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Application of ferrocene and its derivatives in cancer researchw

Cátia Ornelas*
Received (in Montpellier, France) 27th February 2011, Accepted 10th May 2011
DOI: 10.1039/c1nj20172g

The use of ferrocene-based compounds for medicinal applications is an active research area.
Many reports have demonstrated that some ferrocenyl derivatives are highly active against several
diseases, including cancer. This review focuses on the most relevant examples of ferrocene-based
molecules that show anticancer activity.

1. Introduction strategies leading to ferrocene derivatives, and explored their

applications in a wide range of scientific areas.8 Due to
Ferrocene was discovered in 1951,1,2 but its correct structure the favorable electronic properties of ferrocene and its easy
was only elucidated soon afterward independently by Wilkinson functionalization, these compounds have found many applica-
et al. and Fischer and Pfab.3,4 The resemblance of its reactivity tions in materials science including sensors,9–18 catalysts,16,19–24
to that of benzene inspired Woodward et al. to coin the new electroactive materials25–30 and aerospace materials.31,32
iron compound with the name ferrocene.5 The elucidation of The stability of ferrocene in aqueous and aerobic media, the
the structure of ferrocene was a landmark discovery in the history accessibility of a large variety of derivatives, and its favorable
of chemistry, and led to the birth of modern organometallic electrochemical properties have made ferrocenyl compounds
chemistry. The terms ‘‘sandwich compound’’ and ‘‘metallocene’’ very popular molecules for biological applications.33–39
are applied today, not only to ferrocene and its derivatives, but to The use of ferrocene in medicinal applications is an active
a much wider range of compounds that include other metals.6 research area. Many reports have shown that some ferro-
Ferrocene quickly attracted the attention of the scientific and cene derivatives are highly active in vitro and in vivo, against
technical community on account of its fascinating chemistry.6,7 several diseases including fungal and bacterial infections,40,41
Chemists wasted no time and started to develop synthetic malaria,37,42–44 human immunodeficiency virus (HIV),45 and
cancer.33–39
The anticancer potential of ferrocene derivatives was first
College of Chemistry, University of California Berkeley, California, studied in the late 1970s, when Brynes and co-workers reported
94720-1460, USA. E-mail: catiaornelas@berkeley.edu;
Fax: +1 510-643-3079 the antitumor activity of ferrocenyl compounds bearing amine
w This article is dedicated to Professor Didier Astruc, a special mentor or amide groups against lymphocytic leukemia P-388.46 The
and friend, on the occasion of his 65th birthday. compounds were administered to mice intraperitoneally with
either water or water-Tween 80 (surfactant). The antitumor
activity of these compounds was low but significant enough to
Dr Cátia Ornelas received her show that the incorporation of the ferrocenyl group into an
MS degree in chemistry from appropriate carrier could provide an agent with enhanced anti-
the University of Madeira, tumor activity (Fig. 1).46
Portugal, working with Professor Since then, several types of ferrocenyl compounds have been
João Rodrigues. For her PhD
synthesized and evaluated in terms of anticancer properties.
studies, she moved to the Univer-
sity of Bordeaux (France) to The following sections of this review describe the most relevant
work with Professor Didier examples of ferrocene-based compounds that have shown
Astruc on dendrimer chemistry.
From 2008 until the summer of
2010, she was a postdoctoral
fellow in the group of Professor
Marcus Weck at New York
University. Presently, she
Cátia Ornelas works as a postdoctoral fellow
with Professor Jean M. J.
Fre´chet at the University of California at Berkeley. Her interests
are in supramolecular chemistry, catalysis, and dendrimers for Fig. 1 Chemical structures of ferrocene (1); and a ferrocenyl compound
nanomedicine. bearing amide groups (2), tested against lymphocytic leukemia P-388.46

This journal is c The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2011 New J. Chem., 2011, 35, 1973–1985 1973

anticancer activity, which include: (i) ferricenium salts; (ii) ferro-
cene conjugated to biologically active molecules; (iii) DNA
targeting moieties linked to ferrocene; (iv) ferrocenyl derivatives
of selective estrogen modulators; (v) ferrocenyl androgens and
anti-androgens; and (vi) ferrocenyl compounds coordinated to
other metals. Section 8 describes some examples where active
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ferrocenyl compounds were conjugated to drug delivery systems,
and the final section discusses the prospects and future of the field.
2. Ferricenium salts against Ehrlich ascites tumor
and Rauscher leukemia virus
In 1984, Köpf-Maier, Köpf, and Neuse disclosed the anti-
tumor activity of ferricenium salts.47 This group used mice
bearing Ehrlich ascites tumor (EAT) to test ferrocene and
some ferricenium salts bearing different counter anions. Due
to the low solubility of ferrocene in water, it was injected in
mice using propylene glycol, and it was observed that the
neutral ferrocene complex lacked anti-tumor efficacy against
EAT. On the other hand, the ferricenium salts are highly soluble
in water, and could be directly injected in mice using saline
media. Ferricenium chloroferrates such as [Cp2Fe]+[FeCl4]
(3a) caused survival of up to 83% of the animals after treatment
with optimum doses, leading to increases in life-span of 380%,
when compared with the untreated controls (Fig. 2).47
In vivo tests by Popova and co-workers showed that ferri-
cenium tri-iodide (3b) was effective against Rauscher leukemia
virus (RLV), while [Cp2Fe]+[FeCl4] (3a) did not show any
significant activity against this disease (Fig. 2).48
These results suggest that the anticancer activity of the
ferricenium salts strongly depends on the counter anion and
the type of cancer.
Soon thereafter, Neuse and Kanzawa proposed that ferrocenyl
compounds could be oxidized in the cell via normal metabolic
processes, so that both ferricenium and ferrocene derivatives
could yield an anti-proliferative effect.49,50 Further studies
suggested that the mechanism of action of the ferricenium
salts was orchestrated by generation of radicals through the
Fenton pathway that causes DNA damage and consequent
apoptosis of cells.36,51–53
3. Ferrocene conjugated to biologically active
molecules as promising anti-cancer agents
3.1. Ferrocenylalkylazoles with high activity against solid
tumors
Azoles including imidazole, pyrazole and adenine, which
are the central ingredients in many drugs, have been chosen
by Snegur et al. as the objects for chemical modification
Fig. 2 Molecular structure of ferricenium salts 3a47 and 3b48 which
are active against EAT and RLV respectively.
1974 New J. Chem., 2011, 35, 1973–1985 This journal is
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Fig. 3 Two examples of a series of ferrocenylalkylazoles, which are
active against solid tumors.55
by ferrocene.48,54–56 A series of ferrocenylalkyl azoles (Fig. 3)
was synthesized and their tumor growth inhibition and toxicity
was studied in vivo. These ferrocenyl compounds were tolerated
well by animals, showing lower toxicity when compared to
ferrocene and clinically used drugs. Any noticeable visual
alteration of the mice appearance, neither in the condition of
its internal organs were observed.48,54,55 The best results were
obtained with compound 4 (Fig. 3) when tested against solid
tumors, which presented up to 100% of tumor growth inhibition,
and then achieved 45% regression. The success of compound 4
was attributed to: (1) the hydrophilic benzotriazolyl group
provides transport in aqueous media and the lipophilic ferrocenyl
moiety ensures membrane permeability; (2) the ferrocenyl
group is capable of forming ionic bonds (after oxidation to the
ferricenium form), and the azolyl group can form hydrogen
bonds with phosphate groups at cleavage points of DNA;
(3) the planar heterocyclic ring and bulky ferrocenyl group can
intercalate between the planes of DNA nucleic bases; (4) the
swinging alkyl bridge allows for the formation of the ligand–
receptor complexes.55
3.2. Ferrocene conjugated to peptides for lung cancer
Kenny’s group synthesized a series of ferrocenyl compounds
that possess three key components: (i) a ferrocene moiety, (ii) a
conjugated linker that lowers the oxidation potential of the
ferrocenyl group, and (iii) a peptide derivative that can interact
with biomolecules via secondary interactions such as hydrogen
bonding.57–60 All the ferrocenyl-peptide derivatives were tested
in vitro against the human lung carcinoma cell line H1299, and
most of them showed IC50 values below 10 mM (IC50
value indicates the mean compound concentration required to
achieve 50% growth inhibition). In particular, N-(6-ferrocenyl-2-
naphthoyl)-g-aminobutyric acid ethyl ester (compound 6, Fig. 4)
had an IC50 value of 0.62 mM, and is more active in vitro than the
clinical employed anti-cancer drug cisplatin.57–60
3.3. Ferrocenylalkyl nucleobases against carcinoma 755
A few research groups have been trying to combine the
potential antitumor properties of some nucleosides and nucleo-
bases with the properties of ferrocene by attaching them
covalently.61–63 Simenel et al. prepared ferrocenyl derivatives
of thymine, adenine, cytosine and iodo-cytosine.62 The anti-
tumor activity of 1-N-ferrocenylmethyl thymine (compound 7,
Fig. 5) was studied in vivo against some animal tumor systems
such as carcinoma 755 (Ca755), melanoma B16 (B16) and
Lewis lung carcinoma (LLC). Compound 7 showed a signifi-
cant antitumor effect against Ca755 with 70% tumor growth
inhibition in comparison with the control. Furthermore, this
group suggested a synergistic effect of antitumor activity against
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Fig. 4 Structure of N-(6-ferrocenyl-2-naphthoyl)-g-aminobutyric
acid ethyl ester compound 6, which showed in vitro activity against the
human lung carcinoma cell line H1299.60
Fig. 5 Structure of 1N-ferrocenylmethyl thymine (7) that showed
70% tumor growth inhibition on Ca755.62
Ca755, by combining 1-N-ferrocenylmethyl thymine 7 with the
well-known antitumor drug cyclophosphamide.62
3.4. Ferrocenyl derivative of illudin M
Illudin M is a fungal cytotoxin that belongs to a family of
sesquiterpenes, produced by some mushrooms.64 Although the
illudins are highly active against various tumors, their extreme
toxicity has prevented clinical applications.64 Some semisynthetic
illudin derivatives with reduced toxicity are currently in phase II
clinical trials for a number of cancers including prostate, ovarian,
pancreatic, renal, breast and lung.65,66
With the intention to enlarge the therapeutic index and the
cell line specificity of Illudin M (compound 8, Fig. 6), new
esters with 1,1 0 -ferrocenedioic acid and ferrocenoic acid were
prepared by Schobert and co-workers.67 Bis(illudinyl M) 1,10 -ferro-
cenedioate (compound 9, Fig. 6) was by far the less toxic to
nonmalignant fibroblasts, while more cancer selective and more
cell line-specific than the parent Illudin M. This improvement
partially originated from the ferrocene shielding the enone
group against attack of glutathione. TUNEL assays that allow
the detection of late stages of apoptosis indicated that the
ferrocenyl diester 9 induces apoptosis in cancer cells in a similar
pathway than Illudin M.67
Fig. 6 Molecular structures of illudin M (8), and its ferrocenyl
derivative (9).67
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Fig. 7 Retinoyl derivative of ferrocene.70
3.5. Ferrocenyl derivatives of retinoids
Retinoids include active metabolites of vitamin A (retinol) and
play an important role in vertebrate growth and development,
supporting cell differentiation, embryonic development, immune
response, and reproduction.68 Some trans-retinoic acids are
currently used for treatment of dermatological disorders and
as chemotherapeutic agents against various endothelial cancers,
breast cancer, and endometrial cancer. Their actions are mediated
through binding and activation of the retinoic acid receptors
(RARs) or retinoid X receptors (RXRs), which function as
ligand-dependent transcription factors.69
As an attempt to improve the anti-cancer activity of retinoids,
some ferrocenyl derivatives (compound 10, Fig. 7) were prepared,
and their antiproliferative activity toward human lung cancer cell
line (A549), human liver cancer cell line (BEL7404), and human
tongue cancer cell line (Tca) was investigated.70 Although the
results showed that the ferrocenyl analogues exhibited higher
antiproliferative activities than the parent 13-cis-retinoic acid, the
IC50 values obtained can be considered modest (19–40 mM).70
4. Ferrocenyl compounds targeting DNA
4.1. Combination of ferrocene with a DNA intercalator
The attachment of a ferrocenyl group to molecules that bind
DNA is a promising strategy to bring the ferrocene moiety to
close proximity of DNA, which might enhance the probability
of DNA damage and cell apoptosis.
Ong’s group synthesized compound 11 (Fig. 8) by linking
ferrocene to acridine (a DNA intercalator) and compared its
anticancer activity with the analogous ferrocenyl derivative
lacking the acridine moiety (compound 12, Fig. 8).71 The
in vitro studies indicated that the compound containing acridine
(11) was highly toxic to the four cancer cell lines tested, while
compound 12 was inactive. The inability of the phenyl derivative
12 to bind DNA was suggested as the main cause for the lack
of cytotoxicity. These findings are in agreement with the hypo-
thesis that the combination of the cytotoxic effects of the
ferrocenyl group with the DNA binding ability of acridine
Fig. 8 Molecular structures of ferrocenyl compounds linked to
acridine (11) and to a benzyl group (12).71
New J. Chem., 2011, 35, 1973–1985 1975

Fig. 9 Chemical structures of azalactone ferrocene (13) and thio-
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morpholide amido methyl ferrocene (14), potential inhibitors of topo-
isomerase II.74
allows for strong interactions with the key cellular target,
increasing cytotoxicity.71
4.2. Ferrocenyl derivatives as inhibitors of topoisomerase II
Topoisomerases are enzymes that unwind and wind DNA to
facilitate DNA replication, and to allow DNA to control the
synthesis of proteins. In normal cells, the activity of topo-
isomerase II is highly regulated, while it is present at high
levels in rapidly proliferating cancerous cells.72 This difference
in topoisomerase II levels between healthy and cancer cells
make these enzymes potential anticancer targets. Thus, develop-
ment of isoform-specific topoisomerase II inhibitors has been of
great interest for cancer-specific drug targeting.
Kondapi and co-workers reported a series of ferrocenyl
derivatives and studied their inhibitory properties against topo-
isomerase IIa and b.73,74 Based on structure–activity analysis,
two compounds in particular, azalactone ferrocene 13 and
thiomorpholide amido methyl ferrocene 14, presented a signifi-
cant effect against topoisomerase II activity (Fig. 9).74 These
results indicate that the two compounds interacted with topo-
isomerase II and inhibited its activity causing numerous genetic
implications that ultimately resulted in neoplastic cell death.74
5. Targeting breast cancer with selective estrogen
receptor modulators (SERM)
5.1. Ferrocifens, ferrocifenols and ferrocenophanes
Among all the ferrocene derivatives for cancer therapeutics,
the ferrocifens are probably the most widely studied, showing
very promising results for breast cancer.38,39 For patients
diagnosed with ER+ breast cancer, commonly the non-steroidal
selective estrogen receptor modulator (SERM) tamoxifen (15)
is prescribed (Fig. 10).75
In 1996, Jaouen et al. first coupled ferrocene to the active
metabolite tamoxifen 15 by replacing a phenyl group of
4-hydroxytamoxifen 16 with ferrocene (compound 17,
Fig. 10). Since ferrocene is intrinsically aromatic, recognition
of 17 by the estrogen receptor should not be deteriorated. The
hydroxyferrocifens 17 (differentiated by the length of the
dimethyl amino chain, n = 2–5, 8) were designed to combine
the antiestrogenic properties of tamoxifen while simultaneously
targeting the ferrocene moiety to the receptor and thus to DNA,
to possibly obtain new therapeutic advantages.76–78
The antiproliferative activity of the hydroxyferrocifens (17)
was evaluated on MCF-7 cells which are hormone-dependent
breast cancer cells that have an important concentration
of ERa, and on MDA-MB-231 cells, which are classified as
hormone-independent breast cancer cells because they are devoid
of ERa. It was found that on MCF-7 cells, the effect of
1976 New J. Chem., 2011, 35, 1973–1985 This journal is
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Fig. 10 Molecular structures of Tamoxifen (15), hydroxytamoxifen
(16) and hydroxyferrocifens (17).76–78
the hydroxyferrocifens 17 is comparable to that of hydroxy-
tamoxifen 16, being slightly more potent at a concentration of
0.1 mM, and definitely superior at 1 mM. While hydroxy-
tamoxifen was completely inactive on the hormone-independent
cells, the hydroxyferrocifens displayed a strong antiproliferative
effect, presenting a remarkable low IC50 value. Therefore,
two trends could be put forward: one which is similar to
the antiestrogenic role of hydroxytamoxifen on the estrogen
receptor, and one which involved the in situ activation of the
ferrocenyl function.39,76–79
Several studies on the structure–activity relationship of hydroxy-
ferrocifens suggest some trends concerning (a) the stereochemistry
of the compounds, (b) the effect of the N,N-dimethylamino
side chain, (c) the presence and position of the phenol group,
(d) the role and location of the ferrocene moiety, (e) the conju-
gation of the system, and (f) the functionalization of the phenyl
rings.39,80
(a) Under the conditions of relative binding affinity (RBA)
competition with ERa and ERb, the Z isomer of hydroxy-
tamoxifen is clearly better recognized. However, in the few cases
where individual isomers of ferrocifens were used in cell studies,
no difference in activity could be ascertained due to the rapid
isomerization of the hydroxyferrocifens in protic solvents.80
(b) The binding affinity of the hydroxyferrocifens decreases
as the N,N-dimethylamino side chain becomes longer. Further
studies showed that the side chain has a strong influence on
anti-oestrogenicity, however, its impact on cytotoxicity is still
controversial.39,81
(c) The impact of the hydroxyl group position in the
cytotoxicity against breast cancer cells was studied via a series
of para and meta-substituted mono and di-phenols, bearing
one or two ferrocenyl groups.82–84 The trend indicates that
ferrocifens containing only one ferrocenyl moiety and two
phenol groups in the para positions present higher toxicity
towards these cancer cells.39,82–84
(d) The hydroxyferrocifens were compared with analogues
where the ferrocene moiety was replaced by titanium, rhenium
and ruthenium complexes, and it was clearly shown that
among the metal-based tamoxifen derivatives, the ferrocifens
present the best anticancer activity.85,86
(e) To determine the role of the conjugated p-system linking
the ferrocene and phenol groups, compounds containing a sp3
carbon instead of an ethylene group were designed. The cell
studies suggest that compounds possessing a p-system signifi-
cantly outperform their non-conjugated analogues.87,88
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Fig. 11 Ferrocifens with a variety of phenyl substituents.39
(f) The influence of phenyl substituents other than OH was
evaluated by studying a set of ferrocifens analogues containing
Cl, Br, CF3, CN, NH3, NHCOMe, OCOMe, OMe, SCOMe or
SMe (Fig. 11).84,88,89 While ferrocifens bearing Cl (18), Br (19),
CF3 (20), OMe (25), SCOMe (26) or SMe (27) were inactive,
compounds bearing CN (21), NH3 (22), NHCOMe (23) or
OCOMe (24) showed significant anti-proliferative effects at
10 mM (Fig. 11). Compounds containing two OCOMe showed
similar behavior than the diphenol ferrocifen suggesting
that enzymatic hydrolysis occurs inside the cells. Therefore,
compound 24 can be considered as a ‘‘pro-drug’’.39
Rigid molecules usually bind more strongly to a receptor than
their flexible analogues if they have the proper geometry for
entering the active site, while a flexible molecule must adopt such
a geometry causing entropy loss and weaker binding.39 Thus,
Jaouen and co-workers reported a set of compounds containing
the cyclic [3]ferrocenophane moiety, and compared their anti-
cancer activity with their non-cyclic analogues (Fig. 12).90–93 For
each p-R-phenyl substitution pattern investigated, the [3]ferroceno-
phanyl derivatives showed higher cytotoxicity than the corres-
ponding ferrocenyl molecules, with the highest activity found
for compounds with protic substituents (Fig. 12).91,92
Direct comparison between compound 28 that possesses a
direct linkage between the cyclopentadienyl ring and the double
bond, and compound 29 in which the ferrocenyl group is linked to
the double bond through a methylene bridge, showed that the
conjugated compound 28 is one order of magnitude more cyto-
toxic than the non-conjugated analogue. Compound 28 showed
an exceptional antiproliferative effect on the hormone-independent
MDA-MB-231 and PC-3 cells with an IC50 value of 0.09 mM.91,92
The extensive study on tamoxifen derivatives containing the
ferrocenyl moiety has provided the scientific community with a
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Fig. 12 Molecular structures of ferrocenophane compounds structur-
ally related to tamoxifen.91,92
group of complexes active against breast cancer, with a range of
IC50 values between 0.09 and 13 mM.39 It would be interesting
to carry out in vivo studies on the ferrocifen compounds, and
detect if these ferrocenyl analogues of tamoxifen present less
side effects than the tamoxifen itself, which include the increased
risk of endometrial uterine cancer and blood clotting in
the lungs.
5.2. Ferrocenyl raloxifen derivatives
Following the same line as for the tamoxifen derivatives,
Marques and co-workers have explored the possibility to
replace a phenyl ring by a ferrocenyl moiety, on raloxifen
(compound 30, Fig. 13) which is another SERM.94 They
studied raloxifen derivatives containing one ferrocenyl group,
and all the tested compounds showed considerable cytotoxic
activity against ovarian, cervical, lung, colon and breast
cancer cell lines. Among all the compounds, [3-ferrocenyl-6-
methoxybenzo[b]thiophen-2-yl][4-(piperazin-1-yl)methylphenyl]
methanone (compound 31, Fig. 13) is worthy of note, showing
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Fig. 13 Molecular structures of Raloxifen (30) and a ferrocenyl
compound (31) structurally related to Raloxifen.94
IC50 values in the low-micromolar range and more than one
order of magnitude lower than those of cisplatin. In addition,
chemosensitivity tests on resistant phenotypes indicated that
this compound caused no cross-resistance with cisplatin, although
compound 31 is not considered a potential multidrug-resistant
(MDR) substrate. This group also showed that compound 31
activates caspase-3 in ovarian cells, suggesting that the mecha-
nism of cell death was apoptosis rather than necrosis.94
The studies on the SERMs containing ferrocenyl groups
have shown that this type of vectorization can be successful,
because some of the compounds present both anti-oestrogenic
and cytotoxic properties.
One could then imagine that merely transporting the ferrocene
unit into the nucleus via the receptor–bioligand interaction
would be sufficient to produce a cytotoxic effect.39 To investi-
gate this hypothesis, a ferrocenyl group was attached onto
the oestradiol skeleton, and these compounds present lower
anti-cancer activity than the ferrocifens and raloxifen
derivatives.95,96 These results suggest that the anticancer
activity of the ferrocenyl-SERMs compounds is due to a
synergetic effect between the tamoxifen or raloxifen moiety
and the ferrocenyl group, rather than the mere presence of the
ferrocene in the interior of the cells.70,71
6. Targeting prostate cancer with ferrocenyl
androgens and anti-androgens
6.1. Testosterone and dihydrotestosterone ferrocenyl
complexes
Testosterone (32), the endogenous hormone, and its active
metabolite dihydrotestosterone (33) (DHT), can promote the
malignant growth of the prostate gland (Fig. 14). Thus, the
latter therapy for prostate cancer consists in using anti-androgens,
which block the androgen-induced hormonal effect by binding
to the receptor instead of testosterone. The attachment of
ferrocene to anti-androgens could enhance their anticancer
activity. Thus, several ferrocenyl derivatives of testosterone
and dihydrotestosterone (DHT) were synthesized, and their
anticancer activity was studied.
Jaouen and co-workers introduced the ferrocenyl group at
the C-17 position of the steroid skeleton of testosterone and
1978 New J. Chem., 2011, 35, 1973–1985 This journal is
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Fig. 14 Chemical structures of testosterone and dihydrotestosterone
and their ferrocenyl derivatives.97,98
DHT, with an ethynyl substituent (Fig. 14). The androgen
activity of the resulting compounds was rather low, probably
because the receptor does not tolerate substitution in the C-17
position; however compounds 34 and 35 (Fig. 14) presented
strong anti-proliferative activity on hormone-independent
PC-3 prostate cancer cells with IC50 values of 4.7 and
8.3 mM respectively.97
A related study was carried out by Manosroi et al. where
the ferrocenyl group was introduced in the C-2 position of the
testosterone skeleton (compound 36, Fig. 14). Although the
receptor activity of this compound was not yet studied, it showed
high cytotoxic activity (comparable to that of doxorubicin)
against HeLa cells.98
6.2. Ferrocenyl derivative of nilutamide
Nilutamide (37) is a non-steroidal anti-androgen therapeutic
agent used in prostate cancer patients (Fig. 15). As an attempt
to improve the therapeutic activity of nilutamide, ferrocenyl
derivatives were synthesized.99 It was expected to obtain
anticancer activity for the nilutamide-ferrocenyl compounds
through an anti-androgen effect; however, these compounds
showed an unusual behavior. Compound 38 (Fig. 15) showed
significant cytotoxic activity against PC-3 hormone-independent
prostate cancer cells with an IC50 value of 5.4 mM, which
suggests that its activity does not occur via the androgen
receptor, but probably via recognition by other receptors.
Furthermore, this study emphasized that in this case the
introduction of the ferrocenyl group produces the same effect
than a purely organic aromatic moiety.39,99
The idea of attaching ferrocene to androgens and anti-
androgens appeared to be a promising strategy to create efficient
drugs for hormone-dependent prostate cancers. However, the
results obtained for the ferrocenyl derivatives of testosterone,
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Fig. 15 Chemical structures of nilutamide (37) and ferrocenyl
compound 38 which is structurally related to nilutamide.99
dihydrotestosterone and nilutamide contradict this hypothesis
because the resulting compounds showed low androgen activity
and higher cytotoxic activity against hormone-independent
prostate cancer cells. This unexpected behavior is still not
clearly explained but it might be partially due to the fact that the
ferrocenyl group somehow precludes binding to the receptors.
7. Compounds containing ferrocenyl group and
other transition metals
The success of cisplatin100 as an anticancer agent has stimulated
the search for cytotoxic compounds based on platinum and
other transition metals, in a continuous pursuit for fewer side
effects.101–103 Attempts to combine the anti-tumor activity of
ferrocenyl derivatives to that of other transition metals started
in the late 80’s.104–109
7.1. Ferrocene compounds with platinum, palladium, rhodium
and iridium
Since the Rosenberg’s discovery100 of the potent antitumor
activity of cisplatin, several amino-platinum complexes were
prepared and evaluated for their antitumor activity. Among
them, complexes containing ferrocenyl groups were also
studied.105,110,111 Al-Allaf et al. prepared a few Pt(II) complexes
with the formula cis-[Pt(Fc2PhP)(DMSO)X2] and tested their
antitumor activity in vitro, against leukemia cell line P388.110
Complexes 39 and 40 (Fig. 16) showed IC50 values close to
those of cisplatin and 5-fluorouracil.110
Rajput et al. have prepared a series of ferrocenyl compounds
containing pyridine ligands and studied their coordination
behavior with platinum, palladium, rhodium and iridium. The
new complexes were tested for cytotoxic activity and compared
to cisplatin. Several of the complexes displayed significant
cytotoxic activity against the cancer cell line WHCO1, being
the rhodium complexes 41 and 42 the most active, with growth
inhibitory activities similar to that of cisplatin (Fig. 17).112
A recent study by Spencer et al. where a series of palladacycles
were evaluated in vitro as cytotoxic agents against A2780/S
cancer cells suggested that the complexes containing 1,2-bis-
(diphenylphosphino)ethane were more active than their analogues
with 1,2-bis(diphenylphosphino)ferrocene.113
Caires and co-workers carried out interesting in vivo studies
involving chiral cyclopalladated complexes derived from
N,N-dimethyl-1-phenethylamine and the coordinating ligand
1,10 -bis(diphenylphosphine)ferrocene (dppf).114–116 The complexes
were investigated as cathepsin B inhibitors and antitumoral
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Fig. 16 Platinum complexes bearing ferrocenyl groups, which are
active against leukemia cell line P388.110
Fig. 17 Rhodium complexes bearing ferrocenyl groups, which anti-
cancer activity is similar to that of cisplatin.112
Fig. 18 Palladacycles that show high selectivity for tumor cells.115,116
agents against solid tumors. The results revealed that the
palladium compound 43 (Fig. 18) was able to inhibit cathepsin
B activity in a reversible fashion by binding to free cathepsin B
as well as to the enzyme–substrate complex.
The application of this complex, in Walker tumor-bearing
rats, resulted in 90% inhibition of the tumor growth, reducing
the solid tumors mass from 4.0 g to 0.3 g. Toxicological studies
using mice treated with high doses of the complex did not
show any alterations in red or white blood cell morphology
14 days after the drug administration. Similar results were
obtained with hepatic, kidney, and spleen tissues, making
this complex a promising antitumoral drug with reduced
toxicity.114,116
The same research group also showed that the ionic and
mononucleated palladacycle complex 44 (Fig. 18) triggers
lysosomal membrane permeabilization with release of lyso-
somal enzymes, especially cathepsin B to the cytosol of K562
cells, which lack the oncoprotein p53.115 This finding was of
particular importance from the point of view that development
of anticancer agents with different modes of action is a
key step in overcoming clinical therapy resistance. Moreover,
toxicological studies demonstrated that the palladacycle
complex 44 presents low level of toxicity for normal tissue,
suggesting high selectivity for tumor cells.115,116
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Fig. 19 Gold(I) carbene complex bearing two ferrocenyl groups.119
7.2. Gold complexes bearing ferrocenyl groups
In order to combine the anticancer properties of ferrocenyl
compounds, diphenylphosphine derivatives and gold complexes,
several research groups have synthesized a variety of gold
complexes containing dppf. Despite the presence of the three
moieties, all the complexes tested presented only modest anti-
cancer activity, being less active than cisplatin.106,108,109,117
Recently, Raubenheimer and co-workers showed a successful
combination of the anticancer properties of the gold(I) carbene
complexes118 and the ferrocenyl moiety.119 They designed a
gold(I) carbene complex containing two ferrocenyl groups
(compound 45, Fig. 19) and screened it against human HeLa
cervix epithelioid carcinoma cell line, the human colon adeno-
carcinoma line CoLo 320 DM, and the Jurkat leukemia cell
line. The phosphine-free gold(I) complex 45 presented tumor
specificity and achieved growth inhibition at lower concen-
trations than the well-known cisplatin, for two of the three
tested cancer cell lines.119
7.3. Ruthenium complexes containing ferrocenyl groups
Ruthenium complexes have been studied as an alternative to
platinum, due to its range of oxidation states (II, III and IV)
accessible under physiological conditions, and general lower
toxicity than the platinum analogues.120–123 The lower toxicity
of ruthenium complexes towards healthy cells can be partially
explained by the fact that ruthenium compounds specifi-
cally accumulate in rapidly dividing cells, such as tumors. This
accumulation of ruthenium in tumors is due to the ability of
ruthenium to mimic iron in binding to transferrin (the protein
which delivers iron to cells) which receptors are overexpressed
in cancer cells.124
As an attempt to combine the cytotoxic properties of nitrosyl
ruthenium complexes and ferrocene, Von Poelhsitz et al.
reported the ruthenium complex fac-[RuCl3(NO)(dppf)]
(compound 46, Fig. 20).125 This complex was tested on
MDA-MB-231 breast tumor cells and it showed higher cyto-
toxicity than the precursor complex RuCl3NO2H2O and the
free dppf ligand, being six times more active than cisplatin.
Considering the lack of activity of the RuCl3NO2H2O complex,
it is obvious that the ferrocene ligand plays a crucial role on the
anticancer activity of this compound.125
Dyson and co-workers investigated a few arene–ruthenium
complexes containing nitrogen-based ferrocenyl ligands and
tested them against ovarian carcinoma cells; however all the
compounds presented much lower anticancer activity than
cisplatin.126,127
For complexes where the ferrocene is conjugated to the
ruthenium through an ethylene linker (compound 47, Fig. 20),
1980 New J. Chem., 2011, 35, 1973–1985 This journal is
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Fig. 20 Ruthenium compounds bearing ferrocenyl groups, which
present anticancer activity.125,128
Ott et al. showed that their activity against colon carcinoma
and breast cancer cells is relatively close to that of cisplatin.128
Comparison of these complexes with the related monometallic
ruthenium complex and ferrocene derivative indicates that an
enhanced electron delocalization might be of high relevance
for the bioactivity.128
7.4. Ferrocenyl compounds coordinated to iron, nickel, cobalt,
copper or zinc
Kraatz and co-workers have tested the potential anti-cancer
properties of the redox-active ferrocenyl modified pyrazole
ligand and its corresponding complexes with iron, nickel
and cobalt.129 Using the human mammary adenocarcinoma
MCF-7 cell line, they verified that the three metal complexes
induced higher cytotoxicity than the free ligand, however the
obtained IC50 values can be considered modest, ranging from
46 to 73 mM.129
Abd-Elzaher et al. synthesized a ferrocenyl ligand that
contains salicylaldehyde moieties and studied the anti-cancer
properties of its complexes with Co(II), Ni(II), Cu(II), and
Zn(II), against human breast cancer cell line MCF-7.130 Treat-
ments of the MCF-7 cells with gradually increasing doses of
the complexes revealed that the activity of superoxide dismutase
and the level of hydrogen peroxide were significantly increased,
while the activities of catalase and glutathione peroxidase, and
the levels of reduced glutathione were significantly lowered
compared with the control MCF-7 cells. These metal complexes
showed significant anticancer activity comparable to that of
cisplatin, being the highest activity achieved by the zinc complex
(compound 48, Fig. 21). This report suggests that the antitumor
effect of these metal complexes may be exerted partially by the
increasing hydrogen peroxide production and by the depletion
of intracellular catalase, glutathione peroxidase, and reduced
glutathione.130
8. Ferrocenyl-based molecules with anticancer
activity conjugated to drug delivery systems
In the last decade, drug delivery systems have become a promising
solution to increase water-solubility, selectivity and blood
circulation life-time of small molecule drugs. Several drug
delivery systems including polymer microcapsules, liposomes,
nanoparticles and dendrimers are being explored to carry a
wide variety of drugs into diseased tissue.131–146
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Fig. 21 Zinc complex bearing a ferrocenyl ligand with anticancer
activity comparable to that of cisplatin against MCF-7 breast cancer
cells.130
Despite the high anticancer activity of some ferrocenyl
compounds described in this review, only a very few reports
focus on the use of drug delivery systems to improve their bio-
logical properties, which include host–guest complexes with
cyclodextrin,147,148 polyaspartamide copolymers,149–152 polymeric
micelles153,154 and lipid nanocapsules.155,156
8.1 Host–guest complexes of cyclodextrin and anticancer
active ferrocenyl compounds
Cyclodextrin (CD) inclusion complexes are interesting for
pharmaceutical applications due to high water solubility and
stability.157 Other potential benefits of using CD drug delivery
systems in chemotherapy include improved activities and reduc-
tion of toxic side effects.158 CDs are known to form stable inclusion
complexes with a large number of ferrocenyl derivatives,159 there-
fore the CDs have the potential to serve as carriers for cytotoxic
ferrocenyl compounds.
Jaouen’s group have studied the inclusion of ferrocifens
(see Section 5.1) into b-CD.147 It was found that the inter-
action with b-CD significantly increases the water solubility of
ferrocifens, while their cytotoxic properties are not affected.147
A similar approach was undertaken by Romão and co-workers,
in which they used CDs to form host–guest complexes with
1,2-disubstituted ferrocenes.148 The cytotoxicity of the complexes
with b-CD was found to be similar to those obtained in the
absence of cyclodextrin. Interestingly, they also showed that
Fig. 22 Polyaspartamide–ferrocene copolymers.152
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the use of heptakis-2,3,6-tri-O-methyl-b-CD (TRIMEB) or
2-hydroxypropyl-b-CD (HPbCD) instead of b-CD as hosts
for the ferrocenyl compounds significantly increased their
cytotoxic activity (up to 2.5 times).148
The fact that b-CD significantly increases the water solubility
of the ferrocenyl guests without loss of cytotoxic activity seems
to be an important feature that makes these host compounds
interesting ingredients for drug formulations of ferrocenyl
compounds with relevant anticancer activity.147,148 Moreover,
the substituted CDs TRIMEB and HPbCD, not only increase
water solubility of the ferrocenyl compounds, as they also
enhance their cytotoxic activity.148
8.2. Polyaspartamide–ferrocene conjugates
Neuse and co-workers have focused their investigation on the
cytotoxic behavior of polyaspartamide–ferrocene conjugates
against HeLa cells and the Colo 320 DM, a human colon
adenocarcinoma line which is known to be intrinsically
drug-resistant.149–152 Ferrocene was conjugated to water-soluble
polyaspartamide copolymers using a wide variety of linkers
and side groups. A quick glance at the in vitro data revealed a
good performance pattern for most of the conjugates against
both cell lines, with IC50 values in general much lower than
those of cisplatin.152 Copolymers 49 and 50 (Fig. 22) stand out
as top performers giving IC50 values in the range of 3.6–36 mM
of ferrocene. The critical compositional difference between the
ferrocenyl polymers tested is the presence in 49 and 50 of
tertiary amine side groups that enable the polymers to convert
to cationic species through amine protonation at physiological
pH.152 Polymers of this type have shown to undergo preferential
cell entry in the cationic state, which may render them potentially
more cytotoxic than analogous polymers lacking the amine
groups.152
8.3. Polymeric micelles cross-linked with ferrocene
Zhang and co-workers have used 1,1 0 -ferrocenedicarboxylic
acid as a difunctional cross-linker, and developed a novel
ferrocene-containing shell cross-linked thermoresponsive micelle
system via a two-step procedure (Fig. 23): (1) self-assembly of
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Fig. 23 Formation of the ferrocene-containing shell cross-linked
thermoresponsive micelle system (reprinted with permission).154
a poly(N-isopropylacrylamide-co-aminoethyl methacrylate)-
b-polymethyl methacrylate (P(NIPAAm-co-AMA)-b-PMMA)
copolymer into polymeric micelle in aqueous solution; (2) cross-
linking of the hydrophilic shell layer via the amidation reaction
between the amine groups of AMA units and the carboxylic
acid functions of 1,1 0 -ferrocenedicarboxylic acid.154 In vitro
studies demonstrated that the thermoresponsive ferrocene-
containing shell cross-linked micelles exhibited significant
cytotoxicity against HeLa cells, due to the presence of the
ferrocenyl groups.154
8.4. Lipid nanocapsules loaded with dihydroxyferrocifen
Lipid nanocapsules (LNC) of around 50 nm were used to
encapsulate the active ferrocenyl diphenol tamoxifen derivative
(Fc-diOH, see Section 5.1), in order to increase its solubility in
biological media.155 The Fc-diOH was encapsulated in high
loading because of the large hydrophobic core in the LNC
structure. The loaded LNCs were up taken by 9L-glioma cells
and the cytostatic activity of the Fc-diOH was conserved
presenting an IC50 value of about 0.6 mM. Interestingly, the
Fc-diOH-loaded LNCs showed low toxicity levels when in
contact with healthy cells, conferring a functional specificity of
this compound for tumor cells. Promising in vivo experiments
in rats demonstrated that the Fc-diOH-loaded LNC dramati-
cally reduced the tumor mass and glioma volume, showing for
the first time the in vivo efficacy of hydroxyferrocifens.155
This work was then taken to the next level by evaluating the
in vivo efficacy of the Fc-diOH-loaded LNCs in combination
with external radiotherapy in the intracerebral 9L-glioma
model.156 This combination resulted in a significantly longer
survival rate when compared to Fc-diOH-LNC-treated animals
and to the group treated with blank LNCs + radiotherapy,
suggesting a synergetic antitumor activity on 9L-glioma cells,
probably caused by a closely oxidative relationship.156
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9. Conclusion and prospects
Application of ferrocene derivatives in cancer therapeutics is
an active research area, and many reports have demonstrated
that some ferrocenyl compounds are highly cytotoxic in vitro
against several cancer cell lines, including breast, prostate,
lung, colon and leukemia cancer cells. Besides the significant
amount of successful in vitro results for a wide variety of ferro-
cenyl compounds, only a few were tested in vivo. Significant
tumor growth inhibition was obtained in vivo for ferricenium salts
(up to 83% growth inhibition of EAT),47 ferrocenylalkylazoles
(up to 100% growth inhibition and 45% regression of solid
tumors),55 ferrocenyl-nucleobases (up to 70% growth inhibition
of Ca755),62 palladacyles with dppf (up to 90% growth inhibition
of Walker tumors),114–116 and lipid nanocapsules loaded with
hydroxyferrocifen (longer survival rate).155,156 The success of the
in vivo anticancer activity of some ferrocenyl-based molecules is
encouraging and should inspire scientists to design compounds
with even higher efficiency against several cancer types.
It would be of great interest to study the potential side effects
caused by the ferrocenyl compounds, in order to evaluate the
possibility of its use in humans. Particular attention should be
given to the possibility of iron overload in the body, which can
cause liver damage.
I believe that the future of this area relies on the search for
efficient biodegradable drug delivery systems to carry the active
ferrocenyl compounds, which should increase water solubility
and blood circulation life-time, and enhance selectivity towards
cancer tissue. Furthermore, the use of multifunctional drug
delivery carriers would allow the attachment or encapsulation
of the ferrocenyl compounds, together with imaging agents
and/or other drugs, opening the door for the use of these
compounds in theranostics.
Acknowledgements
I am grateful to Prof. Jean M. J. Fréchet and National Science
Foundation (NSF) for support, and to Dr Jackson D. Megiatto
Jr for useful discussions about this review.
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