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Cite this: Metallomics, 2012, 4, 127–138

www.rsc.org/metallomics MINIREVIEW
Copper complexes as therapeutic agents
Clare Duncan and Anthony R. White*
Received 8th November 2011, Accepted 5th December 2011
DOI: 10.1039/c2mt00174h

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The importance of transition metals in biological processes has been well established. Copper (Cu)
is a transition metal that can exist in oxidised and reduced states. This allows it to participate in
redox and catalytic chemistry, making it a suitable cofactor for a diverse range of enzymes and
molecules. Cu deficiency or toxicity is implicated in a variety of pathological conditions; therefore
inorganic complexes of Cu have been investigated for their therapeutic and diagnostic potential.
These Cu complexes have been shown to be effective in cancer treatment due to their cytotoxic
action on tumour cells. Alternatively, Cu complexes can also modulate Cu homeostasis in the brain,
resulting in protective effects in several models of neurodegeneration. In other diseases such as
coronary heart disease and skin disease, the success of Cu complexes as potential therapeutics will
most likely be due to their ability to increase SOD activity, leading to relief of oxidative stress. This
review seeks to provide a broad insight into some of the diverse actions of Cu complexes and
demonstrate the strong future for these compounds as potential therapeutic agents.

Introduction Cu complexes are generated through binding of Cu by an

Metals are essential for many physiological processes in the
human body. Biologically active metals are referred to as trace
metals; however they are more abundant than the term would
suggest. Copper (Cu), in particular, participates in a wide
variety of catalytic functions and molecular interactions.1
Disruption of Cu homeostasis is a pathological feature and
a potential cause or contributor of many disease states.2
inorganic backbone framework. They have been investigated
for their unique biological actions and have strong potential
for therapeutic and diagnostic applications. This review is a
concise summary of some recent advances in the development
of Cu complexes and their potential use as therapeutic agents
(see Table 1 for list of complexes and compounds that can
complex copper and their potential therapeutic action).

Centre for Neuroscience & Department of Pathology, Overview of Cu

The University of Melbourne, Victoria, 3010, Australia.
E-mail: arwhite@unimelb.edu.au; Fax: +61 (3) 8344 4004; Cu is an essential trace metal that exists in oxidised (Cu2+)
Tel: +61 (3) 8344 1805 and reduced (Cu+) states within the body. This makes Cu a

Clare Duncan is a graduate Anthony White is a Principal

research scientist in the Neuro-
proteomics Laboratory at the
Department of Pathology, The
University of Melbourne. Clare
has been a key member of
Dr Anthony White’s research
team developing bis(thiosemi-
carbazone) metal complexes
as potential therapeutic agents
for treatment of neurodegenera-
tive diseases. Clare’s research
has been instrumental in devel-
oping a greater understanding
Clare Duncan of how neuroprotective copper
complexes are trafficked by neu-
ronal cells and how this effects
neuronal vesicle metabolism.
Research Fellow and ARC
Future Fellow in the Department
of Pathology, The University of
Melbourne. Dr White heads the
Neuroproteomics Laboratory
investigating novel therapeutic
approaches to neurodegenera-
tive diseases based on modula-
tion of biometal homeostasis.
Dr White’s group and colla-
borators have pioneered the
development of bis(thiosemi-
carbazone) metal complexes
Anthony R. White as neuroprotective agents to
modulate biometal homeostasis
and cell signaling pathways in
neurons.

This journal is c The Royal Society of Chemistry 2012 Metallomics, 2012, 4, 127–138 127
 128
Table 1 List of potentially therapeutic inorganic copper-complexes

Compound Structure Target disease Proposed Mechanism of Action Key reference

5-chloro-7-iodo-8- Cherny, R.A., et al. Neuron 30,

Alzheimer’s disease -Reduction of Ab
hydroxyquinoline (clioquinol) 665–676 (2001)

-Inhibition of proteasome and Chen, D., et al. Cancer Research 67,

Clioquinol As above Cancer
induction of apoptosis 1636–1644 (2007)
-Decreased huntingtin protein Nguyen, T., et al. Proc. Natl. Acad.
Clioquinol As above Huntington’s disease

Metallomics, 2012, 4, 127–138

aggregation Sci. U. S. A. 102, 11840–11845 (2005)

Adlard, P.A., et al. Neuron 59, 43–55

PBT2 Alzheimer’s disease -Reduction of Ab
(2008)

Lee, J.Y., et al. Neurobiology of Aging

DP-109 Alzheimer’s disease -Reduction of Ab
25, 1315–1321 (2004)

-Reduction of inflammatory cell Omoto, A., et al. Arthritis Research &

Tetra-thiomolybdate (TM) Arthritis
invasion Therapy 7, R1174–R1182 (2005)

Pyrrolidine dithiocarbamate -Induction of apoptosis in tumour Daniel, K.G., et al. Breast Cancer

This journal is
Cancer
(PDTC) cells Research 7, R897–R908 (2005)

c
-Decreased tau phosphorylation-
Malm, T.M., et al. Journal of
PDTC As above Alzheimer’s disease Stimulation of protective
Neuroscience 27, 3712–3721 (2007)
signalling pathways e.g. Akt
-Stimulation of protective
signalling pathways e.g. Akt

Glyoxalbis(N (4)- methyl-3- -Cell cycle arrest of tumour cells

Bica, L., et al. Biometals 24, 117–133
thiosemicarbazonato)copper(II): Cancer due to reduction in cyclin D1
(2011)
(CuII(gtsm)) expression

Crouch, P.J., et al. Proc. Natl. Acad.

CuII(gtsm) As above Alzheimer’s disease -Reduction of Ab
Sci. U. S. A. 106, 381–386 (2009)
-Stimulation of protective signalling
pathways e.g. inhibition of GSK3b

The Royal Society of Chemistry 2012

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 Table 1 (continued )

Compound Structure Target disease Proposed Mechanism of Action Key reference

This journal is
c
Diacetylbis(N (4)-methyl-3-
-Induction of apoptosis of Lewis, J.S., et al. Proc. Natl. Acad. Sci.
thiosemi-carbazonato)copper(II): Cancer
tumour cells U. S. A. 98, 1206 (2001)
(CuII(atsm))

Chakraborty, A., et al. European

-Induction of apoptosis in
Cu(Pyimpy)Cl2 (Cu-P1) Cancer Journal of Pharmacology 647, 1–12
tumour cells
(2010)

Cu- salicylaldehyde Ainscough, E.W., et al. Journal of

The Royal Society of Chemistry 2012

-Induction of apoptosis in
benzoylhydrazone (SBH) Cancer Inorganic Biochemistry 77, 125–133
tumour cells
complexes (1999)

Cu–salicylaldehyde pyrazole -Induction of apoptosis in Fan, C.D., et al. Chemical Research in

Cancer
hydrazone (SPH) complexes tumour cells Toxicology 22, 1517–1525 (2009)

Chen, D., et al. Cancer Research 66,

Cu complexed to disulfiram Cancer -Inhibition of proteasome
10425–10433 (2006)

Hancock, C.N., et al. Free Radical

Cu chelate of thiosemicarbazone -Induction of apoptosis of
Cancer Biology and Medicine 50, 110–121
NSC 689534 tumour cells
(2011)

Bisceglie, F., et al. European Journal of

Cu complexed to 9-retinal -Induction of apoptosis of
Cancer Medicinal Chemistry 42, 627–634
thiosemicarbazone tumour cells
(2007)

Metallomics, 2012, 4, 127–138

129
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 130
Table 1 (continued )

Compound Structure Target disease Proposed Mechanism of Action Key reference

Alcaraz-Zubeldia, M., et al.

-Prevented MPP+ -induced lipid
Cu(II) sulfate Parkinson’s Disease Neurochemical Research 26, 59–64
peroxidation
(2001)

Metallomics, 2012, 4, 127–138

Sitasawad, S., et al. Diabetes Research
Cu(II) sulfate As above Diabetes -Reduction of blood glucose levels
and Clinical Practice 52, 77–84 (2001)

Yasumatsu, N., et al. Bioorganic &

Cu(II)-picolinate Diabetes -Insulin-mimetic activity Medicinal Chemistry 15, 4917–4922
(2007)

Karmaker, S., et al. Macromolecular

CuII-gamma-polyglutamic acid Diabetes -Insulin-mimetic activity
Bioscience 7, 456–466 (2007)

Cu complexes of non-steroidal Dillon, C.T., et al. Chemical Research

Numerous structures Inflammation -SOD-mimetic activity
anti-inflammatory drugs (NSAIDs) in Toxicology 16, 28–37 (2003)

This journal is
c
-Improved ventricular Radovits, T., et al. Rejuvenation
Cu-aspirinate complex Coronary heart disease
contractility Research 11, 945–956 (2008)

UV-induced skin Fujimori, T., et al. Experimental

Cu-aspirinate complex As above -Increased SOD activity
damage Dermatology 16, 746–752 (2007)

Simeon, A., et al. Journal of

Cu complex of tri-peptide -Up-regulation of matrix
Wound healing Investigative Dermatology 112,
glycyl-L-histidyl-L-lysine (GHK) metalloproteinases
957–964 (1999)

The Royal Society of Chemistry 2012

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 suitable cofactor for a variety of enzymes involved in many

Gokhale, N.H. Inorganica Chimica

biological processes; e.g. energy metabolism (cytochrome c

Maffei, R.D., et al. Biometals 22,

oxidase) and antioxidative activity (copper zinc superoxide
dismutase, SOD1).3 Cu can also interact with molecular
oxygen to produce reactive oxygen species.4 Hence Cu

Acta 349 23–29 (2003)

distribution and homeostasis are highly regulated, since free
1095–1101 (2009)
Cu ions are potentially harmful to cells. Transport of Cu
across the cell membrane occurs via the Ctr1 protein during
Key reference

import and the Cu ATP7a/b transporters during export.5–9

Once inside the cell, Cu chaperones such as copper chaperone
for SOD1 and atox1 deliver Cu to specific enzymes and
molecules.10,11 Cu is also important in synaptic function; Cu
is important in axonal targeting and synaptogenesis12 and

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there is evidence of Cu release into the synaptic cleft following
Proposed Mechanism of Action

depolarization.13,14 Cu may have important effects on neuro-

transmission.15 However, the redox activity of Cu also allows
for its incorporation with different ligands to form Cu com-
-Cu(I)-mediated ROS

plexes, both organic and inorganic and this property has been
-Generation of ROS

harnessed for development of unique therapeutic compounds.

Overview of Cu complexes
Due to the physiological importance of Cu and its unique
redox activity, many different Cu complexes and Cu chelators
have been synthesized and investigated for their therapeutic
and diagnostic potential in human disease. Reported Cu
chelating compounds include clioquinol (5-chloro-7-iodo-8-
hydroxyquinoline) (CQ), PBT2, DP-109, tetrathiomolybdate
(TM) and pyrrolidine dithiocarbamate (PDTC).16–20 CQ and
Target disease

Leishmaniasis

PBT2 both belong to the quinoline class of compounds and

Malaria

are moderate chelators of copper and zinc and weak chelators

of iron.21 It is an important feature of these compounds that
they are not high affinity metal depleting compounds; rather
they exhibit moderate metal affinity to remove metals from
extracellular amyloid rather than metals from high affinity
metalloproteins. In addition, recent evidence suggests that
PBT2 and possibly CQ may promote the uptake of Cu/Zn
into cells with potential neuroprotective effects.22,23 Dithio-
carbamates are another class of moderate metal-chelating
compounds.24,25 PDTC is reported to be an antioxidant and
an inhibitor of nuclear factor kb, but can also chelate Cu
and/or modulate cellular Cu homeostasis with neuroprotective
outcomes.20,26 DP-109 is a derivative of 1,2-bis(o-amino-
phenoxy)ethane-N,N,N 0 ,N 0 -tetraacetic acid (BAPTA) known
to chelate transition metals and has shown protective effects in
Structure

animal models of Alzheimer’s disease.18 TM is a selective

extracellular Cu-chelator utilized for the treatment of Wilson
disease.19,27 Penicillamine and trientine have also been success-
fully used in treatment of Wilson disease.28,29 In addition,
copper chelators have been harnessed as a potential thera-
peutic agent for treatment of some types of cancer.30
Cu complexes of fluorinated

Cu complexes of pyridine-2-

Whilst chelators have been investigated extensively in the

a-hydroxy-carboxylates

laboratory, their clinically-approved use has generally been

Table 1 (continued )

carboxamidrazones

restricted to patients with heavy metal poisoning or diseases

with severe metal accumulation (e.g. Wilson disease). The reason
that chelators have failed to be broadly adopted in the clinic
Compound

is that therapeutic use of a metal chelator may result in indiscri-

minate binding of essential metal ions, leading to potentially
harmful effects (e.g. scavenging of iron leading to anemia).

This journal is c The Royal Society of Chemistry 2012 Metallomics, 2012, 4, 127–138 131
Furthermore, many metal chelators are large hydrophilic
molecules, which impair their ability to cross the blood brain
barrier (BBB) and hence limits their potential as therapeutic
compounds for treatment of neurodegeneration, brain
tumours or other brain disorders. Importantly, the addition
of metals such as Cu to some drugs can modify the pharmaco-
logical properties of the compound. In some cases this can lead
to improved specificity and greater control of drug release.31
This concept has led to an increased focus on therapeutic
compounds designed for metal delivery and modulation of
cellular Cu metabolism, i.e., the development of pre-formed
Cu complexes.
Overview of thiosemicarbazones:
a model Cu-complex
Cu complexes of thiosemicarbazone (TSC) compounds have
been investigated for this purpose, as they are able to form
lipophilic, stable complexes with metal ions that can readily
cross cell membranes, including the BBB. Historically,
Cu-TSCs have been explored as antimalarial, anti-fungal
and anti-bacterial agents.32,33 There is a diverse range of
Cu-TSCs, as Cu(II) is able to form complexes with neutral or
anionic TSCs resulting in distorted tetrahedral, square planar,
square pyramidal or octahedral geometries.34 Cu complexes of
bis(thiosemicarbazones) (CuII(btsc)s) have also been investi-
gated as metallodrugs and diagnostic agents.35 More recently,
these complexes have also been investigated as potential agents
to treat neurodegeneration with glyoxalbis(N (4)- methyl-3-
thiosemicarbazonato)copper(II) (CuII(gtsm)) reported to have
neuroprotective action in cell culture and animal models of
Alzheimer’s disease.36–38
Overview of cancer therapeutics
Cancer is the leading cause of death in developed countries
and therefore represents a major health and economic problem
worldwide.39 Cancer is characterised by aberrant cell growth
(often due to disturbed cell cycle or the proteasome pathway)
resulting in tumour formation. Therefore, components of the
cell cycle or proteasome pathway are potential molecular
targets for therapeutic compounds. Historically, platinum-
based drugs (e.g. cisplatin) have been highly effective as cancer
therapeutics; however their application is limited by side effects
and inherited/acquired resistance.40,41 It is therefore useful
to explore the application of more physiologically relevant,
endogenous metals (such as Cu) in cancer therapeutics.
PDTC/CQ
Cu complexed to a variety of well-defined metal chelators has
been shown to be effective in cancer cell treatment. It is
important to note that the use of Cu complexes as cancer
therapeutics is likely to depend more on their cytotoxic action,
rather than modulation of Cu homeostasis. Both PDTC and
CQ, when complexed with Cu, strongly inhibited proteasome
activity and led to the activation of the apoptotic cell pathway
in cancer cells.25,42–44 CQ-Cu complexes have also shown
efficacy against other cancers such as prostate and myeloma.45,46
132 Metallomics, 2012, 4, 127–138
Cu binding to CQ was required for subsequent proteasome-
inhibitory, apoptosis-inducing activity—this did not occur in
the absence of Cu binding.45,47 As it is crucial that any anti-
cancer agent have the ability to distinguish between tumour
and normal cells, it is also important to note that the
proteasome inhibition occurred specifically in tumour cells
following treatment with CQ-Cu.25,48 The reason for this
specificity is still uncertain. However, CQ-Cu-based cancer
treated appears to be a potentially important area of future
cancer therapy development.
Thiosemicarbazones
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TSCs have been investigated for anticancer activity for many
decades. 2-formylpyridine thiosemicarbazone (PT) was
reported to have anti-leukaemic potential.49 This led to the
investigation of the 1-formylisoquinoline thiosemicarbazone
(IQ-1) compound, which was found to be an inhibitor of DNA
replication in sarcoma 180 cells.50 Through this and sub-
sequent work, a role for Cu binding to the ligand was found
to be associated with carcinostatic activity. More recently, a
Cu complex of the novel thiosemicarbazone NSC689534
inhibited tumour growth in vivo.51 This effect was mediated
through induction of apoptosis, possibly as a consequence of
reactive oxygen species (ROS) generation. A Cu complex of
9-retinal thiosemicarbazone was shown to inhibit human
leukaemic U937 cell proliferation via induction of apoptosis.52
Bis(thiosemicarbazones)
Bis(thiosemicarbazones) complexed to Cu also have potentially
important therapeutic applications for cancer. Radiolabelled
CuII(atsm) has been utilized for non-invasive imaging
of hypoxic tumours.53,54 Furthermore, administration of
64
CuII(atsm) to hamsters bearing human colon cancer tumours
resulted in increased survival time.55 A Cu(II) complex of
3-ethoxy-2-oxo-butyraldehyde bis(thiosemicarbazone) (H2kts)
was shown to have potent anti-tumour activity against Walker
256 carcinosarcoma in rats.56 Recently, treatment of human
neuroblastoma cells with CuII(gtsm) resulted in cell cycle
arrest. However, it was not associated with induction of
apoptosis, rather with a reduction in cyclin D1 expression.57
Schiff base complexes
Schiff base complexes of Cu have recently been investigated
for their therapeutic potential. Cu(Pyimpy)Cl2 (also represented
as Cu-P1) is a novel Schiff base Cu complex where Pyimpy is a
tridentate ligand containing 2 pyridine and 1 imidine nitrogen
donor.58 Cu-P1 inhibited tumour growth in rat breast tumour
cells. Other novel Schiff base complexes include complexes
of quinoline-2-carboxaldehyde, which have demonstrated
pro-apoptotic activity in prostate cancer cells.59 Derivatives
of salicylaldehyde benzoylhydrazone (SBH) and salicylaldehyde
pyrazole hydrazone (SPH) complexed to Cu have also been
generated as potential cancer therapeutics.60,61 Cu-SBH and
Cu-SPH complexes inhibited growth of human adenocarcinoma
cells by induction of apoptosis.
This journal is c The Royal Society of Chemistry 2012
Cu complexed to chemotherapeutics
Recently, well-established chemotherapeutics have been
complexed to Cu in an attempt to increase their efficacy and
reduce non-specific cytotoxicity. Doxorubicin is commonly
used in the treatment of a variety of cancers. Administration
of doxorubicin complexed to Cu within the core of liposomes
to mice bearing tumours resulted in a significant decrease in
tumour size compared to doxorubicin alone.62 Disulfiram is a
dithiocarbamate, which has been utilized for the treatment of
alcoholism, however studies have suggested disulfiram may
have anti-tumour activity. A disulfiram-Cu complex inhibited
proteasome activity in cultured breast cancer cells and in mice
bearing tumours.63
Overview of Alzheimer’s disease
AD affects approximately 2% of the industrialised population
and thus creates an immense burden for healthcare systems.64
Studies on AD patients have observed specific morphological
differences in the AD brain compared to age-matched controls,
notably the presence of extracellular deposits of amyloid beta
(Ab) and neurofibrillary tangles consisting of hyperphospory-
lated tau.65,66 Whilst altered biometal homeostasis is evident
during normal ageing, it is more pronounced in the AD brain.
There is evidence of increased Cu and Zn in amyloid plaques
and decreased activity of intracellular cuproenzymes, suggesting
decreased intracellular Cu.67,68 A recent meta-analysis has
supported a deficit of Cu in AD brain.69 Although some AD
drugs may delay cognitive impairment, current treatments
for AD remain largely insufficient, highlighting the need for
development of effective therapeutics.
CQ and PBT2
There is evidence of beneficial effects following administration
of CQ to AD patients and to transgenic APP mice. Treatment
of APP2576 Tg mice with CQ resulted in decreased neuronal
Ab accumulation.70 Accordingly, administration of CQ to AD
patients in a Phase II clinical trial resulted in a significant
decrease in plasma Ab42 levels.71 Furthermore, there was a
slowing of cognitive decline (as measured by the Alzheimer’s
Disease Assessment Scale) in CQ-treated patients compared to
the control group.
Due to issues with purity of large-scale CQ production,
PBT2, a novel 8-hydroxy-quinoline, was developed. Adminis-
tration of PBT2 to Tg2576 and APP/PS1 transgenic mice
resulted in a reduction in Ab levels and improved cognition.72
There was also increased dendritic spine density and increased
expression of key proteins involved in memory processes.22
A clinical trial of PBT2 reported a reduction in CSF Ab and
improved cognitive function.73,74 The therapeutic effects of
PBT2 may be exerted by its ability to remove Cu/Zn from
extracellular amyloid plaques and deliver them into cells, thus
rectifying some of the effects of low intracellular Cu. PBT2 has
been shown to remove Zn from Ab-Zn complexes and trans-
port it into the cell, activating protective signalling pathways.
In turn, this leaves the Ab easier to degrade by matrix metallo-
proteinases. Studies have also shown neuroprotective actions
This journal is c The Royal Society of Chemistry 2012
of both PBT2-Zn and PBT2-Cu complexes in vitro that
correlate with improved cognition in vivo.22
Administration of DP-109 to Tg2576 (APP-overexpressing)
mice resulted in reduced amyloid burden.18 However, using a
metal chelator alone may result in potentially harmful effects,
as mentioned earlier. This is supported by the results of a study
where young APP transgenic mice were treated with CQ alone
and CQ-Cu. CQ treatment alone exacerbated the premature
death phenotype in APP transgenic mice, which was partially
rescued upon CQ-Cu treatment.75 Furthermore, treatment of
CQ-Cu to CHO-APP cells resulted in a reduction of secreted
Ab. This was mediated by PI3K activation (part of a neuro-
protective pathway), resulting in GSK3b inhibition.23,76
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GSK3b inhibition is currently an important therapeutic target
for treatment of neurodegeneration.77
TSCs and PDTC
Thiosemicarbazones and bis(thiosemicarbazones) have also
demonstrated therapeutic potential in AD. Treatment of
CHO-APP cells with CuII(gtsm) resulted in increased Cu
bioavailability and a reduction of secreted Ab.36 Oral adminis-
tration of CuII(gtsm) to an AD (APP/PS1) mouse model
resulted in GSK3b inhibition and restored cognitive perfor-
mance to near normal levels.37 Although PDTC is classed as a
chelator, it is also capable of transporting extracellular Cu into
the cell and can thus increase Cu bioavailability. PDTC
treatment of APP/PS1 mice resulted in decreased tau phos-
phorylation and elevated cerebral Cu levels. This occurred
through down-regulation of the GSK3b signaling cascade and
ultimately led to improvements in spatial memory.26
Parkinson’s disease and its potential treatment with
Cu complexes
Parkinson’s disease (PD) is a progressive neurodegenerative
disorder characterized by motor dysfunction. Pathology of PD
involves neuronal death in the Substantia Nigra (SN), an area
important for motor planning. Analysis of post-mortem brain
tissue from PD patients revealed a decrease in Cu concen-
tration and an increase in Fe content in the SN.78 This has
been supported by reports of decreased Cu in brains of animal
models of PD.79 Furthermore, Cu(II) sulfate administration
has shown neuroprotective effects against MPP+ -induced
neurotoxicity.80 Pre-treatment of rats with Cu attenuated
MPP-induced neurotoxicity by preserving dopamine levels.81
Administration of the Cu-chelating agent diethyldithiocarbamate
(DDC) to mice resulted in increased susceptibility to MPP-induced
neurotoxicity further suggesting that Cu may be protective.82
The neuroprotective effect of Cu may involve modulation of
Fe uptake; i.e. Cu and Fe compete for intestinal absorption so
Cu administration may reduce Fe uptake, thus reducing the
iron load in the SN.83
Huntington’s disease and its treatment with Cu
complexes
Huntington’s disease (HD) is an inherited neurodegenerative
disorder characterized by motor and cognitive deterioration.
Metallomics, 2012, 4, 127–138 133
There have been reports of altered Cu concentration in the
HD brain.78,84 There is also evidence of Cu binding to the
N-terminal fragment of the huntingtin protein.85 Overexpression
of genes involved in Cu metabolism resulted in reduced
toxicity of huntingtin aggregates.86 CQ treatment decreased
mutant huntingtin expression in PC12 cells and also decreased
huntingtin aggregation in a HD mouse model, resulting in an
alleviation of the HD pathology.87 However it was unclear
whether this was due to chelation of Cu or the CQ-mediated
transport of Cu to sites where it is required. Currently there is
only one approved drug for HD, so it is clear that the
development of effective therapeutics is vital and further
investigation of Cu complexes is warranted.88
Amyotrophic lateral sclerosis and its treatment with
Cu complexes
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative
disease characterized by degeneration of neurons in the upper
and lower spinal cord and associated muscle wasting. The
etiology is predominantly sporadic but there are familial
forms; including mutations in the superoxide dismutase
(SOD1) gene and more recently, TAR DNA binding protein
43 (TDP-43).89 SOD1 is a Zn and Cu-dependent antioxidant
enzyme involved in free radical scavenging. ALS-causing
SOD1 mutations do not necessarily result in loss of SOD1
function; rather these mutations result in misfolded SOD1 that
can accumulate in neuronal aggregates.90 It has been suggested
that the toxicity of mutant SOD1 is caused by Cu that is
delivered to it via its Cu chaperone CCS. However, mutant
SOD1 was still shown to cause ALS in CCS-knockout mice.91
The neuronal aggregates characteristic of ALS have also been
shown to contain ubiquitinated TDP-43 protein, which is
suggested to be a major pathological substrate.92 No specific
interaction between TDP-43 and copper has yet been identified.
PDTC treatment decreased survival in a transgenic rat model of
ALS.93 However, other Cu chelators such as DP109, ammonium
tetrathiomolybdate (TTM) and N-acetylcysteine prolonged the
survival in ALS mouse models.94–96 Despite this discrepancy,
these studies demonstrate a potential role for Cu in ALS
pathology. It is not certain if the action of these compounds is
to restore Cu homeostasis or remove Cu from sites of aberrant
Cu-protein interaction. Moreover, the effect of these compounds
in TDP-43 models of ALS is yet to be reported.
Diabetes and its treatment with Cu complexes
Insulin dependent diabetes mellitus (DM) (Type 1) is an
autoimmune disease localized to the endocrine pancreas.
A pathological feature of DM is increased susceptibility of
the insulin-producing cells within the pancreas to oxidative
stress.97 A Cu(II)-picolinate complex was shown to be non-
toxic in rat hepatic cells and exerted a hypo-glycaemic effect in
STZ-induced type 1 diabetic mice.98 Another Cu complex
(CuII-gamma-polyglutamic acid) has been shown to have
insulin-mimetic activity.99 Treatment of STZ-diabetic mice
with Cu sulfate resulted in decreased blood glucose levels
and improved pancreas morphology.100 There was also
134 Metallomics, 2012, 4, 127–138
reduced lipid peroxidation; suggesting that perhaps Cu sulfate
exerts its effects through relief of oxidative stress.
Inflammatory diseases and their treatment with Cu
complexes
Cu metabolism is altered in chronic inflammatory diseases
such as rheumatoid arthritis. While serum Cu content and
ceruloplasmin activity are known to be elevated in rheumatoid
arthritis, SOD activity is decreased in rheumatoid arthritis.101,102
It is possible that this increase in serum Cu content represents
a protective response to decreased SOD activity. Paradoxi-
cally, Cu is thought to possess anti-inflammatory activity.103
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Commonly used anti-inflammatory agents include non-
steroidal anti-inflammatory drugs (NSAIDs), which is a large
group of compounds including ibuprofen, aspirin and naproxen.
NSAIDs have analgesic properties at low doses and anti-
inflammatory properties at high doses.104 However, many
current anti-inflammatory therapies (including NSAIDs) are
associated with side effects such as renal failure and gastro-
intestinal toxicity.105
This has led to the development of Cu complexes of
NSAIDs. Cu-NSAIDs exhibited increased anti-inflammatory
and reduced gastrointestinal toxicity compared to their parent
drugs.106,107 It is proposed that the anti-inflammatory properties
of NSAID-Cu complexes result from SOD-mimetic activity.108
Although there have been long-term veterinary applications of
Cu-NSAIDs (i.e. Cu-indomethacin), there has been little
investigation into the clinical applications of these drugs.109
Alternatively, Cu chelators have been utilised experimentally
for inflammation therapeutics. Tetrathiomolybdate (TM) has
been utilised in a rat model of adjuvant arthritis. TM adminis-
tration resulted in decreased severity, as demonstrated by a
reduction of inflammatory cell invasion into joint tissues.110
Cardiovascular disease and its treatment with Cu
complexes
Coronary heart disease (CHD) is one of the leading causes of
death in the industrialised world. CHD refers to a narrowing
of the arteries, usually caused by atherosclerosis. It can result
in heart attack and stroke.111 There has been conflicting
evidence for the role of Cu in CHD pathogenesis. Cu is
thought to catalyse the oxidative modification of low density lipo-
protein (LDL) which is a major event in atherosclerosis.112,113
However, these studies were performed in vitro at concentra-
tions of Cu much higher than in vivo so are perhaps not
physiologically relevant. Conversely, it has been shown that
Cu deficiency results in hyperlipidemia.114 This is perhaps due
to a decrease in SOD activity, resulting in oxidative stress and
increased LDL susceptibility to oxidation.115 This theory is
supported by studies in which animals fed high cholesterol
diets were supplemented with dietary Cu.116,117 Cu-fed animals
exhibited reduced lipid accumulation in the aorta compared to
control animals. Furthermore, aortic SOD levels were signifi-
cantly higher in Cu-fed animals. Cu supplementation in men
with high plasma cholesterol and in healthy young women
resulted in increased SOD activity.118 A Cu-aspirinate
complex has been investigated as a potential therapeutic for
This journal is c The Royal Society of Chemistry 2012
cardiovascular dysfunction.119 In a rat model of age-related
cardiovascular dysfunction, Cu-aspirinate administration
resulted in improved ventricular contractility.
Skin disorders and their treatment with Cu
complexes
Topical application of Cu-complexes have been useful in the
treatment of various skin conditions such as wounds, ultra-
violet (UV) induced damage and skin cancers. The latter two
conditions involve skin exposure to harmful UV rays that can
generate ROS and cause DNA damage, resulting in the
development of cancer cells.120 SOD has also been implicated
in this process; SOD activity is decreased in response to UVB
exposure.121 Cu-complexes designed as SOD-mimetics have
therefore been studied as treatments for skin conditions.
Administration of Cu-aspirinate to mice following UV exposure
resulted in a suppression of ROS generation and increase of
SOD activity.122
The process of wound healing consists of inflammation to
remove bacteria and debris, and then proliferation and migration
of keratinocytes to create new tissue. Cu has been shown to
have a stimulatory effect on the proliferation of keratinocytes.123
Various studies on wound healing have focused on Cu complexed
to the tri-peptide glycyl-L-histidyl-L-lysine (GHK). Adminis-
tration of Cu-GHK to rats resulted in an up-regulation of
matrix metalloproteinases, which are required to degrade the
extracellular matrix and remove damaged tissue.124 Treatment
of fibroblast cultures with Cu-GHK resulted in stimulation of
collagen synthesis.125 Topical application of Cu-GHK to open
wounds in rabbits resulted in significantly faster neovascular-
ization and formation of new tissue.126,127
Leishmaniasis, malaria and their treatment with Cu
complexes
Leishmaniasis is a tropical disease caused by the parasite
leishmania, which infects macrophages of vertebrate hosts.
Although leishmaniasis affects millions of people worldwide,
current drugs for its treatment are expensive and some are
very toxic. Cu complexes based on fluorinated a-hydroxy-
carboxylates have recently been investigated against
promastigotes of leishmania.128,129 It was found that the most
lipophilic and redox-active compounds had the highest toxi-
city towards promastigotes. This effect was mediated through
the reaction of Cu with endogenous peroxide, which resulted
in generation of ROS and killing of promastigotes.
Malaria is a disease caused by the parasite Plasmodium
falciparum, which is transmitted via infected mosquitoes.
Due to the acquired resistance of Plasmodium falciparum to
many anti-malarial agents, the development of efficacious anti-
malarial drugs is imperative. Heterocyclic thiosemicarbazones
such as 2-acetylpyridine thiosemicarbazones have been investi-
gated for their anti-malarial activity.130 More recently, the
antimalarial activity of pyridine-2-carboxamidrazone deriva-
tives and their Cu complexes has been studied.131,132 The Cu
complexes were found to have increased antimalarial activity
compared to their parent complexes. Cu nanohybrid solids
have also been developed and evaluated as anti-malarial agents.133
This journal is c The Royal Society of Chemistry 2012
The advantage of these smaller compounds is that they have
greater access to parasitic vacuoles, which have been identified
as a promising drug target.
Concluding remarks
Cu complexes have been investigated for their therapeutic
potential in a wide variety of pathological conditions. The
appeal of Cu as a substrate for ligands is due to its ability to
participate in redox and catalytic chemistry. Furthermore, Cu
can co-ordinate ligands in precise three dimensional config-
urations, allowing for interaction with specific molecular
targets. The development of Cu complexes of extant drugs
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may prove more efficacious and less toxic than their parent
drugs. The incorporation of a more physiologically relevant
metal like Cu is particularly pertinent for chemotherapeutics
that contain platinum (e.g. cisplatin), as platinum is only
present in the body in negligible amounts. The efficacy of Cu
complexes as chemotherapeutics is reliant on their cytotoxic
action on tumour cells, whereas the efficacy of Cu complexes
as treatments for neurodegenerative diseases relies more on
delivery of Cu or modulation of Cu homeostasis. Cu can also
interact with pathological protein aggregates or upregulate
signaling pathways, resulting in neuroprotective effects. In
various other diseases (such as CHD and skin disease) the
success of Cu complexes as therapeutics is perhaps due to their
ability to increase SOD activity, leading to relief of oxidative
stress. It is clear that the ability of Cu to participate in redox
reactions combined with the ability of the complex to allow
enhanced Cu delivery results in many efficacious compounds.
The studies summarized in this review contribute to the
mechanistic understanding of Cu complexes, which could lead
to development of Cu-based therapeutics with greater selectivity
and efficacy. The future development of Cu complexes could
have important beneficial outcomes in many diseases; making
the field of Cu complexes an exciting one.
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