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Current Medicinal Chemistry, 2018, Volume 1

Novel Chemotherapeutic Agents - The Contribution of Scorpionates

Marta A. Andradea, Luísa M.D.R.S. Martins*a

a
Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal

Abstract: The development of safe and effective chemotherapeutic agents is one of the uppermost priorities
and challenges of medicinal chemistry and new transition metal complexes are being continuously designed
and tested as anticancer agents. Scorpionate ligands have played a great role in coordination chemistry, since Please provide
their discovery by Trofimenko in the late 1960s, with significant contributions in the fields of catalysis and corresponding author(s)
photograph
bioinorganic chemistry. Scorpionate metal complexes have also shown interesting anticancer properties, and
herein, the most recent (last decade) and relevant scorpionate complexes reported for application in medicinal
chemistry as chemotherapeutic agents are reviewed. The current progress on the anticancer properties of
transition metal complexes bearing homo- or hetero- scorpionate ligands, derived from bis- or tris-(pyrazol-1-
yl)-borate or -methane moieties is highlighted.
Keywords: Scorpionate, metal complexes, cytotoxic agents, CORMs, photosensitizers.
1. INTRODUCTION
Cancer is the second leading cause of death worldwide, The providential discovery of cisplatin’s anticancer
accounting for 8.8 million deaths in 2015 and projected to activity [6] spawned what is today the field of medicinal
rise above 13.1 million deaths in 2030, according to The chemistry, that, for many years was virtually exclusively
World Health Organization report [1]. Lung, prostate, based on organic compounds and natural products. Pt-drugs
colorectal, stomach and liver cancer are the most common are presently first-line therapeutics in a dozen different
types of cancer in men, while breast, colorectal, lung, cervix cancers, whether applied in combination with radiation,
and stomach cancer are the most common among women. other antitumor agents, or novel targeted antitumor drugs.
The advent of the first metal based anticancer agent, Cisplatin, carboplatin and oxaliplatin (Figure 1) are FDA
launched a new era in the application of transition metal approved drugs used throughout Europe and North America
complexes for therapeutic design, being frequently for the clinical treatment of various cancers, while
considered as the beginning of modern research and nedaplatin, lobaplatin, and heptaplatin (Figure 1) are
development of metallodrugs, and placed coordination approved for clinical use in Japan, China and Korea. DNA is
chemistry of metal-based drugs in the frontline of the fight considered the primary target of platinum drugs, that are
against cancer [2-5]. The star of the field of modern believed to induce their therapeutic effect by entering cancer
chemotherapy is the anticancer agent cisplatin (cis- cells and binding to DNA, in a covalent, bifunctional manner
diamminodichloroplatinum(II), Platinol) (Figure 1). [5]. This event distorts DNA secondary structure and blocks
DNA transcription and replication, which through a complex
network of chemical signals triggers cell death through
apoptosis [7-10].
Despite the widespread clinical use of platinum drugs,
their effectiveness has been limited by poorer response of
some neoplasia, due to acquired or inherent resistance, and
their inability to prevent cancer relapse. Moreover, Pt
metallodrugs can also induce severe side effects, as well as
high toxicity, arising from non-specificity. These drawbacks
have fueled research on novel metal-based compounds with
Figure 1- Chemical structures of clinically approved platinum
a more favorable pharmacological profile, i.e., showing the
anticancer drugs.
same or higher efficiency with reduced side effects. The
growing interest of the scientific community on this topic is
*Address correspondence to this author at the Centro de Química Estrutural, clearly reflected by the large number of indexed publications
Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal; Tel: over the last decades (Figure 2) [11-16].
+351-218419269; E-mail: luisamargaridamartins@tecnico.ulisboa.pt

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2 Current Medicinal Chemistry, 2018, Vol. 0, No. 0 Andrade et al.

Table 1- Some examples of metal-based anticancer therapeutic

agents in development or clinical trials or approved for clinical use
[5].
Agent Clinical Use Stage
Dicycloplatin(Pt) Bronchial carcinoma Phase I
and liver cancer
Pt complexes including Targeted and Pre-clinical
nanoparticles combination therapy
Lipoplatin (Pt) (liposomal Lung cancer Phase III
cisplatin)
Lipoxal (Pt) (liposomal Colorectal cancer Phase II
oxaliplatin)
Oxaliplatin(Eloxatin) (Pt) Colorectal cancer Approved
Dinuclear-platinum Various cancers Pre-clinical
complex CT-47463
Figure 2- Rising interest on the development of metal Darinaparsin (As) (Z10- Peripheral T-cell Approved
complexes for cancer therapy. The graph shows the 101/SP-02) lymphoma
Solid tumors (oral)
approximate number of publications/year since 1998. Source:
Trisenox (As) Acute promyelocytic Phase II
ISI Web of Knowledge. Search terms: “Metal complexes AND
cancer therapy OR chemotherapy”. Refined by the Research Lung and others Phase I
Areas: Medicinal Chemistry AND Biochemistry & GSAO (As) Advanced solid Phase I
Biomolecular Biology AND Pharmacology & Pharmacy. tumors
NAMI-A (Ru)/gemcitabine Anti-metastatic agent Phase I/II
Over the last decades, great efforts have been focused on accomplished
the extensive investigation and evaluation in vitro and in NKP-1339 (Ru) Various cancers Phase I
vivo, on numerous transition metal complexes as potential NKP-2235 (Ga) Cancers with high Phase I
cancer chemotherapeutic agents [10,12,13]. Although none incidence of
metastases
of these compounds have been approved clinically to the
Belinostat (PXD101): Relapsed or refractory Phase I
present date, significant advancements have been made, histone deacetylase acute leukemia or
including clinical studies with some of the most promising inhibitor (chelates Zn) myelodysplastic
candidates (Table 1). syndrome
Vorinostat: HDAC Cutaneous T cell Approved
Medicinal inorganic chemistry offers additional inhibitor (chelates Zn) lymphoma
opportunities for the design of metal-based Advanced staged Phase I
chemotherapeutics agents, given the wide range of oropharyngeal
squamous cell
coordination spheres, oxidation states, redox potentials, carcinoma and brain
thermodynamic and kinetic characteristics, and ligand cancer
designs. Novel therapeutic agents with unique mechanisms Givinostat: HDAC Chronic Phase II
of action are possible and therefore the understanding of inhibitor (chelates Zn) myeloproliferative
both the kinetics and thermodynamics of reactions of the neoplasms
coordination compound and its components (the metal and Boronophenylalanine- Head and neck cancer Phase I
based boron neutron
the ligands) under conditions of biological relevance are of capture therapy
extreme importance. Regarding the mechanism of action, the Tetrathiomolybdate (Mo) Breast cancer and Phase II
metal could play distinct roles, whether functional or esophageal carcinoma
structural, be a carrier for active ligands that are delivered in Mozobil (plerixafor): Stem cell mobilization Approved
vivo, or also protect the ligands before delivery; could (potential chelator-Zn)
VT-464 (lyase selective Prostate cancer Phase I
behave as a catalyst in vivo through the production of metalloenzyme inhibitor
reactive oxygen species, or as a photosensitizer. The choice (Fe in CYP17))
of appropriate ligands is also of paramount importance, since Auranofin (Au) Chronic lymphocytic Phase II
these also play critical roles in determining the biological leukemia (CLL)
activities of complexes, affecting their thermodynamic and Small lymphocytic
kinetic stability, as well as solubility and lipophilicity, that lymphoma
can therefore be modulated by varying ligand architectures
[9,16]. Research in this field during the past few decades has
2. SCORPIONATE METAL COMPLEXES
covered a large range of coordination compounds with
metals all along the periodic table, namely ruthenium, gold, Polydentate ligands are fascinating due to their versatility
titanium, copper, cobalt, gallium, just to cite a few [5,11,12]. and relative ease of modification. Among these, tripodal
Further advances in this field will most definitely imply nitrogen scorpionate ligands, introduced by S. Trofimenko in
exploring alternative chelating systems, as tridentate ligands the late 1960s [17-20], are recognized as one of the most
(e.g., scorpionates). flexible and versatile class of ligands, with important
applications in a vast array of fields, such as homogeneous
Scorpionates as Chemotherapeutic Agents
catalysis, magnetic materials or bioinorganic chemistry [21-
25]. Throughout the last five decades, the on-going interest
on this class of ligands, constituted mainly by poly(pyrazol-
1-yl)borates and their neutral analogues, poly(pyrazol-1-
yl)alkanes (Figure 3), arises from their coordinative
versatility, given the easy modification of the type and
number of pyrazolyl groups and the substituents thereon or
at the B or C centers to obtain compounds with different
steric and electronic profiles [26-29].
Figure 3- Schematic representation of the structural versatility
of scorpionates.
The suggestively designation of these chelators, arises
from their peculiar coordination mode to a metal, like a
scorpion attack, that pictorially can be compared to an
embrace of the metal-ion, like the pincers and tail of a
scorpion catch and sting its victim (Figure 4). The three
nitrogen heteroatoms of the corresponding pyrazolyl rings
can occupy three facially adjacent vacant positions of the
coordination sphere of a metal center. The interchange
between the bidentate and tridentate coordination modes of
these ligands is at the core of the structural and chemical
versatility of many metal complexes of this kind.
Figure 4- Parallel between the tris(pyrazol-1-yl)methane metal (M)
binding and the scorpion attack.
Despite the advances in the coordination chemistry of
this type of chelators, studies concerning biomedical
applications of scorpionate complexes are scarce. The
contribution of this diversified family of ligands for the
development of anticancer agents, has been done to these
days, essentially based on complexes of Co, Cu, Ag, Ru and
lanthanides [22,25,30]. This review intends to account for
the most recent and relevant contributions of transition metal
complexes bearing homo- or hetero- scorpionates comprising
Current Medicinal Chemistry, 2018, Vol. 0, No. 0 3
the replacement of a pyrazolyl group by coordinating or non-
coordinating functions, as cancer therapeutic agents.
In the following sections, the given examples will be
classified according to the metal center of the complex.
Beyond their antiproliferative activity, examples of other
clinical therapeutic approaches that have also been the object
of research using scorpionate metal complexes, namely their
use as photosensitizers, and carbon oxide releasing
molecules (CORMs), both rapidly expanding fields in cancer
therapy research, will also be mentioned.
3. CYTOTOXIC ACTIVITY OF SCORPIONATES
The search for new metal complexes with antiproliferative
activity as alternatives for Pt-drugs is a growing need, as
stated above. Several metal complexes bearing scorpionate
ligands have already demonstrated their potential as in vitro
cytotoxic agents. Moreover, the scorpionate compounds can
themselves exhibit anti-tumor activity, as it will also be
presented.
3.1 Potassium scorpionate complexes
Tumor cells are known to have a high demand for iron,
expressing higher levels of the iron-containing enzyme
ribonucleotide reductase, which is a critical rate-limiting step
for DNA synthesis [31,32]. Therefore, tumor cells are far
more sensitive than normal ones to iron depletion, and iron
deprivation is considered as a potential therapy for inhibiting
tumor growth.
Hydrotris(pyrazol-1-yl)borate ([HB(C3N2H3)3]-, Tp)
ligand is known to chelate ferrous iron [32], although very
little research has been developed focused on its biological
properties. An example is the choice of potassium
hydrotris(pyrazol-1-yl)borate (K[HB(C3N2H3)3], KTp) and
derivatives for evaluating their anticancer activity against
human hepatocellular carcinoma, in HCC, HepG2 and
Hep3B cell lines via 3-(4,5-dimethylthiazol-2-yl)-2,5-
diphenyltetrazolium bromide (MTT) assay. Potassium
hydrotris(4-methyl-pyrazol-1-yl)borate (KTp4-Me, 1, Figure
5) exhibited a remarkable anti-tumor activity, showing high
iron chelating ability, thus, inhibiting the production of
Fenton-derived radicals, as demonstrated by in vitro plasmid
DNA degradation assay. The results of the MTT assay
suggested that KTp4-Me markedly inhibited the proliferation
of Hep3B and HepG2, disrupting cell iron uptake and thus,
affecting signaling pathways of iron regulation in HCC cell
lines. Moreover, KTp4-Me arrested cell cycle in S phase and
induced cell apoptosis in both Hep3B and HepG2 cells.
KTp4-Me was also much more effective against HCC cell lines
when compared with the clinically used iron chelator
desferrioxamine.
Additionally, the authors observed [32] a modest Cu2+
chelating activity for KTp4-Me, although with a lower affinity
than for that observed for Fe2+. The results were a promising
starting point for future development and application of Tp
and its derivatives as iron chelators, offering new
opportunities for the treatment of human hepatocellular
carcinoma.
4 Current Medicinal Chemistry, 2018, Vol. 0, No. 0 Andrade et al.

Figure 5- Chemical structure of potassium hydrotris(4-

methyl-pyrazol-1-yl) borate, KTp4-Me.

3.2 Cobalt scorpionate complexes

Cobalt coordination compounds present an enormous
potential for biomedical applications. Their relevance arises
from their unique electronic structures and redox properties,
being able to mimic some metalloenzymes. Cobalt
complexes have been widely studied for application as
enzyme inhibitors, hypoxic selective agents, nucleic acid
probes, DNA binding and cleavage, drug delivery devices,
hypoxic selective agents and positron emission tomography
agents [33]. The interest in cobalt complexes in experimental
cancer therapy research results from their ability to achieve
redox-dependent targeting the malignant tissue of solid
tumors. Aiming to demonstrate the potential of cobalt
complexes in the design of chemotherapeutic agents, the role
of novel water-soluble scorpionate Co half-sandwich
complexes as cytotoxic agents has been investigated [34].
Three tris(pyrazol-1-yl)methane ([RC(C3N2H3)3], Tpm)
Co(II) complexes, [CoCl2(H2O).(TpmPy)]
[TpmPy=PyCH2OCH2C(C3N2H3)3, Py=pyridine] (2), Figure 6- Chemical structures of Co(II) complexes bearing
[CoCl2(H2O)(TpmOMs)] (3) TpmOH, TpmPy or TpmOMs.
[TpmOMs=MeO2SOCH2C(C3N2H3)3] and Later on, in 2014, the same authors studied the coordination
[Co(TpmOH)2]·[Co(TpmOH)(H2O)3]2(Cl)6·6H2O (4) behavior of the sterically hindered phenyl-substituted
[TpmOH=HOCH2C(C3N2H3)3] (Figure 6), were prepared tris(pyrazol-1-yl)methane at a Co(II) center [35]. Complex
through the reactions of CoCl2 with the appropriate C- [CoCl2(HpzPh)4] (5) was obtained by reaction of CoCl2 and
functionalized Tpm, XCH2C(pz)3 (X=OCH2Py, OSO2Me or HpzPh, (HpzPh=3-phenylpyrazole, Figure 7). The cytotoxic
OH). In all of them, the scorpionate ligand is 3-coordinated activity of the water-soluble compound 5 was tested in vitro
by the N atoms of the pyrazolyl rings, being the Co(II) by the MTS metabolism assay in two human cancer cell
hexacoordinated. lines, HCT116 colorectal and MCF-7 breast cancer
The in vitro antiproliferative activities of the water- carcinomas, and in one normal human fibroblast cell line.
soluble complexes 2-4 were evaluated using the 3-(4,5- The cytotoxicity of 5 toward the colorectal HCT116 tumor
dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4- cell line was higher than its cytotoxicity toward the breast
sulfophenyl)-2H-tetrazolium (MTS) metabolism assay in MCF-7 tumor cell line, but still, much lower than that
HCT116 colorectal carcinoma and HepG2 hepatocellular exhibited by cisplatin or doxorubicin. Nevertheless, the very
carcinoma human cancer cell lines. They exhibit moderate low cytotoxicity of the complex observed in the normal
activities, lower than that of cisplatin, toward the human (nonmalignant) human fibroblast cell line was considered a
cancer cell lines tested. A marked decrease in cell viability promising result, since that for the highest concentration
was observed in the presence of complex 4, that was found tested for this complex (500 µm), 81.8% of viable cells were
to be the most effective concerning cell viability reduction. observed.
This viability loss was correlated with an increase of cell The authors stressed the need to perform viability assays
death by apoptosis. Nevertheless, the water solubility of the in normal epithelial cell lines to confirm the higher
complexes may allow direct parenteral administration. In cytotoxicity of 5 in the colorectal carcinoma cell line. No
vitro DNA studies showed that Co(II) scorpionate complexes clear correlation was observed between the redox potential
2 and 3 induce plasmid DNA double strand breaks cleavage of the complex and its cytotoxicity, that corroborates the
in the absence of any activating agent, thus, providing the bioactive oxidation state (2+) for the cobalt compounds.
first observed double-strand plasmid DNA cleavage
promoted by cobalt complexes bearing scorpionate ligands.

Current Medicinal Chemistry, 2018, Volume
Figure 7- Chemical structure of [CoCl2(HpzPh)4].
3.3 Copper scorpionate complexes
Copper has gained a rising interest among the alternative
metals to platinum for the development of anticancer drugs,
with many classes of copper(I) and copper(II) complexes
being extensively investigated as potential antitumor
metallodrugs [36-39]. Being an endogenous metal, copper
may be less toxic for normal cells over cancer cells,
overcoming some drawbacks presented by Pt(II) derivatives,
especially their high toxicity and intrinsic or acquired
resistance. On the other hand, as any essential metal that
escapes its normal metabolic pathways, copper complexes
may be toxic to the organism, thus, serving as effective
cytotoxic agents. Copper toxicity comes about from its
ability to produce reactive oxygen species, displace other
metal ions, and directly cleave DNA and RNA. High levels
of copper have been found in many types of human cancers,
including prostate, breast, colon, lung and brain. The altered
metabolism of cancer cells and differential response between
normal and tumor cells to copper are the basis for
development of copper complexes endowed with
antineoplastic characteristics. The anticancer action of some
Cu complexes has been clearly demonstrated in in vitro and
in vivo experiments, that are likely to have different
mechanisms of actions, biodistribution, and toxicity, from
those of currently used platinum drugs, and might be
effective, at least in principle, against human cancers that are
poorly chemosensitive or have acquired resistance to
conventional platinum drugs.
In 2013, the cytotoxicity activity of mixed-ligand
copper(I) complexes comprising a panel of scorpionate and
phosphine ligands has been studied [40]. Hence, a series of
charged and neutral Cu(I) compounds of the ‘2+1+1’ or
‘3+1’ type was synthesized through ligand-exchange
reactions of the precursors ([Cu(CH3CN)4][BF4] or CuCl)
with a panel of bis(pyrazol-1-yl)borates or poly(pyrazol-1-
yl)methanes and a tertiary phosphine (PTA=1,3,5-triaza-7-
phosphaadamantane; PCN=tris(cyanoethyl)phosphine; 6-17,
Figure 8). A distorted tetrahedral molecular structure, with
the coordination sphere comprising the scorpionate ligand,
attached as a tripodal chelator through the N, N, N or N,N,O
donor atoms, and the monodentate P-donor phosphine was
observed for the obtained complexes.
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5
Figure 8- Chemical structures of mixed-ligand Cu(I) complexes 6-
17.
In vitro cytotoxicity studies were performed for all
copper compounds using the MTT test toward a panel of
several human tumor cell lines, including examples of breast
(MCF-7), colon (HCT-15 and LoVo), lung (A549), cervix
(A431) and ovarian (2008 and its cisplatin resistant variant,
C13*) carcinoma, melanoma (A375) and promyelocytic
leukemia (HL60) (Table 2). For comparison purposes, the
cytotoxicity of cisplatin was also evaluated. The results of
the MTT assays suggest that copper complexes have an in
vitro antitumor activity comparable to that of cisplatin.
Among the ‘2+1+1’-type species, complexes 6 and 7,
bearing the less hydrophilic dihydrobis(pyrazol-1-yl)borate
ligand, originated the highest cytotoxic potency. The PTA-
containing complex 6 elicited IC50 values better than those
calculated for cisplatin against human breast (MCF-7), colon
(HCT-15) and lung (A549) cancer cells and against
promyelocytic leukemia cells (HL60). Remarkably, the
cytotoxicity of 6 exceeded that of the reference metallodrug
by a factor of about 2, against HCT-15 colon cancer cells,
which are barely chemosensitive to cisplatin. Among the
neutral ‘3+1’ species, the less effective complexes were the
positively charged derivatives 16 and 17. On the other hand,
compounds 14 and 15, bearing the bis(3,5-dimethylpyrazol-
1-yl)acetate ligand, were pointed out as the most promising
derivatives from all the newly synthesized copper(I)
derivatives. The cytotoxicity of complex 14 proved to be
similar or even better to that of cisplatin, with IC50 values
approximately 2- and 4-fold lower than those of the
reference drug against lung A549 and colon HCT-15 cancer
cells, respectively. The in vitro antitumor activity of complex
15 also exceeded that of cisplatin up to 16 times against the
HCT-15 cell line with a mean IC50 value of 2.4 µM (1.05-
4.34 µM) compared to the mean value of 9.9 µM (1.65-20.15
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Current Medicinal Chemistry, 2018, Volume 6

Table 2- In vitro cytotoxic activity of the complexes toward a panel of several human tumor cell lines [40].
IC50 [µM] ±SD
MCF-7 A431 HCT-15 A549 A375 HL60 LoVo
6 6.53±1.29 8.16±2.11 9.32±2.21 9.32±1.54 4.92±1.87 12.64±2.52 8.52±1.16
7 8.97±1.54 7.25±1.71 13.33±3.27 23.31±2.54 5.54±1.69 21.28±4.18 10.32±1.03
8 26.42±1.95 13.65±1.21 37.41±4.29 23.31±2.54 14.53±3.52 28.87±3.47 31.52±2.02
9 ND ND ND ND ND ND ND
10 27.11± 2.12 22.48±3.25 19.84±1.98 29.35±3.32 27.17±2.42 36.37±4.18 19.89±2.15
11 19.41±1.84 18.18±3.44 19.22±2.17 26.31±3.15 18.40±2.16 33.17±3.27 18.21±1.74
12 30.30±1.39 19.34±2.06 16.41±2.22 33.42±2.62 34.91±2.49 36.21±3.31 30.86±2.24
13 35.31±2.89 21.27±1.48 19.27±1.86 41.32±3.27 21.23±2.26 37.46±2.21 19.84±3.37
14 6.82±1.47 6.74±1.32 4.32±0.21 6.00±1.02 7.19±2.19 8.86±3.72 5.13±0.83
15 2.27±1.21 1.65±1.26 1.05±0.31 3.11±1.49 3.07±1.96 4.34±0.97 1.09±0.67
16 34.28±1.68 31.66±2.92 25.78±2.52 15.27±2.56 15.84±3.15 22.12±3.24 31.6±2.18
17 17.19±1.35 27.74±2.13 17.37±2.25 10.26±2.01 14.19±2.55 20.17±1.85 13.33±1.77
cisplatin 7.60±0.21 1.65±0.51 16.65±2.63 12.64±0.81 3.11±0.98 20.15±3.16 7.63±1.53

µM) shown by the reference metallodrug. Overall, this study
suggested that neutral complexes were more effective as
cytotoxic agents than charged ones, being possible to tune
their physicochemical properties by changing systematically
both phosphine and scorpionate ligands to achieve better
cytotoxic activity.
Furthermore, the authors investigated the
structure/activity relationship of CuTpP-type species by
modification of the nature of the phosphine or the
substituents, while maintaining the tridentate backbone
(Figure 9) [41]. The first series included the CuTp(PR3)-type
complexes 18−24, PR3= PCN, PTA, DAPTA (3,7-diacetyl-
1,3,7-triazaphosphabicyclo[3.3.1]nonane), PTA-SO2 (2-thia-
1,3,5-triaza-phosphaadamantane-2,2-dioxide), thp (tris-
(hydroxymethyl)phosphine), PPh3 (triphenylphosphine) and
P(C6H4F)3, respectively. In a second and third series, the
phosphine (PCN or PTA) was kept unaltered and the Tp
framework was modified by introduction of electron-donor
(Me) or -acceptor (NO2 and CF3) groups (complexes 25−32)
at the pyrazolyl rings. All copper compounds and the
corresponding uncoordinated ligands were evaluated
regarding their cytotoxic activity towards a panel of human
tumor cell lines, including breast (MCF-7), cervical (A431),
colon (HCT-15), pancreatic (BxPC3) and lung (A549)
cancers, neuroblastoma (SHSY5Y) and melanoma (A375).
Some of the chosen tumor cell lines were selected due to
their resistance to cisplatin or for retaining the multidrug-
resistant phenotype. For comparison purposes, the
cytotoxicity of cisplatin was also evaluated. Uncoordinated
Tp, PTA, PTA-SO2, DAPTA, PCN, and [P(p-C6H4F)3]
phosphine ligands proved to be scarcely effective in
decreasing cancer cell viability over all cell lines, while the
lipophilic phosphine PPh3 presented average IC50 values.
The considerably higher cytotoxic activity of the complexes,
exceeding by at least 1 order of magnitude those of the
uncoordinated ligands, indicates that the coordination to
copper ion led to an increase of antitumor efficacy.
Additionally, all synthesized CuTpP-type complexes
were able to circumvent clinically relevant models of drug
resistance, namely, cisplatin and multidrug resistances, thus
confirming a peculiar behavior of phosphine-containing
copper(I) complexes, being consistent with the hypothesis of
a mechanism of action different from Pt(II) metallodrugs.
Complexes 18−24, where the structural modification
concerns the phosphine ligand, exhibited significant
cytotoxic activities, for phosphines of moderate
hydrophilicity. Complexes [CuTp(PCN)] (18) and
[CuTp(PTA)] (19) elicited the most promising
antiproliferative activity in this series, whereas the
coordination of more hydrophilic phosphines or lipophilic
phosphines resulted in moderate cytotoxic activity.
Figure 9- Chemical structures of TpCuP-type complexes 18-32.
The encouraging results of complex [CuTp(PCN)] (18)
led to a subsequently evaluation of its potential antitumor
effects in a model of solid tumor, the murine LLC, exhibiting
tumor growth inhibition comparable to that promoted by
cisplatin. The cytotoxicity of complexes 18 and 19 was also
evaluated against the human embryonic kidney HEK293
cells, nontumor cells in rapid proliferation, where a cytotoxic
activity roughly 4 times higher than for cisplatin treatment

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Scorpionates as Chemotherapeutic Agents
was observed. The results therefore reinforce the previous
findings on neutral CuTpP-type species, as attractive
copper(I) species for the development of copper-based
anticancer agents.
In 2017, two novel mixed-ligand copper(I) complexes of
the type [CuCl(PPh3)(L)] [L=(4-carboxyphenyl)bis(3,5-
dimethylpyrazol-1-yl)methane (33) and (3-carboxyphenyl)-
bis(3,5-dimethylpyrazol-1-yl)methane (34), Figure 10] were
prepared by interaction of bis(3,5-dimethylpyrazol-1-yl)-
derived scorpionate ligands with the precursor CuCl in the
presence of PPh3 [42].
Figure 10- Chemical structures of mixed-ligand Cu(I) complexes
33 and 34.
The cytotoxic effect of both complexes was investigated
by the MTT assay towards cultured HepG2 liver carcinoma
cells (Table 3). The complexes have shown inhibition of the
growth of the liver cancer cells in a dose-dependent manner,
and complex 33 showed effective cytotoxic activity against
the liver cancer cell compared to cisplatin.
Table 3- In vitro cytotoxicity activity of the complexes against
HepG2 human hepatocellular carcinoma cells for 24 h. n.a. means
not active [42].
IC50 [µM] ±SD
33 3.3±0.02
34 n.a.
cisplatin 7.2±0.04
Furthermore, in vitro DNA binding studies, performed to
assess the ability of the complexes to interact with native calf
thymus DNA, indicated a more avid binding of complex 33.
The in vitro cytotoxicity study strongly suggested that this
complex would bind to DNA-topo complex in a specific
mode to damage the DNA and/or perturb the replication of
DNA, thus, killing cancer cells in general, and
hepatocarcinoma cells, in particular. The results obtained
were considered very promising, encouraging further studies
Current Medicinal Chemistry, 2018, Vol. 0, No. 0 7
for the assessment of the chemotherapeutic potential of this
compound.
3.4 Ruthenium scorpionate complexes
Ruthenium compounds have been considered suitable
candidates for chemotherapeutic drugs, being successfully
used in clinical research volumes over the past few decades.
Their interesting anticancer and anti-metastatic properties, in
addition to lower toxicity, makes them an alternative to Pt(II)
anticancer drugs. Ruthenium has several oxidation states,
Ru(II) to Ru(IV), that can be tunable under physiological
conditions [43-45].
In fact, two ruthenium(III)-based compounds, NAMI-A
imidazolium trans-[tetrachloro(dimethylsulfoxide)(1H-
imidazole)ruthenate(III)] and KP1019 trans-
[tetrachlorobis(1-H-indazole)ruthenate(III)] (Figure 11) are
undergoing advanced clinical trials as anticancer drugs.
KP1019 is currently on phase I of clinical trials and NAMI-
A went to phase II trials, but unfortunately it did not go
through to phase III. KP1019 is active against primary
cancers cells while NAMI-A is active against metastatic
tumor cells. These two compounds are a clear example of the
huge potential of ruthenium compounds in the development
of new cytotoxic agents, boosting the study of other
ruthenium compounds as anticancer drugs, namely
scorpionate Ru(II) complexes. The different toxicity profiles
between platinum- and ruthenium-based compounds could
probably be due to different targets. Although the
mechanisms by which ruthenium-based drugs exert their
anticancer effects remain to be fully clarified, recent
evidence suggests that ruthenium compounds are most likely
to be multitargeted. The antineoplastic properties of platinum
compounds rely on their interaction with DNA, which, in
turn, activates cell death.
Figure 11- Chemical structures of Ru complexes NAMI-A and
KP1019.
The [tris(pyrazol-1-yl)methane]ruthenium(II) complexes
[RuCl(Tpm)(solv)2][PF6], [solv=MeCN or DMSO] and
[Ru(Tpm)Cl(LL)][PF6], [LL=κ2-dppe, κ2-dppp, κ2-dppb or
(PMePh2)2; dppe=1,2-bis(diphenylphosphino)ethane,
dppp=1,3-bis(diphenylphosphino)propane, dppb=1,4-
8 Current Medicinal Chemistry, 2018, Vol. 0, No. 0 Andrade et al.

bis(diphenylphosphino)butane, 35-40, Figure 12] were
prepared through the reduction of methanol suspensions of
[RuCl3(Tpm)] with a slight excess of zinc dust in the
presence of excess MeCN or DMSO, followed by salt
metathesis with [NH4][PF6] [46].
thus requiring further investigation on the function and
activity of these and related complexes.
In 2010, Garcia-Fernandéz and co-workers evaluated the
DNA binding properties and in vitro cytotoxicity of a series
of Tp ruthenium(II) complexes containing the water-soluble
phosphanes PTA and 1-CH3-PTA and ancillary ligands with
different electronic or steric properties (41-57, Figure 13)
[47]. Complexes of the type [RuXTp(L)(PTA)] [X=Cl or H;
L=PMe2Ph, PMe3, P(OMe)3 or P(OPh)3] were obtained by
reaction of [RuXTp(PPh3)(PTA)] with the corresponding
phosphane or phosphite. Treatment of these complexes with
MeCF3SO3 (OTf) have led to the congeners [RuXTp(L)(1-
CH3-PTA)][OTf] bearing the 1-CH3-PTA phosphane ligand.

Figure 12- Chemical structures of TpmRu complexes, 35-40.

Complexes 35-40 were screened for their

antiproliferative properties in vitro against the MCF-7
(breast) and HeLa (cervical) cancer cell lines using the MTT
assay, and compared with the arene analogue of complex 38,
specifically [RuCl(η6-p-cymene)(κ2-dppp)]Cl, and cisplatin
(Table 4). Although the solvent complexes showed no
significant activity under the conditions used, the phosphane
complexes 37–40 exhibited a remarkable cytotoxic activity,
being more active than cisplatin, even on the MCF-7 breast
cancer cells, which showed greater resistance towards
cisplatin.
Table 4- Cytotoxic activity of complexes 35-40, [(ƞ6-p-
cymene)RuCl(ƙ2-dppp)]Cl and cisplatin on MCF-7 (breast) and
HeLa (cervical) cancer cells after 72 h of exposure [46].
IC50 [µM] ±SD
MCF-7 HeLa
35 >50 >50
36 >50 >50
37 8.1±4.6 4±0.00
38 2.9±0.07 6.9±1.31
39 2.9±0.07 5.8±0.35
40 4.7±0.007 7.4±0.21
[(ƞ -p-cymene)RuCl(ƙ -dppp)]Cl
6 2
0.8±0.00 1.4±0.07
cisplatin >18 12.4±0.85

The arene complex [RuCl(η6-p-cymene)(κ2-dppp)]Cl also

displayed remarkable activity. The relatively small
differences in activity between the complex with
monophosphanes (40) and those with chelate phosphanes
(37-39) suggested that the linkage between donor atoms is
not critical, as the case of chelate ring size. The authors
hypothesize a correlation between the enhanced cytotoxicity
of the phosphane complexes and an increase in the lipophilic
character, which could facilitate cellular uptake. The roles of
the phosphane and Tpm ligands were not clear at the time,
Figure 13- Chemical structures of TpRu complexes 41-57.
The plasmid DNA binding properties of the new
complexes were studied by a mobility shift assay. MALDI
experiments confirmed the coordination of the fragments
[RuTp(PTA)] or [RuTp(1-CH3-PTA)] to a single strand
DNA chain. Most of the complexes described have shown
interaction with DNA and displayed an inhibitory effect
against human tumor cell lines. The in vitro cytotoxic
activity of these compounds was evaluated by examining cell
Scorpionates as Chemotherapeutic Agents Current Medicinal Chemistry, 2018, Vol. 0, No. 0 9

viability inhibition in several human cancer cell lines (NCI- carboxybenzaldehyde or 3-carboxybenzaldehyde [49]. X-ray
H460, SF-268 or MCF-7) and non-tumor human umbilical studies showed that ruthenium adopts a pseudo-octahedral
vein endothelial cells (HUVEC) (Table 5). The complex geometry with the heteroscorpionate ligand coordinated by
[RuCl2(p-cymene)(PTA)] (RAPTA-C), a well-known two N atoms of the bis(pyrazol-1-yl)methane moiety, and the
ruthenium complex with antitumor activity, and doxorubicin, ƞ6-arene occupying three facial sites.
a drug currently used in clinical treatment, were used for
comparison purposes.
Table 5- In vitro cytotoxic activity of ruthenium complexes 35-40
on tumor and normal cells [47].
IC50 [µM] ±SD
NCI-H460 SF-268 MCF-7 HUVEC
41 >100 >100 >100 5.0±0.8
42 27.0±1.4 28.2±2.2 11.3±1.4 25.3±1.1
43 >100 29±1.3 >100 40.1±4.9
45 32.1±1.3 31.3±1.4 30.3±1.5 93.6±2.2
47 3.1±0.4 3.4±0.5 4.1±0.5 10.6±0.4
48 >100 >100 >100 9.9±0.7
50 >100 >100 >100 3.6±0.4
52 >100 >100 >100 58.6±1.4
53 3.4±0.3 2.6±0.2 3.1±0.3 6.6±0.3
54 3.1±0.3 3.1±0.3 3.3±0.4 27.9±2.7
55 5.1±0.5 4.8±0.5 4.2±0.4 67.0±8.4
56 4.6±0.4 4.3±0.3 4.7±0.5 24.0±0.5
57 6.1±0.7 2.8±0.1 2.0±0.1 1.9±0.2
Doxorubicin 0.3±0.1 0.3±0.1 0.3±0.1 0.2±0.1
RAPTA-C >100 >100 >100 >100

The cytotoxic activity of complexes 41, 43, 48, 50, 52

and RAPTA-C was not significant towards the cancer cell
lines, while compounds 42 and 45 were 10 times more
effective (IC50 in the range of 10-5 µM). The most active
compounds were 47 and 53-57, with an IC50 against all the
analyzed tumor cell lines in the range of low micromolar
concentration, only one order of magnitude lower than the
antitumor drug doxorubicin. Furthermore, all the ruthenium
complexes analyzed were less toxic for HUVEC normal cells
than doxorubicin. The compounds 41, 50, 53 and 57 had IC50
values in the range of 10 -6 µM which represents a 10 times
lower toxicity than doxorubicin. Compounds 47 and 53-56
were the only ones more efficient against tumor cells than
against normal HUVEC cells. Overall, complexes 47 and 54-
56 were considered as the most promising candidates for a
future clinical application, requiring further investigation. Figure 14- Chemical structures of complexes 58-61.

New four half-sandwich arene Ru(II) compounds
[RuCl(ƞ6-arene)(L)]Cl (58-61, arene=p-cymene and L=L1;
arene=p-cymene and L=L2; arene=benzene and L=L1;
arene=benzene and L=L2; L1=bis(3,5-dimethylpyrazol-1-
yl)parabenzoic acid and L2=bis(3,5-dimethylpyrazol-1-
yl)metabenzoic acid, Figure 14) were developed in 2014 by
Pettinari’s group, through the reaction of the
heteroscorpionates with the [RuCl2(ƞ6-p-cymene)]2 or
[RuCl2(ƞ6-benzene)]2 precursors [48]. The synthesis of the
ligands was previously reported, through the reaction of
bis(3,5-dimethylpyrazol-1-yl)ketone with 4-
DNA interaction studies proved that the scorpionate
ligand has more influence than the arene on the DNA
binding affinity of the complexes. A higher binding affinity
for the bis(3,5-dimethylpyrazol-1-yl)parabenzoic acid-
containing complexes was observed compared with the ones
bearing the bis(3,5-dimethylpyrazol-1-yl)metabenzoic acid.
The anticancer activity of complexes 58 and 60 was screened
on 15 cell lines of different histological origin. The results
showed good potential of the complexes as drug candidates,
although 58 showed activity at lower concentration when
compared with 60. Interestingly, complex 58 showed
10 Current Medicinal Chemistry, 2018, Vol. 0, No. 0
specificity and significantly good cytotoxic activity against
HOP62, A2780, Zr-75-1, HeLa, whereas complex 60
exhibited activity against HOP62 and A2780. The reason for
its selectivity requires future research.
In 2016, researchers from the University of Camerino
reported an important study focused on the development and
validation of a prototype compound, an organometallic
ruthenium(II)-arene complex, designed UNICAM-1 (62,
Figure 15), as a novel potent anticancer drug [50]. The
complex [Ru(p-cymene)(bis(3,5-dimethylpyrazol-1-
yl)methane)Cl]Cl, was obtained by reaction of the bis(3,5-
dimethylpyrazol-1-yl)methane with the precursor [RuCl2(ƞ6-
p-cym)]2 [51].
Figure 15- Chemical structure of UNICAM-1.
The potential antitumor effect of UNICAM-1 was
compared to that of NAMI-A and cisplatin, being estimated
by MTT assay using the human MDA-MB-231 cells and the
murine A17 cells as models of triple negative breast cancer
(TNBC) (Table 6). TNBC represents a molecular subtype of
breast cancer, with the worst negative outcome and
prognosis, exhibiting an aggressive metastatic behavior and
with limited targeted therapeutic options.
Table 6- Cytotoxic activity of complexes towards A17 and MDA-
MB231 cell lines for 72 h with increasing concentrations of tested
compounds [50].
IC50 [µM] ±SD
A17 MDA-MB 231
NAMI-A 485.58±0.02 840.21±0.03
UNICAM-1 230.66±0.02 409.89±0.04
Cisplatin 6.93±0.14 38.70±0.03
Hence, the is an urgent unmet medical need of new
therapeutically strategies against this breast cancer subtype
[52]. Although ruthenium(II) complexes were less effective
than cisplatin, they could inhibit cell viability in a dose-
dependent manner, where UNICAM-1 proved to be more
effective than NAMI-A. UNICAM-1 leads to apoptosis of
TNBC cells, showing promising in vitro anticancer activity.
The in vivo anti-tumoral activity of UNICAM-1 against an
experimental TNBC model, in tumor-bearing mice, was also
investigated. The results reveal that UNICAM-1 is capable
to suppress TNBC growth by significantly reducing the
number of tumor infiltration regulatory T cells. Moderate
kidney toxicity levels, similar for the three drugs were
observed, while liver toxicity was much less evident in
UNICAM-1 than in cisplatin or NAMI-A treated mice.
Andrade et al.
According to the authors, the outstanding efficacy of
UNICAM-1 appears to be due to its unique
immunomodulatory action, that influences tumor-host
interaction, through activation of an immune response
specific for malignant cells.
3.5 Silver scorpionate complexes
Metallic silver or silver complexes present great potential
for biological applications, due to its low toxicity, a great
advantage over other medicinally relevant metals. Silver
complexes are currently applied for the treatment of several
diseases as antibacterial agents in therapeutic protocols.
Additionally, silver complexes have also shown to possess
anticancer properties, following a different mechanism of
action than those of platinum derivatives, in terms of its
DNA interaction, mitochondrial membrane targeting, leading
to mitochondria-initiated apoptosis [52-55]. The activity of
silver complexes against bacteria and cancer cells is strictly
connected with their water solubility and stability,
lipophilicity, redox ability and rate of release of the silver
ions. These properties are rigidly ruled by the choice of
suitable ligands, and by slight modulations in their steric and
electronic effects, that can be tuned by varying the number
and type of ligands.
Following a series of studies on complexes formed upon
reactions of silver(I) oxyanions salts with uni- and bi-dentate
ligands, Pettinari’s group pursued the development of Ag(I)
compounds of the ‘3+1’ type bearing the tris(pyrazol-1-
yl)methanesulfonate (O3SC(C3N2H3)3, Tpms) ligand and
different monodentate phosphines [56]. They reported the
synthesis and bioactivity of new Ag(I) derivatives namely,
[Ag(Tpms)(L)] (L= PPh3 (64), PCy3 (65) or PTA (66),
Figure 16), that were obtained by reaction of the precursor
Ag[BF4] with Li(Tpms) in the presence of the corresponding
monodentate phosphine. The antiproliferative activity of the
silver(I) complexes [Ag(Tpms)] (63) and 64-66 against
Figure 16- Chemical structures of Ag(I) complexes 63-66.
human malignant melanoma cancer cell lines (A375) was
assessed, as well as of AgNO3, used as a control (Table 7).
Complexes 64 and 65 presented pronounced cytotoxic
effects, being 2 and 4 times more active than silver nitrate.
The activity inhibition followed the order:
65>64>63>66>AgNO3, in line with the values of the DNA
binding constants of the compounds. Therefore, the
antitumor action of the complexes appears to involve
interactions with DNA, a similar interaction that also seems
to be the cause of their antibacterial action.
Scorpionates as Chemotherapeutic Agents
Table 7- Cytotoxic activity of complexes 63-66 on A375 human
malignant melanoma cell line [56].
IC50 [µM]
63 1.62
64 0.97
65 0.42
66 1.90
AgNO3 2.03
3.6 Lanthanides and group 3 metal scorpionates
Scorpionate complexes of lanthanides and group 3 metals
have also been explored in the development of anticancer
agents [57,58]. In a work by Saturnino and collaborators, the
cytotoxic activity of a series of monomeric group 3 and
lanthanide (N,N,N)-heteroscorpionate-triflate complexes was
evaluated on several human cancer cell lines [59].
Complexes [Ln(cybpamd)(THF)(OTf)2] (Ln= Sc, Y, La, Nd,
Sm, Dy or Yb (67-73), Figure 17, cybpamd: N,N’-
dicyclohexyl-2,2-bis-(3,5-dimethylpyrazol-1-yl)-
acetamidinate) were investigated regarding their cytotoxic
towards epithelial lung adenocarcinoma (A549), human
melanoma (A375), human epithelial cervix adenocarcinoma
(HeLa), human embryonic kidney (HEK-293) and murine
macrophage (J774.A1) cell lines, using the MTT assay.
Figure 17- Chemical structures of complexes 67-73.
The simple lanthanide triflate and the free ligand, have
also been tested, and complexes 69 and 73 were tested
against only HEK-293 cell lines. Complexes 70 and 72 have
shown reasonable activities on the cell line HEK-293, while
for the murine macrophage cell line (J774.A1) all
complexes, except that of scandium, have shown a
reasonable activity. The complexes were poorly active on
human health adenocarcinoma lung epithelial (A549) and
human melanoma (A375). Complexes 68, 70 and 71 were
significantly more active than cisplatin towards HeLa cells.
Complex 70 is more active on HEK-293, A375 and A549
cell lines than cisplatin. Given the different behavior of the
examined complexes, cytotoxic activity was related to the
molecule as a whole and not only to the ligand or the metal
ion separately. The lanthanide triflate compounds showed no
cytotoxic activity on any of the cell lines tested, and the
uncoordinated ligand, cybpamd, presented a relatively good
cytotoxicity activity only on HeLa cell line, however lower
than that observed for 68, 70 and 71.
Current Medicinal Chemistry, 2018, Vol. 0, No. 0 11
4. SCORPIONATE METAL COMPLEXES AS
CARBON MONOXIDE-RELEASING MOLECULES
(CORMS)
Carbon monoxide is an essential signaling molecule in
the human body, performing a biological role that is
probably as important as that of nitric oxide. CO is
recognized nowadays as a well-known therapeutic molecule
and has received considerable attention due to its reported
antihypertensive, anti-inflammatory and cell-protective
effects. The development of Carbon Monoxide-Releasing
Molecules (CORMs) as pharmaceutical agents, pro-drugs
capable of delivering CO to cells and tissues in vivo,
constitute the most valid strategy to grasp the therapeutic
potential of CO. Metal–carbonyl complexes are a promising
way to safely achieve controlled delivery of CO for
therapeutic applications and in fact, most CORMs developed
to date are transition-metal carbonyl complexes [60-62].
Although such CORMs have shown promising results in the
treatment of several animal models of disease, they still lack
the necessary attributes for clinical development. The huge
potential of CORMs in medicinal applications can be
explored as a cytoprotective or cytotoxic agent. In high
enough concentrations CO is toxic, since it binds to
hemoglobin about 200-fold stronger than O2, disabling
hemoglobin from its function of oxygen carrier in the body.
To overcome the toxicity issue, it is crucial to deliver the CO
molecules to the target tissues in a controlled manner.
CORMs that can be targeted to specific sites in the body and
locally liberate CO are thus are urgently needed for research
and possibly for clinical applications. Therefore, various
methods have been devised to deliver CO precisely to the
target locations without off-target effect.
The first examples of CORMs emerged from the work
developed by Motterlini and co-workers, that in 2002
published the first reports on the identification,
characterization and pharmacological effects of transition
metal carbonyls as CORMs [63]. Schatzschneider’s group
was the first to study the potential of a scorpionate M(I)
tricarbonyl complex as a CORM, [Mn(CO)3(Tpm)][PF6] (74,
Figure 18), prepared through the reaction of Tpm with
[MnBr(CO)5] in anhydrous acetone under heating [64-66].
Figure 18- Chemical structure of [Mn(CO) 3(Tpm)][PF6], 74.
12 Current Medicinal Chemistry, 2018, Vol. 0, No. 0
The photoinduced CO release from 74 was observed upon
irradiation with UV light, with the loss of two out of three
CO ligands, acting as a PhotoCORM, under these conditions
[67]. Cell viability studies of HT29 colon cancer cells treated
with [Mn(CO)3(Tpm)][PF6] revealed a significant
photoinduced cytotoxicity comparable to that of the
established agent 5-fluorouracil, while controls kept in the
dark were unaffected at up to 100 µM. 74 resulted as a new
light-activatable prodrug with activity against cancer cells
comparable to that of an established clinical agent.
Therefore, manganese(I) tricarbonyl complexes with
tripodal ligands, especially, tris(pyrazol-1-yl)methane
compounds, represent a new class of photoactivable CORMs
with potential to be used as chemotherapeutic agents,
deserving further evaluation in the design of target-specific
metallodrugs for therapy. These promising results have
boosted the study of alternative delivery systems to tumor
cells based on the conjugation to nanoplatforms [68,69].
Recent advances on biorthogonal click chemistry
proportionate plenty of possibilities to attach the
biomolecules, offering interesting opportunities to prepare
functionalized bioconjugates, namely through the boron and
carbon central atoms of anionic and neutral scorpionates,
respectively. The conjugation of [Mn(CO)3(Tpm)]+ to SiO2
nanoparticles and nanodiamonds was performed via copper-
catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC
‘‘click” addition). The nanoconstructs have shown the ability
to release CO molecules with irradiation with UV light,
similarly to the free complex. The use of such functionalized
silicon dioxide nanoparticles as delivery agents for CORMs
in solid tumors is foreseen.
In 2015 Burzlaff and co-workers have studied the Mn
complexes [Mn(L)(CO)3] (bdmpza=bis(3,5-dimethylpyrazol-
1-yl)acetate (75), bpza=bis(pyrazol-1-yl)acetate (76),
bdmpzp=3,3-bis(3,5-dimethylpyrazol-1-yl)propionate (77)
and bpzp-=3,3-bis(pyrazol-1-yl)propionate (78), obtained
through the reaction of [MnBr(CO)5] with the potassium salt
of the respective heteroscorpionate ligand, and also the
cationic complex fac-[Mn(HIm)3(CO)3]Br (HIm= imidazole)
(79), and the neutral pyrazole (Hpz) complex fac-
[MnBr(Hpz)2(CO)3] (80) (Figure 19) obtained from the
addition of imidazole or pyrazole to the Mn(I) precursor,
respectively [70]. The utility of these compounds as
PhotoCORMs was investigated using the UV/Vis
spectroscopy-based myoglobin assay. The results showed
that compounds 75-77 act as PhotoCORMs with fast release
of about two equivalents of CO per mole of complex upon
excitation with UV light, being stable in aqueous solution in
the absence of light. The manganese(I) complexes of the
monodentate imidazole and pyrazole ligands lack, however,
stability in solution, with fast CO release already in the dark,
that may be influenced by the substitution pattern and the
chain length of the carboxylate moiety.
Andrade et al.
Figure 19- Chemical structures of Mn complexes 75-78.
5. SCORPIONATE METAL COMPLEXES AS
PHOTOSENSITIZERS
Photodynamic therapy (PDT) is a technique that involves
the administration of a non-toxic drug, known as a
photosensitizer, followed by its activation with light of a
specific wavelength. This drug can be either applied
systemically, locally, or topically to a patient bearing a
lesion, which is frequently, but not always, cancer. In the
presence of tissue oxygen, the photoactive sensitizer triggers
a series of photochemical and photobiological processes that
may lead to direct cancer cell damage, tumor microvascular
occlusion and host immune response. Due to these multiple
actions, PDT has increasingly gained recognition as a
potential adjuvant for several types of cancer as well as other
degenerative diseases [71-73]. Preclinical studies suggest
that the use of PDT in combination with established
treatments or with newly-developed modalities may be of
benefit as compared to the individual modalities. Another
strategy to improve selectivity is to design and synthesize
targeted photosensitizers or nanoparticles, which can identify
and selectively accumulate within tumor tissues. Besides
metalloporphyrins, that are among the most studied
photosensitizers, a large variety of metal complexes has been
investigated, including M(II) and M(III) scorpionate
complexes.
In this context, the study of the photoinduced DNA-
cleavage activity of 3d-metal scorpionates using bivalent
metal ions was reported. The aim of the work was to explain
the effect of the electronic structure of the 3d-metal ions in
the presence of sterically demanding anionic hydrotris(3-
phenylpyrazol-1-yl)borate ligand [HB(3-Phpz)3-, TpPh] on
their DNA-cleavage activity in visible light [74,75]. Ternary
3d-metal complexes [M(TpPh)(B)][ClO4] (81-88, Figure 20),
M=Co(II), Ni(II), Cu(II) or Zn(II); B=N,N-donor
heterocyclic base, namely, 1,10-phenanthroline (phen), (81-
84) or dipyrido[3,2-d:2′,3′-f]quinoxaline (dpq), (85-88), were
Scorpionates as Chemotherapeutic Agents
prepared from a reaction of the perchlorate salt of the metal
with KTpPh and B in CH2Cl2. DNA binding studies, carried
out using various spectral techniques, showed only moderate
binding propensity of the complexes to calf thymus DNA
and very poor DNA-cleavage activity in the dark, even in the
presence of activators like 3-mercaptopropionic acid or
hydrogen peroxide.
Figure 20- Chemical structures of complexes 81-88.
These findings seem to be due to steric factors related
with the presence of the TpPh protector ligand, with a
negative effect in the case of phen complexes. Nonetheless, a
relatively positive effect was observed in the case of dpq
congener complexes, the paramagnetic [Co(TpPh)(dpq)]+ (d7)
and [Cu(TpPh)(dpq)]+ (d9), showing a significantly superior
DNA cleavage activity upon UV-A and visible light
irradiation. The Ni(II) and Zn(II) did not show any
significant photoinduced DNA-cleavage activity in visible
light. The observed steric encumbrance of the
photosensitizer by the molecular bowl of the metal
scorpionate moiety is of special relevance, since it generates
cytotoxic singlet oxygen species, leading to enhanced DNA
cleavage. This feature offers further opportunities for the
design of potential new photosensitizers that oxidatively
cleave DNA for phototherapeutic applications, an emerging
treatment option for patients diagnosed with age-related
macular degeneration, precancerous conditions, and
localized cancers that include inoperable neoplasms.
CONCLUSIONS
The development of new and more efficient antitumor
metallodrugs, that can overcome the problems of clinically
used drugs while maintaining their efficacy still remains an
important topic of research in medicinal chemistry. In this
review, recent contributions of scorpionate-based metal
complexes in medicinal chemistry as anticancer agents were
highlighted. Although in many of the cases promising results
were obtained regarding the cytotoxic activity of scorpionate
compounds, research on this topic is still underdeveloped.
We are convinced that scorpionate metal complexes would
Current Medicinal Chemistry, 2018, Vol. 0, No. 0 13
contribute significantly in the design of target-specific
metallodrugs for safe and effective anticancer therapy.
LIST OF ABBREVIATIONS
bdmpzp- 3,3-bis(3,5-dimethylpyrazol-1-yl)propionate;
bpea- bis(pyrazolyl)ethylamine;
bpza- 3,3-bis(pyrazol-1-yl)acetate;
bpzp- 3,3-bis(pyrazol-1-yl)propionate;
CORMs- Carbon Oxide releasing molecules;
CuAAC- copper-catalyzed azide-alkyne 1,3-dipolar
cycloaddition, ‘‘click” addition;
cybpamd- N,N’-dicyclohexyl-2,2-bis-(3,5-dimethylpyrazol-
1-yl)-acetamidinate);
p-cymene- 1-isopropyl-4-methyl-benzene;
DAPTA- (3,7-diacetyl-1,3,7-
triazaphosphabicyclo[3.3.1]nonane);
dpq- dipyrido[3,2-d:2’,3’-f]quinoxaline;
dppb- 1,4-bis(diphenylphosphino)butane;
dppe- 1,2-bis(diphenylphosphino)ethane;
dppp- 1,3-Bis(diphenylphosphino)propane;
HCC- human hepatocellular carcinoma;
HER2- human epidermal growth factor2;
Hpz- pyrazole;
HpzPh- 3-phenylpyrazole;
HUVEC- human umbilical vein endothelial cells;
IC50- half maximal inhibitory concentration;
KP1019- trans-[tetrachlorobis(1-H-indazole)ruthenate(III)];
KTp4-Me- potassium tris(4-methyl-1-pyrazolyl)-borohydride;
MTS-[3-(4,5-dimethylthiazol-2-yl)-5-(3-
carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium];
MTT- [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide];
NAMI-A- imidazolium trans-
[tetrachloro(dimethylsulfoxide)(1H-
imidazole)ruthenate(III)];
OTf- trifluoromethanesulfonate;
PCN- tris(cyanoethyl)phosphine;
PCy3- tricyclohexylphosphine;
PDT- photodynamic therapy;
Ph- phenyl;
Phen- 1,10-phenanthroline;
PTA- 1,3,5-triaza-7-phosphaadamantane;
Py- pyridine;
pz- pyrazolyl;
RAPTA-C- [RuCl2(p-cymene)(PTA)]
RNA- ribonucleic acid;
Thp-tris(hydroxymethyl)phosphine;
Tp- tris(pyrazol-1-yl)borate;
Tpm- tris(pyrazol-1-yl)methane;
TpmOH- 2,2,2-tris(pyrazol-1-yl)ethanol;
TpmOMs- 2,2,2- tris(pyrazol-1-yl)mesyloxymethyl;
TpmPy- 4-{[tris-2,2,2-(pyrazol-1-yl)ethoxy]methyl}pyridine;
Tpms- tris(pyrazolyl-1-yl)methanesulfonate;
TpPh- tris(3-phenylpyrazolyl)borate;
TNBC- triple negative breast cancer;
UNICAM-1- [Ru(p-cymene)(bis(3,5-dimethylpyrazol-1-
yl)methane)Cl]Cl.
14 Current Medicinal Chemistry, 2018, Vol. 0, No. 0
ACKNOWLEDGEMENTS
Support for this work was provided by FCT through
UID/QUI/00100/2013 and PTDC/QEQ-ERQ/1648/2014
projects. M.A. Andrade acknowledges financial support
from BL/CQE-2017-022 FCT grant.
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Accepted: