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Carbohydrate-Metal Complexes and their Potential as Anticancer Agents

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2574 Current Medicinal Chemistry, 2008, 15, 2574-2591

Carbohydrate-Metal Complexes and their Potential as Anticancer Agents

Christian G. Hartinger*,1,2, Alexey A. Nazarov*,1,2, Shaheen M. Ashraf1, Paul J. Dyson2 and Bern-
hard K. Keppler1
1
University of Vienna, Institute of Inorganic Chemistry, Waehringer Str. 42, A-1090 Vienna, Austria
2
Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne,
Switzerland
Abstract: Platinum complex-based chemotherapy is one of the major treatment options of many malignancies. Although
severe side effects occur, and only a limited spectrum of tumors can be cured, Pt compounds are used in every second
therapy scheme. Thus, many different drug design strategies have been employed for improving the properties of antican-
cer drugs including pH or redox activation in the tumor, variation of the metal center and therefore the redox and ligand
exchange properties, the application of multinuclear metal complexes, the development of targeted approaches, etc. Ap-
plication of carbohydrate–metal complexes is an example of a targeted approach exploiting the biochemical and metabolic
functions of diverse sugars in living organisms for transport and accumulation. Natural carbohydrates and synthetic de-
rivatives possess a manifold of donors endowing them with the ability to coordinate metal centers and providing some ad-
ditional advantages over other ligands, e.g., biocompatibility, non-toxicity, enantiomeric purity, water solubility, and well-
explored chemistry. In recent years, several examples of carbohydrate compounds have been developed for diverse me-
dicinal applications ranging from compounds with antibiotic, antiviral, or fungicidal activity and anticancer compounds.
Herein, metal complexes with carbohydrate ligands are reviewed and the role of the carbohydrate carriers on the antineo-
plastic activity of these compounds, both in vitro and in vivo, is described.
Keywords: Antitumor chemotherapy, carbohydrates, metal complexes, review.

1. INTRODUCTION The success of cisplatin in treating solid tumors was fol-

Malignant diseases cause approximately 25% of the
deaths in developed countries and chemotherapy is a central
component in preventing such deaths along with surgery and
radiation therapy [1]. A variety of chemotherapeutics are
available including alkylating agents, antimetabolites, anti-
tumor antibiotics, natural products, hormones, hormone
antagonists, and metal complexes (often considered as alky-
lating agents).
Medicinal applications of metal compounds can be traced
back to ancient times, with precious metals like gold and
silver being applied by the ancient Chinese, Egyptians,
Greeks and Indians for treatment of various diseases [2].
Chemotherapeutic use against cancer started with the devel-
opment of cisplatin 1, cis-diamminedichloridoplatinum (II)
(Fig. (1)), which was approved for the treatment of cancer
worldwide in 1978. Cisplatin was first prepared by Peyrone
in 1844 [3], and its structure was correctly proposed by
Werner in 1893 [4], but the antineoplastic activity of cis-
platin was only discovered (somewhat serendipitously) in
1969 by Rosenberg [5,6]. Cisplatin is now one of the most
widely used and most effective chemotherapeutic agents in
the treatment of epithelial malignancies such as lung, head,
neck, ovarian, bladder and testicular cancers [7-10]. How-
ever, the treatment of tumors with cisplatin is compounded
by severe side effects such as renal toxicity, gastrointestinal
toxicity, peripheral neuropathy, asthenia, myelosuppression
and ototoxicity [9,11,12]. The problem of intrinsic and ac-
quired drug resistance during treatment further limits the
application of cisplatin [13].
*Address correspondence to these authors at the University of Vienna,
Institute of Inorganic Chemistry, Waehringer Str. 42, A-1090 Vienna,
Austria; Tel: +43 1 4277 52609; Fax: +43 1 4277 9526;
E-mail: christian.hartinger@univie.ac.at; alex.nazarov@univie.ac.at
lowed by the synthesis of a plethora of cisplatin analogues in
the hope of finding superior agents [14]. The second genera-
tion platinum compounds carboplatin 2, cis-diammine(1,1-
cyclobutanedicarboxylato)platinum(II), and oxaliplatin 3,
[(1R,2R)-cyclohexane-1,2-diamine](oxalato)platinum(II),
were approved for worldwide clinical use [15]. Oxaliplatin in
combination with 5-fluorouracil has emerged as the first line
therapy for metastatic colorectal cancer [16]. Other plati-
num-based drugs have been regionally approved (nedaplatin
in Japan, lobaplatin in China, and heptaplatin in South Ko-
rea) and several platinum complexes are currently in clinical
trials as single agent therapies or in combination with estab-
lished drugs [15,17-21].
In order to circumvent the side effects of the prevalent
anticancer drugs, to enhance the cytotoxicity profile, and to
augment the efficacy and specificity of the antitumor agents,
many new compounds have been prepared and evaluated
[9,15,22-27]. Several complexes based on different metals
including ruthenium [28-31], gallium [32-35], rhodium and
osmium, [36-38], copper and iron [32,39-41], molybdenum
[42], gold [43], palladium [44,45] and titanium [46,47] have
been synthesized and investigated for antineoplastic proper-
ties.
The role of ligands in tuning the cytotoxic characteristics
of the complex is of considerable importance. Lipophilicity
and stability of a metal complex strongly depend on the
nature of the ligands [13]. Carefully designed/selected
ligands for metal-based drugs impart desirable features that
influence the toxicity, bioavailability, and the specificity of a
metallodrug candidate [31,48].
Carbohydrates represent an excellent class of tunable
ligands for use in medicinal inorganic chemistry, they are
often inexpensive, available in enantiomerically pure form,
naturally available and possess functional groups for modu-

0929-8673/08 $55.00+.00 © 2008 Bentham Science Publishers Ltd.

Anticancer Sugar-Metal Complexes
H3N Cl H3N
Pt
H3N Cl H3N
1 2
O NH2 O
H3N O O
Pt
H3N O O
4 5
Fig. (1). Pt-based anticancer complexes cisplatin 1, carboplatin 2 and oxaliplatin 3 (approved for worldwide clinical use) and nedaplatin 4,
heptaplatin (SKI2053R) 5 and lobaplatin 6 (regionally approved).
lation according to the desired properties. Non-functiona-
lized carbohydrates are week donor ligands, but carbohy-
drates can easily be modified with a broad range of func-
tional groups, e.g., amino, carboxylato, thiol, and different
phosphorus containing moieties, capable of serving as strong
ligands [49].
Carbohydrate chemistry links organic chemistry with
medicinal chemistry and biology, due to the role that carbo-
hydrates play in glycobiology, in anti-infective therapy as
components of antibiotics, antitumor, and antiviral agents,
and in related biomedical areas [50]. Attaching a carbohy-
drate moiety to a metal-binding ligand invariably leads to
reduced toxicity, and also to improved solubility and mo-
lecular targeting. Carbohydrate ligands can be used for
chelating metal ions in order to generate a well-defined bind-
ing environment and to enhance the stability of the resulting
complexes. Accordingly, the carbohydrate unit remains pen-
dant and is (potentially) available to interact with carbohy-
drate transporters in the body [48]. Modified carbohydrates
and oligosaccharides are known to interfere with carbohy-
drate–protein interactions and can inhibit cell–cell recogni-
tion and adhesion phenomena, which are crucial in cancer
growth and progression [51]. Moreover, there are several
organic compounds in clinical use as anticancer agents or at
an advanced clinical stage possessing a sugar moiety, e.g.,
the DNA strand break-inducing compound bleomycin [52],
the alkylating agent glufosfamide [53], and the DNA interca-
lator doxorubicin (trade name adriamycin) [54].
Carbohydrate-metal chemistry has been extensively stud-
ied and several important reviews [49,55,56] dealing with
carbohydrate-metal complexes have been published in recent
years. Herein, the role of metallodrugs based on carbohy-
drates and their derivatives for the treatment of cancer is
discussed. The other medicinal applications of carbohydrate-
metal complexes, e.g. in diagnosis, are beyond the scope of
this review, and also pharmaceutical compositions contain-
ing cyclodextrins and having no covalent bond between the
metal complex and the organic moiety are not covered (for a
recent review see ref. [57]).
Current Medicinal Chemistry, 2008 Vol. 15, No. 25 2575
O
H2
O N O O
Pt Pt
O N O
H2 O
O
3
O
CH3
NH2 O
Pt Pt
NH2 O NH2 O O
O
6
2. PLATINUM COMPLEXES DERIVED FROM CAR-
BOHYDRATE LIGANDS
2.1. N Donors for Coordination to Pt Centers
All of the clinically established anticancer agents based
on platinum are equipped with nitrogen-donor ligands that
are strongly bound to the metal center. In general, these
ligands are not substituted (released) as the platinum com-
pound exerts its anticancer effect. Nevertheless, the nature of
the N-donor ligands dramatically influences the anticancer
properties of platinum complexes and leads to activity
against different types of cancers [9].
2.1.1. Mono- and Disaccharide Ligands with Amino Func-
tionalities
2.1.1.1. Simple Aminosugar Ligands
Exploiting the high affinity of platinum towards N-donor
ligands readily affords aminosugar–platinum complexes in
which the carbohydrate moiety is bound to the platinum
center via an amino group. Shortly after the approval of
cisplatin in the clinic there was a considerable interest in
carbohydrate-analogues of cisplatin. The simplest represen-
tatives of these compounds are based on glucosamine and
their general structures are shown in Fig. (2) [58-60]. Fur-
thermore, a series of platinum(II) complexes based on 2-
amino-2-deoxy-D-glucopyranose and related derivatives with
a variety of leaving groups were reported [58,61-64]. Unfor-
tunately, for these compounds very little in vitro and in vivo
anticancer data was reported, the only data we are aware of
is in the patent literature proving the applicability of these
compounds as anticancer agents [65,66]; the characterization
of the compounds was not described. In comparison to cis-
platin, used as a standard control, higher doses of the carbo-
hydrate complexes were required to observe the same anti-
cancer effect. Notably, the carbohydrate does not seem to
have much influence on the anticancer activity since the
median survival times for complexes with different sugar
ligands were very similar in single cancer models.
Tsubomura et al. used chelate-forming 2,3-diamino sug-
ars to obtain [PtCl2(methyl 2,3-diamino-2,3-dideoxy-
-D-
2576 Current Medicinal Chemistry, 2008 Vol. 15, No. 25 Hartinger et al.

mannopyranoside)]·H2O 10 and [PtCl2(2,3-diamino-2,3- Structurally similar compounds to 11 were obtained by

dideoxy-D-glucose)]·H2O 11 (Fig. (3)). Both compounds replacing the leaving chlorido ligands by iodido 13, oxalato
were found to exhibit promising antitumor activity against 14 and malonato 15 (Fig. (3)) and the cytotoxicities were
sarcoma 180 in mice with the glucose derivative 11 being determined in four cell lines (CH1, HeLa, SW480, U2OS),
more efficient (T/C = 411 vs. 230%) [67]. Compound 11 was with IC50 values being in the low micromolar range, see
found to be active in sarcoma 180-bearing mice, prolonged Table (1) [71]. The cytotoxicity of the chlorido complex 11
their survival time by 311% at 50 mg/kg, i.p. [68]. The ap- is one to two orders of magnitude lower than that of ox-
plied dose was 50 mg/kg for the carbohydrate–complexes vs. aliplatin (l-OHP) and its (S,S)-enantiomer (d-OHP), but
8 mg/kg for cisplatin, however, the LD50 of cisplatin was comparable to carboplatin in two of the four cell lines. To
determined in the mouse model at 13 mg/kg indicating the gain insights into the mode of action of the compounds the
significantly lower toxicity of the sugar derivatives. Fur- binding affinity toward the DNA model nucleotide dGMP
thermore, an influence of the conformation of the NH 2 was studied. Compound 11 binds to dGMP in a similar way
groups was elucidated [69], which is in agreement to the to cisplatin, whereas the iodido compound 13 reacts at a
results observed for oxaliplatin (compare R,R- vs. S,S-chxn) much lower rate, probably due to slower hydrolysis. For the
[70]. The most promising compounds in the study were de- complexes with the chelating oxalato and malonato ligands
termined as [PtCl2(benzyl 3,4-diamino-3,4-dideoxy-ß-L- 14 and 15, the stability of the dicarboxylato ligands resulted
arabinopyranoside)] 12 with a lifespan increase of 390% vs. in a lower reactivity to dGMP (similar to other series of Pt
the controls at low dose and 10 with a T/C of 410% at a compounds).
higher dosage [69]. Furthermore, the complexes were not
Diaminosugar–Pt complexes with methyl 2,3-diamino-
active against BDF1 mice bearing the L1210 tumor, with the
2,3-dideoxy-L-xylopyranoside and 2,3-diamino-2,3-dideoxy-
exception of 12 showing a T/C value of 250%, following a
1,5-anhydro-L-xylitol (Fig. (4)) have been synthesized by
single treatment with 32 mg/kg of the complex [69].
Hanessian and Wang [72,73]. The 4-hydroxo complexes 16
sugar
-
sugar sugar sugar
and 18 exhibited cytotoxicity against P338 leukemia in vitro,
and in vivo they are comparable to cisplatin, while 17 was
H2N Cl H2N NH2 H2N NH2 found to be less active (Table (2)). It was proposed that the
Pt Pt Pt
hydroxy group at C-4 position in 16 and 18 effects the solu-
Cl Cl Cl Cl Cl Cl
bility, hydrophilicity, electronic stabilization, distribution of
7 8 9 the complex in the plasma, and cytotoxicity. In analogy to
Fig. (2). Generic structures of mono- and diaminosugar–platinum the cisplatin/carboplatin couple, complex 19 showed much
complexes 7–9 (sugar = glucose, galactose, mannose, arabinose, reduced activity in comparison to 16 and 18, which is proba-
etc.). bly due to the stability of the cyclobutane-1,1-dicarboxylate
ligand as a leaving group lowering the reactivity towards
H2 DNA. Compounds 16 and 18 were active against L1210,
HO N HO
O O DDP5, P388 and their resistant cell lines although being less
HO HO BnO O
H2N H2N OH HO
potent than oxaliplatin.
NH2 NH2
Pt OMe Pt NH2 In a series of patents, Sasamori et al. reported the use of
Cl X Pt complexes derivatized with L-xylopyranose and L-
Cl X Cl Pt
xylopyranoside ligands combined with different leaving
11 X = Cl 12 Cl groups, including chlorido, nitrato, isocyanato, oxalato, etc.
10
13 X=I
14 X = oxalato [74-80] (Fig. (4)). In particular, the inhibition of mice leu-
15 X = malonato kemia (L1210) was observed, leading to increased survival
rates of >275 and >375% for the chlorido complex 20a and
Fig. (3). Structures of diaminosugar–platinum complexes 10-15.

Table 1. Cytotoxicity of Diaminoglucose-Based Platinum Complexes Compared to Carboplatin, Oxaliplatin (l-OHP) and d-OHP in
Four Human Cancer Cell Lines [71]

IC50 (
M) a
Compounds
CH1 HeLa SW480 U2OS

11 5.1 ± 0.3 7.3 ± 0.8 67 ± 13 82 ± 24

13 7.9 ± 2.3 14 ± 2 79 ± 4 119 ± 16
14 4.1 ± 0.1 10 ± 1 87 ± 3 175 ± 20
15 6.3 ± 0.4 23 ± 7 151 ± 8 > 250
Carboplatin 0.52 ± 0.01 5.4 ± 1.5 61 ± 10 34 ± 1
Oxaliplatin, l-OHP 0.34 ± 0.09 0.30 ± 0.08 0.30 ± 0.08 0.72 ± 0.24
d-OHP 1.0 ± 0.1 1.1 ± 0.4 1.3 ± 0.3 2.6 ± 0.7
a
50% inhibitory concentrations in CH1 (ovarian carcinoma), HeLa (cervix carcinoma), SW480 (colon carcinoma), and U2OS (osteosarcoma) cell lines determined using the MTT
assay.
Anticancer Sugar-Metal Complexes Current Medicinal Chemistry, 2008 Vol. 15, No. 25 2577

O OH
O OR O MeO
OH NH2
MeO NH2 NH2 H2N
H2N H2N Pt O
Pt Cl Pt Cl O
Cl Cl O

16 R = H O
18
17 R = Me
19

H2 H2 OH
O O N O
N
RO N Pt Cl
EtO N Pt Cl HO NH2
HO H2 Cl HO H2 Cl HO H2N
OH
Pt O
O
20a R = H 21 22 O
20b R = benzyl

Fig. (4). Structures of xylose-derived platinum complexes 16-22.

Table 2. In Vivo Antitumor Evaluation of Xylose-Derived Platinum Complexes 16-19 [72,73]

Complex Leukemia tumor model Dose i.p. / mg/kg T/C /%

16 P388 25 227
17 25 191
18 12.5 236
19 25 114
Cisplatin 4 236
16 L1210 50 323
17 50 218

its benzyl pyranoside analogue 20b in mice transplanted with R and L5178Y-S being defective in the incision step of the
L1210 leukemic cells at 1.6 and 0.9 mg/kg per day i.p., re- nucleotide excision repair system and the double-strand
spectively. In addition, the ethyl xylopyranoside Pt(IV) com- break repair mechanism, respectively. The IC50 values were
pound 21 and other related derivatives were prepared and 21 found to be similar for 23 in both cell lines, whereas the Pd
was shown to prolong lifespan by >375% at 3.1 mg/kg per compound 24 was 3-times more active in L5178Y-R com-
day in the same tumor model. pared to L5178Y-S cells. Overall, the Pt complex was more
cytotoxic than the Pd analogue, and in vitro results did not
In addition to xylopyranoses with the amino functionali-
correlate with the ability of the complexes to modify DNA
ties in vicinal positions, compounds with amino substituents
by inducing crosslinks, with the Pd compound leading to
in 3 and 5 positions were prepared [75,79]. Notably, 22 with
the 2-hydroxoacetato ligand was found to increase the sur- higher retardation of DNA than the Pt species, proposing a
non-DNA-related mode of action for at least one of the com-
vival rate by 264% at 3.8 mg/kg-day i.p. in L1210 leukemia
pounds.
bearing mice. Kolar also patented the application of platinum
complexes comprising 6-membered rings with diamino sug- +
Me Me
ars as anticancer agents. In this case a large number of ex- H2N O H2N O
amples of 2,4-diaminoglucopyranose Pt complexes were OMe OMe
Cl M Cl Pt NO3-
reported, in particular with regard to different leaving co-
NH2 NH2
ligands, and their biological activity was studied and com- Cl DMSO
pared to cisplatin. The compounds were shown to exhibit in
vitro activity at lower toxicity than cisplatin [81], but it is not 23 M = Pt 25
clear if the results are statistically significant. 24 M = Pd
Samochocka et al. studied platinum(II) (23) and palla- Fig. (5). Structures of L-lyxo-hexapyranoside-derived complexes
dium(II) (24) complexes based on methyl 3,4-diamino- 23-25.
2,3,4,6-tetradeoxy-
-L-lyxo-hexopyranoside (Fig. (5))
[82,83]. In vitro evaluation of the neutral platinum(II) com- The cationic platinum(II) complex [PtCl(methyl 3,4-
plex with the diaminosugar revealed antitumor activity diamino-2,3,4,6-tetradeoxy-
-L-lyxopyranoside)(DMSO)]NO3
against mouse lymphoma cell lines (L5178Y), with L5178Y- 25 was tested for the inhibition of mouse L1210 lymphoma
cell growth with reference to cisplatin [84]. In contrast to
2578 Current Medicinal Chemistry, 2008 Vol. 15, No. 25 Hartinger et al.

O and protein syntheses did not allow the mode of action to be

CH3
clearly defined. Thymidine incorporation into DNA was
HN found to be 77% after a 16 hour-incubation period and
uridine and labeled amino acids were incorporated into RNA
HO O N and protein to an extent of 17 and 100%, respectively.
PtCl2
O
There are a large number of platinum complexes with
nucleotides reported in the literature, most of which originate
from the reaction of dGMP and other nucleosides and nu-
NH2
2 cleotides as model substrates for metal complexes with
DNA. However, virtually all these species were not isolated
26 and tested on their anticancer activity.

Fig. (6). Formula of the nucleoside-Pt complex 26.

cisplatin, at concentrations of up to 0.1 mg/ml no signs of
toxicity were observed. The ID50 (50% inhibitory dose) val-
ues were determined to be similar for 25 and cisplatin, but
for the ID90 cisplatin was about two times more toxic.
2.1.1.2. Nucleoside-Aminoribose Ligands
Nucleoside-Pt complexes were introduced by Lin et al. as
anticancer agents [85]. The replication of murine L1210 cells
in vitro was studied for several compounds, but only dichlor-
idobis(3-amino-3-deoxythymidine)platinum(II) 26 (Fig.
(6)) was found to be a potent inhibitor with an ED50 of 0.8
μM (320 mg/kg, 2 per day for 3 consecutive days). A dose
dependent increase in survival time was observed in mice
bearing the L1210 tumor (Table (3)). However, 26 was less
potent than cisplatin (T/C of 205% for cisplatin at a single
treatment with 8 mg/kg). Inhibition assays on RNA, DNA
2.1.1.3. Polynuclear Pt Complexes
The concept of applying polynuclear metal complexes as
anticancer agents has been shown to improve anticancer
activity and to extend the range of treatable tumors including
those that are otherwise resistant to platinum chemotherapy
[86]. Sachinvala et al. prepared platinum complexes based
on disaccharides by linking two sugar moieties. The sucrose-
based complexes were found to exhibit good water solubility
and cytotoxicities comparable to that of cisplatin (Fig. (7)).
A comparison of the mononuclear complexes 27–30, di-
(31) and trinuclear (32) and (33) Pt(II) complexes was re-
ported [87,88]; the mononuclear complexes were not cyto-
toxic, whereas 31 (with notably high solubility of 10
mg/mL) was comparable to that of cisplatin in vitro in hu-
man KB cells and in vivo against implanted Lewis lung car-
cinoma and P388 leukemia in mice with T/C  310 and 
291%, respectively. In contrast to cisplatin, the treatment of
the mice with 31 was not accompanied by severe toxicity,

Table 3. Effect of the Dinucleoside-Platinum Complex 26 on the Survival of Mice Bearing the L1210 Ascites Neoplasm and Com-
parison to Cisplatin [85]

Compound Dose / na
mg/kg Average survival / days T/C / %

26 control 10.3 0
6  80 10.7 104
6  160 13.2 128
6  320 18.0 175
cisplatin [212] 18 - 205
a
number of injections.

X H3N H3N
H2N Pt X H2N Pt Cl H2N Pt X
H3N Cl H3N X
Cl X
Pt Pt
MeO O HO O MeO O
NH2 H2N Cl H2N X
MeO HO MeO
MeO O O O MeO O
O O O
MeO
X NH2
OMe OH Pt OMe
MeO HO X NH3 MeO

27 X = iodido 31 32 X = chlorido
28 X = oxalate 33 X = malonate
29 X = malonate
30 X = cyclopropylmalonate

Fig. (7). Mono-, di- and trinuclear platinum complexes derived from sucrose.
Anticancer Sugar-Metal Complexes
although weight loss was observed during the 50-day obser-
vation period. The structurally similar trinuclear compound
32 was reasonably soluble in water (though being fully
methyl-protected) and was slightly more active in vitro than
the dinuclear compound 31 and in vivo a life time prolonga-
tion of T/C
355% was observed, which might also be due
to the higher lipophilicity of the compound leading fre-
quently to higher drug concentrations in the cell, although no
cellular uptake data was reported to substantiate this hy-
pothesis.
Evaluation of the anticancer activity of 34 and 35 (Fig.
(8)) against P388 leukemia revealed high anticancer activity
with IC50 values in the high nM range [89], notably, inde-
pendent of the number of Pt centers coordinated to the sugar
moiety.
Ph O OH Ph O OH
O O O O
NH OMe NH OMe
Pt(NH3)Cl2
Pt Cl
Cl2(H3N)Pt
OMe HN Cl OMe NH
O O
O O
OH O Ph OH O Ph
34 35
Fig. (8). Mono- and dinuclear mannose-based Pt(II) complexes.
In a patent dinuclear aminosugar Pt compounds based on
an anthracenedione-linker were claimed as potential antican-
cer agents [90], but no biological data was reported.
2.1.1.4. Multifunctional and Organometallic Complexes
Another strategy for overcoming resistance problems
during chemotherapy is the development of multifunctional
drugs, i.e., attaching a known organic drug to a platinum
center [91,92]. By linking two cytotoxic moieties Pasini et
al. synthesized the platinum-doxorubicin compound 36 (Fig.
(9)) (doxorubicin and also daunorubicin are used to treat a
wide range of different cancer types, and cisplatin does not
show cross-resistance to anthracyclines) [93]. Compound 36
was tested against murine P388 and L1210 leukemia and the
cisplatin- and doxorubicin-resistant sublines L1210/DDP and
P388/Dx, respectively, and against the naturally doxorubi-
cin-resistant solid murine early colon carcinoma #26. Prom-
ising activity, also in comparison to the parent compounds
cisplatin and doxorubicin, was found against the P388 tumor
model, whereas all the tested compounds were not very ac-
tive against L1210 leukemia. In the drug resistant tumor
models, similar activity as for cisplatin and doxorubicin was
reported, yielding only a low number of long-term survivors.
Against murine early colon carcinoma #26 36 exhibited
similar activity to doxorubicin and was less active than cis-
platin. Preliminary results on the mode of action suggest
intercalation of the doxorubicin moiety into DNA, rather
than covalent binding via the Pt center [94]. The preclinical
evaluation of this complex was extended to the solid doxoru-
bicin-resistant tumors BI6 melanoma (acquired resistance)
and MXT mammary carcinoma (intrinsic resistance) and to
Current Medicinal Chemistry, 2008 Vol. 15, No. 25 2579
sensitive tumors (Gross leukemia and Lewis lung tumor).
However, no advantage over treatment with doxorubicin was
found in these tumor models.
O
O OH
OH
OH
OMe O OH O
Me O
NH2
OH
NH2 Pt Cl
t-Bu
Cl
36
Fig. (9). Structure of the platinum-doxorubicin complex 36.
Dinuclear Pt compounds based on doxorubicin have also
been reported, but without biological data [95]. Notably, the
Pt centers were found to coordinate to the hydroxyquinone
group. The same was observed for a series of multinuclear
neomycin B complexes [96].
A series of Pt ammine quinone complexes with naphtho-
quinone derivatives as ligands were prepared and at a dose of
3  30 mg/kg i.p. a long term survival in 8 of 10 mice bear-
ing an Ehrlich ascites tumor cells was observed [97]. In the
same tumor model the positive control animals were treated
with cisplatin and 4 out of 10 survived for more than 60
days. Related complexes based on Pd(II) and Fe(III) coordi-
nated to the anthracyclines doxorubicin and daunorubicin
were reported with antitumor activity against P388 leukemia
cells [98,99]. The interaction of the complexes with plasma
was studied and no binding was observed. It was also found
that the Pd–anthracycline bond was not cleaved on binding
to DNA. Furthermore, the complexes did not increase
superoxide formation in contrast to their anthracycline
ligands alone.
Metallocenes covalently linked to doxorubicin [100] have
also been studied. The zirconocene-doxorubicin compound
was found to be inactive, whereas the Ti analogues exhibited
antitumor activity similar to that of titanocene dichloride.
The mode of action is thought to involve the dissociation of
the complex, and the presence of metal ions induces binding
to DNA and erythrocyte ghosts, although it is possible that
the doxorubicin ligand is released from the Ti center prior to
entry into the cell.
Other organometallic compounds derived from the reac-
tion of [{PtMe3(H2O)2}2SO4] with (amino)-D-glucitol and
glucosamine gave rise of compounds of the general formula
[PtMe3L]2SO4, whereas reaction with (2-amino)-D-gluconate
and D-threonate resulted in the complexes [PtMe3L] and
[PtMe3L(H2O)], respectively [101]. Although proposed as
anticancer drugs no biological data was reported. The same
is true for Pt organometallics coordinated via the C1 atom of
the sugar ligands [63] and (acetyl)glucose and ribose deriva-
tives via organic linkers [102].
2.1.1.5. Platinum(IV) Complexes
The platinum(IV) unit represents an excellent motif to
which functional ligands can be attached, which are subse-
2580 Current Medicinal Chemistry, 2008 Vol. 15, No. 25
quently lost by reduction to Pt(II) inside cells [103,104].
With sugars there are few examples although Pt(IV) sugar
complexes were claimed in a patent by Kay et al. [105].
However, the characterization of the compounds was not
provided and the suggested structure, including coordination
to the ring-oxygen, is uncertain. Within the series of tested
compounds the Pt compounds containing either a methyl
-
D-mannopyranoside or D-glucosamine ligand were the most
active and in some of the tumor models were more active
than cisplatin.
2.1.2. Coordination to Pt via a Linker
Coordination of sugars to Pt centers via donor-atom bear-
ing spacers offers several advantages over direct coordina-
tion of the Pt moiety to aminosugars: cell penetration and
drug-receptor interactions are thought to be improved and
the sugar functionality helps to maintain high solubility
without preventing the Pt from exhibiting its anticancer ac-
tivity.
Recently Chen et al. synthesized the cisplatin analogous
glucose-Pt compound (Fig. (10); 37 sugar = glucose] and di-
and trisaccharide derivatives with a 2-hydroxy-1,3-
diaminopropane linker, with the in vitro antitumor activity of
37 being comparable to that of cisplatin against human ovar-
ian cancer A2780S and melanoma cancer MeWo cell lines.
No activity against the cisplatin-resistant variant A2780cP
was observed. As far as we are aware no biological data
concerning the di- and trisaccharide complexes has been
reported [106,107].
O O
NH2 Cl
sugar-C1
O Pt
Cl H2N NH2
sugar-C1 NH2
Pt
Cl Cl
37 38
Fig. (10). Carbohydrate-pendant platinum complexes, with the Pt
center being linked via an amine linker.
Shigenobu and co-workers reported analogous com-
pounds with the sugar being varied from D-glucose, D-
mannose, D-galactose, D-xylose, to L-glucose (Fig. (10), 37),
coordinated to the Pt center via a (2S)-2,3-diamino-1-
propanol linking ligand (Fig. (10), 38). These sugar-
appended platinum(II) complexes were found to be active
against P388 cells implanted in mice [108]. Significant dif-
ferences between
- and -D-galactose anomers were ob-
served. The former exhibited a T/C value of 194% at 400
mg/kg dose, whereas the latter exhibited low toxicity at the
same dose. Comparison of D- and L-glucose reveals a higher
toxicity of the non-natural carbohydrate, and the (2S)-2,3-
diamino-1-propanol linked compounds show higher toxicity
than the 1,3-diamino-2-propanol derivatives. For all the
studied compounds, the carbohydrate moiety was found to
reduce the toxicity significantly in comparison to cisplatin
(LD50 10 mg/kg) [69]. It is supposed that the uptake into
cancer cells, and the differing intracellular processing may
be responsible for the differences in the antitumor activity of
this complex class [108]. The same group reported the
analogous palladium(II) complexes with their profiles differ-
ing significantly from the platinum analogues [109]. Bio-
Hartinger et al.
logical evaluation of these complexes in vivo against P388
leukemia cells implanted in mice revealed most of the palla-
dium complexes to be inactive with the exception of a disac-
charide maltose-Pd complex which had a T/C value of 120%
at a dose of 400 mg/kg. The lower antineoplastic activity of
the palladium(II) complexes in comparison to Pt(II) com-
pounds is thought to be due to low genotoxicity of Pd com-
plexes, differing DNA damage, and lower stability of the
complexes, especially in biological fluids.
Talebian et al. synthesized Pt compounds linked via an
ethylendiamine moiety to glucose, galactose and mannose
units, in pyranose, furanose and 2-amino-2-deoxy forms
[110]. The respective N-(6-deoxy-1,2:3,4-di-O-isopropyli-
dene-
-D-6-galactopyranosyl) cis-dichloridoplatinum(II)
complex 39 (Fig. (11)) was administered i.p. at a single dose
of 150 mg/kg and resulted in a 72% life span increase, i.e., a
16.3 days survival time, in mice with leukemia. The com-
parison with cisplatin reveals a slightly higher activity of the
established anticancer drug (83% and 17.4 days at 10
mg/kg). The D-galactose and D-ribose compounds were re-
ported without biological data [111].
H2
N
Cl
Pt
Cl
NH
O
O
O
O
39
Fig. (11). Structure of cis-dichlorido[N-(6-deoxy-1,2:3,4-di-O-
isopropylidene-
-D-6-galactopyranosyl)-1,2-ethylenediamine-N,N']
platinum(II) 39.
As far as we are aware, there is only one report dealing
with cyclodextrin derivatives of Pt compounds coordinated
via an amine functionality [112]. However, there are many
papers describing the application of such carbohydrates for
solving formulation problems in pharmaceutical research
[57]. PtCl2(NH3) or PtCl2 fragments coordinated to amino-
and ethylenediamino-- and
-cyclodextrins administered to
mice bearing a standard P388 tumor model gave a maximal
T/C of 121% [112].
2.2. Ligands with O Donors Capable of Releasing the Pt
Center
2.2.1. Carboxylate Ligands
In view of the reported cytotoxicity of Pt(II) complexes
containing oxaliplatin-type chxn ligands against murine
leukemia L1210 [70,113], Kidani et al. reported the synthe-
sis of platinum(II) complexes with D-glucuronate, D-
gluconate, 1,2,3,4-tetra-O-acetyl-
- or -D-glucuronate and
2,3,4,6-tetra-O-acetyl-D-gluconate as leaving groups.
The D-glucuronato compounds of both chxn and 2-
(aminomethyl)cyclohexylamine 40 [amcha; Fig. (12))
ligands were found to be water soluble and were very active
against the P388 leukemia tumor model. Notably, similar to
Anticancer Sugar-Metal Complexes
NH2
-OOC
HO
HO
H2N
40
Fig. (12). Structural formulae of amcha 40, D-glucuronate 41, and D-gluconate 42.
oxaliplatin, a dependence on the conformation of the chxn
ligand was shown, and both the trans- and cis-(1R,2R) com-
pounds were more active than the (1S,2S)-enantiomers. In
the case of the amcha ligands, the D-glucuronato complexes
with the cis-d and the trans-d ligands were more active than
the l-analogues. From this study the amcha complexes ap-
pear to be more active and of lower general toxicity than the
chxn compounds. In combination with their high water solu-
bility, these compounds were considered suitable for further
development. Compounds with other carbohydrate-based
leaving groups, i.e., D-glucuronate 41, D-gluconate 42 (Fig.
(12)) as well as acetylated D-glucuronate and D-gluconate,
were found to exhibit antitumor activity in mice against the
murine L1210 tumor. The anticancer activity was found to
be higher for the more lipophilic compound Pt(1,2,3,4-tetra-
O-acetyl-
-D-glucuronate)2[(1R,2R)-chxn] in comparison to
Pt(D-gluconato)(NO3)(cis-amcha) (T/C values of 388 and
317%, respectively, at a dose of 50 mg/kg) [114,115]. The
comparison of these compounds is perhaps not appropriate
due to their structural dissimilarity. The galactose analogue
Pt(galacturonate)2[(1R,2R)-chxn] was tested against L1210
leukemia in vitro and in vivo and resulted in a T/C value of
238% at a single administration of 12.5 mg/kg [116]. In
addition, the latter compound and its analogous sacchara-
tolactonato and saccharato complexes were shown to be
active in the cisplatin-resistant variant of the L1210 cell line,
with the saccharato complex being more active in the cis-
platin-resistant cells compared to normal L1210 cells [117].
This suggests that the biochemical mechanisms of cisplatin
resistance, including detoxification and repair mechanisms,
do not affect such compounds. Comparing the in vivo activ-
ity of the latter complexes revealed at dosages of 25–50
mg/kg T/C values of about 220%, as also observed for cis-
platin. However, for cisplatin a lower number of long term
survivors was observed (1 in 6 for cisplatin vs. 4 in 6 for the
galacturonato complex), and the sugar complexes were of
markedly lower general toxicity.
Compounds of the latter type, viz. with the sugar ligand
coordinated via a carboxylate, were not very stable under
H2N
O O
OR OR O Pt
N HN
H2
RO O N
N H
H
OR OR O O
43
Fig. (13). Structures of gluconate (43a, R = H; 43b, R = acetyl) and glucosamine-derived complexes with anticancer activity.
Current Medicinal Chemistry, 2008 Vol. 15, No. 25 2581
OH OH O
O
OH HO
O-
OH
OH OH
41 42
physiological conditions with PtCl(D-glucuronato)[(1R,2R)-
chxn] showing half-lives of 56 and 52 min in water and
physiological saline solution, respectively [118]. However,
the compound was highly active against L1210 and its cis-
platin-resistant variant, whereas no tumor-inhibiting poten-
tial was observed against Lewis lung carcinoma and B16
melanoma models. In contrast, the related complex with a
nitrato leaving group, i.e., Pt(D-glucuronato)(NO3)[(1R,2R)-
chxn], only displayed marginal activity against these models,
demonstrating the importance of the appropriate selection of
co-ligands.
Talebian et al. synthesized and examined the bone mar-
row cytotoxicities of platinum(II) complexes in which the
sugar is attached to the Pt center via a malonic acid bridge
(Fig. (13)) [119]. The non-acetylated compound 43a was
found to be much more water soluble than 43b and was
tested for antitumor activity in P388 leukemia, L1210 and its
cisplatin resistant variant L1210/DDP. Compound 43a was
found to exhibit activity similar to cisplatin and carboplatin,
but with reduced nephrotoxicity and less leucopenia than the
established drug compounds [120].
By linking a glucosamine moiety via an L-aspartate
linker, compound 44 (Fig. (13)) was obtained [121]. How-
ever, at a quite high dosage of 400 mg/kg no advantage in
comparison to cisplatin was observed for the treatment of
P388 leukemia in mice, and raising the dose to 800 mg/kg
resulted in death of test mice.
Compound 45 (Fig. (14)) was selected as a lead structure
from a series of compounds having a malonate-derivative as
linker connecting the sugar unit to the Pt moiety [122]. Glu-
cose, galactose and mannose, as well as their 6- and 1-amino
forms and the acids were all attached to the platinum center
using this linker. The in vitro and in vivo cytostatic activity
of the platinum complexes was determined against a variety
of human cancer cell lines, including breast, cervix, prostate
and small cell lung cancer cells. None of the tested com-
pounds were remarkably active in all tumor models, although
45 was more active than the established drugs in human
AcO
AcO O
H2N
AcO S O O
AcHN Pt
N
H2
O
44
2582 Current Medicinal Chemistry, 2008 Vol. 15, No. 25
O HO
O NH
O H2
HO
N Pt
NH Pt
HO O O
H2N HO
O OH
HO OH
OH
45
Fig. (14). Malonate-linked sugar-Pt conjugates.
TUR myeloid leukemia cells, and 46 showed the best activ-
ity in the cervix and prostate cancer cell lines. Studies on the
effect of inhibiting sugar transport revealed a high depend-
ence for 45, whereas the activity of cisplatin was not ef-
fected. In an in vivo study against several tumor models, 45
proved an effective inhibitor of tumor growth. Notably, 45
was highly tolerated with a promising therapeutic index. For
the similar glucosamine derivative, 47, uptake was studied
but no other biological data was reported [123].
Reedijk and co-workers designed the
-glucuronyl-
platinum conjugate 48 (Fig. (15)) with an (1R,2R)-
cyclohexane-1,2-diamine (chxn) ligand, with the intention
that the enzyme
-glucuronidase can cleave the sugar-benzyl
bond inducing the release of the active drug moiety [124].
The platinum complex was characterized as Pt(chxn)(4-
hydroxybenzylmalonate) after enzymatic cleavage, demon-
strating the concept, but further biological data has not been
reported.
NaOOC
H2N
HO O
O O
HO O
Pt N Functionalization of dextran and conjugation to platinum
OH H2
O
O are retained is dependent on the size of the compound. In
48
Fig. (15). Structure of the
-glucuronyl-platinum(II) conjugate 48,
activated by
-glucuronidase.
2.2.2. Dextran and Macromolecular Compounds
Employing a similar strategy as for the compounds de-
scribed in section 2.2.1, i.e., employing a malonato group to
link the sugar moiety to a Pt center, resulted in a series of
macromolecular drugs with antibodies, polymers or oligo-
saccharide carriers linked covalently to (typically) more than
one platinum center. Such carrier units attached to drugs
have been found to facilitate the delivery of drugs to the
target tissue. Moreover, such platinum conjugates were
found to have superior water solubility properties and also
introduce a certain degree of inertness to the platinum center
with regard to reaction with biomolecules in the blood-
stream, which has been proposed to lead to the deactivation
of Pt compounds or even to species exhibiting unwanted
side-effects [125].
Ohya et al. reported the synthesis of cisplatin-polymer
conjugates to 4 galactose units 49 (Fig. (16)) and compared
Hartinger et al.
OH
O
HO OH
OH H2N O
O O O
N
O H
N O H2 O
Pt NH3
O O O O
NH3
46 47
the anticancer activity against human hepatoma cells HepG2
with the same compound being linked only to a single galac-
tose moiety (50) and to the analogue without sugar units. The
cytotoxicity was in the same dimension as observed for cis-
platin and 49 was found to be the most cytotoxic agent, pos-
sibly due to a mediation of the cellular uptake by galactose
receptors expressed on the surface of the cells [126,127].
However, no data on cellular uptake was provided.
Malonate modified dextran was linked to cisplatin-
[128,129] and oxaliplatin-type [130,131] fragments. The
former compound was tested in vivo in mice bearing Colon
26 mouse cancer cells and was shown to be more effective
than cisplatin. The platinum content in the organs remained
high for at least 24 hours after injection, with no accompany-
ing side-effects observed. The oxaliplatin-type complex with
a chxn ligand was investigated against p388D1 lymphocytic
leukemia cells in vitro and was as active as the dichlorido
precursor. The stability of the administered conjugate in
serum was found to be high [130], whereas half of the cis-
platin immobilized on the dextran was released within 48
hours in physiological phosphate buffer solution [132].
moieties resulted, as envisaged, in a longer circulation time
and higher serum levels. The extent to which the compounds
addition, the compounds were less prone to protein binding
than cisplatin and its aqua analogue [133]. Some of the com-
pounds were tested in vitro against murine and human tumor
models and were of similar or lower activity in comparison
to the drug precursors. No correlation between activity and
the molecular weight of the carrier was observed [134,135].
In contrast, in vivo the conjugates were more active than
cisplatin and also the size of the carrier was shown to influ-
ence the activity, with the higher molecular weight conjugate
being the most active. Repeated injections led to 100% sur-
vival of test animals. The binding of the metal fragment is,
however, reversible upon reaction with biological target
molecules such as DNA. In another study dextran and inulin
were modified in a similar manner, but only minor antican-
cer activity was observed in human or murine leukemia, lung
and colon cancer models [136].
Dextran and starch were modified by malonic anhydride
and reacted in situ to form monodentate platinum complexes
of cisplatin- and oxaliplatin-type [137-139]. T/C values of
329% were reached against L1210 leukemia in mice, with
some of the mice even cured, an effect which could not be
Anticancer Sugar-Metal Complexes Current Medicinal Chemistry, 2008 Vol. 15, No. 25 2583

OH
OH OH

O
OH H H
HO O
HO N O N O
OH O O O
HO 3 H H
O N O N
OH NH N O O
OH H n
OH
O O O Pt NH3
O O O
OH H NH3
HO O NH
HO N O
OH
HO 3
O

OH
OH OH

O
OH H H
HO O
HO N O N O O
OH O
HO 3
O NH
OH NH
OH OH
O
O
OH H
HO O NH
HO N O
OH
HO 3
O

49
OH
OH OH

O
OH H H NH3
HO O
HO N O N O O O
OH O Pt NH
HO 3 H 3
O N O
N N
H H
O O
50

Fig. (16). Galactose-based macromolecular Pt conjugates.

achieved by treatment with cisplatin. Similar to the previ-
ously described carbohydrate complexes, much higher doses
than that required for cisplatin were applicable.
Oxidized polysaccharides have been attached to platinum
centers [140]. Amylose and dextran of different molecular
weights, amylopectin, polygalacturonic acid and alginic acid
were thereby linked to a Pt(chxn) moiety. In general, at low
doses excellent results were obtained against L1210 leuke-
mia in mice with T/C values up to 357% (for cisplatin 175%)
and 5 of 6 mice cured. Screening the amylose compound,
which was the most active against L1210, in solid tumor
models revealed up to complete inhibition of tumor growth.
Schechter and colleagues followed a different approach
by linking the cytotoxic platinum moiety in a similar manner
as described above to a monoclonal antibody directed against
the epidermal growth factor receptor which is over-expressed
on KB cells [141]. The carrier-conjugated drug was still
capable of interacting with DNA and was pharmacologically
active against tumor cells. Notably, the antibody conjugation
and also biotinylation proved to be important for anticancer
activity. By using antibodies specifically reactive to B lym-
phoma cells preferential cytotoxicity to this cell type was
observed [142], albeit at maintained level as for the parent
inorganic drug molecules. The conjugation of platinated
dextranes with antibodies resulted in stable compounds un-
der bloodstream conditions and a strong influence on the
systemic clearance and distribution of platinum into tissues
[143].
2.2.3. Organometallic Compounds
Partly inspired by the finding of Lowe and coworkers,
who reported that platinum(II) complexes of 4’-substituted
2,2’:6’,2’’-terpyridine were cytotoxic to human ovarian
carcinoma cells [144] as well as to Trypanosoma and
Leishmania parasites [145], Ma et al. synthesized water
soluble luminescent platinum terpyridine complexes with
glycosylated acetylide and arylacetylide ligands and studied
their DNA binding properties [146,147]. Spectroscopic stud-
ies showed that the Pt(II)-glycosylated acetylide or arylacet-
ylide moieties remain intact in aqueous solution for 72 hours
at room temperature. The compounds were found to bind to
DNA in an intercalative manner, as indicated by spectropho-
tometric studies, and the substitution pattern of the terpyri-
dine ligand was shown to influence the extent of intercala-
tion. The complexes with arylacetylide (51) and glycosylated
acetylide (such as 53) ligands were tested for their cytotoxic-
ity against human carcinoma cell lines in comparison to
cisplatin and the non-glycosylated arylacetylide derivative
52. The most active compound was identified as 51 (Fig.
(17)), which is approximately 10-times more active than the
non-glycosylated compound 52 and one order of magnitude
2584 Current Medicinal Chemistry, 2008 Vol. 15, No. 25 Hartinger et al.

t-Bu t-Bu

N OAc N N OAc
AcO OAc AcO
O OAc
t-Bu N Pt O N Pt t-Bu N Pt O O
OAc OAc
N N N

51 t-Bu 52 53 t-Bu

Fig. (17). Organometallic terpyridine-Pt complexes.

Table 4. IC50 Values (
M) of 51–53 in Human Carcinoma Cell Lines (HeLa, HepG2, SF-268, NCl-H460, MCF-7) and Normal 293
Cells in Comparison to Cisplatin [146,147]

Complex Cell linesa

HeLa HepG2 SF-268 NCI-H460 MCF-7 293

51 0.1 ± 0.03 0.1 ± 0.01 0.06 ± 0.02 0.1 ± 0.03 0.08 ± 0.04 0.5 ± 0.1
52 2.7 ± 0.7 3.0 ± 1.1 2.1 ± 0.8 2.5 ± 0.8 3.4 ± 1.0 4.6 ± 1.2
53 17.8 ± 0.5 22.9 ± 0.8 17.1 ± 0.4 28.5 ± 1.9 17.1 ± 0.4 50.3 ± 7.2
cisplatin 11.6 ± 0.2 20.6 ± 1.9 15.6 ± 0.2 25.1 ± 3.4 19.1 ± 1.7 > 100
a
HeLa, cervix carcinoma; HepG2, hepatocellular carcinoma; SF-268, human glioma; NCI-H460, lung cancer; MCF-7, breast adenocarcinoma; 293, non-tumorigenic kidney cell line.

more potent than the acetylide complex 53, the latter being
slightly less active than cisplatin. All the compounds showed
the lowest activity in the non-tumorigenic kidney cell line
293, with cisplatin being non-toxic in this model. Further-
more, cancer cell death was induced in about 52% of the
cells by apoptosis and a much lower fraction of necrosis was
observed (ca. 4.8%). Notably, these organometallic com-
pounds represent rare examples of Pt complexes linked to
sugar molecules exhibiting lower IC50 values than cisplatin
in cell culture studies.
2.3. Pt complexes of P-Containing Sugars
In an attempt to overcome resistance problems occurring
during the treatment of cancer patients with cisplatin and
other platinum complexes, P-containing sugar derivatives
have been developed. Shi and co-workers synthesized sugar
complexes bases on carbohydrates with a PPh2 group at the
2-position, such as in ligand 54 (Fig. (18)), or at C3
[148,149]. The respective Pt complex 55 was proposed to
exert a potential activation/deactivation mechanism by form-
ing singly- (56) and doubly ring-closed (57) species [148] by
exploiting pH differences between tumor and normal tissue,
as shown for similar aminoalcohol complexes [150]. Fur-
thermore, such a ring-opening/-closing mechanism might
prevent platinum complexes from undergoing reactions with
biomolecules after intravenous administration, with protein
interactions possibly contributing to the toxic side-effects of
Pt-based drugs [151-153]. Compounds 55–57 were active
against P388 leukemia with an inhibition ratio of 60% at
high nM concentrations. However, detailed biological data is
not available.
The dinuclear complex 58 (Fig. (18)), in which bisphos-
phonate ligands bridge the two Pt centers, was reported to be
slightly active in sarcoma S180 ascites and L1210 leukemia
tumor models at a high single dose of 320 mg/kg [154].
Treatment resulted in an increased life span of 28% in the
sarcoma mice vs. 58% for cisplatin.
3. NON-PLATINUM CARBOHYDRATE-BASED
METAL COMPLEXES
3.1. Auranofin Analogues
In modern clinical protocols, auranofin [(2,3,4,6-tetra-
O-acetyl-1-thio- ß- D-glucopyranosato-S)(triethylphosphine)]-

OH

HO O
OH OH OH
HO
PPh2 NH
Ph O
O O OH P Cl P Cl P O
OMe Pt Pt Pt O O
= O
P Cl P O P O P P
OH P
O O O O 58
OH Pt
Pt NH2
H2N
54 55 56 57 NH2 H2N

Fig. (18). Ring-closing Pt-phosphinesugar complexes based on ligand 54, and a bisphosphonate-based dinuclear Pt complex.
Anticancer Sugar-Metal Complexes Current Medicinal Chemistry, 2008 Vol. 15, No. 25 2585

gold(I) 59, Fig. (19)) is used in the treatment of rheumatoid
arthritis [155-158]. Auranofin and other Au complexes [both
Au(I) and Au(III) based] have also been evaluated for the
treatment of cancer [147,159-163], AIDS [147], bronchial
asthma, and malaria [158,164].
AcO
AcO O activity of Au(54)(2-mercaptobenzimidazole) was found in
AcO S the high nM range [168].
Au
OAc X
Fig. (19). Structures of auranofin and selected derivatives;
P(CH2CH3)3 auranofin 59, P(CH3)3P 60, P[(CH3)2CH]3
P[(CH3)3N]3 62, P(C6H5)3 63, P(CH3CH2)2(C6H5)
P[(CH3CH2)(C6H5)2] 65, P[(CH3CH2)2(CH3CH2O)]
P(CH3CH2)2[(CH3)2CH] 67, P(CH3CH2)2[HO(CH2)4] 68.
Auranofin was found to be active in several tumor mod-
els [159,160,162,165], affecting the mitochondrial function
[166] and inducing apoptosis. The thioredoxin reduc-
tase/thioredoxin system in the mitochondria might play a
central role in the mode of action of auranofin, with au-
ranofin being an inhibitor of thioredoxin reductase leading to
an elevated level of hydrogen peroxide in the mitochondria.
A large number of auranofin analogues with different sub-
stituents (see examples in Table 5) and other sugar-based
Au(I) complexes have been reported [167] and some of them
were found to exhibit potent antitumor activity in vitro and
in vivo. Replacing the triethylphosphine ligand in auranofin
by other phosphines, phosphinites or amidophosphites did
not significantly alter the antitumor activity in B16 cells and
in the P388 leukemia tumor model. A similar observation
was made on replacing the tetraacetylglucose moiety by
glucose (both
and ), galactose and xylose.
Shi et al. reported the synthesis and characterization of
several gold(I) complexes based on ligand 54 (Fig. (18)),
also used in platinum complexes (see section 2.3.), and the
analogous compound with the PPh2 group in the 3-position
[165,168]. These complexes have been found to be effective
in inhibiting the growth of P388 leukemia, in particular, the
Baker, Berners-Price and co-workers reported the synthe-
X = sis of organometallic Au(I) N-heterocyclic carbene com-
61, plexes 69 (Fig. (20)) as analogues of auranofin [169]. Such
64, ligand systems were found to be suitable for tuning lipophil-
66, icity, and in preliminary biological studies the complexes
were shown to exhibit antimitochondrial activity which
could be correlated to their lipophilicity.
The dinuclear Au(I) complex 70 (Fig. (20)) proved to be
active in murine tumor models. It was shown to induce an S-
phase arrest in human promyelocytic leukemia HL-60 cells
at low concentrations, whereas at higher concentrations a
secondary block in the G1/S transition was observed [170].
3.2. Ru(II) and Ru(III)-Sugar Complexes
Ruthenium(III) complexes are among the most exten-
sively studied anticancer compounds (after those based on
platinum) and the two most promising compounds KP1019
71 and NAMI-A 72 (Fig. (21)) are currently undergoing
clinical trials [28,29,171]. Their proposed mode of action is
different from that of Pt anticancer agents, thus Ru com-
pounds might extend the range of treatable tumors. In gen-
eral, Ru complexes are less generally toxic and therefore less
prone to inducing unwanted side-effects in patients, a major

Table 5. Biological Activity of Auranofin and Related Analogues In Vitro in B16 Mouse Melanoma Cells and In Vivo Against P388
Leukemia in Mice [167]

Compound B16, IC50 / μmol/kg MTD / μmol/kg P388, ILSmax / %

59 (auranofin) 1.5 18 70
60 2 9 45
61 4 14 46
62 2 8 60
63 4 7 36
64 2 13 55
65 4 6 32
66 1 14 70
67 2 17 90
68 8 17 58

AcO OH
AcO O HO
R O HO
AcO S HO OH
Au N HO S S O
OAc Au Au
OH Ph2P Ph2P OH
N
R
69 70

Fig. (20). Structures of organometallic Au(I) N-heterocyclic carbene compounds, and a dinuclear Au complex.
2586 Current Medicinal Chemistry, 2008 Vol. 15, No. 25 Hartinger et al.

HN +
H H R
NH R
N N N N
Cl Cl HN Cl Cl O
Ru Ru Ru
Cl Cl Cl Cl
HN Cl Ru N
H2N Cl Ru
O
Cl P Cl P
N NH2 Cl O
S
HN O N O
N
OR2
OR1
71 72 73 74 75

Fig. (21). Ruthenium complexes of interest for anticancer research.

draw-back in Pt-based chemotherapy. Their low toxicity is
thought to stem from the selective transport into the tumor
via the transferrin pathway [152,172-174] and reduction of
Ru(III) species to Ru(II) in the cell, leading to their activa-
tion [175,176]. Recently, organometallic Ru(II)-arene com-
pounds were found to exhibit potential as anticancer agents,
and such compounds were found to be active both against
primary tumors (74) and metastasis (73) [36,37,177-187].
A large number of ruthenium complexes with different
ligands have been synthesized and tested for their anticancer
properties, although only a few carbohydrate complexes with
anticancer activity have been reported.
In particular, a bleomycin-Ru(III) complex was reported
to be ineffective in DNA strand scission whilst exhibiting
anticancer activity against murine leukemia L1210 cells,
with a similar magnitude to cisplatin [188]. It seems likely
that DNA strand cleavage is not responsible for the in vitro
toxicity and some other mechanism is in operation.
Recently, organometallic Ru(II)-arene complexes of the
general formula 75 (Fig. (21)) with phosphite-carbohydrate
ligands have been reported [189-191], and the compounds
were found to be moderately active against human colon
adenocarcinoma (SW480), ovarian carcinoma (CH1, A2780
and cisplatin-resistant A2780), lung carcinoma (A549),
melanoma (Me300), glioblastoma (LNZ308) and HCEC
endothelial cells in vitro [192], as was also observed for
certain RAPTA-type complexes and NAMI-A [178,193].
Similar IC50 values in A2780 and the cisplatin-resistant phe-
notype suggest a different mode-of-action as compared to
cisplatin. Importantly, the lowest activity was found against
the non-tumoral endothelial cell line, indicating selectivity
for cancer cells.
Following a different approach by using Ru-sugar com-
plexes for imaging purposes, a
-emitting ruthenocene moi-
ety (103Ru) was linked to sugar residues, in particular ami-
nosorbit, tetraacetylglucosamine, aminomannit and ami-
nodulcit derivatives were prepared [194]. The compounds
were observed to be highly stable in vivo and after applica-
tion to mice bearing Ehrlich’s ascites tumor, it was found
that the compounds accumulated in the liver and kidneys
[195]. However, excretion was markedly accelerated for the
sugar compounds in comparison to the administration of
103
RuCl3.
3.3. Metallocene-Based Compounds
Titanocene dichloride 76 (Fig. (22)) was introduced as a
putative anticancer drug at the end of the 1970’s and entered
clinical trials in 1993 [46,196]. Nephrotoxicity was identified
as dose-limiting, but the absence of bone marrow toxicity
was thought to be promising and clinical phase II trials were
initiated. In these studies, setup as a single agent therapy, no
improved effects in comparison to other treatment regimens
were observed and accordingly the development was abon-
doned.
There are only a few examples in literature of sugar-
derived titanium compounds with biological data [197,198].
One appears to be a titanocene-cyclodextrin derivative with
the titanocene group bridging two cyclodextrin moieties
[197]. The compound was observed to exhibit potent cyto-
toxicity against the human MCF-7 breast cancer cells and
was significantly more active than titanocene dichloride.
Another series of Ti compounds bearing either one (77) or
two (78) ribofuranose moieties was tested and compared to
cisplatin, titanocene dichloride and titanocene bisbenzoate
against L929 mouse fibroblasts, A-431 epithelial carcinoma,

OMe OH
O
OMe
O HO O
MeO Cl O O
O Ti
Cl Cl O O O O
Cl OMe
Ti Ti
O O a R=H
Cl Cl
b R = CH3 R R
O O Fe
R R
R R
76 77 78 79

Fig. (22). Organometallic complexes of interest for anticancer research.

Anticancer Sugar-Metal Complexes
A-498 renal cancer and KB 3.1 cervix carcinoma cell lines
[198]. Titanocene 78a appeared to be the most active com-
pound of the series, exhibiting similar activity as cisplatin in
L929 and KB 3.1 cells. Furthermore, the synthesis of several
other sugar-derived Ti and also Zr compounds was reported,
but no biological data was published [199-204].
Ferrocene derivatives have gained significant interest in
medicinal application, largely motivated by the pioneering
work of Jaouen and co-workers on the tamoxifen derivatives
of ferrocene [205] and by the development of ferroquine as
an antimalarial [206]. Itoh et al. have reported on the synthe-
sis of a series of ferrocene-conjugated glucose derivatives
such as 79 and tested them in a mouse cancer cell line
(FM3A) and also against the malaria parasite P. falciparum
[207,208]. Only moderate activity was observed against this
cancer model and against other human tumor cell lines, in-
cluding 41M, CH1 (both ovarian carcinoma), SK-BR-3
(mammarycarcinoma), and SW480 (colon carcinoma) [209].
4. CONCLUSIONS AND OUTLOOK
Carbohydrates and their derivatives are the constituents
of many natural antibiotics, including bleomycin, anthracy-
clines, neocarzinostatin chromophore, and other DNA-
targeting agents. Sugar compounds such as glucose are re-
quired to a higher degree by tumors, indicated by the over-
expression of glucose receptors on the cell surface, offering a
degree of selective transport to cytotoxic compounds at-
tached to carbohydrates. This requirement is also related to
the up-regulation of the glycolytic activity for energy pro-
duction (due to lower nutrition supply because of slow
neovascularization), one of the major metabolic alterations in
cancer cells [210,211].
Linking metal complexes to sugars usually results in im-
proved solubility in biologically compatible media (com-
pared to established anticancer drugs and drug candidates in
advanced stages of development). They are suitable for in-
travenous application, and result in compounds with a re-
duced general toxicity, which might be related to a type of
targeted approach. This feature allows the drug candidates to
be applied at much higher doses and endows them with a
broader therapeutic window. Notably, many examples have
been reported with higher anticancer activity, both in vitro
and in vivo, than standard chemotherapeutics, but no clear-
cut structure-activity relationships were found. Also, the
mechanism of action of the sugar complexes is not clear yet.
For platinum complexes a similar mode of action as for the
compounds in clinical routine is assumed, whereas not much
is known about the targets for non-platinum complexes.
As far as we are aware metal-carbohydrate compounds
have not yet entered clinical trials, although for example,
chxn-Pt sugar complexes were more active than oxaliplatin
itself. The lack of clinical data might be at least in part due to
higher preparative demands in comparison to the relatively
simple benchmark chemotherapeutics. However, carbohy-
drate chemistry is extensively developed, but frequently
includes multi-step synthetic procedures, which is a draw-
back for commercialization of such compounds. Further-
more, a lot of the data in this field is found exclusively in the
Current Medicinal Chemistry, 2008 Vol. 15, No. 25 2587
patent literature, which could also hamper scientific pro-
gress.
When comparing the type of linkages used to connect
metal complexes to sugars there are two different classes.
First, where the metal center is linked to the carbohydrate via
a group capable of releasing the cytotoxic moiety and the
sugar being mainly responsible for the transport, and can be
considered a carrier molecule. Second, in complexes with
aminosugars, the sugar moiety should have a significant
influence on the anticancer activity, and if DNA is consid-
ered the ultimate target, on the structural changes induced in
DNA.
Although carbohydrate-metal compounds have been
shown to exhibit cytostatic activities in several cases, many
facets remain to be explored. Future research should cer-
tainly include more detailed studies on the uptake of sugar
compounds mediated by sugar transporters, since this argu-
mentation is frequently used as a justification, and the me-
tabolization of such compounds in biological environment.
Also the type of linker, the ligand sphere of the cytotoxic
moiety, the release of the metal center, etc. need fine tuning,
and offer scope for further investigations. Finally, it would
be interesting to see the performance of a carbohydrate-
based metal complex in clinical trials as some described in
this review appear to be significantly superior to the existing
chemotherapeutic agents currently available.
5. ACKNOWLEDGEMENTS
The authors are indebted to the Higher Education Com-
mission of Pakistan, the Austrian Exchange Service, the FFG
– Austrian Research Promotion Agency (811591), the Aus-
trian Council for Research and Technology Development
(IS526001), the FWF – Austrian Science Fund (J2613-N19),
the Swiss National Science Foundation (individual short
visit, No. 120985) and COST D20 and D39 for financial
support.
ABBREVIATIONS
ADEPT = antibody-directed enzyme prodrug therapy
Amcha = 2-(aminomethyl)cyclohexylamine
chxn = cyclohexane-1,2-diamine
dGMP = 2-deoxyguanosine 5’-monophosphate
ED = effective dose
IC50 = 50% inhibitory concentration
ID50 50% inhibitory dose
=
i.p. = intraperitoneal
ILS = increased life span
T/C = treated to control
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Received: June 01, 2008 Revised: August 10, 2008 Accepted: August 15, 2008

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