes exhib-
iting improved stability, lower toxicity and favorable in vitro
pharmacological properties were found [163]. A series of 2-
[(dimethylamino)methyl]phenyl) (DAMP) organogold(III)
compounds was developed and showed encouraging results
in vitro and moderate activity in vivo [164, 165].
N N
Au
HO
CH
3
CH
3
PF
6
-
Fig. (21). Chemical structure of [Au(bipyc-H)(OH)][PF6].
To improve the stability of the Au(III) center, polyden-
tate ligands (polyamines, cyclam, terpyridine, phenathroline,
bipyridine) were employed in a variety of gold(III) com-
plexes [166-169]. The nitrogen atoms seem to produce a
strong stabilization of the Au(III) center and a decrease in
the reduction potential and opened the way for pharmacol-
ogical testing. These gold compounds revealed a high cyto-
toxicity and were found to overcome resistance to cisplatin
[170]. The compound shown in Fig. (21) was found to be the
most active with a twofold higher activity than cisplatin in
the A2780/R cell line (resistant to cisplatin). This suggests
that the biochemical mechanisms of resistance to cisplatin –
most likely a more efficient intracellular detoxification and
an increased repair of DNA domage – are only modestly
effective toward these gold complexes.
Silver Complexes
For many years silver compounds have been used as an-
timicrobials, and more recently, they have found applications
as antiseptics [171]. All the silver compounds evaluated ap-
pear to have the same mode of action. Ag
+
ions are released
and enter cell membranes and disrupt their function. It seems
to be important that the silver complexes can release Ag
+
ions and in that way, very strongly coordinating ligands are
avoided. One problem lies in the fact that existing drugs, like
sulfadiazine, lose their activity because of the rapid release
of the Ag
+
ions. To solve this problem, an organometallic
approach was employed using silver N-heterocyclic carbene
compounds (Fig. (22)).
In the polymeric molecule, it was shown that the carbene
ligands slow down the release of Ag
+
ions. As a result a
much lower silver content was required for the effective in-
hibition of the growth of clinically relevant bacteria such as
E. coli, S. aureus and P. aeruginosa.
The dinuclear cage compound, encapsulated into an elec-
trospun polymer, was shown to be an extremely effective
antimicrobial against E. coli, S. aureus and P. aeruginosa but
also against resistant organisms including B. dolosa, organ-
isms with no effective therapy option currently available. It
destroys completely the bacteria (even after several additions
of organisms). Furthermore, antifungicidal activity was ob-
served against A. niger and S. cervisiae. The compound was
found to be non-toxic in rats.
N
N
N
N
O
O
Ag O
O
a
N
N N
N N
Ag
OH HO
n
n
m
(OH-m)m
b
N N
N
Ag
N
HO OH
Ag
N
N
N
N
HO
OH
c
Fig. (22). Mononuclear (a), dinuclear (b) and polymeric (c) silver
antimicrobial agents.
CONCLUSION
The reported examples in this review illustrate the grow-
ing importance of the bioorganometallic chemistry in phar-
macology, especially in case of drug resistance. New solu-
tions appear now for the treatment of cancer and viral, bacte-
rial and parasitic infections. While the mechanism of action
of these organometallic complexes was poorly understood,
significant insights have been proposed by combining bio-
physical and biochemical approaches. In the future, or-
ganometallic drugs should afford new tools for medicinal
chemistry.
Organometallic Complexes Current Medicinal Chemistry, 2010 Vol. 17, No. 25 2741
ACKWOLEDGEMENTS
CB is grateful to Dr. JM Kwasigroch for his assistance
with the PyMol software. Dr. Mathy Froeyen is acknowl-
edged for proofreading the manuscript.
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Received: March 14, 2010 Revised: June 19, 2010 Accepted: June 21, 2010
