New platinum(II)-based DNA intercalator: Synthesis, characterization and anticancer activity

Article abstract of DOI:10.1016/j.inoche.2019.04.039

Platinum agents with different action mechanisms from current platinum drugs can be effective candidates overcoming the resistance of platinum-based drugs. Platinum(II)-based DNA intercalators are potent candidate which act through mechanisms distinct fro

Full text of DOI:10.1016/j.inoche.2019.04.039

InorganicChemistryCommunications105(2019)182–187
Contents lists available at ScienceDirect
Inorganic Chemistry Communications
journal homepage: www.elsevier.com/locate/inoche
Short communication
New platinum(II)-based DNA intercalator: Synthesis, characterization and
anticancer activity
⁎
⁎
Feng-Yang Wanga,b, Romg Liub, Ke-Bin Huangb, , Hai-Wen Fengb, You-Nian Liua, , Hong Lianga,b
a College of Chemistry and Chemical Engineering, Central South University, Changsha, Hunan 410083, PR China
b State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry & Pharmacy of Guangxi Normal University, Guilin 541004,
PR China
G R A P H I C A L A B S T R A C T
In present work, we describe the synthesis and characterize of two platinum (II)-based DNA intercalators containing 2-substituted quinoline derivatives as ligands.
Mechanistic experiments indicate that Qui-Pt-2 can induce the apoptotic death of Bel-7404 cancer cells through intrinsic and extrinsic pathways involved ATP
depletion, loss of mitochondrial membrane potential.
A R T I C L E I N F O
A B S T R A C T
Keywords:
Platinum agents with different action mechanisms from current platinum drugs can be effective candidates
overcoming the resistance of platinum-based drugs. Platinum(II)-based DNA intercalators are potent candidate
which act through mechanisms distinct from cisplatin. Here, we describe the synthesis and characterize of two
platinum (II)-based DNA intercalators containing 2-substituted quinoline derivatives as ligands. In comparison to
cisplatin, Qui-Pt-2 exhibited a greater in vitro cytotoxicity overall, and lower resistance factor than cisplatin
against SK-OV-3/DDP (1.29 to 3.32). Mechanistic experiments indicate that Qui-Pt-2 can induce the apoptotic
death of Bel-7404 cancer cells through intrinsic and extrinsic pathways involved ATP depletion, loss of mi-
tochondrial membrane potential. To the best of our knowledge, Qui-Pt-2 is the first platinum(II)-based DNA
intercalator which can simultaneously activate the intrinsic and extrinsic pathways of apoptosis, therefore, Qui-
Pt-2 is a promising model compound for anticancer drug development.
Platinum (II) compounds
DNA intercalator
Anticancer activity
Intrinsic pathway
Extrinsic pathway
Cisplatin and its two analogues, carboplatin and oxaliplatin, have
been used in chemotherapy to successfully treat a variety of solid tu-
mors, including testicular cancer, ovarian cancer, lung cancer and head
and neck cancers [1,2]. However, drug resistance and severe side ef-
fects, including nephrotoxicity and neurotoxicity, limit the clinical ap-
plication of these platinum-based drugs [3,4]. In efforts to develop
novel complexes that overcome these obstacles, several types of non-
classical platinum complexes with antitumor activities have been de-
scribed, including platinum(IV) complexes [5–7], platinum(II)-based
DNA intercalators [8]，multi-nuclear platinum complexes [9], trans
geometry complexes [10,11] and mono-functional complexes [12–14],
all of which have shown potential in the circumvention of the drug
⁎ Corresponding authors.
E-mail addresses: kbhuang@mailbox.gxnu.edu.cn (K.-B. Huang), liuyounian@csu.edu.cn (Y.-N. Liu).
https://doi.org/10.1016/j.inoche.2019.04.039
Received 29 March 2019; Received in revised form 25 April 2019; Accepted 26 April 2019
Availableonline27April2019
1387-7003/©2019PublishedbyElsevierB.V.

F.-Y. Wang, et al.
InorganicChemistryCommunications105(2019)182–187
resistance and side effects of cis-platin and its analogues. Among these
novel complexes, platinum(II)-based DNA intercalators are prominent
platinum complexes which are an intercalating moiety made up of
planar aromatic ring systems capable of π–π stacking interactions and
display activity across an impressive spectrum of tumor types as well as
action mechanisms distinct from the current platinum drugs [15–18]. It
is worth noting that most of these platinum(II)-based DNA intercalators
are of the type [Pt(IL)(AL)]2+ (where IL is an intercalating ligand and AL
is an ancillary ligand), which are the absence of anionic ligands (e.g.,
chloride) that serve as leaving groups in traditional platinum antitumor
agents that act by platination of DNA and filled with four relatively
stable, bound nitrogen of two chelating ligands [19–21].
two platinum compounds are stable in the TBS buffer for 48 h at room
temperature.
According to Lipinski's rule, appropriate hydrophilicity and lipo-
philicity are of vital importance in drug development [32]. Excessive
hydrophilicity decreases the ability of a drug to penetrate phospholipid
bilayer membranes. On the contrary, a high lipophilicity can hinder
biomedical applications [33]. The lipophilicity (log Po/w values) of the
platinum complexes was determined using the shake-flask method,
according a procedure in the literature [34]. the log Po/w values of Qui-
Pt-1 and Qui-Pt-2 are 3.32 and 4.19, respectively. These values indicate
that both Qui-Pt-1 and Qui-Pt-2 are sufficiently lipophilic to satisfy the
general lipophilicity requirement of drugs. Qui-Pt-2, with one methoxyl
groups, possesses a higher log Po/w value, which translates into a higher
membrane permeability than Qui-Pt-1, as corroborated by the results of
cellular uptake experiments.
The synthesis of metal complexes with biologically active ligands is
a promising strategy in the development of anticancer drugs, as metal
ions can significantly alter the physical and chemical properties of such
ligands [22–24]. Our previous work focused on metal complexes con-
taining bioactive alkaloid ligands [25–28]. We previously reported a
series of metal-based compounds with bioactive quinoline alkaloid li-
gands. These complexes show a remarkable, and synergistic cytotoxic
effect in different human cancer cell lines. This was especially true of
those metal complexes with 8-hydroxyl quinoline alkaloid ligands,
which presented the highest synergistic effect and selective cytotoxi-
city. The synergistic DNA intercalating between metal center and qui-
noline alkaloid ligands is an important factor affecting the activity of
cytotoxicity [29–31]. Here, we explore the potential antitumor activity
of platinum(II)-based DNA intercalators, using 2-substituted quinoline
derivatives and two chloride as ligands. In our study, we synthesized
two platinum complexe Qui-Pt-1 and Qui-Pt-2 (Scheme 1), and in-
vestigated their in vitro anticancer activity and mechanism of action.
The synthesis of two ligands was carried out starting from 2-qui-
nolinecarbaldehyde and Aniline or 4-Methoxyaniline via one synthetic
step (Scheme 1). The platinum (II) complexes Qui-Pt-1 and Qui-Pt-2
were synthesized by adding cis-Pt(DMSO)2(Cl)2 into the un-purified li-
gands in C2H5OH at room temperature, the mixture was stirred in the
dark at room temperature for 1 day. The resulting yellow solution was
filtered and single crystals were obtained by slow evaporation of the
filtrate. We characterized the two platinum complexes by elemental
analysis, ESI-MS and single crystal X-ray diffraction analysis. Two Pt (II)
complexes crystallize in the monoclinic space group P21/n and C2/c for
Qui-Pt-1 and Qui-Pt-2, respectively. The molecular structures are de-
picted in Fig. 1; the details of the crystallographic data and structure
refinement parameters are summarized in Table S1. The Pt(II) center is
coordinated by two chlorine leaving groups and a N, N-bidentate che-
lating ligand. One five-membered chelating ring is formed; the Pt atom
is in a cis-square planar environment with a N − Pt − N bite angle
deviating from 90° due to the bite of the N, N-ligand. The N atom can be
viewed as strongly coordinated to the metal, e.g., in Qui-Pt-2, Pt
(1) − N (1) = 2.054 (3), Pt (1) − N (2) = 2.006 (3) Å, while the
chloride ion forms a weaker bond to Pt (II) (Pt (1) − Cl (1) = 2.3090
(10), Pt (1) − C l(2) = 2.2770 (11) Å).
Despite the presence of other biological targets in tumor cells in-
cluding RNA, enzyme and protein, it is generally accepted that DNA is
one of primary targets for many metal-based anticancer drugs [35].
Transition metal complexes can bind to DNA via covalent and/or non-
covalent interactions (including intercalative, electrostatic and groove
binding). The melting technique is a sensitive and easy tool to detect
even slight DNA conformational changes. It is known that a destabi-
lizing interaction with the double helix (typically, covalent) is observed
as a decrease in the Tm, while a stabilizing interaction (usually by in-
tercalation) induces an increase of the Tm [36]. To either prove or rule
out the possibility of a DNA-drug interaction, thermal denaturation
experiments of DNA interacting with two platinum complexes were
carried out. The melting curves of DNA and the DNA − compounds
system are shown in Fig. 2. As seen from figures, all Tm values of DNA in
the presence of two compounds have a similar increasement, which
represent that two compounds possess a main ability of intercalation
toward DNA, although the coordination mode of platinum is similar.
The intercalation of two platinum complexes toward DNA were similar
because of their similar planar structure. It is generally accepted that
covalent binding and intercalative binding can influence the tertiary
structure of DNA and induce changes in the CD spectra of DNA, whereas
other noncovalent binding modes such as electrostatic interaction or
groove binding cannot significantly perturb the CD spectra [31]. To
further confirm the interaction of Qui-Pt-1/2 complexes with DNA, As
shown in Fig. S2. For the [DNA]/[compound] concentration from 2:1 to
1:1, two platinum complexes induced decrease on the positive and
negative absorption of ct-DNA, it further suggests that the interaction
mode of Qui-Pt-1/2 with DNA are the intercalative binding [36]. Al-
though the new two platinum complexes are like the structure of cis-
platin, their main interaction with DNA is the intercalation because of
the planar structure of quinoline ligand. We can't sure whether the Pt
metal centre interact with DNA, maybe the covalent binding is weaker
than intercalation binding.
We investigated the in vitro cytotoxicity of platinum complexes Qui-
Pt-1 and Qui-Pt-2 against CT-26, SK-OV-3, Bel-7404, MGC-803 and HL-
7702 cell lines, using cisplatin for comparison. As shown in Fig. 3A,
among the two novel compounds, Qui-Pt-2 showed a higher cytotoxi-
city against the cancer cell lines, and a part of IC50 values of Qui-Pt-2
were significantly smaller than that of cisplatin. It should be noted that
the two platinum complexes displayed lower cytotoxicity in the normal
The stability of platinum complexes were investigated by methods
of HPLC under physiological conditions (Tris-KCl-HCl buffer, pH 7.35).
As shown in Fig. S1 (supporting information), the time-dependent (12,
24 and 48 h) HPLC chromatograms demonstrate that the solution of
incubation have no any other occurrence of change, which mean that
Scheme 1. The synthetic route of Qui-Pt-1 and Qui-Pt-2. a: ethanol, Aniline or 4-Methoxyaniline; b: ethanol and Pt(DMSO)2Cl2.
183

F.-Y. Wang, et al.
InorganicChemistryCommunications105(2019)182–187
Fig. 1. Two structures at 30% ellipsoid probability. Selected bond lengths (Å) and angles (°), for Qui-Pt-1: Pt(1) − N(1) = 2.057(5), Pt(1) − N(2) = 1.996(5)，Pt
(1) − Cl(1) = 2.2967(18), Pt(1) − Cl(2) = 2.2755(17). N(1)–Pt(1)–N(2) 79.9(2), Cl(1)–Pt(1)–N(1) 99.29(15), Cl(2)–Pt(1)–N(2) 93.49(16). For Qui-Pt-2: Pt(1) − N
(1) = 2.054 (3), Pt(1) − N(2) = 2.006 (3)，Pt(1) − Cl(1) = 2.3090 (10), Pt(1) − Cl(2) = 2.2770 (11). N(1)–Pt(1)–N(2) 79.62(12), Cl(1)–Pt(1)–N(1) 99.03(9), Cl
(2)–Pt(1)–N(2) 93.67(9).
experiments aimed at elucidating the mechanism(s) of cytotoxicity in
the Bel-7404 cancer cell line.
Acquired resistance is known to be a major impediment in drug
therapy [37]. Based on our above results, the cytotoxicities of the
platinum complexes were further evaluated in the cisplatin-sensitive
(SK-OV-3) and -resistant (SK-OV-3/CDDP) cancer cell lines using the
MTT assay; cisplatin was used as a positive control. The results, shown
in Fig. 3B, indicate that Qui-Pt-2 exhibits a more potent cytotoxicity
against the SK-OV-3 and SK-OV-3/CDDP cancer cell lines than cisplatin.
Perhaps more importantly, both Qui-Pt-1 and -2 possess smaller re-
sistance factors (RFs) of 1.43 and 1.29, respectively, while the RF value
of cisplatin was 3.32. The large RF difference between the new pla-
tinum complexes and cisplatin may be related to the complexes' re-
spective spatial configurations, resulting in different cellular targets and
mechanisms of action.
The cellular uptake properties of metal-based anticancer drugs are
important factors that influence their antiproliferative performance
[38]. In order to probe the cellular uptake kinetics of Qui-Pt-1 and Qui-
Pt-2, we used ICP-MS to determine their cellular levels in Bel-7404
Fig. 2. The melting curves of ct-DNA in the absence and presence of complexes.
cells, using cisplatin for comparison. The ICP-MS results show that after
exposure to a Pt complexes (5 μM) for 24 h, the amounts of these
human liver HL-7702 cells, compared to the tested cancer cells, sug-
gesting a certain extent of selectivity to cancer cells for Qui-Pt-1 and
Qui-Pt-2. This complexes almost elicited a similar toxicity in HL-7702
cells compared to cisplatin. Based on their structures, we propose that
the cytotoxicity of these complexes originates from their interactions
with DNA and proteins via the planar quinoline ligands and platinum
metal centre [30,36]. Since Qui-Pt-2 displayed a higher anticancer ac-
tivity overall, it was used as a representative compound in later
complexes in whole-cell lysates were the following:
n
Qui-Pt-2
(5.43 nM) > nQui-Pt-1 (4.45 nM) > ncisplatin (4.02 nM) (Fig. 4A). The
difference in uptake may be a function of the complexes' lipophilicity.
Furthermore, the in vitro antiproliferative activity of the complexes
might be related to their uptake and consequent intracellular levels.
It has been confirmed that the distribution of the metal complex in
subcellular organelles is associated with different cellular pathways.
Fig. 3. (A) IC50 (μM) values for Qui-Pt-1/2 complexes against five human tumor cell lines and one human liver cell line; (B) IC50 (μM) and resistance factors of Qui-Pt-
1, Qui-Pt-2 and cisplatin in SKOV-3 and SKOV-3/CDDP cell lines; resistance factor (RF) is defined as IC50 in SK-OV-3 CDDP/IC50 in SK-OV-3.
184

F.-Y. Wang, et al.
InorganicChemistryCommunications105(2019)182–187
Fig. 4. (A) Uptake, as determined by ICP-MS, by Bel-7404 cells after 24 h of exposure to 5 μM of the indicated complexes; (B) Uptake of complexes by Bel-7404 cells
pre-incubated with chloroquine (50 μM) or CCCP (10 μM) for 1 h.
Fig. 5. (A) Loss of ΔΨm by Qui-Pt-2 treatment. Cells were incubated with Qui-Pt-2 for 0.5 h, stained with JC-1 and examined by fluorescence microscopy; (B)
Depletion of cellular ATP levels in Bel-7404 cells treated with Qui-Pt-2. Cells were incubated with the indicated concentrations of Qui-Pt-2 for 12 h. The luminescence
intensity was measured in a microplate reader. **p < 0.02.
The distribution of the two Pt complexes in subcellular compartments
was investigated. The most uptake of the two Pt complexes was in the
cytoplasm among all detected subcellular compartments. Meanwhile,
the accumulation of two platinum complexes was almost equal in mi-
tochondria and nuclei respectively, but the accumulation of Qui-Pt-2 is
more than Qui-Pt-1 and cisplatin in the mitochondria and nuclei, which
may be related to the in vitro antiproliferative activity.
pre-treatment of the cells with CCCQ (10 μM) or incubated at 277 K
showed no obvious alteration (Fig. 4B). These results collectively in-
dicate that Qui-Pt-1 and Qui-Pt-2 complexes enter cells via a passive
diffusion transport pathway.
Mitochondria act as a point of integration for death signals origi-
nating from both the extrinsic and intrinsic pathways. Mitochondrial
dysfunction and the release of death factors are critical events in trig-
gering various death-pathways. To further delineate the importance of
mitochondria in platinum complexes induced cancer cell death, varia-
tions in the mitochondrial membrane potential, which is an important
indicator of mitochondrial dysfunction, were measured by the JC-1
probe. In the normal cells, JC-1 exists as a monomer in the cytosol
(green) and accumulates as aggregates (red) in the mitochondria. The
accumulation is induced by the mitochondrial membrane potential. In
mitochondria-dependent apoptotic cells, JC-1 does not aggregate in the
depolarized mitochondria, only existing in the green, monomeric form
The cellular uptake mechanisms of small molecules include energy-
dependent (endocytosis and active transport) or energy-independent
(facilitated diffusion and passive diffusion) pathways. We incubated
cells at low temperatures or pre-treated them with carbonyl cyanide 3-
chlorophenylhydrazone (CCCP,
a potent mitochondrial oxidative
phosphorylation uncoupler) or chloroquine (CQ, an endocytosis in-
hibitor) [39] to interrogate the mechanism of uptake of the platinum
complexes. Bel-7404 cells pre-treated with CQ (50 μM) exhibited a
markedly reduced intracellular uptake of Qui-Pt-1 and Qui-Pt-2, while
185

F.-Y. Wang, et al.
InorganicChemistryCommunications105(2019)182–187
Fig. 6. Annexin V/propidium iodide staining of Bel-7404 cells treated by Qui-Pt-2 measured by flow cytometry.
cells, further confirming that mitochondria dysfunction is involved in
Qui-Pt-2-induced death.
The mitochondrial dysfunction is a critical event in the triggering of
various death-pathways. In particular, apoptosis is thought to be one of
the key mechanisms resulting from mitochondrial dysfunction. Thus,
we investigated whether apoptosis was induced by Qui-Pt-2 in Bel-7404
cells. The process of apoptosis is generally accompanied by distinct
morphological characteristics, including cytoplasmic and nuclear con-
densation, DNA breakage, membrane dysfunction, and loss of micro-
villi. Phosphatidylserine (PS) exposure usually precedes the loss of
plasma membrane integrity in apoptosis. Healthy cells are unreactive to
annexin V-FITC, a marker of PS, and propidium iodide (PI), which only
enters cells with disrupted plasma membranes, while cells undergoing
apoptosis are reactive to annexin V-FITC but remain unreactive to PI.
Cells in the later stages of apoptosis and necrotic cells are reactive to
both annexin V-FITC and PI [42]. After treatment with 5 μM Qui-Pt-2
for 12 and 24 h, the percentage of apoptotic (annexin V-positive and PI-
negative) cells (Q4) was time-dependently enhanced from 24.31% to
39.54% (Fig. 6). Taken together, these results suggest that apoptosis
was a major modes of Bel-7404 cell death caused by Qui-Pt-2.
In general, apoptosis occurs via two major pathways: the death re-
ceptor-dependent (extrinsic) pathway and the intrinsic pathway. Both
pathways involve an ordered activation of a set of caspases, which, in
turn, cleave cellular substrates, leading to morphological and bio-
chemical changes [43]. In order to better understand the apoptotic
pathway involved in Qui-Pt-2-induced apoptosis, we assessed the pro-
teolytic activity of executioner caspase-3 and initiator caspases, cas-
pase-8/10 (extrinsic) and caspase-9 (intrinsic, Fig. 7) [43]. A dose-de-
pendent increase in both caspase-3 and caspase-9 proteolytic activities
was observed upon treatment with 5 μΜ Qui-Pt-2. Meantime, there was
also obvious change in caspase-8/10 activity, indicating that both the
intrinsic and extrinsic pathways are activated and induced apoptosis in
Bel-7404 cells.
Fig. 7. Western blot analysis of proteins involved in mitochondria-mediated
apoptosis after treatment with extrinsic and intrinsic (at the IC50 concentra-
tion) for the indicated durations, caspase-3/8/9/10 represent the proteolytic
activity of caspase.
[35]. As shown in Fig. 5A, Bel-7404 cells treated with Qui-Pt-2 ex-
hibited a time-dependent increase in green fluorescence compared to
controls. This result suggests that the mitochondrial membrane poten-
tial was altered by treatment with Qui-Pt-2 and supports our hypothesis
that mitochondrial dysfunction is involved in the cell death induced by
Qui-Pt-2.
In this work, two platinum(II)-based DNA intercalators with 2-
substituted quinoline derivatives as ligands were synthesized and
characterized. The stability, DNA interaction, lipophilicity, cellular
uptake, anticancer activity and cell resistance to the complexes were
investigated in detail. The two platinum complexes are stable in TBS
solutions and show similar intercalation toward DNA because of their
similar planar structure. Both Qui-Pt-1 and Qui-Pt-2 are sufficiently
lipophilic to satisfy the general lipophilicity requirement of drugs, but
Qui-Pt-2, with one methoxyl groups, possesses a higher log Po/w value,
and exhibited fairly or greater anti-proliferative activity against several
cancer cell lines compare to cisplatin overall，and Qui-Pt-2 also
Mitochondria are the energy producers of cells, and, as such, are
vital for ATP production [40]. Mitochondrial dysfunction in cancer cells
manifests as various alterations in energy-production pathways, which
makes mitochondrial metabolism a potential target for cancer therapy
[41]. We used the Cell Titer-Glo® luminescence-based cell viability
assay to detect the impact of Qui-Pt-2 on ATP production (Fig. 5B). A
dose-dependent decrease in cellular ATP concentration was observed in
Qui-Pt-2-treated cells. After 15 μM Qui-Pt-2 treatment for 12 h, the ATP
level decreased by 74.9
2.4%. These results indicate that Qui-Pt-2
can effectively impair mitochondrial energy metabolism in Bel-7404
186

F.-Y. Wang, et al.
InorganicChemistryCommunications105(2019)182–187
showed the selectivity of toxicity against (non-tumoral) HL-7702 cells
and lower resistance factor against Skov-3/DDP. Qui-Pt-2 induced the
death of apoptosis against Bel-7404 cells through intrinsic and extrinsic
pathways involved ATP depletion, loss of mitochondrial membrane
potential, although Qui-Pt-2 mainly localized to cytoplasm. Taken al-
together, our results suggest that Qui-Pt-2 is a promising candidate
anticancer drug or model compound for anticancer drug development.
[13] X.L. Gao, X.X. Wang, J. Ding, L.P. Linc, Z.J. Guo, Inor. Chem. Commun. 9 (2006)
722–726.
[14] T.C. Johnstone, S.J. Lippard, J. Am. Chem. Soc. 136 (2014) 2126–2134.
[15] V. Cepeda, M.A. Fuertes, J. Castilla, C. Alonso, C. Quevedo, J.M. Perez, Anti Cancer
Agents Med. Chem. 7 (2007) 3–18.
[16] F. Liu, J. Suryadi, U. Bierbach, Chem. Res. Toxicol. 28 (2015) 2170–2178.
[17] N.J. Wheate, R.I. Taleb, A.M. Krause-Heuer, R.L. Cook, S. Wang, V.J. Higgins,
J.R. Aldrich-Wright, Dalton Trans. (2007) 5055–5064.
[18] L.A. Graham, G.M. Wilson, T.K. West, C.S. Day, G.L. Kucera, U. Bierbach, ACS Med.
Chem. Lett. 2 (2011) 687–691.
[19] A.M. Krause-Heuer, R. Grünert, S. Kühne, M. Buczkowska, N.J. Wheate,
D.D. Pevelen, L.R. Boag, D.M. Fisher, J. Kasparkova, J. Malina, P.J. Bednarski,
V. Brabec, J.R. Aldrich-Wright, J. Med. Chem. 52 (2009) 5474–5484.
[20] J. Shao, J.-X. Wei, Y. Zhang, J.-Y. Xu, Inor. Chem. Commun. 102 (2019) 35–39.
[21] B.J. Pages, K.B. Garbutcheon-Singh, J.R. Aldrich-Wright, Eur. J. Inorg. Chem.
(2017) 1613–1624.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (Nos. 21401031, 21761005), and the Natural
Science Foundation of Guangxi Province (2016GXNSFGA380005) and
the Program for Key Scientific Research of Guangxi Normal University
(2014ZD005).
[22] C.G. Hartinger, P.J. Dyson, Chem. Soc. Rev. 38 (2009) 391–401.
[23] B. Therrien, Chem. Eur. J. 19 (2013) 8378–8386.
[24] D. Pucci, A. Crispini, B.S. Mendiguchía, S. Pirillo, M. Ghedini, S. Morelli, L. De
Bartolo, Dalton Trans. 42 (2013) 9679–9687.
[25] Z.-F. Chen, Y.-F. Shi, Y.-C. Liu, X. Hong, B. Geng, Y. Peng, H. Liang, Inorg. Chem. 51
(2012) 1998–2009.
Appendix A. Supplementary material
[26] K.-B. Huang, Z.-F. Chen, Y.-C. Liu, Z.-Q. Li, J.-H. Wei, M. Wang, X.-L. Xie, H. Liang,
Eur. J. Med. Chem. 64 (2013) 554–561.
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.inoche.2019.04.039.
[27] K.-B. Huang, Z.-F. Chen, Y.-C. Liu, Z.-Q. Li, J.-H. Wei, M. Wang, G.-H. Zhang,
H. Liang, Eur. J. Med. Chem. 63 (2013) 76–84.
[28] Z.-F. Chen, Q.-P. Qin, J.-L. Qin, J. Zhou, Y.-L. Li, N. Li, Y.-C. Liu, H. Liang, J. Med.
Chem. 58 (2015) 4771–4789.
References
[29] Y.-C. Liu, J.-H. Wei, Z.-F. Chen, M. Liu, Y.-Q. Gu, K.-B. Huang, Z.-Q. Li, H. Liang,
Eur. J. Med. Chem. 69 (2013) 554–563.
[30] Z.-F. Chen, J.-H. Wei, Y.-C. Liu, M. Liu, Y.-Q. Gu, K.-B. Huang, M. Wang, H. Liang,
Eur. J. Med. Chem. 68 (2013) 454–462.
[1] L. Kelland, Nat. Rev. Cancer 7 (2007) 573–584.
[2] X. Wang, X. Wang, S. Jin, N. Muhammad, Z. Guo, Chem. Rev. 119 (2019)
1138–1192.
[31] Z.-F. Chen, Y.-Q. Gu, X.-Y. Song, Y.-C. Liu, Y. Peng, H. Liang, Eur. J. Med. Chem. 59
(2013) 194–202.
[3] T.C. Johnstone, K. Suntharalingam, S.J. Lippard, Chem. Rev. 116 (2016)
3436–3486.
[32] A. Ganesan, Curr. Opin. Chem. Biol. 12 (2008) 306–317.
[33] C.K. Lee, T. Uchida, K. Kitagawa, A. Yagi, N. Kim, S. Goto, Biol. Pharm. Bull. 17
(1994) 1421–1424.
[4] F.Y. Wang, K.B. Huang, H.W. Feng, Z.F. Chen, Y.N. Liu, H. Liang, Free Radic. Biol.
Med. 129 (2018) 418–429.
[34] H. Huang, P. Zhang, B. Yu, Y. Chen, J. Wang, L. Ji, H. Chao, J. Med. Chem. 57
(2014) 8971–8983.
[5] J. Ma, Q. Wang, Z. Huang, X. Yang, Q. Nie, W. Hao, P.G. Wang, X. Wang, J. Med.
Chem. 60 (2017) 5736–5748.
[35] K.-B. Huang, Z.-F. Chen, Y.-C. Liu, M. Wang, J.-H. Wei, X.-L. Xie, J.-L. Zhang, K. Hu,
H. Liang, Eur. J. Med. Chem. 70 (2013) 640–648.
[6] V.E.Y. Lee, C.F. Chin, W. H. Dalton Transactions 17 (2019) 5461–5844.
[7] Z. Wang, Z. Xu, G. Zhu, Angew. Chem. Int. Ed. 55 (2016) 15564–15568.
[8] B.J. Pages, K.B. Garbutcheon-Singh, J.R. Aldrich-Wright, Eur. J. Inorg. Chem. 12
(2017) 1613–1624.
[36] K.-B. Huang, Z.-F. Chen, Y.-C. Liu, X.-L. Xie, H. Liang, RSC Adv. 5 (2015)
81313–81323.
[37] F. Liu, S. Gou, F. Chen, L. Fang, J. Zhao, J. Med. Chem. 58 (2015) 6368–6377.
[38] C. Qian, J.-Q. Wang, C.-L. Song, L.-L. Wang, L.-N. Ji, H. Chao, Metallomics (5)
(2013) 844–854.
[9] Đ. Miodragović, A. Merlino, E.P. Swindell, A. Bogachkov, R.W. Ahn, S. Abuhadba,
G. Ferraro, T. Marzo, A.P. Mazar, L. Messori, T.V. O'Halloran, J. Am. Chem. Soc.
141 (2019) 6453–6457.
[39] Y. Li, C.-P. Tan, W. Zhang, L. He, L.-N. Ji, Z.-W. Mao, Biomaterials 39 (2015)
95–104.
[10] J. Pracharova, T. Saltarella, T. Radosova Muchova, S. Scintilla, V. Novohradsky,
O. Novakova, F.P. Intini, C. Pacifico, G. Natile, P. Ilik, J. Med. Chem. 58 (2014)
847–859.
[40] D. Stock, A.G. Leslie, J.E. Walker, Science 286 (1999) 1700–1705.
[41] S.E. Weinberg, N.S. Chandel, Nat. Chem. Biol. 11 (2015) 9–15.
[42] M.P. Murphy, Biochem. J. 417 (2009) 1–13.
[11] Z. Zhu, Z. Wang, C. Zhang, Y. Wang, H. Zhang, Z. Gan, Z. Guo, X. Wang, Chem. Sci.
10 (2019) 3089–3095.
[43] H.-U. Simon, A. Haj-Yehia, F. Levi-Schaffer, Apoptosis 5 (2000) 415–418.
[12] X. Xue, C. Zhu, H. Chen, Y. Bai, X. Shi, Y. Jiao, Z. Chen, Y. Miao, W. He, Z. Guo,
Inorg. Chem. 56 (2016) 3754–3762.
187