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Drug Design, Development and Therapy 2017:11 599–616
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REVIEW
open access to scientific and medical research
Open Access Full Text Article
http://dx.doi.org/10.2147/DDDT.S119488
Metal complexes in cancer therapy – an update
from drug design perspective
Umar Ndagi
Ndumiso Mhlongo
Mahmoud E Soliman
Molecular Modelling and Drug Design
Research Group, School of Health
Sciences, University of KwaZulu-
Natal, Westville, Durban, South Africa
Abstract: In the past, metal-based compounds were widely used in the treatment of disease
conditions, but the lack of clear distinction between the therapeutic and toxic doses was a
major challenge. With the discovery of cisplatin by Barnett Rosenberg in 1960, a milestone
in the history of metal-based compounds used in the treatment of cancers was witnessed.
This forms the foundation for the modern era of the metal-based anticancer drugs. Platinum
drugs, such as cisplatin, carboplatin and oxaliplatin, are the mainstay of the metal-based
compounds in the treatment of cancer, but the delay in the therapeutic accomplishment of
other metal-based compounds hampered the progress of research in this field. Recently, how-
ever, there has been an upsurge of activities relying on the structural information, aimed at
improving and developing other forms of metal-based compounds and nonclassical platinum
complexes whose mechanism of action is distinct from known drugs such as cisplatin. In
line with this, many more metal-based compounds have been synthesized by redesigning the
existing chemical structure through ligand substitution or building the entire new compound
with enhanced safety and cytotoxic profile. However, because of increased emphasis on the
clinical relevance of metal-based complexes, a few of these drugs are currently on clinical
trial and many more are awaiting ethical approval to join the trial. In this review, we seek
to give an overview of previous reviews on the cytotoxic effect of metal-based complexes
while focusing more on newly designed metal-based complexes and their cytotoxic effect on
the cancer cell lines, as well as on new approach to metal-based drug design and molecular
target in cancer therapy. We are optimistic that the concept of selective targeting remains the
hope of the future in developing therapeutics that would selectively target cancer cells and
leave healthy cells unharmed.
Keywords: cancer, DNA, platinum, metal complexes, apoptosis, selective target
Introduction
Therapeutic potentials of metal-based compounds date back to ancient time.
1
During
this period, the ancient Assyrians, Egyptians and Chinese knew about the importance
of using metal-based compounds in the treatment of diseases,
1
such as the use of
cinnabar (mercury sulfide) in the treatment of ailments.
1
The advent of “theoretical
science”, by Greek philosophers (Empedocles and Aristotle) in the 5th and 4th century
BC,
1
boosted the knowledge of metal-based compounds as therapeutic agents. This
was supported by the information handed down by Pliny and Aulus Cornelius Celsus
(Roman physicians) on the use of cinnabar in the treatment of trachoma and venereal
diseases.
1
In the 9th and 11th century BC, the contributions of ancient scientists such
as Rhazes (Al-Razi) and Avicenna (Ibn Sina) were applauded,
1
sequel to the discovery
of toxicological effects of mercury in the animals and the use of mercury (quicksilver
ointment) for skin diseases respectively.
Correspondence: Mahmoud E Soliman
Molecular Modelling and Drug Design
Research Group, School of Health
Sciences, University of KwaZulu-Natal,
Westville, Durban 4000, South Africa
Tel +27 31 260 7413
Fax +27 31 260 779
Email soliman@ukzn.ac.za
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Ndagi et al
Arsenic trioxide (ATO) was used as an antiseptic
2
and in
the treatment of rheumatoid diseases, syphilis and psoriasis
by traditional Chinese medical practitioners.
2
Certainly,
ATO was among the first compounds suggested for use in
the treatment of leukemia
3
during 18th and 19th centuries,
until in the early 20th century when its use was replaced by
radiation and cytotoxic chemotherapy.
3
Therapeutic use of
gold and copper can be traced to the history of civilization,
4
where the Egyptians and Chinese were famous users in the
treatment of certain disease conditions, such as syphilis.
4
The discovery of platinum compound (cisplatin) by Barnett
Rosenberg in 1960s
5
was a milestone in the history of
metal-based compounds used in the treatment of cancer.
6
This forms the foundation for the modern era of the metal-
based anticancer drug.
5
Despite the wide use of the metal-
based compounds, the lack of clear distinction between the
therapeutic and toxic doses was a major challenge. This
was so because practitioners of ancient time lack adequate
knowledge of dose-related biological response.
7
The advent
of molecular biology and combinatorial chemistry paves the
way for the rational design of chemical compounds to target
specific molecules.
7
Generally, metals are essential components of cells
chosen by nature.
8
They are frequently found in the enzyme
catalytic domain
9
and are involved in multiple biological
processes, from the exchange of electrons to catalysis
and structural roles.
9
They are extensively used in cellular
activities.
9
Such metals include gallium, zinc, cobalt, silver,
vanadium, strontium, manganese and copper, which are
required in trace amounts to trigger catalytic processes.
10
To this end, a balance between cellular need and the
amount available in the body is important for the normal
physiological state. Comparatively, metals, including nickel,
cadmium, chromium and arsenic, can induce carcinogenesis
and hence are less beneficial to the body.
10
These limitations
have triggered a search for platinum-based compounds
that show lower toxicity, higher selectivity and a broader
spectrum of activity.
8,11,12
Platinum(II) complexes such as
carboplatin and oxaliplatin as well as other platinum ana-
logs are the products of this search. Other metal complexes
containing ions such as zinc(II), gold and copper chelating
agents have received considerable interest as anticancer
agents.
8,13
Recently, the chemistry of ruthenium and gold-
based compounds has received intensive scrutiny, due to
renewed interest in providing an alternative to cisplatin,
because of their promising cytotoxic and potential anticancer
properties.
4,14,15
Nevertheless, metal-based compounds, especially tran-
sition metals, exhibit definite properties including their
potential to undergo a redox reaction.
5
Therefore, metals
and their redox activities are tightly regulated to maintain
normal wellbeing.
5,16–21
Recently, there has been a growing demand for metal-
based compounds in the treatment of cancer. This may be
due to the scourge of cancer and, to the greater extent, the
level of in vitro cytotoxic effect exhibited by metal-based
compounds, particularly those synthesized recently. In
addition, ligand substitution and modification of existing
chemical structures led to the synthesis of a wide range of
metal-based compounds, some of which have demonstrated
an enhanced cytotoxic and pharmacokinetic profile. Again,
a different approach of cytotoxic drug design has recently
been adopted. This involves conjugating metallic compounds
with bile acid, steroid, peptide or sugar to allow direct drug
delivery to the cancer cells, thereby circumventing some
pharmacokinetic challenges. The objective of this review is
to provide an overview of previous reviews on the cytotoxic
effects of metal-based compounds while focusing more on
newly designed metal-based compounds and their cytotoxic
effect on the cancer cell line, as well as on new approach to
metal-based drug design in cancer therapy.
Properties of metal complexes and
metal-based compounds
Transition metals are member elements of the “d” block and
are included in groups III–XII of the periodic table.
22
They
possess unique properties that include:
•Charge variation: In aqueous solution, metal ions exist
as positively charged species. Depending on the existing
coordination environment, the charge can be modified to
generate species that can be cationic, anionic or neutral.
23
Most importantly, they form positively charged ions in
aqueous solution that can bind to negatively charged
biological molecules.
8
•Structure and bonding: Relative to organic molecules,
metal complexes can aggregate to a wide range of coordi-
nation geometries that give them unique shapes. The bond
length, bond angle and coordination site vary depending
on the metal and its oxidation state.
23
In addition to this,
metal-based complexes can be structurally modified
to a variety of distinct molecular species that confer a
wide spectrum of coordination numbers and geometries,
as well as kinetic properties that cannot be realized by
conventional carbon-based compounds.
8,24,25
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Metal complexes in cancer therapy
•Metal–ligand interaction: Different forms of metal–ligand
interaction exist; however, these interactions usually
lead to the formation of complexes that are unique from
those of individual ligands or metals. The thermody-
namic and kinetic properties of metal–ligand interac-
tions influence ligand exchange reactions.
23
The ability
of metals to undergo this reaction offers a wide range of
advantages to the metals to interact and coordinate with
biological molecules.
8
•Lewis acid properties: Characterized by high electron
affinity, most metal ions can easily polarize groups
that are coordinated to them, thus facilitating their
hydrolysis.
8,23
•Partially filled d shell: For transition metals, the vari-
able number of electrons in the d shell or f shell (for
lanthanides) influences the electronic and magnetic
properties of transition metal complexes.
23
•Redox activity: Many transition metals have a tendency to
undergo oxidation and reduction reactions.
23
The oxida-
tion state of these metals is an important consideration in
the design of the coordination compound. In biochemi-
cal redox catalysis, metal ions often serve to activate
coordinated substrates and to participate in redox-active
sites for charge accumulation.
Metal complexes and metal-based compounds possess
the ability to coordinate ligands in a three-dimensional con-
figuration, thereby allowing functionalization of groups that
can be shaped to defined molecular targets.
8
Scope of metal complexes in the
treatment of cancer
Therapeutic potential of metal complexes in cancer therapy
has attracted a lot of interest mainly because metals exhibit
unique characteristics, such as redox activity, variable coor-
dination modes and reactivity toward the organic substrate.
8
These properties become an attractive probe in the design of
metal complexes
8
that selectively bind to the biomolecular
target with a resultant alteration in the cellular mechanism
of proliferation. Table 1 provides a summary of in vitro
cytotoxic effect of various metal-based compounds within the
period of 6 years with particular reference to their proposed
mechanism of action and target.
Several metal-based compounds have been synthesized
with promising anticancer properties, some of which are
already in use in clinical practice for diagnosis and treat-
ment while some are undergoing clinical trials. Metal-based
compounds synthesized recently are products of drug design
targeted at achieving specific objectives that the original
compound could not achieve and such compounds exhibit a
different spectrum of cytotoxicity. Compounds in this group
include the following.
Platinum complexes and associated
ligands
Platinum compounds, particularly cisplatin, are the heart-
beat of the metal-based compounds in cancer therapy.
Clinical use of platinum complexes as an adjuvant in cancer
therapy is based on the desire to achieve tumor cell death
26
and the spectrum of activity of the candidate drug.
26
Such
complexes are mostly indicated for the treatment of cervical,
ovarian, testicular, head and neck, breast, bladder, stom-
ach, prostate and lung cancers. Their anticancer activities
are also extended to Hodgkin’s and non-Hodgkin’s lym-
phoma, neuroblastoma, sarcoma, melanoma and multiple
myeloma.
26
Although resistance to cisplatin emerged, it
was the fundamental basis that triggered the search for
alternative metallic compounds with improved anticancer
and pharmacokinetic properties. On this basis, alternative
platinum compounds were derived. Carboplatin, oxaliplatin,
satraplatin, ormaplatin, aroplatin, enloplatin, zeniplatin,
sebriplatin, miboplatin, picoplatin, satraplatin, and ipro-
platin are all products of extensive research of platinum
complexes (Figure 1).
The US Food and Drug Administration (FDA) in 1978
approved Platinol
®
, a brand of cisplatin, as a combination
therapy in the management of metastatic testicular, ovarian
and bladder cancers.
27
FDA also approved Paraplatin
®
(carboplatin) as a combination therapy in the management
of ovarian cancer.
27
Numerous other platinum derivatives
have been synthesized with established clinical success,
including Eloxatin
®
(oxaliplatin), Aqupla
®
(nedaplatin)
approved for use in Japan and lobaplatin approved for
use in China.
Oxaliplatin was initially launched in France in 1996
and formally available in the countries of Europe in 1999
and the US in 2002.
27
This is a platinum-based drug with
oxalate and diaminocyclohexane ligand (DACH). The
DACH plays a major role in cytotoxicity and protects it
against cross-resistance with cisplatin and oxaliplatin. It is
licensed to be used as a combination therapy with other
chemotherapeutic agents in the management of colon cancer
and non-small-cell lung cancer.
28
This drug has better safety
profile than cisplatin, as such is used in patients who cannot
tolerate cisplatin.
27
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Table 1 An update on the anticancer activities of metal-based complexes (2010–2016)
Metal complexes Molecular formula Proposed mechanism
of action
Target enzymes/cell lines/
therapeutic indications
IC
50
range (µM)
Carbene–metal complexes and related ligands
Novel gold(I) and
gold(III) NHC
complexes
62
C
52
H
44
Au
2
N
12
P
2
F
12
C
26
H
24
AuCl
2
OF
6
N
6
P
Induction of apoptosis
Inhibition of TrxR
62
Induction of ROS
62
TrxR
A549, HCT116, HepG2,
MCF7
Chemotherapy of solid
tumors
62
C
52
H
44
Au
2
N
12
P
2
F
12
5.2±1.5 (A549)
3.6±4.1 (HCT-116)
3.7±2.3 (HepG2)
4.7±0.8 (MCF7)
62
C
26
H
24
AuCl
2
OF
6
N
6
P
5.2±3.0 (A549)
5.9±3.6 (HCT-116)
5.1±3.8 (HepG2)
6.2±1.4 (MCF7)
62
Caffeine-based
gold(1) NHCs
81
[Au(Caffeine-2-yielding)
2
]
[BF
4
]
81
Inhibition of protein
PARP-1
81
DNA
A2780, A2780R, SKOV3,
A549 and HEK-293T
0.54–28.4 (A2780)
17.1–49 (A2780/R)
0.75–62.7 (SKOV3)
5.9–90.0 (A549)
0.20–84 (HEK-293T)
Ester- and amide-
functionalized
imidazole of NHC
complexes
82
{[Im
A
]AgCl}
{[Im
A
]AuCl}
{[Im
B
]
2
AgCl}
{[Im
B
]AuCl}
HIm
A
Cl = [1,3-bis
(2-ethoxy-2-oxoethyl)-1H-
imidazol-3-ium chloride]
HIm
B
Cl = {1,3-
bis[2(diethylamino)-2-
oxoethyl]-1H-imidazol-3-ium
chloride}
Inhibition of tyrosine
by gold(I) NHC ligands,
thereby targeting TrxR
82
CuNHC cell cycle arrest
progression in GI phase
82
Anticancer activity of
Ag
1
NHC is based on
highly lipophilic aromatic-
substituted carbenes
82
TrxR
82
A375, A549, HCT-15 and
MCF7
Human colon
adenocarcinoma,
82
leukemia
and breast cancer
82
{[Im
A
]AgCl}
24.65 (A375)
22.14 (A549)
20.32 (HCT-15)
21.14 (MCF7)
{[Im
A
]AuCl}
44.64 (A375)
42.37 (A549)
41.33 (HCT-15)
38.53 (MCF7)
{[Im
B
]
2
AgCl}
24.46 (A375)
16.23 (A549)
14.11 (HCT-15)
15.31 (MCF7)
82
Novel Ru(II) NHCs
83
[(η
6
-p-cymene)
2
Ru
2
(Cl
2
)
2
]
NHC
Mimic iron
84
Interact with plasmidic
DNA
84
DNA as target
Caki-1 and MCF7
Chemotherapy of solid
tumor
66
13–500 (Caki-1)
2.4–500 (MCF7)
83
Caffeine-derived
rhodium(I) NHC
complexes
85
[Rh(I)Cl(COD)(NHC)]
complexes
Inhibition of TrxR
85
Increase in ROS
formation
85
DNA damage
85
Cell cycle arrest
85
Decrease in mitochondria
membrane potential
85
TrXR
85
MCF7, HepG2 MDA-MB-231,
HCT-116, LNCaP, Panc-1
and JoPaca-1
Chemotherapy of solid
tumor
85
84 (HepG2)
20 (HCF-7)
23 (MDA-MB-231)
35 (JoPaca-1)
49 (Panc-1)
80 (LNCaP)
9.0 (HCT-116)
85
NHC–amine Pt(II)
complexes
86
NHC (PtX2)–amine
complexes
86
Nuclear DNA
platination
86
Target DNA
86
KB3-1, SK-OV3, OVCAR-8,
MV-4-11, A2780 and A2780/
DPP
Chemotherapy of solid and
non-solid tumors
86
2.5 (KB3-1)
4.33 (SK-OV3)
1.84 (OVCAR-8)
0.60 (MV-4-11)
4.00 (A2780)
8.5 (A2780/DPP)
86
2-Hydroxy-3-
[(hydroxyimino)-4-
oxopentan-2-ylidene]
benzohydrazide
derivatives
87
[(HL)Cu(OAc)(H
2
O)
2
]⋅H
2
O
C1
4
H
21
N
3
O
9
Cu
Bind to DNA
87
Target DNA
87
HepG2
Chemotherapy of solid
tumors
87
2.24–6.49 (HepG2)
87
Molybdenum(II)
allyl dicarbonate
complexes
88
[Mo(allyl)(CO)
2
(N-N)(py)]PF
6
DNA fragmentation
88
Induction of apoptosis
88
Target DNA
88
NALM-6, MCF7 and HT-29
Chemotherapy of solid and
non-solid tumors
88
1.8–13 (NALM-6)
2.1–32 (MCF7)
1.8–32 (HT-29)
88
(Continued)
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Metal complexes in cancer therapy
Table 1 (Continued)
Metal complexes Molecular formula Proposed mechanism
of action
Target enzymes/cell lines/
therapeutic indications
IC
50
range (µM)
Metal-arene complexes and other ligands
Ru(II)–arene
complex
89
[(η
6
-arene)Ru(II)(en)Cl]
+
DNA damage
89
Cell cycle arrest
89
Induction of apoptosis
89
Target DNA
AH54 and AH63
Chemotherapy of colorectal
cancer
89
C
15
H
18
C
l
F
6
N
2
PRu
16.6 (AH54)
89
C
16
H
2
OC
l
F
6
N
2
PRu
10.9 (AH63)
89
Novel ruthenium–
arene pyridinyl
methylene
complexes
90
[(η
6
-p-cymene)RuCl
(pyridinylmethylene)]
DNA binding
90
Target DNA
90
MCF7 and HeLa
Chemotherapy of solid
tumor
90
07.76–25.42 (MCF7)
07.10–29.22 (HeLa)
90
Multi-targeted
organometallic
Ru(II)–arene
91
[(η
6
-p-cymene)RuCl
2
]2-PARP
and PARP-1 inhibitors
91
DNA binding
91
PARP-1 inhibition
91
Transcription inhibition
91
Target DNA
91
A549, A2780, HCT-116,
HCC1937 and MRC-5
Chemotherapy of solid
tumors
91
85.1–500 (A549)
38.8–500 (A2780)
46.0–500 (HCT-116)
93.3–500 (HCC1937)
143–500 (MRC-5)
91
Ru(II)–arene
complexes with
2-aryldiazole ligands
92
[(η
6
-arene)RuX(k
2
-N,N-L)]Y
DNA binding
92
Inhibition of CDK1
Target DNA
92
A2780, A2780cis, MCF7 and
MRC-5
Chemotherapy of solid
tumors
11–300 (A2780)
11–34 (A2780cis)
26–300 (MCF7)
25–224 (MRC-5)
92
Osmiun(II)–arene
carbohydrate
base anticancer
compound
93
Osmium(II)-bis [dichloride(η
6
-
p-cymene)]
DNA binding
93
Target DNA
93
CH1, SW480 and A549
50–746 (CH1)
215–640 (SW480)
640 (A549)
93
Ru(II)–arene
complexes with
carbosilane
metallodendrimers
94
G
n
-[NH
2
Ru(η
6
-p-cymene)
Cl
2
]m
Interaction with DNA
94
Interaction with HSA
94
Inhibition of cathepsin B
94
Target DNA
94
HeLa, MCF7, HT-29 MDA-
MB-231 and HEK-239T
Chemotherapy of solid and
non-solid tumors
94
6.3–89 (HeLa)
2.5–56.0 (MCF7)
3.3–41.7 (HT-29)
4–74 (MDA-MB-231)
5.0–51.9 (HEK-239T)
94
Ru(II) complexes
with aroylhydrazone
ligand
95
[Ru(η
6
-C
6
H
6
)Cl(L)]
Induction of apoptosis
95
Fragmentation of DNA
95
Target DNA
95
MCF7, HeLa, NIH-3T3
Chemotherapy of solid
tumor
95
10.9–15.8 (MCF7)
95
34.3–48.7 (HeLa)
152.6–192 (NIH-3T3)
Cyclopentadienyl complexes and other ligands
Iridium(III) complexes
with 2-phenylpyridine
ligand
96
[(η
5
-Cp*)Ir(2-(R′-phenyl)-R-
pyridine)Cl]
Interaction with DNA
nucleobases
96
Catalysis of NADH
oxidation
96
Target DNA
96
A2780, HCT-116, MCF7 and
A549
Chemotherapy of solid
tumor
96
1.18–60 (A2780)
3.7–57.3 (HCT-116)
4.8–28.6 (MCF7)
2.1–56.67 (A549)
96
New iron(II)
cyclopentadienyl
derivative
complexes
97
[Fe(η
5
-C
5
H
5
)(dppe)L][X]
Interaction with DNA
97
Induction of apoptosis
97
Target DNA
HL-60
Chemotherapy of non-solid
tumors
97
0.67–5.89 (HL-60)
Ru(II)
cyclopentadienyl
complexes with
carbohydrate
ligand
98
[Ru(η
5
-C
5
H
5
)(PP)(L)][X]
Induction of apoptosis
98
Activation of caspase-3
and -7 activity
98
HCT116CC, HeLa
Chemotherapy of solid
tumors
98
0.45 (HCT116CC)
3.58 (HeLa)
98
Ru(II)
cyclopentadienyl
complexes with
phosphane
co-ligand
98
[Ru(η
5
-C
5
H
5
)(PP)(L)][X]
Induction of apoptosis
98
HeLa
Chemotherapy of solid
tumor
98
2.63 (HeLa)
98
Organoiridium
cyclopentadienyl
complexes
99
[(η
5
-Cpx)Ir(L^L′)Z]
Intercalation of DNA
99
Coordination with DNA
guanine
99
HeLa
Chemotherapy of solid
tumor
99
0.23 (HeLa)
99
Abbreviations: IC
50
, half maximal inhibitory concentration; NHC, N-heterocyclic carbene; TrxR, thioredoxin reductase; ROS, reactive oxygen species; PARP-1,
Poly(ADP-ribose) polymerase-1; CDK1, cyclin-dependent kinase 1; HSA, human serum albumin; ADP, adenosine diphosphate.
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