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Chemical biology of anticancer gold(III) and

gold(I) complexes
Cite this: DOI: 10.1039/c5cs00132c
Taotao Zou,ab Ching Tung Lum,a Chun-Nam Lok,a Jing-Jing Zhanga and
Chi-Ming Che*ab

Received 10th February 2015
DOI: 10.1039/c5cs00132c
www.rsc.org/csr
Gold complexes have recently gained increasing attention in the design of new metal-based anticancer
therapeutics. Gold(III) complexes are generally reactive/unstable under physiological conditions via intracellular
redox reactions, and the intracellular AuIII to AuI reduction reaction has recently been ‘‘traced’’ by the
introduction of appropriate fluorescent ligands. Similar to most Au(I) complexes, Au(III) complexes can
inhibit the activities of thiol-containing enzymes, including thioredoxin reductase, via ligand exchange
reactions to form Au–S(Se) bonds. Nonetheless, there are examples of physiologically stable Au(III)
and Au(I) complexes, such as [Au(TPP)]Cl (H2TPP = 5,10,15,20-tetraphenylporphyrin) and [Au(dppe)2]Cl
(dppe = 1,2-bis(diphenylphosphanyl)ethane), which are known to display highly potent in vitro and
in vivo anticancer activities. In this review, we summarize our current understanding of anticancer gold
complexes, including their mechanisms of action and the approaches adopted to improve their
anticancer efficiency. Some recent examples of gold anticancer chemotherapeutics are highlighted.

Introduction well-known orally active gold(I)–phosphine–thiolate complex,

Gold has been utilized as a therapeutic for thousands of years,
its use dating as far back as ancient Chinese and Arabic
medicines.1 In the late 19th century and early 20th century,
[Au(CN)2] and Au(I) thiolates were discovered to be effective in
tuberculosis treatment.2 In 1929, Forestier identified the utility
of gold in the treatment of rheumatoid arthritis (RA).3 Later, the
a
State Key Laboratory of Synthetic Chemistry, Institute of Molecular Functional
Materials, Chemical Biology Centre and Department of Chemistry, The University
of Hong Kong, Pokfulam Road, Hong Kong, China. E-mail: cmche@hku.hk
b 2,2 0 :6 0 ,200 -terpyridine,12,13 2,2 0 -bipyridine,12 porphyrin ligand4),
HKU Shenzhen Institute of Research and Innovation, Shenzhen 518053, China
auranofin, was developed to treat RA in a clinical setting.1,2,4
In recent years, there have been extensive studies on the
therapeutic applications of gold complexes as anticancer agents.5–10
Gold(III) complexes were originally studied as potential alternatives to
the anticancer drug cisplatin. In early work, DNA was conceived to be
the anticancer target, but later studies showed that thiol-containing
proteins/enzymes, such as thioredoxin reductase (TrxR), can
play important roles in the mechanisms of action of anticancer
gold complexes.11 In recent years, anticancer-active gold(I)
complexes containing multidentate N-donor ligands (e.g.,

Taotao Zou obtained his bachelor’s
degree in chemistry from Wuhan
University in 2010. Then he went
to the University of Hong Kong
(HKU) to pursue his PhD study
under the supervision of Professor
Chi-Ming Che and obtained the
degree in 2015. His PhD studies
were focused on the anticancer
properties and sensory applications
of metal complexes in biological
systems. He is now a postdoctoral
Taotao Zou fellow in the Department of
Chemistry of HKU.
Ching Tung Lum obtained a PhD
degree in molecular biology, the
University of Hong Kong. She is
currently working as a postdoctoral
research fellow in Prof. Chi-Ming
Che’s group. Her research
interest is in the development of
novel metal-containing compounds
as chemotherapeutic agents for
treating cancers.
Ching Tung Lum

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or cyclometalating ligands (e.g., deprotonated N,N-dimethyl-1-
phenylmethanamine,14 6-(2-phenylpropan-2-yl)-2,20 -bipyridine,15
>2,6-diphenylpyridine4) or dithiocarbamate16 ligands have been
extensively studied. The antiarthritic auranofin was reported to
exhibit potent in vitro anticancer effects in human cancer cell lines
and to display in vivo effects in the P388 leukemia mouse model.17
Gold(I) complexes containing phosphine,18 N-heterocyclic carbene
(NHC),19,20 thiolate,21,22 alkynyl,23,24 thiourea,25 triazole–peptide26
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or other ligands have been reported to inhibit the activities of thiol-
containing enzymes, including TrxR, at low nanomolar levels. As
the mechanisms of action of anticancer gold complexes are likely to
be different from that of cisplatin, most of the reported cytotoxic
gold complexes are also effective against cisplatin-resistant cancer
cells, revealing the promising prospect in the development of gold
chemotherapeutics to resolve the problem of cisplatin resistance.
Some of the reported Au(I)–Au(III) complexes have also been
demonstrated to display significant in vivo anticancer effects.
Chun-Nam Lok obtained his BSc
in biology from Hong Kong Baptist
University and PhD in physiology
from the University of Hong Kong.
He pursued his postdoctoral
studies in biomedical sciences in
Lady Davis Institute for Medical
Research at McGill University and
Cancer Research Institute at
Queen’s University, Canada. He
is currently Research Assistant
Professor in the Department of
Chun-Nam Lok Chemistry and Chemical Biology
Centre at the University of Hong
Kong. His research interests include metals in biology and medicine,
and drug discovery.
Jing-Jing Zhang received her
bachelor’s degree in chemistry
and master’s degree in Organic
Chemistry (with Prof. Guo-Yuan
Lu) from Nanjing University in
2006 and 2009, respectively.
Thereafter, she got her PhD
degree in chemical biology (with
Prof. Chi-Ming Che) from the
University of Hong Kong in 2014.
She currently works in Technische
Universität Braunschweig (with
Jing-Jing Zhang Professor Ingo Ott) and
Universität Heidelberg (with
Professor Stefan Wölfl) and is sponsored by Alexander von
Humboldt Research Fellowship. Her research interests focus on
metal-based cytotoxic and anti-angiogenic drugs and the potential
mechanism of their anti-cancer action.
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This review outlines the recent developments of gold complexes
as antitumor agents, together with their general mechanisms of
action and the approaches which have been used to improve their
anticancer efficacy. In particular, several gold complexes, which
exhibit promising in vivo antitumor effects, as well as the details of
selected complexes’ mechanisms of action, are discussed.
Gold–sulfur binding interactions
The common oxidation states of gold compounds are +3, +1 and 0.
Gold nanoparticles have been used widely in drug delivery but this
aspect of gold chemistry is beyond the scope of this article. Under
physiological conditions, the reduction of Au(III) to Au(I) readily
occurs, and the as formed gold(I) species can also undergo ligand
exchange reactions. Both of these events can lead to a high affinity
of the gold ions towards cellular thiols.
Glutathione (GSH) is the most abundant intracellular thiol
having concentrations of 0.5–10 mM in cancer cells.27 The
majority of the reported gold(III) complexes are electrophilic
and can be reduced to Au(I) or Au(0) by intracellular thiols.
As Au(III) is usually four-coordinated and Au(I)/Au(0) usually
contains fewer than four coordinated ligands, the reduction of
Au(III) will be accompanied by the release of (a) coordinated
ligand(s) as depicted in Scheme 1. With a judicious choice, the
released ligand could also confer biological activities.
Cyclometalated gold(III) complexes coordinated with depro-
tonated C-donor atoms (C) exhibit high stability even in the
presence of cellular reducing agents. The C-deprotonated
bidentate C^N, and tridentate C^N^C and C^N^N ligands,
(Fig. 1) have been extensively used in the synthesis of gold(III)
Scheme 1 Reduction of a four-coordinated Au(III) to a two-coordinated
Au(I) or Au(0) accompanied by the release of the coordinated ligand.
Chi-Ming Che received his PhD
degree in 1982 from the
University of Hong Kong and
worked at California Institute of
Technology from 1980 to 1983.
He is Dr Hui Wai-Haan Chair of
Chemistry, a member of the
Chinese Academy of Sciences
and a Foreign Associate of
National Academy of Science
(USA). He is the First Class Prize
awardee of State Natural Science
Chi-Ming Che Award from China (2007). His
research interests include
synthetic chemistry, metal–ligand multiple bonds, metal-
catalyzed organic transformations, inorganic photophysics and
photochemistry, phosphorescent metal complexes and materials,
and inorganic medicines.
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Fig. 1 Reported C-deprotonated cyclometalated ligands used in anti-
cancer gold(III) complexes.
complexes; the gold(III) complexes stabilized by these ligands
are relatively stable against reduction under physiological con-
ditions and have been observed to display promising anticancer
activities. A recent review by Ruiz and co-workers describes
the different types of anticancer cyclometalated complexes of
platinum group metals, including those of gold.28 In the early
2000s, Che and co-workers reported the use of porphyrin
ligands to stabilize Au3+ ions, and gold(III)–porphyrin com-
plexes have since been found to display both high stability
and strong antiproliferative effects towards a panel of cancer
cell lines.29
Under physiological conditions, the naked Au+ ion is unstable
and tends to undergo disproportionation to yield Au3+ and Au0.
Au+ - Au3+ + Au0
Thus, the Au+ ion needs to be stabilized by ligands. The
ligands commonly used include thiolate (RS), phosphine (PR3),
NHC, and acetylide (RCRC). Gold(I) complexes can be two-,
three- or four-coordinated but two-coordinated gold(I) complexes
are mostly encountered.30 In biological systems, gold(I) com-
plexes can undergo a two-step ligand exchange reaction via a
three-coordinated gold(I) intermediate (Scheme 2).1
Upon administering a gold(I) complex to cells, a ligand
exchange reaction with GSH can rapidly occur.2 In animal
studies, the ligand exchange reaction of gold(I) complexes with
Cys34 of serum albumin (SA) to form gold(I)–SA adducts has
been reported.31 It has been suggested that SA may serve as a
drug carrier or, more likely, function as a drug ‘‘scavenger’’
to abrogate the activity of gold(I) complexes.24,32 Sadler and
co-workers reported that the thermodynamic stability of gold
complexes is dependent on the auxiliary ligands in the following
order:1
CN B Scys B PR3 c SMet B NHis 4 Cl c COO
Scheme 2 Ligand exchange reaction of gold(I) complexes with thiolate.
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Enzymes as targets – structural
evidence
Unlike cisplatin and its derivatives that target DNA, gold
complexes exhibit a high propensity to target enzymes, especially
those that contain thiols. This targeting feature is attributed to the
strong binding affinity of gold ions with thiols. Most of the thiol-
containing enzymes, such as TrxR, glutathione reductase (GR), and
cysteine protease, are overexpressed in cancer cells, thus providing
potential anticancer targets for gold complex therapy.11,33,34 Several
structures of gold(I)–protein adducts have been solved using X-ray
crystallography, most of which feature SCys–Au–SCys and/or SCys–Au–
ligand binding interactions in the active site of the enzyme. The
Au–S bonding is believed to be responsible for the observed strong
inhibition of enzyme activity.35
Disulfide reductases
GR and TrxR are disulfide reductases that contain cysteinyl
thiols (TrxR also contains selenocysteine) in their active sites.
Both enzymes play a key role in the redox regulation of
important cellular processes such as DNA synthesis, transcrip-
tion, cell growth, and drug resistance.36,37 A number of gold(I)–
phosphine, gold(I)–NHC, and gold(III) complexes have been
reported to be strong disulfide reductase inhibitors with inhibitory
IC50 values down to nanomolar levels.11 Becker and co-workers
reported a gold(I) phosphole complex that acts as an irreversible
inhibitor of human disulfide reductases.34 The crystal structure of
the gold(I)–GR adduct reveals an almost linear Scys–AuI–Scys coordi-
nation and a Scys–AuI–phosphole coordination in the active site
(Fig. 2a). Similar coordination modes have been found in adducts
of gold with thioredoxin–glutathione reductase (TGR, a parasite
enzyme similar to TrxR) obtained from the reaction of auranofin
with TGR (Fig. 2b).38 In the Au(I)–TGR adduct, the coordinated
triethylphosphine and thioglucose ligands of auranofin have not
been observed but there are two linear Scys–AuI–Scys coordination
modes. Moreover, the activity of trypanothione reductase (TR), a
disulfide reductase that regulates leishmania infantum polyamine-
dependent redox metabolism, can be significantly inhibited by
auranofin.39 The crystal structure of the Au(I)–TR adduct shows the
release of the coordinated ligand(s) of auranofin as well, allowing
the naked Au+ ion to coordinate with two cysteinyl thiols and a
chloride (Fig. 2c). All these structural data indicate that gold(I)
complexes can be tightly binding inhibitors of disulfide reductases
through the formation of Au–S bond(s) with active site cysteinyl
thiols.
Cysteine proteases
The cysteine protease cathepsin contains a nucleophilic cysteinyl
thiol in its active site.33 The molecular mechanism of proteolysis by
cysteine proteases includes: (1) deprotonation of thiol by an
adjacent histidine; (2) nucleophilic attack of carbonyl group carbon
by the S atom of the deprotonated thiol; (3) hydrolysis of the
thioester bond (Scheme 3).40 In the literature, cathepsins K and S
have been reported to be efficiently inhibited by auranofin and are
at least ten times more efficiently inhibited by gold thiomalate.41
The crystal structure of the gold thiomalate–cathepsin K adduct
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Fig. 2 Crystal structure of gold(I)–protein adducts: (a) Au(I)–GR adduct (PDB code: 2AAQ, gold source: Au(I)–phosphole).34 (b) Au(I)–TGR adduct (PDB
code: 3H4K, gold source: auranofin).38 (c) Au(I)–TR adduct (PDB code: 2YAU, gold source: auranofin).39 (d) Au(I)–cathepsin K adduct (PDB code: 2ATO,
gold source: gold(I) thiolate).41
Scheme 3 Catalytic cycle of cysteine proteases. The covalent (coordination)
binding of Au(I) with cysteinyl thiol can block the catalytic cycle.
(Fig. 2d) shows a linear Scys–AuI–Sthiomalate coordination, with
the thiomalate group surrounded by several amino acid residues
that form hydrogen bonds with thiomalate, leading to an
increased stability of the covalent adduct. It is noted that
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deprotonation of thiol by the adjacent base (e.g., His) plays a
crucial role in the enzyme inhibition by gold complexes.
Protein tyrosine phosphatases (PTP)
PTPs catalyse the removal of phosphate groups from phosphorylated
tyrosine residues on proteins (Scheme 4). PTPs play important
roles in various physiological processes including regulation of
signalling pathways such as T-cell signalling, cell growth, cell
differentiation, immune response, and survival. PTPs contain a
highly activated cysteine residue in their active site with an
unusually low pKa (B4.7);42 therefore, the thiol is mainly in the
deprotonated form at physiological pH and can be a molecular
target of anticancer gold(I) complexes. Barrios and co-workers
have identified a library of [Au(PR3)Cl] complexes that show
micromolar IC50 values (1.5–33 mM) for the inhibition of the
lymphoid tyrosine phosphatase (LYP).43
Other enzymes
Besides the redox regulation of disulfide reductases, cysteine
proteases and protein tyrosine phosphatases, other thiol/selenol-
containing enzymes may also be involved in the mechanisms of
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Scheme 4 Catalytic cycle of protein tyrosine phosphatases. The covalent

binding of Au(I) with cysteine can block the catalytic cycle.

action of anticancer gold complexes. For example, glutathione

peroxidase (GPx)44 and iodothyronine deiodinase (ID)45 have
been reported to be effectively inhibited by gold(I) complexes.
The activity of IkB kinase (IKK) can be blocked by thiol-reactive
auranofin, aurothiomalate, aurothioglucose, and AuCl3, leading
to blocked activation of NF-kB, a transcription factor involved in
the expression of many inflammatory genes and cancer develop-
ment. This inhibition is probably caused by the binding of gold
with the cysteinyl thiol in the catalytic subunits of IKK.46
Though there are no direct structural data of an Au(III)–
protein adduct yet, the intracellular reduction of Au(III) to Au(I) is
well documented. This lends support to redox reactive gold(III)
complexes as potential inhibitors of the aforementioned enzymes.
By using high resolution mass spectrometry, the binding of gold(III)
with thiol–proteins has also been observed.49 Very recently, the
membrane water/glycerol channel protein (aquaporin 3)47,48 and
a deubiquitinase49 have been reported to be potential targets of
gold(III) complexes due to the binding of gold(III) with cysteinyl
thiols.
Unlike the redox and/or substitution reactive gold(III)–gold(I)
complexes that can form tight Au–S/Se bonds, gold(III) porphyrins,
which are not reactive towards thiols, have been reported to be
anticancer-active. These compounds harbor quite different anti-
cancer mechanisms of action as discussed in the next section.
Although cysteine is widely considered to be the primary
binding site of gold ions, in some cases, coordination of
N-donor ligands, such as histidine, to gold ions has also been
observed. Sadler and co-workers reported the crystal structure
of an adduct of [Au(PEt3)Cl] with cyclophilin 3 (Cyp3) that
contains four cysteine residues, two of which (Cys163 and
Cys168) are accessible for Au–S bonding (Fig. 3). However, the
crystal structure of the Au(I)–Cyp3 adduct does not show any
Scys–AuI coordination. Instead, there is NHis–AuI–PEt coordina-
tion. A chymotrypsin-coupled assay revealed that the binding of
His133 of Cyp-3 to a gold ion can significantly inhibit the
PPIase activity with gold in the nanomolar range.50 Messori
and co-workers recently reported the crystal structures of a
ribonuclease A–gold adduct and a hen egg white lysozyme–gold
adduct, where the gold ion is coordinated with His groups,
Fig. 3 (a) Crystal structure of gold(I)–cyclophilin 3 adduct (PDB code:
1E3B, gold source: [Au(PEt3)Cl]).50 (b) Crystal structural of ribonuclease
A–gold adduct (PDB code: 4MXF, gold source: Auoxo6).52
forming His–AuI–His or His–AuI–Cl (Fig. 3b).51,52 A possible
reason for binding with His, but not Cys, based on DFT
calculations, is that the activation enthalpy for Cys binding is
higher than His binding despite the reaction free energy for the
latter being much higher than the former. That is, the reaction
of gold(I) complex with His is kinetically favorable while the
reaction with Cys is thermodynamically favorable.53
Anticancer gold(III) complexes
As mentioned in the previous section, gold(III) complexes are
redox active and can be easily reduced to Au(I)/Au(0). Thus,
choosing the appropriate ligand to stabilize the Au3+ ion is of great
importance. A majority of the currently developed anticancer gold(III)
agents contain multidentate ligands, including N^N, N^N^N, C^N,
C^N^N, C^N^C, porphyrin, and dithiocarbamate (Fig. 1 and 4). Most
of these gold(III) complexes are stable in aqueous solution; the
cyclometalated gold(III) complexes having C-deprotonated carbon
(C) donor atoms exhibit redox stability against cellular reducing
agents (e.g., ascorbic acid, GSH).
Gold(III) porphyrins
Although a number of gold(III) complexes containing non-
porphyrin ligands have been shown to be cytotoxic to cancer
cells, the high toxicity and instability of these complexes under
physiological conditions hamper their potential clinical appli-
cations. In 2003, a gold(III) porphyrin complex (gold-1a or
[Au(TPP)]Cl, Fig. 5) was reported to be stable in a physiological
reducing environment (in the presence of GSH) and to display

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Fig. 4 Reported N- and S-containing multidentate ligands utilized to
stabilize gold(III) complexes.
Fig. 5 Chemical structure of gold(III)–porphyrin complexes.
in vitro cytotoxicity down to low micromolar or even nanomolar
levels in different cancer cell lines.29 Gold-1a is also equally
potent in cisplatin-resistant cancer cell lines, which is indicative of
a molecular mechanism different from cisplatin. Transcriptomic,
proteomic, and biochemical analyses have revealed that gold-1a
induces apoptosis through mitochondrial dysfunction and Bcl-2
protein suppression. In addition, gold-1a can abrogate the cell
cycle at G0–G1, activate p38 and inhibit TrxR to some extent.54
In vivo studies have shown that gold-1a is a promising anticancer
agent for the treatment of nasopharyngeal carcinoma (NPC),55
NPC metastasis,56 hepatocellular carcinoma (HCC),57 colon
cancer,58 neuroblastoma59 and melanoma.60 Recently, Che
and co-workers found that gold-1a is also extremely active
against U-87 MG cancer stem-like cells (CSCs).61 Acute toxicity
experiments indicated a safe dosage of this complex, by intra-
venous injection (i.v.) of below 3 mg kg1.61 Subsequent blood-
vessel irritation tests using rabbits and in vivo mutagenicity
tests (the micronucleus of bone marrow) in mice revealed that
gold-1a does not cause blood-vessel irritation or significant
genotoxicity.61 More importantly, in a mouse model simulta-
neously bearing cisplatin-resistant and cisplatin-sensitive
human ovarian A2780 tumors, the usefulness of gold com-
plexes for the treatment of cisplatin resistant tumors in vivo
was evaluated.62 Treatment with gold-1a significantly inhibited
both kinds of tumors while cisplatin was only effective in
suppressing cisplatin-sensitive tumors. Meanwhile, an analo-
gue of gold-1a with a meso-hydroxyl phenyl group (gold-2a,
Fig. 5) was developed. Gold-2a is highly cytotoxic to breast
carcinoma and can significantly suppress breast tumor growth
in nude mice by means of intraductal injection. The mecha-
nism of action of gold-2a involves attenuation of Wnt/b-catenin
signalling through the inhibition of class I histone deacetylase
(HDAC) activity.63
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Fig. 6 Chemical structure of gold(III) corrole.
Gold(III) corrole
Gray, Gross and co-workers recently described a gold(III) corrole
complex (Fig. 6).64 This gold(III) complex displays high cytotoxicity
to cisplatin-resistant cancer cells. Emission quenching experiments
and mass spectrometry analysis indicated that gold(III) corrole
binds only weakly to BSA; such low affinity with BSA was proposed
to contribute to the higher cytotoxicity compared to the Ga-corrole
variant.
Gold(III) complexes with tridentate C-deprotonated C^N^C
ligands
To find an alternative to porphyrin ligands for stabilizing Au3+,
Che and co-workers introduced a tridentate C-deprotonated
C^N^C (H2C^N^C = 2,6-diphenylpyridine) ligand for coordina-
tion to gold(III). None of the [AuIII(C^N^C)L]n+X complexes
(Fig. 7a) underwent reduction to Au(I) in the presence of cellular
reducing agents for 72 h (though ligand substitution may have
occurred). Early studies showed that the bioactivity of
[AuIII(C^N^C)L]n+X is strongly dependent on the substitution
of the L ligand.65 Thus, the [AuIII(C^N^C)]+ moiety may serve as
both a toxic ligand carrier and a thiol-containing enzyme inhibitor.
Notably, a dinuclear gold(III) complex, [Au2(C^N^C)2(dppp)](OTf)2,
with a bridging bis(diphenylphosphino)propane (m-dppp) ligand
displays potent in vitro cytotoxicity towards a panel of cancer cell
lines with IC50 values ranging from 0.043 to 0.21 mM. These
compounds are less cytotoxic to the non-cancerous lung fibroblast
cell line CCD-19Lu (IC50 value of 1.6 mM).65,66 Importantly,
[Au2(C^N^C)2(dppp)](OTf)2 was observed to display promising inhi-
bition of tumor growth in animal models. The administration of
[Au2(C^N^C)2(dppp)](OTf)2 at 10 mg kg1 through intraperitoneal
injection (i.p.) twice a week elicited a 77% inhibition of tumor
growth in mice bearing PLC (hepatocellular carcinoma) xenografts.
The administration of the same compound via intravenous injec-
tion (i.v.; 4 mg kg1) twice a week also significantly suppressed the
tumor growth in mice bearing H22 (hepatocarcinoma) and
S180 (sarcoma) tumors, with inhibition of 38.6% and 48.9%,
respectively. Furthermore, the i.p. administration of the Au(III)
complex to rats twice a week for four consecutive weeks at 0.5 and
0.75 mg kg1 substantially prolonged survival time from 30 days to
40 and 43 days, respectively. Bioluminescence contour mapping
revealed that the tumor size in rats treated with the Au(III) complex
at 0.5 mg kg1 was considerably smaller than that in the vehicle
control group after treatment for 14 days (Fig. 7b).66
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Fig. 7 (a) Chemical structures of [AuIII(C^N^C)L]n+X complexes. (b) The
sizes of tumor nodules in [Au2(C^N^C)2(dppp)](OTf)2-treatment or non-
treatment (NT) group as examined by Xenogen Imaging System (upper)
and dissection (lower). Reproduced with permission of The Royal Society
of Chemistry.66
The acute (single-dose) toxicity of [Au2(C^N^C)2(dppp)](OTf)2
has also been examined. The median lethal dose (LD50) in nude
mice was determined to be 13.7 mg kg1 after i.v. administration
for 14 days. The minimal lethal dose (MLD) was found to lie
between 9.0 and 13.5 mg kg1 upon a single i.v. administration.
Together, these data indicate that [Au2(C^N^C)2(dppp)](OTf)2
can inhibit in vivo tumor growth at a relatively safe dosage.
Transcriptomic and connectivity map analyses indicated that
TrxR inhibition and induction of endoplasmic reticulum (ER)
stress may be involved in the anticancer mechanisms of the
compound. This is supported by the findings of enzyme/cell-
based TrxR inhibition assay and western blot assay experiments.
Moreover, the transcriptomic analysis also revealed that TNF-
related apoptosis-inducing ligand (TRAIL), which is a ligand for
death receptor 5 (DR5), may have a synergistic effect in the
treatment of cancer cells.66
[AuIII(C^N^C)L]n+X complexes containing a relatively non-toxic L
ligand (e.g., 1-methyl-1H-imidazole, pyridine, triphenylphosphine,
Fig. 7a) exhibited only modest toxicity comparable to that of
cisplatin.65 However, the use of a non-toxic but electron donating
NHC ligand significantly increased the anticancer activity of
[AuIII(C^N^C)L]n+X.66,67 For example, [AuIII(C^N^C)(NHC2nBu)]OTf is
highly cytotoxic to HeLa cells with an IC50 value as low as 0.084 mM,
while that for [AuIII(C^N^C)(MeIm-1)] and [AuIII(C^N^C)(Py)] (Fig. 7a)
are 8.0 and 8.2 mM, respectively, around 100-fold less toxic than
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[AuIII(C^N^C)(NHC2nBu)]OTf.65,66 UV-vis absorption titration,
emission and gel mobility shift assay experiments indicate that
[AuIII(C^N^C)(NHC2Me)]OTf is able to intercalate into DNA
(binding constant K = 5.4  105 M1). Subsequent studies
revealed that these Au(III) complexes can prevent topoisomerase
I (TopoI) mediated relaxation of supercoiled DNA. The in vivo
anticancer activity of these complexes was also studied. Admin-
istration (i.p.) of [AuIII(C^N^C)(NHC2Me)]OTf at 10 mg per kg
per week into nude mice bearing PLC tumors for 28 days
significantly suppressed (47%) tumor growth with no death
or loss in bodyweight.67
Organogold(III) complexes with C-deprotonated C^N and
C^N^N ligands
In 1996, Parish, Buckley and co-workers described a series of
organogold(III) complexes [AuX2(damp)] (damp = o-C6H4CH2NMe2;
X = Cl, OAc or X2 = dithiocarbamate, malonato).14,68 Among them,
[AuCl2(damp)] (Fig. 8) showed relatively high cytotoxicity to differ-
ent cancer cell lines including colon, breast, rectum, bladder and
ovary cancers. In a mice xenograft model, administration (i.p.) of
the gold(III) complexes at 12.5 mg kg1 elicited up to a 60%
inhibition of tumor growth after 28 day treatment.14 This finding
was followed by the development of a series of cyclometalated
gold(III) anticancer agents containing other C-deprotonated
C^N and C^N^N ligands. For example, replacement of Cl in
[AuCl2(damp)] by an acetate group (Fig. 8) led to submicromolar
inhibition (0.6 mM) of the cysteine protease cathepsin B.69 Messori
and co-workers described a series of gold(III) complexes containing
2-(2-phenylpropan-2-yl)pyridine (pydmb-H) and 6-(2-phenylpropan-2-
yl)-2,20 -bipyridine (bipydmb) ligands (Fig. 8) that are stable against
reduction in cellular conditions.15 These gold(III) complexes also
selectively inhibited TrxR activity. Biotin-conjugated iodoacetamide
assays suggested that the inhibition was probably caused by
progressive oxidative damage of cysteine and selenocysteine
residues of the TrxR active site.70 Proteomic study and bioin-
formatics analysis indicated [Au(bipydmb-H)(OH)]PF6 can disrupt
mitochondrial function and glycolytic pathway in A2780/S ovarian
cancer cell line.71 Another [Au(C^N)(dtc)]PF6 (HC^N = N,1,1,1-
tetraphenyl-l5-phosphanimine) complex (Fig. 8) showed selective
Fig. 8 Chemical structures of cyclometalated gold(III) complexes bearing
C^N and C^N^N ligand.
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cytotoxicity towards T-cell leukemia Jurkat cells than normal
lymphocyte PBMC cells. These effects could be attributed to
mitochondria dysfunction induced by reactive oxygen species
(ROS) and Bax/Bak activation.72,73 In recent years, Che and
co-workers have developed two series of cyclometalated gold(III)
complexes bearing another type of C-deprotonated C^N (HC^N =
2-phenylpyridine) ligand. With biguanide as the other auxiliary
ligand, the water soluble [Au(nBuC^N)(biguanide)]Cl (Fig. 8) was
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prepared. ESI-MS revealed that this complex is able to form the
AuIII–GSH adduct. [Au(nBuC^N)(biguanide)]Cl showed higher
cytotoxicity towards different cancer cell lines (2.1–17.1 mM) than
normal lung fibroblast cells (CCD-19Lu, IC50 value of 32.8 mM).
The toxicity was probably caused by ER swelling/stress and this
has been confirmed by oligonucleotide microarray analysis and
western blotting assays.74 [Au(nBuC^N)(dedt)]Cl (Fig. 8) with the
same C^N ligand and a dithiocarbamate ligand (dedt) showed
selective inhibition towards breast cancer MCF-7 cells but was
less toxic to non-tumorigenic immortalized liver cells (MIHA).
ESI-MS experiments revealed that this complex could form
adducts with cysteine-containing peptides and proteins (such
as deubiquitinases). Oligonucleotide microarray and connectivity
map analysis together with the cell-based deubiquitinase inhibition
assay, indicated that deubiquitinases could be cellular targets of
this anticancer gold(III) complex.49
Gold(III) complexes with other multidentate N-donor ligands
Messori and co-workers reported the anticancer activities of a
series of Au(III) complexes supported by bipyridine or terpyridine
ligands (Fig. 9).12 These complexes are rather effective at inhibiting
the growth of cancer cells, including those that are cisplatin
resistant. Compared to the reported organogold(III) complexes, these
complexes are less stable in the presence of reducing agents,
such as ascorbic acid, and thus can cause oxidative damage of
biomolecules.6,12 Combining mass spectrometry analysis and
biochemical assays, several thiol-containing enzymes have been
identified as potential anticancer targets. These include TrxR,11
the copper chaperone Atox-1,75 and aquaporin.47,48 Notably, the
relatively stable [Au(cyclam)](ClO4)2Cl (cyclam = 1,4,8,11-tetraaza-
cyclotetradecane) is non-toxic to cancer cells even at 100 mM.
In view of the facile reduction of Au(III) to Au(I), Che and
co-workers developed a class of Au(III) complexes bearing
N-heterocyclic carbene (NHC) and 2,6-bis(imidazol-2-yl)pyridine
(H2IPI) or 2,6-bis(benzimidazol-2-yl)pyridine (H2BPB) ligands
(Fig. 9) that can dually serve as fluorescent thiol probes and
anticancer agents.76 The rationale is as follows: (1) Au(III) is four-
coordinated while Au(I) is usually two-coordinated, and hence
the reduction of Au(III) to Au(I) would be accompanied by the
release of the ligand, (2) Au(III) complexes are usually non-
emissive because of the relatively low energy 5dx2y2 orbital,
and thus if the ligand is fluorescent, the Au(III) to Au(I) reduction
will switch on the ligand emission, and (3) the NHC ligand is
well known to stabilize Au(I) against reduction to Au(0) and
Au(I)–NHC complex is also known to be anticancer active.
Evaluation of these compounds showed that these AuIII–
NHC complexes are sensitive to thiols that cause reduction of
Au(III) to Au(I) with the release of the fluorescent H2N^N^N
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Fig. 9 Chemical structures of gold(III) complexes containing N^N,
N^N^N, or N^N^N^N ligands.
ligand (Fig. 10a), and therefore can act as a switch-on probe for
thiols in biological systems (Fig. 10b). Fluorescence microscopy
studies showed that the blue fluorescence of the H2N^N^N
ligand was switched on within 10 min after treatment of HeLa
cells with one of these Au(III) complexes, and the fluorescence
mainly located in mitochondria (Fig. 10c), where the potential
molecular target TrxR resides. These Au(III) complexes, through
the formation of Au(I)–NHC upon reduction, can inhibit cellular
TrxR activity and are cytotoxic to several cancer cell lines. Further
in vivo studies revealed that treatment with [AuIII(IPI)(NHCMe,C16)]OTf
(3 mg kg1) can significantly suppress tumor growth in mice
bearing HeLa xenografts (76% inhibition) with no mouse death
or bodyweight loss.76
Recently, Munro and co-workers reported a series of gold(III)
complexes supported by a macrocyclic ligand ([Au(bis(pyrrolide-
imine))]+, Fig. 9).77 The complex, with a –(CH2)4– linkage, was
identified to act as either a TopoI poison or a TopoI inhibitor,
while the inhibition of TopoII was much weaker. The Au3+ ion
plays a crucial role in the DNA binding (intercalation) and TopoI
inhibition. Investigation of the inhibition mechanism through
molecular mechanics (MM) simulation showed that the gold(III)
complex binds to TopoI specific sequence through major groove
binding, and such binding with DNA possibly blocks substrate
recognition by TopoI, thus accounting for the inhibition mechanism.
Gold(III)–dithiolcarbamate complexes
The diethyldithiocarbamate (DEDT) ligand was previously used
as a chemoprotective agent for cisplatin because of the ligand’s
capability of shielding platinum from protein thiols without the
reversal of platinum–DNA adducts. Fregona and co-workers
showed that dithiocarbamate ligands can stabilize Au3+ ions
(Fig. 11). [AuIII(DMDT)Br2] can inhibit the activity of a purified
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Fig. 10 (a) Reduction of [AuIII(IPI)(NHC)]OTf by GSH leads to the formation of free H2IPI ligand and [AuI(NHC)(GS)]. (b) Emission responses of
[Au(BPB)NHC2Me]OTf in the presence (blue line) or absence (red line) of GSH. (c) fluorescence microscopy analysis of HeLa cells treated with
[AuIII(BPB)(NHC2Me)]OTf and Mito-Tracker after 10 min. Left: ex 365 nm; middle: ex 546 nm; right: merged image. Reproduced with permission.76
Copyright r 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

as alkynyl and thiourea have also been utilized; gold(I) com-

plexes with these ligands have been shown to display promising
in vitro and in vivo anticancer prospects.

Fig. 11 Chemical structures of gold–dithiocarbamate compounds. Auranofin and other gold(I)–thiolate complexes
Auranofin (Fig. 12) has long been known to inhibit the growth
of different cancer cells in vitro. This compound was reported to
rabbit 20S and 26S proteasomes in breast cancer cells (MDA-
effectively increase the lifespan of mice inoculated with the
MB-231).78 This complex can potently inhibit TrxR activity due
lymphocytic leukemia P388 cells in a concentration and dose
to its irreversible binding to the enzyme’s catalytic site.79
frequency dependent manner.17 However, later studies showed
Subcutaneous injection (s.c.) of [AuIII(DMDT)Br2] at 1 mg per
that auranofin (administered via an i.p. route) neither prolongs
kg per day for 29 successive days resulted in a 50% inhibition of
lifespan nor inhibits tumor growth in several s.c.-implanted
tumor growth in mice inoculated with MDA-MB-231 cells. The
solid tumor models. It was reported that, even for mice bearing
proteasomal chymotrypsin-like activity of the tumor tissue was
the P388 leukemia model, auranofin was only effective when it
inhibited by 40% in the treatment group.78 Treatment (s.c.) of
was administered via an i.p. route but remained inactive when
PC3 prostate tumor xenografts in nude mice at a dosage of 1 mg
administered via an i.v. or s.c route.87 Mechanistic studies have
per kg per day with the same compound for 19 days caused an
revealed that auranofin rapidly reacts with Cys-34 of serum
85% reduction tumor growth, and no detectable damage to the
albumin (free –SH concentration is B400 mM in the blood-
major organs of the animals.80
stream),2 and that over 80% of the equivalent gold content of
auranofin was observed to covalently bind to albumin.1 Despite
Anticancer gold(I) complexes the fact that cell membrane thiol protein(s) can mediate the
uptake of gold ions that bind to albumin, the cellular uptake is
Ligand displacement is an important reaction of gold(I) com-
much slower, leading to low cytotoxicity. This may be one
plexes in biological systems. However, the auxiliary ligand can
affect the compound’s lipophilicity, stability and the binding
affinity of gold(I), and hence the intracellular transformation of
gold(I) species under both in vitro and in vivo conditions. Most
previously reported anticancer gold(I) complexes contain a
thiolate group (S) and/or phosphine ligand. The NHC ligand
has emerged as a promising ancillary ligand in recent years as Fig. 12 Chemical structures of the clinically used antirheumatic gold(I)
discussed in several related reviews.20,81–86 Other ligands such complexes with anticancer effects.

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pivotal reason for the inefficacy of auranofin in the in vivo
tumor models.
Auranofin is a well-known selective inhibitor of TrxR.5,11 The
drug can induce ROS formation and activate p38 mitogen-
activated protein kinase (p38 MAPK).88 A recent study indicated
that inhibition of proteasome-associated deubiquitinases
(DUBs) by auranofin is a possible anticancer mechanism.89,90
Proteomic analysis of the cysteine proteome showed that
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auranofin-induced TrxR inhibition caused a 36% Cys oxidation
of 606 Cys-containing peptides while only 10% Cys oxidation
was inducible by buthionine sulfoximine (BSO; specifically
depletes GSH levels).91 Moreover, auranofin was able to induce
oxidation of 41 of the 60 BSO-oxidized peptides. Together, these
data suggest that auranofin can induce a broad and distinctive
oxidation of Cys peptides, highlighting the potential of TrxR
inhibition by gold complexes for cancer treatment.
Kamei and co-workers investigated the in vivo antitumor
activities of another antiarthritic gold(I) drug, aurothiomalate
(ATM; Fig. 12). Treatment with ATM at 30 mg per kg per day
(s.c.) or by oral administration (p.o.) at 75 mg per kg per day
significantly increased the survival time of mice inoculated
with syngenic Meth/A cells.21 Fields and co-workers identified
aurothioglucose (ATG) and ATM as potent inhibitors that disrupt
the interaction of protein kinase Ci (PKCi) with its downstream
effector Par6. Administration of ATG at 200 mg kg1 per one or
two days for 14 days significantly suppressed tumor growth in
mouse inoculated with human non-small-cell lung cancer A549
cells. Such an effect is probably caused by the cytostatic effect,
rather than cytotoxic effect, of ATG.22
Gold(I) phosphine complexes
Gold(I)–phosphine complexes have been studied as anticancer
agents for more than twenty years. Mirabelli, Sadler and co-workers
reported the anticancer properties of a four-coordinated gold(I)
complex, [Au(dppe)2]Cl (dppe = bis(diphenylphosphino)ethane;
Fig. 13). Unlike the linear two-coordinated gold(I) complexes,
[Au(dppe)2]Cl is rather stable. 31P NMR studies revealed no reaction
of this complex with a large excess of GSH (50 equivalents) in
8 days.92 [Au(dppe)2]Cl showed significant in vivo antitumor
activity against a range of mouse tumor models, including both
leukemia and solid tumors. However, severe toxicity to heart,
liver and lung in dogs and rabbits was identified in preclinical
toxicological studies.32 This was probably caused by the high
lipophilicity and stability, which led to mitochondrial dysfunc-
tion. Later studies have focused on developing anticancer
gold(I) complexes having decreased lipophilicity and increased
reactivity. For example, replacing the phenyl substituents with
pyridyl groups led to a series of structural analogues of
[Au(dppe)2]Cl (Fig. 13). The 2-pyridyl complex, [Au(d2pype)2]Cl,
with intermediate lipophilicity, was observed to be active in
colon 38 tumors in mice.32 By using propyl-bridged 2-pyridyl
phosphine ligands (d2pypp), [Au(d2pypp)2]Cl was found to exhi-
bit increased inhibition of TrxR activity. [Au(d2pypp)2]Cl showed
selective cytotoxicity to breast cancer cells but was not cytotoxic
to normal breast cells.93
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Fig. 13 Chemical structures of four-coordinated gold(I) complexes.
In 2003, Katti and co-workers described another four-
coordinated gold(I) complex, [Au[P(CH2OH)3]4]Cl (Fig. 13) that can
inhibit the growth of different cancer cells, including prostate
cancer (LNCaP, PC-3), human colon carcinoma (HCT-15) and
human gastric carcinoma (HCT-15). Administration of syngenic
meth/A cells-inoculated mice with [Au[P(CH2OH)3]4]Cl at a dose
range of 25 mg per kg per dose (total dose of 75 mg kg1) to 125 mg
kg per dose (total dose of 375 mg kg1) significantly prolonged
survival time. In addition, no acute toxicity was found after three
injections ranging from 10 to 125 mg kg1.94
Recently, Che and co-workers identified a panel of gold(I)–
phosphine complexes (Fig. 14a; [Au3(C^N^C)(dppm)2]Cl, Au(PPh3)Cl,
Au2(dppe)Cl2 and Au3(dpmp)Cl3) that can induce autophagy.95
Treatment of HeLa cells with these gold–phosphine complexes
induced the formation of RFP/GFP-LC3 vesicles (LC3 is used to
assess autophagosome formation) and the up-regulation of LC3-II
protein. Meanwhile, various vacuoles in the cytoplasm of HeLa cells
were found (Fig. 14b). The accumulation of autophagosomes
subsequently initiated autophagy and led to cell death.95
Discussion of additional anticancer gold–phosphine complexes
can be found in a recent review by Rodrı́guez and co-workers.18
Gold(I)–NHC complexes
NHC is relatively non-toxic, has strong electron-donating properties,
and can be easily modified to tune lipophilicity and reactivity.
Gold(I)–NHC complexes have been extensively investigated in recent
years. Berners-Price and co-workers reported a family of linear
[Au(NHC)2]+ complexes which display a wide range of lipophilicity
(log P = 1.09 to 1.73) depending on the functional group(s) on the
NHC ligand. Initial studies showed that [Au(NHC)2]+ can induce
mitochondrial membrane permeabilization (MMP) in isolated rat
liver mitochondria.96 Subsequent studies focused on the inhibition
of the redox enzyme TrxR. By using 1H NMR, a two-step inhibition
mechanism with stepwise ligand exchange of the NHC ligand was
proposed for TrxR inhibition. The rate constants were also estimated
(Scheme 5). [Au(NHC)2]+, with bulkier substituent(s) on the NHC
ligand, has a slower reaction rates with cysteines and the reaction
with Sec is faster than that with Cys. Importantly, there are examples
of [Au(NHC)2]+ being selectively toxic to two highly tumorigenic
breast cancer cell lines and not to normal breast cells.19
Ott and co-workers described a series of [Au(NHC)Cl] (where
NHC is a 1,3-diethylbenzimidazol-2-ylidene N-heterocyclic carbene)
complexes as potent TrxR inhibitors. [Au(NHC)Cl] increased ROS
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Fig. 14 (a) Chemical structure of gold(I)–phosphine complex that could
induce autophagy. (b) TEM analysis of HeLa cells showing vacuoles and
double-membraned autophagosomes upon the treatment with gold(I)–
phosphine complexes. Reproduced by permission of The Royal Society of
Chemistry.95
formation, inhibited mitochondrial respiration, induced apoptosis,
and strongly affected cellular metabolism.97 Systematic investigation
of [Au(NHC)L] (L = Cl, NHC, or PPh3, Fig. 15) complexes using
atomic absorption spectrometry (AAS) revealed that the binding
reactions with serum albumin followed the order [Au(NHC)Cl] 4
[Au(NHC)(PPh3)]I 4 [Au(NHC)2]I. The TrxR inhibition activities of
these gold complexes followed the same order with EC50 values
being 0.36, 0.66, 4.89 mM, respectively.98 The reactivities of
[Au(NHC)(PR3)]I, having different substituents on the phosphine
ligand, were compared.99 The Au–P(PPh3) bond in [Au(NHC)(PPh3)]I
was found to be more reactive than the Au–P(PR3) (R = alkyl) bond in
the [Au(NHC)(PR3)]I complexes. To further improve the activity of the
compound, a DNA intercalating naphthalimide moiety was incorpo-
rated into the NHC ligand.100 [Au(NHCNap)Cl] (Fig. 15) can inhibit
TrxR activity and synergistically target DNA through intercalation.
In view of the strong s donor properties of NHC to form
strong metal–NHC bonds, Che and co-workers prepared a
dinuclear gold(I) complex [Au2(dcpm)(bisNHC2C4)]X2 (Fig. 16)
containing a diphosphine and a bisNHC ligand that attained
sufficient stability to avoid attack by blood thiols and enough
reactivity towards thiols in order to suppress the activity of
Scheme 5 Step by step ligand exchange reaction of [Au(NHC)2]+ with Cys
or Sec.
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Fig. 15 Chemical structures of [Au(NHC)L]n+ complexes.
thiol-containing enzymes.101 ESI-MS combined with ICP-MS
experiments revealed that while auranofin reacted rapidly and
almost completely with GSH (1–10 mM) and serum albumin
(35–50 mg mL1) present in blood, the dinuclear gold(I)
complex exhibited decent stability towards both thiols under
similar conditions. Meanwhile, this complex could still potently
inhibit TrxR activity in a time and concentration dependent manner
even in the presence of GSH. By using a model TrxR C-terminal
GCUG (glycine–cysteine–selenocysteine–glycine) peptide, high
resolution ESI-MS together with 1H NMR experiments showed
a 1 : 1 adduct formed between the GCUG motif and the dinuclear
gold(I) complex, revealing simultaneous coordination of the
dinuclear [Au2(dcpm)]+ unit to respective S(Cys) and Se(Sec) of
the GCUG accompanied by the release of the bis(NHC), but not
the dcpm, ligand. A sphere formation assay revealed the inhibition
of cancer stem-like cell activity by the dinuclear gold(I) complex.
Treatment of mice bearing HeLa xenografts (5 mg kg1, i.p.) and
highly aggressive mouse B16-F10 melanoma tumors (15 mg kg1,
i.p.) with this gold(I) complex resulted in statistically significant
inhibition (p o 0.05) of tumor growth by 81% and 62%,
respectively. Importantly, the treatment dosage varied from
0.6 to 15 mg kg1 with no mouse death or bodyweight loss. In
addition, immunohistochemical detection of CD31 in the tumor
tissues was suggestive of an inhibition of angiogenesis (Fig. 16d).
Thus, [Au2(dcpm)(bisNHC2C4)]X2 represents the first example of
a gold(I) complex eliciting antiangiogenesis in tumor models.
The safety toxicology revealed that [Au2(dcpm)(bisNHC2C4)](PF6)2
did not cause systemic anaphylaxis on guinea pigs or localized
irritation on rabbits.101
Gold(I)–alkynyl complexes
Recently, Ott and co-workers described a series of [Au(PPh3)(alkynyl)]
complexes (Fig. 17) that exhibit promising anticancer properties.24
These complexes can selectively inhibit TrxR activity over the struc-
turally related enzyme GR. In addition, treatment of MCF-7 cells with
[Au(PPh3)(alkynyl)] was observed to affect tumor cell metabolism and
mitochondrial respiration. Similar to the gold(I)–phosphine–thiolate
compound,102 [Au(PPh3)(alkynyl)] can significantly inhibit
the formation of blood vessels in a zebrafish embryo model.24
Kan, Leung, Wong and co-workers reported a dinuclear gold(I)
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Fig. 16 (a) Chemical structures of [Au2(dcpm)(bisNHC2C4)L]X2. (b) The
residual gold complex after incubation with GSH as determined by ESI-
QTOF-MS. (c) Changes of tumor volume after treatment of mice bearing HeLa
xenografts with 5 mg kg1 of the dinuclear gold(I) complex. (d) Immunohisto-
chemical detection of CD31 in the tumor tissues. Arrows indicate CD31
microvessels. Reproduced with permission.101 Copyright r 2014 Wiley-VCH
Verlag GmbH & Co. KGaA, Weinheim.
species, [Au2(PPh3)2(bis-alkynyl)] (Fig. 17) with a diethynylfluorene
linkage. [Au2(PPh3)2(bis-alkynyl)] is cytotoxic to Hep3B, SKHep-1
and MDA-MB-231 cells with IC50 values ranging from 1.7 to 5.1 mM.
Treatment of mice bearing Hep3B tumors with the dinuclear
complex with 2.5 mg per kg per day (i.p.) for nine successive days
elicited a significant inhibition of tumor growth with limited
adverse effects on vital organs, including the liver and kidney.23
Gold(I)–thiourea complexes
Thiourea and the related thiosemicarbazones are another pro-
mising class of ligands to stabilize Au+. Che and co-workers
found that an Au(I)–thiourea complex (Fig. 18) can specifically
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Fig. 17 Chemical structures of gold–alkynyl complexes.
inhibit TrxR activity with a binding constant at the low nano-
molar level. Au(I)–thiourea is cytotoxic towards different cancer
cell lines including HeLa, HepG2, SUNE1 and NCI-H460 with
IC50 values in the range of 3.7 to 17.4 mM.25 Further in vivo
experiments in mice bearing NCI-H460 non-small cell lung
cancer cells at 100 mg kg1 (i.p.) of Au(I)–thiourea twice a week
resulted in a reduction of tumor size by 38% after a 28 day
treatment.
Nano-carriers to improve anticancer
efficiency
Although significant achievements have been made in the
development of gold-based anticancer complexes which show
improved stability and promising in vitro/in vivo cytotoxicity,
obstacles such as poor bioavailability and selectivity, and
serious toxicity have hampered the fruition of anticancer gold
complexes into clinical use. Efforts such as using encapsulation
and supramolecular gels as drug carriers in order to improve
anticancer efficiency have recently been described.
Encapsulation of gold(III) complexes with particles such as
microcapsules, nanoparticles and micelles have been applied
to improve bioavailability and reduce toxicity. Taking the
aforementioned gold-1a as an example, the poor aqueous
solubility and the fact that the dosage required for in vivo
anticancer efficacy is close to the fatal dose altogether disfavors
the clinical application of gold-1a.103,104 In 2010, Che and co-workers
reported the use of bioavailable and biodegradable gelatin–acacia
microcapsules to encapsulate gold-1a, and improved the com-
pound’s in vivo efficacy through a sustained-release of gold-1a, when
compared to treatment with free gold-1a.103 Wong and co-workers
reported a nanoparticle formulation, which was made of cetyl
alcohol and Brij 78 surfactant, to incorporate gold-1a to reduce the
side effects. Such encapsulated gold-1a nanoparticles had an average
diameter of around 164 nm. This nanoparticle formulation
enhanced the preferential uptake of gold-1a into tumor tissue,
rather than major organs, thereby leading to an increased in vivo
Fig. 18 Chemical structure of the gold(I)–thiourea complex.
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antitumor effect.104 Au(III)–dithiocarbamate complexes encapsu-
lated by micelles have also been reported.105
Very recently, mesoporous silica nanoparticles (MSNs) were
introduced as a delivery vehicle for anticancer gold complexes.106
MSNs have attracted intense attention as drug delivery systems due
to merits that include high drug loading efficiency, ease of surface
modification and low toxicity. In order to improve biocompatibility
and targeting efficiency, MSNs were coated with biodegradable
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chitosan (CTS) linked to cancer cell targeting RGD (arginylglycyl-
aspartic acid) peptides to form MSN(R). Encapsulation of gold-1a to
form gold-1a@MSN(R) (Fig. 19a and b) significantly improved the
cytotoxicity of gold-1a to cancer cells but only slightly increased
their cytotoxicity to noncancerous L02 cells (Fig. 19c). Mechanistic
studies showed that gold-1a@MSN(R) could induce higher levels of
ROS formation and oxidative stress in cancer cells when compared
to unencapsulated gold-1a.
Another promising strategy is to apply supramolecular polymers
as drug carriers. It has been reported that a supramolecular polymer
has the potential to reduce the frequency of drug administration
through a sustained-release and overcome systemic toxicity issues
by localized drug delivery. However, reports in this endeavour
are sparse. A recent study showed that an organogold(III) supra-
molecular polymer, self-assembled from [Au(C^N^C)(4-dpt)]OTf
(4-dpt = 2,4-diamino-6-(4-pyridyl)-1,3,5-triazine, Fig. 19d and f),
displays a sustained-release property of the antiangiogenic ligand
4-dpt in physiologically relevant solutions and a sustained-cytotoxic
property towards cancer cells. This organogold(III) supramolecular
polymer has been observed to act as a carrier for other cytotoxic
agents like gold-1a (Fig. 19e), eliciting a sustained cytotoxicity.107
Gao and co-workers reported interesting anticancer activities
of gold nano-cluster Au25 coated with positively charged trideca-
peptides.108 The peptides facilitated the cellular uptake and
binding interactions with proteins. Cluster Au25 was found to
significantly inhibit the activity of purified TrxR1 and TrxR in
cancer cells, contributing to a dramatic increase in ROS and
Fig. 19 (a) Schematic of the structure of gold-1a@MSN(R). (b) TEM
images of gold-1a@MSN(R). (c) Cytotoxicity of gold-1a@MSN(R) and
gold-1a to various cancer cells (A549, HeLa, MCF-7, HepG-2) and normal
L02 cells. (a–c) are reproduced with permission.106 Copyright r 2014
Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. (d) Formation of viscous
fluid after cooling down the solution of [Au(C^N^C)(4-dpt)]OTf in acet-
onitrile to 298 K. (e) Formation of viscous fluid from the mixture of
[Au(C^N^C)(4-dpt)]OTf and gold-1a. (f) Chemical structure of the
[Au(C^N^C)(4-dpt)]OTf. (d and e) are reproduced with permission.107
Copyright r 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
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subsequent apoptosis. Importantly, the gold cluster is emissive
in physiological solutions, which is useful for tracing its cellular
uptake into cancer cells. In view of their nano-structures, it is
conceived that these gold nano-clusters could potentially serve
as useful self-delivery systems of Au+ ions for cancer treatment.
Summary and outlook
After several decades of development, gold complexes have
been shown to have good prospects to resolve the cisplatin
resistance problem. Physiological stability in the presence of
thiols is a key issue for both gold(III) (against reduction) and
gold(I) (against ligand exchange) complexes. Meanwhile, thiol–
enzymes are generally considered key molecular targets of anticancer
gold complexes due to the high binding affinity of gold ions with
thiols. There are X-ray crystal structures of gold–protein adducts
reported in the literature. New techniques such as high resolution
mass spectrometry also provide important information for gold–
protein interactions. Particularly, ‘‘omics’’ technologies, such as
proteomics and transcriptomics, emerge as important tools to elicit
anticancer pathways and anticancer molecular targets.
For gold(III) complexes, their instability (reduction and sub-
stitution) in the face of extracellular thiols and their poor
selectivity for tumor cells are key issues that remain to be
resolved. For gold(I) complexes, most studies have focused on
cytotoxicity and molecular mechanisms in vitro. Indeed, good
to excellent inhibition of thiol–enzymes and potent cytotoxi-
cities have been reported with gold(I) complexes; however,
studies on the in vivo anticancer activity of gold(I) complexes
are quite sparse. One possible way to improve the in vivo
activities of both gold(I) and gold(III) complexes is to increase
their stability towards thiols (serum albumin and extracellular
GSH). In this regard, carbon donor atom ligands, either neutral or
anionic, may be used in the design of new anticancer gold
complexes. An alternative strategy is to take advantage of drug
micro-/nano-carriers to improve stability and efficacy. Collectively,
through appropriate ligand design to tune the redox reactivity and
ligand exchange reactions of Au(III)/Au(I) with thiols, it is feasible to
develop anticancer gold compounds having promising chemother-
apeutic potential.
Acknowledgements
This work was supported by the University Grants Committee of the
HKSAR of China (Area of Excellence Scheme AoE/P-03/08), the
National Key Basic Research Program of China (2013CB834802),
and the Special Equipment Grant of UGC (SEG_HKU02).
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