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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

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
Received 10th February 2015 (dppe = 1,2-bis(diphenylphosphanyl)ethane), which are known to display highly potent in vitro and
DOI: 10.1039/c5cs00132c 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
www.rsc.org/csr anticancer efficiency. Some recent examples of gold anticancer chemotherapeutics are highlighted.

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

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

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

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or cyclometalating ligands (e.g., deprotonated N,N-dimethyl-1- This review outlines the recent developments of gold complexes
phenylmethanamine,14 6-(2-phenylpropan-2-yl)-2,20 -bipyridine,15 as antitumor agents, together with their general mechanisms of
>2,6-diphenylpyridine4) or dithiocarbamate16 ligands have been action and the approaches which have been used to improve their
extensively studied. The antiarthritic auranofin was reported to anticancer efficacy. In particular, several gold complexes, which
exhibit potent in vitro anticancer effects in human cancer cell lines exhibit promising in vivo antitumor effects, as well as the details of
and to display in vivo effects in the P388 leukemia mouse model.17 selected complexes’ mechanisms of action, are discussed.
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-

Gold–sulfur binding interactions
containing enzymes, including TrxR, at low nanomolar levels. As The common oxidation states of gold compounds are +3, +1 and 0.
the mechanisms of action of anticancer gold complexes are likely to Gold nanoparticles have been used widely in drug delivery but this
be different from that of cisplatin, most of the reported cytotoxic aspect of gold chemistry is beyond the scope of this article. Under
gold complexes are also effective against cisplatin-resistant cancer physiological conditions, the reduction of Au(III) to Au(I) readily
cells, revealing the promising prospect in the development of gold occurs, and the as formed gold(I) species can also undergo ligand
chemotherapeutics to resolve the problem of cisplatin resistance. exchange reactions. Both of these events can lead to a high affinity
Some of the reported Au(I)–Au(III) complexes have also been of the gold ions towards cellular thiols.
demonstrated to display significant in vivo anticancer effects. 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.
Chun-Nam Lok obtained his BSc As Au(III) is usually four-coordinated and Au(I)/Au(0) usually
in biology from Hong Kong Baptist contains fewer than four coordinated ligands, the reduction of
University and PhD in physiology Au(III) will be accompanied by the release of (a) coordinated
from the University of Hong Kong. ligand(s) as depicted in Scheme 1. With a judicious choice, the
He pursued his postdoctoral released ligand could also confer biological activities.
studies in biomedical sciences in Cyclometalated gold(III) complexes coordinated with depro-
Lady Davis Institute for Medical tonated C-donor atoms (C) exhibit high stability even in the
Research at McGill University and presence of cellular reducing agents. The C-deprotonated
Cancer Research Institute at bidentate C^N, and tridentate C^N^C and C^N^N ligands,
Queen’s University, Canada. He (Fig. 1) have been extensively used in the synthesis of gold(III)
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, Scheme 1 Reduction of a four-coordinated Au(III) to a two-coordinated
and drug discovery. Au(I) or Au(0) accompanied by the release of the coordinated ligand.

Jing-Jing Zhang received her Chi-Ming Che received his PhD

bachelor’s degree in chemistry degree in 1982 from the
and master’s degree in Organic University of Hong Kong and
Chemistry (with Prof. Guo-Yuan worked at California Institute of
Lu) from Nanjing University in Technology from 1980 to 1983.
2006 and 2009, respectively. He is Dr Hui Wai-Haan Chair of
Thereafter, she got her PhD Chemistry, a member of the
degree in chemical biology (with Chinese Academy of Sciences
Prof. Chi-Ming Che) from the and a Foreign Associate of
University of Hong Kong in 2014. National Academy of Science
She currently works in Technische (USA). He is the First Class Prize
Universität Braunschweig (with awardee of State Natural Science
Jing-Jing Zhang Professor Ingo Ott) and Chi-Ming Che Award from China (2007). His
Universität Heidelberg (with research interests include
Professor Stefan Wölfl) and is sponsored by Alexander von synthetic chemistry, metal–ligand multiple bonds, metal-
Humboldt Research Fellowship. Her research interests focus on catalyzed organic transformations, inorganic photophysics and
metal-based cytotoxic and anti-angiogenic drugs and the potential photochemistry, phosphorescent metal complexes and materials,
mechanism of their anti-cancer action. and inorganic medicines.

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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
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Fig. 1 Reported C-deprotonated cyclometalated ligands used in anti- cysteine protease, are overexpressed in cancer cells, thus providing
cancer gold(III) complexes.
potential anticancer targets for gold complex therapy.11,33,34 Several
structures of gold(I)–protein adducts have been solved using X-ray
complexes; the gold(III) complexes stabilized by these ligands crystallography, most of which feature SCys–Au–SCys and/or SCys–Au–
are relatively stable against reduction under physiological con- ligand binding interactions in the active site of the enzyme. The
ditions and have been observed to display promising anticancer Au–S bonding is believed to be responsible for the observed strong
activities. A recent review by Ruiz and co-workers describes inhibition of enzyme activity.35
the different types of anticancer cyclometalated complexes of
Disulfide reductases
platinum group metals, including those of gold.28 In the early
2000s, Che and co-workers reported the use of porphyrin GR and TrxR are disulfide reductases that contain cysteinyl
ligands to stabilize Au3+ ions, and gold(III)–porphyrin com- thiols (TrxR also contains selenocysteine) in their active sites.
plexes have since been found to display both high stability Both enzymes play a key role in the redox regulation of
and strong antiproliferative effects towards a panel of cancer important cellular processes such as DNA synthesis, transcrip-
cell lines.29 tion, cell growth, and drug resistance.36,37 A number of gold(I)–
Under physiological conditions, the naked Au+ ion is unstable phosphine, gold(I)–NHC, and gold(III) complexes have been
and tends to undergo disproportionation to yield Au3+ and Au0. reported to be strong disulfide reductase inhibitors with inhibitory
IC50 values down to nanomolar levels.11 Becker and co-workers
Au+ - Au3+ + Au0 reported a gold(I) phosphole complex that acts as an irreversible
inhibitor of human disulfide reductases.34 The crystal structure of
Thus, the Au+ ion needs to be stabilized by ligands. The the gold(I)–GR adduct reveals an almost linear Scys–AuI–Scys coordi-
ligands commonly used include thiolate (RS), phosphine (PR3), nation and a Scys–AuI–phosphole coordination in the active site
NHC, and acetylide (RCRC). Gold(I) complexes can be two-, (Fig. 2a). Similar coordination modes have been found in adducts
three- or four-coordinated but two-coordinated gold(I) complexes of gold with thioredoxin–glutathione reductase (TGR, a parasite
are mostly encountered.30 In biological systems, gold(I) com- enzyme similar to TrxR) obtained from the reaction of auranofin
plexes can undergo a two-step ligand exchange reaction via a with TGR (Fig. 2b).38 In the Au(I)–TGR adduct, the coordinated
three-coordinated gold(I) intermediate (Scheme 2).1 triethylphosphine and thioglucose ligands of auranofin have not
Upon administering a gold(I) complex to cells, a ligand been observed but there are two linear Scys–AuI–Scys coordination
exchange reaction with GSH can rapidly occur.2 In animal modes. Moreover, the activity of trypanothione reductase (TR), a
studies, the ligand exchange reaction of gold(I) complexes with disulfide reductase that regulates leishmania infantum polyamine-
Cys34 of serum albumin (SA) to form gold(I)–SA adducts has dependent redox metabolism, can be significantly inhibited by
been reported.31 It has been suggested that SA may serve as a auranofin.39 The crystal structure of the Au(I)–TR adduct shows the
drug carrier or, more likely, function as a drug ‘‘scavenger’’ release of the coordinated ligand(s) of auranofin as well, allowing
to abrogate the activity of gold(I) complexes.24,32 Sadler and the naked Au+ ion to coordinate with two cysteinyl thiols and a
co-workers reported that the thermodynamic stability of gold chloride (Fig. 2c). All these structural data indicate that gold(I)
complexes is dependent on the auxiliary ligands in the following complexes can be tightly binding inhibitors of disulfide reductases
order:1 through the formation of Au–S bond(s) with active site cysteinyl
thiols.
CN B Scys B PR3 c SMet B NHis 4 Cl c COO
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
Scheme 2 Ligand exchange reaction of gold(I) complexes with thiolate. 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

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
Scheme 3 Catalytic cycle of cysteine proteases. The covalent (coordination) micromolar IC50 values (1.5–33 mM) for the inhibition of the
binding of Au(I) with cysteinyl thiol can block the catalytic cycle. lymphoid tyrosine phosphatase (LYP).43

(Fig. 2d) shows a linear Scys–AuI–Sthiomalate coordination, with Other enzymes

the thiomalate group surrounded by several amino acid residues Besides the redox regulation of disulfide reductases, cysteine
that form hydrogen bonds with thiomalate, leading to an proteases and protein tyrosine phosphatases, other thiol/selenol-
increased stability of the covalent adduct. It is noted that 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 Fig. 3 (a) Crystal structure of gold(I)–cyclophilin 3 adduct (PDB code:
to blocked activation of NF-kB, a transcription factor involved in 1E3B, gold source: [Au(PEt3)Cl]).50 (b) Crystal structural of ribonuclease
A–gold adduct (PDB code: 4MXF, gold source: Auoxo6).52
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
forming His–AuI–His or His–AuI–Cl (Fig. 3b).51,52 A possible
Though there are no direct structural data of an Au(III)–
reason for binding with His, but not Cys, based on DFT
protein adduct yet, the intracellular reduction of Au(III) to Au(I) is
calculations, is that the activation enthalpy for Cys binding is
well documented. This lends support to redox reactive gold(III)
higher than His binding despite the reaction free energy for the
complexes as potential inhibitors of the aforementioned enzymes.
latter being much higher than the former. That is, the reaction
By using high resolution mass spectrometry, the binding of gold(III)
of gold(I) complex with His is kinetically favorable while the
with thiol–proteins has also been observed.49 Very recently, the
reaction with Cys is thermodynamically favorable.53
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.
Anticancer gold(III) complexes
Unlike the redox and/or substitution reactive gold(III)–gold(I) As mentioned in the previous section, gold(III) complexes are
complexes that can form tight Au–S/Se bonds, gold(III) porphyrins, redox active and can be easily reduced to Au(I)/Au(0). Thus,
which are not reactive towards thiols, have been reported to be choosing the appropriate ligand to stabilize the Au3+ ion is of great
anticancer-active. These compounds harbor quite different anti- importance. A majority of the currently developed anticancer gold(III)
cancer mechanisms of action as discussed in the next section. agents contain multidentate ligands, including N^N, N^N^N, C^N,
Although cysteine is widely considered to be the primary C^N^N, C^N^C, porphyrin, and dithiocarbamate (Fig. 1 and 4). Most
binding site of gold ions, in some cases, coordination of of these gold(III) complexes are stable in aqueous solution; the
N-donor ligands, such as histidine, to gold ions has also been cyclometalated gold(III) complexes having C-deprotonated carbon
observed. Sadler and co-workers reported the crystal structure (C) donor atoms exhibit redox stability against cellular reducing
of an adduct of [Au(PEt3)Cl] with cyclophilin 3 (Cyp3) that agents (e.g., ascorbic acid, GSH).
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 Gold(III) porphyrins
Scys–AuI coordination. Instead, there is NHis–AuI–PEt coordina- Although a number of gold(III) complexes containing non-
tion. A chymotrypsin-coupled assay revealed that the binding of porphyrin ligands have been shown to be cytotoxic to cancer
His133 of Cyp-3 to a gold ion can significantly inhibit the cells, the high toxicity and instability of these complexes under
PPIase activity with gold in the nanomolar range.50 Messori physiological conditions hamper their potential clinical appli-
and co-workers recently reported the crystal structures of a cations. In 2003, a gold(III) porphyrin complex (gold-1a or
ribonuclease A–gold adduct and a hen egg white lysozyme–gold [Au(TPP)]Cl, Fig. 5) was reported to be stable in a physiological
adduct, where the gold ion is coordinated with His groups, 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. 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.
Fig. 5 Chemical structure of gold(III)–porphyrin complexes.

Gold(III) complexes with tridentate C-deprotonated C^N^C

in vitro cytotoxicity down to low micromolar or even nanomolar ligands
levels in different cancer cell lines.29 Gold-1a is also equally To find an alternative to porphyrin ligands for stabilizing Au3+,
potent in cisplatin-resistant cancer cell lines, which is indicative of Che and co-workers introduced a tridentate C-deprotonated
a molecular mechanism different from cisplatin. Transcriptomic, C^N^C (H2C^N^C = 2,6-diphenylpyridine) ligand for coordina-
proteomic, and biochemical analyses have revealed that gold-1a tion to gold(III). None of the [AuIII(C^N^C)L]n+X complexes
induces apoptosis through mitochondrial dysfunction and Bcl-2 (Fig. 7a) underwent reduction to Au(I) in the presence of cellular
protein suppression. In addition, gold-1a can abrogate the cell reducing agents for 72 h (though ligand substitution may have
cycle at G0–G1, activate p38 and inhibit TrxR to some extent.54 occurred). Early studies showed that the bioactivity of
In vivo studies have shown that gold-1a is a promising anticancer [AuIII(C^N^C)L]n+X is strongly dependent on the substitution
agent for the treatment of nasopharyngeal carcinoma (NPC),55 of the L ligand.65 Thus, the [AuIII(C^N^C)]+ moiety may serve as
NPC metastasis,56 hepatocellular carcinoma (HCC),57 colon both a toxic ligand carrier and a thiol-containing enzyme inhibitor.
cancer,58 neuroblastoma59 and melanoma.60 Recently, Che Notably, a dinuclear gold(III) complex, [Au2(C^N^C)2(dppp)](OTf)2,
and co-workers found that gold-1a is also extremely active with a bridging bis(diphenylphosphino)propane (m-dppp) ligand
against U-87 MG cancer stem-like cells (CSCs).61 Acute toxicity displays potent in vitro cytotoxicity towards a panel of cancer cell
experiments indicated a safe dosage of this complex, by intra- lines with IC50 values ranging from 0.043 to 0.21 mM. These
venous injection (i.v.) of below 3 mg kg1.61 Subsequent blood- compounds are less cytotoxic to the non-cancerous lung fibroblast
vessel irritation tests using rabbits and in vivo mutagenicity cell line CCD-19Lu (IC50 value of 1.6 mM).65,66 Importantly,
tests (the micronucleus of bone marrow) in mice revealed that [Au2(C^N^C)2(dppp)](OTf)2 was observed to display promising inhi-
gold-1a does not cause blood-vessel irritation or significant bition of tumor growth in animal models. The administration of
genotoxicity.61 More importantly, in a mouse model simulta- [Au2(C^N^C)2(dppp)](OTf)2 at 10 mg kg1 through intraperitoneal
neously bearing cisplatin-resistant and cisplatin-sensitive injection (i.p.) twice a week elicited a 77% inhibition of tumor
human ovarian A2780 tumors, the usefulness of gold com- growth in mice bearing PLC (hepatocellular carcinoma) xenografts.
plexes for the treatment of cisplatin resistant tumors in vivo The administration of the same compound via intravenous injec-
was evaluated.62 Treatment with gold-1a significantly inhibited tion (i.v.; 4 mg kg1) twice a week also significantly suppressed the
both kinds of tumors while cisplatin was only effective in tumor growth in mice bearing H22 (hepatocarcinoma) and
suppressing cisplatin-sensitive tumors. Meanwhile, an analo- S180 (sarcoma) tumors, with inhibition of 38.6% and 48.9%,
gue of gold-1a with a meso-hydroxyl phenyl group (gold-2a, respectively. Furthermore, the i.p. administration of the Au(III)
Fig. 5) was developed. Gold-2a is highly cytotoxic to breast complex to rats twice a week for four consecutive weeks at 0.5 and
carcinoma and can significantly suppress breast tumor growth 0.75 mg kg1 substantially prolonged survival time from 30 days to
in nude mice by means of intraductal injection. The mecha- 40 and 43 days, respectively. Bioluminescence contour mapping
nism of action of gold-2a involves attenuation of Wnt/b-catenin revealed that the tumor size in rats treated with the Au(III) complex
signalling through the inhibition of class I histone deacetylase at 0.5 mg kg1 was considerably smaller than that in the vehicle
(HDAC) activity.63 control group after treatment for 14 days (Fig. 7b).66

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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
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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
Fig. 7 (a) Chemical structures of [AuIII(C^N^C)L]n+X complexes. (b) The
C^N and C^N^N ligands. For example, replacement of Cl in
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) [AuCl2(damp)] by an acetate group (Fig. 8) led to submicromolar
and dissection (lower). Reproduced with permission of The Royal Society inhibition (0.6 mM) of the cysteine protease cathepsin B.69 Messori
of Chemistry.66 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
The acute (single-dose) toxicity of [Au2(C^N^C)2(dppp)](OTf)2 reduction in cellular conditions.15 These gold(III) complexes also
has also been examined. The median lethal dose (LD50) in nude selectively inhibited TrxR activity. Biotin-conjugated iodoacetamide
mice was determined to be 13.7 mg kg1 after i.v. administration assays suggested that the inhibition was probably caused by
for 14 days. The minimal lethal dose (MLD) was found to lie progressive oxidative damage of cysteine and selenocysteine
between 9.0 and 13.5 mg kg1 upon a single i.v. administration. residues of the TrxR active site.70 Proteomic study and bioin-
Together, these data indicate that [Au2(C^N^C)2(dppp)](OTf)2 formatics analysis indicated [Au(bipydmb-H)(OH)]PF6 can disrupt
can inhibit in vivo tumor growth at a relatively safe dosage. mitochondrial function and glycolytic pathway in A2780/S ovarian
Transcriptomic and connectivity map analyses indicated that cancer cell line.71 Another [Au(C^N)(dtc)]PF6 (HC^N = N,1,1,1-
TrxR inhibition and induction of endoplasmic reticulum (ER) tetraphenyl-l5-phosphanimine) complex (Fig. 8) showed selective
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) Fig. 8 Chemical structures of cyclometalated gold(III) complexes bearing
are 8.0 and 8.2 mM, respectively, around 100-fold less toxic than 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 Fig. 9 Chemical structures of gold(III) complexes containing N^N,
map analysis together with the cell-based deubiquitinase inhibition N^N^N, or N^N^N^N ligands.
assay, indicated that deubiquitinases could be cellular targets of
this anticancer gold(III) complex.49
ligand (Fig. 10a), and therefore can act as a switch-on probe for
Gold(III) complexes with other multidentate N-donor ligands thiols in biological systems (Fig. 10b). Fluorescence microscopy
Messori and co-workers reported the anticancer activities of a studies showed that the blue fluorescence of the H2N^N^N
series of Au(III) complexes supported by bipyridine or terpyridine ligand was switched on within 10 min after treatment of HeLa
ligands (Fig. 9).12 These complexes are rather effective at inhibiting cells with one of these Au(III) complexes, and the fluorescence
the growth of cancer cells, including those that are cisplatin mainly located in mitochondria (Fig. 10c), where the potential
resistant. Compared to the reported organogold(III) complexes, these molecular target TrxR resides. These Au(III) complexes, through
complexes are less stable in the presence of reducing agents, the formation of Au(I)–NHC upon reduction, can inhibit cellular
such as ascorbic acid, and thus can cause oxidative damage of TrxR activity and are cytotoxic to several cancer cell lines. Further
biomolecules.6,12 Combining mass spectrometry analysis and in vivo studies revealed that treatment with [AuIII(IPI)(NHCMe,C16)]OTf
biochemical assays, several thiol-containing enzymes have been (3 mg kg1) can significantly suppress tumor growth in mice
identified as potential anticancer targets. These include TrxR,11 bearing HeLa xenografts (76% inhibition) with no mouse death
the copper chaperone Atox-1,75 and aquaporin.47,48 Notably, the or bodyweight loss.76
relatively stable [Au(cyclam)](ClO4)2Cl (cyclam = 1,4,8,11-tetraaza- Recently, Munro and co-workers reported a series of gold(III)
cyclotetradecane) is non-toxic to cancer cells even at 100 mM. complexes supported by a macrocyclic ligand ([Au(bis(pyrrolide-
In view of the facile reduction of Au(III) to Au(I), Che and imine))]+, Fig. 9).77 The complex, with a –(CH2)4– linkage, was
co-workers developed a class of Au(III) complexes bearing identified to act as either a TopoI poison or a TopoI inhibitor,
N-heterocyclic carbene (NHC) and 2,6-bis(imidazol-2-yl)pyridine while the inhibition of TopoII was much weaker. The Au3+ ion
(H2IPI) or 2,6-bis(benzimidazol-2-yl)pyridine (H2BPB) ligands plays a crucial role in the DNA binding (intercalation) and TopoI
(Fig. 9) that can dually serve as fluorescent thiol probes and inhibition. Investigation of the inhibition mechanism through
anticancer agents.76 The rationale is as follows: (1) Au(III) is four- molecular mechanics (MM) simulation showed that the gold(III)
coordinated while Au(I) is usually two-coordinated, and hence complex binds to TopoI specific sequence through major groove
the reduction of Au(III) to Au(I) would be accompanied by the binding, and such binding with DNA possibly blocks substrate
release of the ligand, (2) Au(III) complexes are usually non- recognition by TopoI, thus accounting for the inhibition mechanism.
emissive because of the relatively low energy 5dx2y2 orbital,
and thus if the ligand is fluorescent, the Au(III) to Au(I) reduction Gold(III)–dithiolcarbamate complexes
will switch on the ligand emission, and (3) the NHC ligand is The diethyldithiocarbamate (DEDT) ligand was previously used
well known to stabilize Au(I) against reduction to Au(0) and as a chemoprotective agent for cisplatin because of the ligand’s
Au(I)–NHC complex is also known to be anticancer active. capability of shielding platinum from protein thiols without the
Evaluation of these compounds showed that these AuIII– reversal of platinum–DNA adducts. Fregona and co-workers
NHC complexes are sensitive to thiols that cause reduction of showed that dithiocarbamate ligands can stabilize Au3+ ions
Au(III) to Au(I) with the release of the fluorescent H2N^N^N (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 Fig. 13 Chemical structures of four-coordinated gold(I) complexes.
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 In 2003, Katti and co-workers described another four-
oxidation of Cys peptides, highlighting the potential of TrxR coordinated gold(I) complex, [Au[P(CH2OH)3]4]Cl (Fig. 13) that can
inhibition by gold complexes for cancer treatment. inhibit the growth of different cancer cells, including prostate
Kamei and co-workers investigated the in vivo antitumor cancer (LNCaP, PC-3), human colon carcinoma (HCT-15) and
activities of another antiarthritic gold(I) drug, aurothiomalate human gastric carcinoma (HCT-15). Administration of syngenic
(ATM; Fig. 12). Treatment with ATM at 30 mg per kg per day meth/A cells-inoculated mice with [Au[P(CH2OH)3]4]Cl at a dose
(s.c.) or by oral administration (p.o.) at 75 mg per kg per day range of 25 mg per kg per dose (total dose of 75 mg kg1) to 125 mg
significantly increased the survival time of mice inoculated kg per dose (total dose of 375 mg kg1) significantly prolonged
with syngenic Meth/A cells.21 Fields and co-workers identified survival time. In addition, no acute toxicity was found after three
aurothioglucose (ATG) and ATM as potent inhibitors that disrupt injections ranging from 10 to 125 mg kg1.94
the interaction of protein kinase Ci (PKCi) with its downstream Recently, Che and co-workers identified a panel of gold(I)–
effector Par6. Administration of ATG at 200 mg kg1 per one or phosphine complexes (Fig. 14a; [Au3(C^N^C)(dppm)2]Cl, Au(PPh3)Cl,
two days for 14 days significantly suppressed tumor growth in Au2(dppe)Cl2 and Au3(dpmp)Cl3) that can induce autophagy.95
mouse inoculated with human non-small-cell lung cancer A549 Treatment of HeLa cells with these gold–phosphine complexes
cells. Such an effect is probably caused by the cytostatic effect, induced the formation of RFP/GFP-LC3 vesicles (LC3 is used to
rather than cytotoxic effect, of ATG.22 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
Gold(I) phosphine complexes subsequently initiated autophagy and led to cell death.95
Gold(I)–phosphine complexes have been studied as anticancer Discussion of additional anticancer gold–phosphine complexes
agents for more than twenty years. Mirabelli, Sadler and co-workers can be found in a recent review by Rodrı́guez and co-workers.18
reported the anticancer properties of a four-coordinated gold(I)
complex, [Au(dppe)2]Cl (dppe = bis(diphenylphosphino)ethane; Gold(I)–NHC complexes
Fig. 13). Unlike the linear two-coordinated gold(I) complexes, NHC is relatively non-toxic, has strong electron-donating properties,
[Au(dppe)2]Cl is rather stable. 31P NMR studies revealed no reaction and can be easily modified to tune lipophilicity and reactivity.
of this complex with a large excess of GSH (50 equivalents) in Gold(I)–NHC complexes have been extensively investigated in recent
8 days.92 [Au(dppe)2]Cl showed significant in vivo antitumor years. Berners-Price and co-workers reported a family of linear
activity against a range of mouse tumor models, including both [Au(NHC)2]+ complexes which display a wide range of lipophilicity
leukemia and solid tumors. However, severe toxicity to heart, (log P = 1.09 to 1.73) depending on the functional group(s) on the
liver and lung in dogs and rabbits was identified in preclinical NHC ligand. Initial studies showed that [Au(NHC)2]+ can induce
toxicological studies.32 This was probably caused by the high mitochondrial membrane permeabilization (MMP) in isolated rat
lipophilicity and stability, which led to mitochondrial dysfunc- liver mitochondria.96 Subsequent studies focused on the inhibition
tion. Later studies have focused on developing anticancer of the redox enzyme TrxR. By using 1H NMR, a two-step inhibition
gold(I) complexes having decreased lipophilicity and increased mechanism with stepwise ligand exchange of the NHC ligand was
reactivity. For example, replacing the phenyl substituents with proposed for TrxR inhibition. The rate constants were also estimated
pyridyl groups led to a series of structural analogues of (Scheme 5). [Au(NHC)2]+, with bulkier substituent(s) on the NHC
[Au(dppe)2]Cl (Fig. 13). The 2-pyridyl complex, [Au(d2pype)2]Cl, ligand, has a slower reaction rates with cysteines and the reaction
with intermediate lipophilicity, was observed to be active in with Sec is faster than that with Cys. Importantly, there are examples
colon 38 tumors in mice.32 By using propyl-bridged 2-pyridyl of [Au(NHC)2]+ being selectively toxic to two highly tumorigenic
phosphine ligands (d2pypp), [Au(d2pypp)2]Cl was found to exhi- breast cancer cell lines and not to normal breast cells.19
bit increased inhibition of TrxR activity. [Au(d2pypp)2]Cl showed Ott and co-workers described a series of [Au(NHC)Cl] (where
selective cytotoxicity to breast cancer cells but was not cytotoxic NHC is a 1,3-diethylbenzimidazol-2-ylidene N-heterocyclic carbene)
to normal breast cells.93 complexes as potent TrxR inhibitors. [Au(NHC)Cl] increased ROS

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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
Fig. 14 (a) Chemical structure of gold(I)–phosphine complex that could
inhibit TrxR activity in a time and concentration dependent manner
induce autophagy. (b) TEM analysis of HeLa cells showing vacuoles and
double-membraned autophagosomes upon the treatment with gold(I)– even in the presence of GSH. By using a model TrxR C-terminal
phosphine complexes. Reproduced by permission of The Royal Society of GCUG (glycine–cysteine–selenocysteine–glycine) peptide, high
Chemistry.95 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
formation, inhibited mitochondrial respiration, induced apoptosis,
dinuclear [Au2(dcpm)]+ unit to respective S(Cys) and Se(Sec) of
and strongly affected cellular metabolism.97 Systematic investigation
the GCUG accompanied by the release of the bis(NHC), but not
of [Au(NHC)L] (L = Cl, NHC, or PPh3, Fig. 15) complexes using
the dcpm, ligand. A sphere formation assay revealed the inhibition
atomic absorption spectrometry (AAS) revealed that the binding
of cancer stem-like cell activity by the dinuclear gold(I) complex.
reactions with serum albumin followed the order [Au(NHC)Cl] 4
Treatment of mice bearing HeLa xenografts (5 mg kg1, i.p.) and
[Au(NHC)(PPh3)]I 4 [Au(NHC)2]I. The TrxR inhibition activities of
highly aggressive mouse B16-F10 melanoma tumors (15 mg kg1,
these gold complexes followed the same order with EC50 values
i.p.) with this gold(I) complex resulted in statistically significant
being 0.36, 0.66, 4.89 mM, respectively.98 The reactivities of
inhibition (p o 0.05) of tumor growth by 81% and 62%,
[Au(NHC)(PR3)]I, having different substituents on the phosphine
respectively. Importantly, the treatment dosage varied from
ligand, were compared.99 The Au–P(PPh3) bond in [Au(NHC)(PPh3)]I
0.6 to 15 mg kg1 with no mouse death or bodyweight loss. In
was found to be more reactive than the Au–P(PR3) (R = alkyl) bond in
addition, immunohistochemical detection of CD31 in the tumor
the [Au(NHC)(PR3)]I complexes. To further improve the activity of the
tissues was suggestive of an inhibition of angiogenesis (Fig. 16d).
compound, a DNA intercalating naphthalimide moiety was incorpo-
Thus, [Au2(dcpm)(bisNHC2C4)]X2 represents the first example of
rated into the NHC ligand.100 [Au(NHCNap)Cl] (Fig. 15) can inhibit
a gold(I) complex eliciting antiangiogenesis in tumor models.
TrxR activity and synergistically target DNA through intercalation.
The safety toxicology revealed that [Au2(dcpm)(bisNHC2C4)](PF6)2
In view of the strong s donor properties of NHC to form
did not cause systemic anaphylaxis on guinea pigs or localized
strong metal–NHC bonds, Che and co-workers prepared a
irritation on rabbits.101
dinuclear gold(I) complex [Au2(dcpm)(bisNHC2C4)]X2 (Fig. 16)
containing a diphosphine and a bisNHC ligand that attained Gold(I)–alkynyl complexes
sufficient stability to avoid attack by blood thiols and enough
Recently, Ott and co-workers described a series of [Au(PPh3)(alkynyl)]
reactivity towards thiols in order to suppress the activity of
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
Scheme 5 Step by step ligand exchange reaction of [Au(NHC)2]+ with Cys the formation of blood vessels in a zebrafish embryo model.24
or Sec. Kan, Leung, Wong and co-workers reported a dinuclear gold(I)

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Fig. 17 Chemical structures of gold–alkynyl complexes.

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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
Fig. 16 (a) Chemical structures of [Au2(dcpm)(bisNHC2C4)L]X2. (b) The
reported the use of bioavailable and biodegradable gelatin–acacia
residual gold complex after incubation with GSH as determined by ESI-
QTOF-MS. (c) Changes of tumor volume after treatment of mice bearing HeLa
microcapsules to encapsulate gold-1a, and improved the com-
xenografts with 5 mg kg1 of the dinuclear gold(I) complex. (d) Immunohisto- pound’s in vivo efficacy through a sustained-release of gold-1a, when
chemical detection of CD31 in the tumor tissues. Arrows indicate CD31 compared to treatment with free gold-1a.103 Wong and co-workers
microvessels. Reproduced with permission.101 Copyright r 2014 Wiley-VCH reported a nanoparticle formulation, which was made of cetyl
Verlag GmbH & Co. KGaA, Weinheim.
alcohol and Brij 78 surfactant, to incorporate gold-1a to reduce the
side effects. Such encapsulated gold-1a nanoparticles had an average
species, [Au2(PPh3)2(bis-alkynyl)] (Fig. 17) with a diethynylfluorene diameter of around 164 nm. This nanoparticle formulation
linkage. [Au2(PPh3)2(bis-alkynyl)] is cytotoxic to Hep3B, SKHep-1 enhanced the preferential uptake of gold-1a into tumor tissue,
and MDA-MB-231 cells with IC50 values ranging from 1.7 to 5.1 mM. rather than major organs, thereby leading to an increased in vivo
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 Fig. 18 Chemical structure of the gold(I)–thiourea complex.

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antitumor effect.104 Au(III)–dithiocarbamate complexes encapsu- subsequent apoptosis. Importantly, the gold cluster is emissive
lated by micelles have also been reported.105 in physiological solutions, which is useful for tracing its cellular
Very recently, mesoporous silica nanoparticles (MSNs) were uptake into cancer cells. In view of their nano-structures, it is
introduced as a delivery vehicle for anticancer gold complexes.106 conceived that these gold nano-clusters could potentially serve
MSNs have attracted intense attention as drug delivery systems due as useful self-delivery systems of Au+ ions for cancer treatment.
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 Summary and outlook
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chitosan (CTS) linked to cancer cell targeting RGD (arginylglycyl- After several decades of development, gold complexes have
aspartic acid) peptides to form MSN(R). Encapsulation of gold-1a to been shown to have good prospects to resolve the cisplatin
form gold-1a@MSN(R) (Fig. 19a and b) significantly improved the resistance problem. Physiological stability in the presence of
cytotoxicity of gold-1a to cancer cells but only slightly increased thiols is a key issue for both gold(III) (against reduction) and
their cytotoxicity to noncancerous L02 cells (Fig. 19c). Mechanistic gold(I) (against ligand exchange) complexes. Meanwhile, thiol–
studies showed that gold-1a@MSN(R) could induce higher levels of enzymes are generally considered key molecular targets of anticancer
ROS formation and oxidative stress in cancer cells when compared gold complexes due to the high binding affinity of gold ions with
to unencapsulated gold-1a. thiols. There are X-ray crystal structures of gold–protein adducts
Another promising strategy is to apply supramolecular polymers reported in the literature. New techniques such as high resolution
as drug carriers. It has been reported that a supramolecular polymer mass spectrometry also provide important information for gold–
has the potential to reduce the frequency of drug administration protein interactions. Particularly, ‘‘omics’’ technologies, such as
through a sustained-release and overcome systemic toxicity issues proteomics and transcriptomics, emerge as important tools to elicit
by localized drug delivery. However, reports in this endeavour anticancer pathways and anticancer molecular targets.
are sparse. A recent study showed that an organogold(III) supra- For gold(III) complexes, their instability (reduction and sub-
molecular polymer, self-assembled from [Au(C^N^C)(4-dpt)]OTf stitution) in the face of extracellular thiols and their poor
(4-dpt = 2,4-diamino-6-(4-pyridyl)-1,3,5-triazine, Fig. 19d and f), selectivity for tumor cells are key issues that remain to be
displays a sustained-release property of the antiangiogenic ligand resolved. For gold(I) complexes, most studies have focused on
4-dpt in physiologically relevant solutions and a sustained-cytotoxic cytotoxicity and molecular mechanisms in vitro. Indeed, good
property towards cancer cells. This organogold(III) supramolecular to excellent inhibition of thiol–enzymes and potent cytotoxi-
polymer has been observed to act as a carrier for other cytotoxic cities have been reported with gold(I) complexes; however,
agents like gold-1a (Fig. 19e), eliciting a sustained cytotoxicity.107 studies on the in vivo anticancer activity of gold(I) complexes
Gao and co-workers reported interesting anticancer activities are quite sparse. One possible way to improve the in vivo
of gold nano-cluster Au25 coated with positively charged trideca- activities of both gold(I) and gold(III) complexes is to increase
peptides.108 The peptides facilitated the cellular uptake and their stability towards thiols (serum albumin and extracellular
binding interactions with proteins. Cluster Au25 was found to GSH). In this regard, carbon donor atom ligands, either neutral or
significantly inhibit the activity of purified TrxR1 and TrxR in anionic, may be used in the design of new anticancer gold
cancer cells, contributing to a dramatic increase in ROS and 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).
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 Notes and references
L02 cells. (a–c) are reproduced with permission.106 Copyright r 2014
Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. (d) Formation of viscous 1 P. J. Sadler and R. E. Sue, Met.-Based Drugs, 1994, 1, 107–144.
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2 C. F. Shaw, Chem. Rev., 1999, 99, 2589–2600.
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