Phenoxide chelated Ir(iii) N-heterocyclic carbene complexes: Synthesis, characterization, and evaluation of their in vitro anticancer activity

Article abstract of DOI:10.1039/c8dt03159b

Twelve novel half-sandwich Ir^III-NHC complexes [(η⁵-Cp^x)Ir(C^O)Cl] were synthesized and characterized. These complexes showed higher cytotoxic activity toward A549 cells and HeLa cells than cisplatin. An increase in the nu

Full text of DOI:10.1039/c8dt03159b

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PAPER
Joseph T. Hupp, Omar K. Farha et al.
Efficient extraction of sulfate from water using
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Phenoxide Chelated Ir(III) N-Heterocyclic Carbene Complexes:
Synthesis, Characterization, and Evaluation of the in Vitro
Anticancer Activity
Received 00th January 20xx,
Accepted 00th January 20xx
Yujiao Zhang, Shumiao Zhang*, Zhenzhen Tian, Juanjuan Li, Zhishan Xu, Shanshan Li, Zhe Liu*
DOI: 10.1039/x0xx00000x
Twelve novel half-sandwich IrIII-NHC complexes [(η5-Cpx)Ir(C^O)Cl] were synthesized and characterized. These complexes
showed well cytotoxic activity toward A549 cells and HeLa cells than cisplatin. The more phenyl group contained, the
better the anticancer activity appeared. The reaction of complexes with nucleobases 9-MeA, nucleobases 9-EtG, plasmid
DNA and CT-DNA showed no significant effect. These complexes captured hydrogen from NADH and converted it to NAD+,
which produced the ROS. ROS led to a decrease in mitochondrial membrane potential and lysosomal damage, and finally
induced apoptosis.
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iridium complexes have potential to be new anticancer agents. To
the best of our knowledge, this is the first report of this kind of half-
sandwich IrIII phenate chelated NHC complexes as anticancer drugs.
Introduction
During the past several decades, it has been witnessed that
transition metal complexes of N-heterocyclic carbenes (NHC) had
developed a great deal,1, 2 with high stability as one of their main
characteristics.3 Besides wide use of the metal NHC complexes in
catalysis,4, 5 their application in medicinal and biological chemistry
also plays an important role.6-9 As anticancer agents, platinum
complexes such as cisplatin, carboplatin and oxaliplatin have
achieved great success.10 Au and Ag complexes have illustrated
considerable potential for development11-13 and other transition
metal compounds are also explored for their structure–activity
relationships, such as ruthenium,14-21 palladium,22-24 osmium.25, 26
Recently, metal iridium complexes with the chelating ligand such as
[N, N], [C, N], and [C, C] type showed better anticancer activity.27-35
In this paper, with the purpose of designing iridium NHC
complexes as effective anticancer drugs, we tried to retain a
carbene functionality, and added hard anionic building blocks
because of its excellent stabilizing ability for IrIII. The introduced
anionic groups could reduce the dissociation of the ligand by
enhancing the bond between the NHCs and the metal center.36 Here
we prepared twelve novel phenoxide chelated IrIII-NHC complexes
and studied these complexes for cell toxicity, hydrolysis chemistry,
DNA binding, catalytic hydride transfer analysis, cell cycle, induction
of apoptosis, reactive oxygen species induction, mitochondrial
membrane assay and lysosomal damage. The results suggested that
the twelve complexes had significant inhibitory effect on A549 cell
proliferation than cisplatin and a preliminary understanding of their
mechanisms of action. This work demonstrated that such class of
Results and discussion
Synthesis and Characterization
IrIII complexes (Chart 1) of the type [(η5-Cpx)Ir(C^O)Cl] were
synthesized and characterized, where Cpx includes Cp* and its
biphenyl derivatives (Cpxbiph), C^O-chelating ligands are NHC-
phenoxide ligands. These complexes were obtained in a four step
procedure (Scheme 1).37, 38 Initially the ligands were synthesized via
copper catalyzed 1H-imidazole or 1H-benzimidazole with 2-
bromoanisole in DMSO. Then the corresponding anisole derivative
reacted with 48% HBr at reflux temperature for demethylation.
Finally the desired salts were accomplished by reaction of 2-(1H-
imidazol-1-yl) phenol or 2-(1H-benimidazol-1-yl) phenol with a
series of halogenated hydrocarbons at reflux temperature overnight.
The target complexes were then obtained in a one-pot reaction by
treating the respective ligand with Ag2O followed by reaction with
[IrCpxCl2]2. These compounds were purified by filtration over celite
and recrystallized. All complexes were characterized by 1H NMR, 13
C
NMR, elemental analysis, and mass spectrometry.
Scheme 1. The Synthesis Steps of Ligands L1 - L8 and Complexes 1 - 12
OH
OMe
OMe
Br
N
48% HBr
HN
a
N
N
+
N
N
X-R
Cpx
OH
X
O
Ir Cl
i.Ag2O,CH2Cl2,r.t,2 h
ii.[IrCpxCl2]2, r.t,4h
R
R2
N
N
N
N
R1
1-12
L1-L8
Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory
of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of
Natural Medicine, Department of Chemistry and Chemical Engineering, Qufu Normal
University, Qufu 273165, China.
a. 1H-imidazole and 2-bromoanisole reaction: K2CO3, CuO, DMSO, 150oC, 10h; 1H-
benzimidazole and 2-bromoanisole reaction: KOH, Cu2O, DMSO, 150 oC, 24h.
*Corresponding author. Email: zkz_mao@163.com; liuzheqd@163.com
Electronic Supplementary Information (ESI) available.
See DOI: 10.1039/x0xx00000x
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Cpx
α (deg)
β (deg)
65.73(3)
80.57(3)
74.82(3)
1296.8(6)
2
90
O
Ir Cl
95.9780(10)
90
3314.37(49)
4
1.604
4.145
R2
N
N
γ (deg)
Volume (Å3)
Z
R1
CpxH
R2
density (Mg/m3)
Absorption
1.698
5.475
Cpxbiph
H
F
Cp*H
Cl
c
coefficient (mm-1)
reflns collected
indep reflns
b
d
a
Complex
Cpx
R1
H
R2
a
b
c
L
9851
6371
16304
5827
[R(int)= 0.0796]
R1=0.0446,
wR2=0.1046
1
Cp*
L1
L2
L3
L4
L5
L6
L7
L8
L5
L6
L7
L8
[R(int)=0.0354]
indices R1=0.0475,
wR2 = 0.1177
2
Cp*
H
Final
[I>2σ(I)]
R
3
Cp*
H
4
Cp*
H
d
a
b
c
Table 2. Selected bond lengths [Å] and angles [deg] for C23H30ClIrN2O (1) and
5
Cp*
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
C41H36ClIrN2O (10)
Complex 1
2.125(7)
2.133(7)
2.156(6)
2.220(6)
2.230(6)
1.7981
2.019(6)
2.096(5)
2.4136(17)
82.4(2)
Complex 10
2.132(7)
2.138(7)
2.163(7)
2.210(8)
2.220(7)
2.002
2.002(7)
2.104(5)
2.4079(18)
83.5(2)
6
Cp*
Ir1-C
(cyclopentadienyl)
7
Cp*
8
Cp*
d
a
b
c
9
Cpxbiph
Cpxbiph
Cpxbiph
Cpxbiph
10
11
12
Ir1-C (centroid)
Ir1-C1
Ir1-O1
Ir1-Cl1
C1-Ir1-O1
C1-Ir1-Cl1
O1-Ir1-Cl1
Cytotoxicity assay in vitro
The MTT assay is a widely used method of determining IC50 (the
half maximal inhibitory concentration) values for complexes of
cancer cell lines. The A549 cell line and HeLa cell line have a degree
of representativeness and stability, which provides accurate
feedback on drug response. Complexes 1 - 12 had a significant
inhibitory effect on A549 cells and HeLa cells proliferation than
cisplatin. The IC50 values of complexes 1-12 for A549 cells and HeLa
cells ranged from 2.51-20.76 μM and 2.24-6.69 μM, respectively
d
Chart 1. Iridium (III) complexes 1-12
X-ray crystal structures
Single crystals of complexes 1 and 10 (Fig. 1) were obtained by
diffusion of n-hexane into CH2Cl2 solutions. Their structures were
determined via the single-crystal X-ray diffraction analysis. The
crystal data of complexes 1 and 10 were shown in Table 1 and Table
2. The crystal exhibited half-sandwich pseudo-octahedral, which
proved the coordination of NHC and phenate groups with the
iridium center. The observed Ir-Ccarbene (2.019 Å and 2.002 Å,
respectively) and Ir-O (2.096 Å and 2.104 Å, respectively) bond
distance were in excellent agreement with those reported earlier for
similar substances.38 The distances from the iridium center to the
89.3(2)
85.28(13)
84.45(19)
83.34(14)
η5-cyclopentadienyl centroid were respectively 1.7981
Å and
1.7994 Å for complexes 1 and 10, both in the expected range.39 And
the Ir-Cl bond distances were respectively 2.4136 Å and 2.4079 Å in
line with previous reports.39 CCDC-1544033 (1) and CCDC-1852809
(10) include the detailed crystallographic data for this paper.
(Table 3), which were smaller than cisplatin (IC50 = 21.30 μM, IC50
=
7.50 μM). The IC50 value of complex 6 were the smallest among the
Cp* complexes, about 5 times and 2 times more potent than
cisplatin for A549 cells and HeLa cells, respectively. The Cpxbiph
complexes showed higher antiproliferative activity than their Cp*
analogs. We found that the activity of the complexes performed
better as the number of phenyl groups in the complex increased.
However, the anticancer activity did not seem to change a lot while
halogens were added to the para-position on the benzyl group as
compared to that of the benzyl group. Unfortunately, the IC50 values
of complexes 2 and 6 were small in the antiproliferative activity test
of BEAS-2B human normal lung epithelial cells. This type of
Fig.
1 X-ray crystal structure of complexes 1 (a) and 10 (b). Ellipsoids were 50%
probability level and H atoms were omitted for clarity.
Table 1. Crystal data and structure refinement for C23H30ClIrN2O (1) and C41H36ClIrN2O
(10)
complexes did not show selectivity for cancer cells and normal cells.
Table 3. IC50 values of complexes 1-12 and cisplatin towards A549 cells, HeLa cells and
BEAS-2B
Complex 1
C23H30ClIrN2O,
CH2Cl2
Complex 10
Complex
IC50(µM)
A549
IC50(µM)
HeLa
IC50(µM)
formula
C41H36ClIrN2O
BEAS-2B
MW
663.06
293(2) K
Triclinic
800.37
298(2) K
Monoclinic
P2(1)/c
0.30×0.18×0.14
mm
10.2202(9)
15.4052(13)
21.1662(18)
1
2
3
4
5
6
7
8
9
20.8±2.2
16.7±2.2
16.5±0.8
13.7±1.3
8.5±0.9
3.9±0.1
5.3±0.9
5.4±0.4
3.0±0.4
6.7±0.2
5.6±0.2
5.9±0.1
6.4±0.4
4.0±0.7
3.1±0.1
3.5±0.2
3.6±0.4
3.0±0.2
Temperature (K)
Crystal system
space group
Crystal size
2.5±0.2
3.2±0.1
P-1
0.14×0.12×0.11
mm
9.2934(19)
11.622(2)
13.674(3)
a (Å)
b (Å)
c (Å)
2 | J. Name., 2012, 00, 1-3
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10
11
12
Cisplatin
2.5±0.6
2.6±0.2
2.4±0.1
2.2±0.5
7.5±0.2
Then the complexes 2, 4 and 6 with DNA binding were monitored
by UV-Vis spectroscopy. Absorption titration experiments were
performed by keeping a constant complex concentration (20 μM)
and continuously adding CT-DNA concentration (0–108 μM) in the
buffer. As seen from the Fig. S9, ESI†, aꢁer adding to incremental
amounts of CT-DNA, the absorption band of the three complexes
showed hypochromism and a little bathochromism, displaying a
little binding affinity to double stranded DNA. According to
absorption spectral titration data, the binding constants ꢀꢁ was
calculated by the following equation.
2.6±0.1
3.3±0.5
21.3±1.7
Hydrolysis studies
The hydrolysis ability was then studied, owing to the fact that the
hydrolysis of M-Cl bonds to M-OH bonds indicated an activation
step for transition metal anticancer complexes.39 Complexes 2, 4, 5
and 6 were used as model. Hydrolysis of complex 4 was carried out
at 310 K in 80% MeOD-d4/20% D2O (v/v) to monitor its changes by
1H NMR (Fig. S2, ESI†). The methanol was used to dissolve the
complex and ensure that the complex did not precipitate after the
addition of water. The other complexes 2, 5 and 6 were tested in the
same way (Fig. S1, S3 and S4, ESI†). The change of the 1H NMR
spectroscopy was little compared 5 min with 24 h. In order to
ensure that the complex did undergo a hydrolysis reaction, 16 mol
equivalents NaCl were added to the solution after hydrolysis
equilibrium. It was clear that the peak of the hydrated adducts
disappears.
ꢆꢇ
ꢆꢇ
ꢂꢃ
ꢅ
ꢊ
ꢂ ꢄ ꢂꢃ ꢈꢆꢁ ꢄ ꢆꢇ ꢉ
ꢀꢁꢋꢆꢁ ꢄ ꢆꢇꢌꢍꢎꢏꢂꢐ
where A0 and A respectively correspond to the initial absorbance of
the free complex and absorbance of the complex in the presence of
DNA, ꢆꢇ is the extinction coefficient of the free compound and ꢆꢁ is
the extinction coefficient of the compound when fully bound to
⁄
⁄
DNA. The curve of ꢂꢃ ꢈꢂ ꢄ ꢂꢃꢉ versus 1 ꢍꢎꢏꢂꢐgives the straight
line and the ꢀꢁ is calculated as the intercept / slope ratio (Table S3,
ESI†). These spectral characterisꢀcs obviously suggest that these
Hydrolysis kinetics of complexes 2, 4, 5 and 6 were studied by UV
at 298 K in 20% MeOH/ 80% H2O (v/v) (Fig. S5-S6, ESI†). Based on
the formation of the hydrate adducts in accordance with the pseudo
first order kinetics, we calculated the hydrolysis rate constant and
half-lives (Table S1, ESI†). The results showed that the hydrolysis
rates of complexes 2, 4, 5 and 6 were relatively rapid. These
complexes rapidly underwent hydrolysis in water because of the
replacement of the chloride ligand. According to what has been
reported for similar IrIII complexes containing Cl, in the case of
hydrolysis, the other ligands are stable in addition to the
substitution of Cl.40 This indicates that the complexes have good
stability in 80% MeOD-d4/20% D2O.
complexes interact with CT-DNA probably through
intercalation or quasi-intercalation.
NADH catalytic reaction
a semi-
The NAD+/NADH couple is an important redox couple in
numerous biochemical reactions. Previously, IrIII cyclopentadienyl
complexes were reported that could interfere with NAD+/NADH
hydrogen transfer reactions in cells and produce the ROS H2O2.44, 45
We did some related research of NAD+/NADH with complex 2, 4, 5
and 6 by NMR and UV-vis to investigate. The solution of complex 6
(1 mM) was prepared with 80% methanol and 20% water, then
added NADH (3.5 mol equiv.). The change of NADH and complex 6
from 10 min to 7 h was monitored by NMR at 310 K. The 1H NMR
Solubility Experiment
spectrum showed
a new peak at 8.97, 9.35 and 9.56 ppm
The solubility of the complexes 2, 4 and 6 were measured by the
UV-spectroscopy.35, 41 The solution of complexes were prepared in
DMSO with the concentration of 10 mM. The stock solutions were
diluted in concentrations ranging from 5× 10-6 to 5 × 10-4 mol/L in
80% HEPES (pH=7.2-7.4) and 20% acetonitrile. The acetonitrile acts
as a cosolvent to prevent precipitation. The saturated solution of
the complexes were monitored by the UV-spectroscopy. Complexes
2, 4 and 6 had 301.68mg/L, 332.55 mg/L, and 48.79 mg/L,
respectively (Fig. S7, ESI†). Complex 4 bearing F shows better
solubility than complex 2, while complex 2 has better solubility than
complex 6 with more than one phenyl group.
corresponding to the positions of the C4, C6 and C2 hydrogen atoms
of the NAD+ nicotinamide ring, which indicated the conversion of
NADH to NAD+ (Fig. 2A). Especially, a sharp single peak was
observed at -9.06 ppm, which was the Ir-H bond (Fig. 2A). In
addition, the reactions of NADH with complex 2, 4 and 5 also had
new peaks in the low field and a sharp single peak in the negative
field (Fig. S10-S12, ESI†).
The catalytic ability of NADH with these complexes was
monitored via UV-vis within 8 h in 10% MeOH / 90% H2O at room
temperature. In the UV spectrum, NADH showed absorption at 339
nm, whereas NAD+ did not. In Fig. 2B and Fig. S13, ESI†, the
absorbance at 339 nm decreased significantly after NADH reacting
with complex 2, 4, 5 and 6，which showing NADH was converted to
NAD+. It was simple that the turnover numbers (TON) of complexes
2 (16.3), 4 (7.9), 5 (14.2) and 6 (23.5) were calculated according to
measuring absorbance changes at 339 nm (Fig. 2C).
Interaction with nucleobases
In the search for biomedical and anticancer drug mechanisms,
DNA is regarded as a target for anticancer drugs.42, 43 In our study,
the experiments of complexes 2, 4, 5 and 6 with 9-ethylguanine (9-
EtG) and 9-methyladenine (9-MeA) were performed. Equilibrated
solutions of complexes 2, 4, 5 and 6 (1.0 mM) in 80% MeOD-d4 / 20%
D2O (v / v) were prepared at 310 K, to which then were added 1 mol
equiv of 9-EtG or 9-MeA. From the Table S2, ESI†, no formaꢀon of
any nucleobase adducts were shown by 1H NMR after 24 h.
Cleavage of plasmid DNA
We performed experiments on the ability of complexes to cleave
DNA. Plasmid pBR322 DNA (10 μM) and various concentrations of 2,
4, 5 and 6 were incubated at 37 °C for 24 hours. The mixture was
added to the sample tank of the prepared agarose gel using a
micropipette. Then the contents were detected for 1 h by agarose
Gel electrophoresis in TAE buffer (40 mM Tris-HCl/1 mM EDTA,
pH=8.3). From Fig. S8, ESI†, DNA cleavage with various
concentrations of complexes 2, 4, 5 and 6 was not observed.
DNA binding
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Reactive oxygen species
Reactive oxygen species (ROS) are mainly produced in
mitochondria as products of cellular metabolism and closely related
to apoptosis. ROS are typically generated by a redox cycle via
electron transfer groups such as metal complexes.46, 47 Therefore,
we performed ROS experiment and observed ROS levels in A549
cells treated with complexes 6 and 12 for 24 h. From Fig. 4, and Fig.
S21, Table S13, ESI†, the ROS levels were significantly increased in
the A549 cells after treatment with complexes 6 and 12, and twice
higher than in the negative controls.
Fig. 2 (A) The reaction of complex 6 (1 mM) and NADH (3.5 mM) was monitored by 1H
NMR in 80%MeOD-d4/20% D2O (v/v) at 310 K after 10 min, 2 h and 7 h. The peaks
marked with ● represent the resulꢀng formaꢀon of Ir-H complexes and ■ correspond to
the Ir-H hydrogen peak at -9.06 ppm (B) The reaction of complex 6 (1 μM) and NADH
(100 μM) was monitored by UV-Vis spectrum in 10% MeOH/90% H2O (v/v) at 298 K
over 8 h. (C) the TONs of complexes 2, 4, 5 and 6.
Cell cycle assay
Then the cell cycle progression was analyzed for complexes 2, 4, 6
and 12 treated A549 cells by flow cytometry. As shown in Fig. S14-
15 and Table S4-S7, ESI† complex 2 and 12 resulted in increasing G1
phase values. The values of G1 phase of complex 2 treatment group
varied from 57.81% to 69.67% with increasing treated concentration,
the percentage of G1 phase of complex 12 treatment group
increased from 56.71% to 66.40%. For complex 4 and 6, the
percentage of the cell cycle did not significantly change as the
concentration increasing.
Fig.4 ROS levels for A549 cells treated with complex 6 and 12 at 0.25×IC50 and
0.5×IC50 were analyzed by flow cytometry.
Induction of Mitochondrial Dysfunction
We previously reported experimental evidence that ruthenium
complex affected the alteration of the mitochondrial membrane
potential and might be related to anticancer activity.15 The
mitochondrial membrane potential (MMP, ΔΨm) implicated
mitochondrial dysfunction and participated in induction apoptosis.
We investigated the effects of complexes 2, 4, 6 and 12 (at
concentrations of 0.25, 0.5, 1 and 2 × IC50) on MMP in A549 cancer
cells via JC-1 (a fluorescent probe). In the negative control, JC-1
emits red fluorescence, which corresponds to high MMP. In the
positive control, A549 cells were with low MMP showing green
fluorescence. From Fig. 5, and Fig. S22-S25, Table S14-S17, ESI†, the
low MMP increased with the concentration increasing. Complexes 2,
4, 6 and 12 can induce a decrease in the MMP and appear a
concentration-dependent manner.
Apoptosis assay
We further investigated apoptosis by flow cytometry and
determined the percentages of apoptosis. A549 cells were treated
with complexes 2, 4, 6 and 12 for 24 h, stained with the solution of
annexin V/ propidium iodide (PI), followed by cell apoptosis analysis
via flow cytometry. When A549 cells incubated with complex 2 at
different concentrations, the percentage increased from 0.68% to
2.89% in early apoptotic cells and 6.71% to 51.11% in late apoptotic
cells (Fig. S16 and Table S8, ESI†). For complex 4 at concentration of
3×IC50, cells were 7.17% in the early apoptotic phase and 44.49% in
the late apoptotic phase (Fig. S17 and Table S9, ESI†). A549 cells
treated with complex 6 showed no obvious changes in early
apoptosis. At a concentration of 3×IC50, late apoptotic cells were
27.31%, and non-viable cells were 10.92% (Fig.3, and Fig. S18, Table
S10, ESI†). When A549 cells treated with complex 12 at 3×IC50 after
24 h, the early apoptotic phase cells were 2.27% and the late
apoptotic phase cells were 26.13% (Fig. S20, ESI† and Table S12,
ESI†). As shown in these figures and tables, more apoptotic cells
were observed because of the increasing concentration of the
complexes. Furthermore, A549 cells were treated with complex 6
for 12 hours, and the results are shown in the Fig. S19 and Table
S11, ESI†. Compared with 24 hours, the cells increased in early
apoptosis after treatment with complex 6 for 12 hours. And the late
apoptosis gradually increased as the concentration of the
compound increased.
Fig.5 Mitochondrial membrane potential of A549 cancer cells treatment with complex 6
at concentrations of 0.25, 0.5, 1 and 2 × IC50 were determined by JC-1.
Lysosomal damage
Acridine orange (AO) is a fluorochrome which can effectively
reflect the functional status of lysosomes. When AO enters cells and
accumulates in lysosomes, the fluorescence emission is changed
from cytosolic green to lysosomal red.48 From the Fig. S26, ESI†, the
green fluorescence of A549 cytoplasm increased and the red
fluorescence decreased as increasing concentration of the complex
6. The result indicated lysosomal membrane permeability was
increased and lysosomes was damaged. In addition to causing
increased mitochondrial membrane permeability and involvement
Fig. 3 Apoptosis of A549 cancer cells of exposure to complex 6 was detected by flow in apoptosis, intracellular ROS could directly damage lysosomal
membranes.49
cytometry after 24 h at 310 K.
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Conclusions
The development of metal-NHCs in medicinal and biological
chemistry is very rapid. In this paper, we designed twelve phenoxide
chelated IrIII-NHC complexes and studied their anticancer activity.
Complexes 1-12 showed activity towards A549 cells and HeLa
cells, especially these complexes had even higher inhibitory effect
than cisplatin. Altering the complexes' structure may influence their
anticancer activity. The tested complexes hydrolyzed in aqueous
solution. However, these complexes displayed no bounding to 9-
MeA and 9-EtG and no cleavage to pBR322 DNA. They showed a
little binding affinity to CT-DNA, probably through non-covalent
binding modes. Thus, DNA may not be the primary target of these
complexes. Complexes interfere with NADH/NAD+ hydrogen transfer,
which produce the ROS. ROS level detection increased in the cells
after addition complexes 6 and 12. Complex 2 and 12 influenced the
cell cycle at the G0/G1 phase. Apoptotic cells and mitochondrial
dysfunction were observed, which may be contributed to anticancer
activity. Complex 6 cause lysosomal damage through confocal
microscopy observation. The findings demonstrated that half-
sandwich IrIII-NHC complexes converted NADH to NAD+, which
produced the ROS. ROS level detection confirmed that ROS levels
12.
13.
14.
15.
16.
17.
18.
10.1002/asia.201801058.
Q. Du, L. Guo, M. Tian, X. Ge, Y. Yang, X. Jian, Z. Xu, Z. Tian
and Z. Liu, Organometallics, 2018, DOI:
did increase. The production of ROS led to
a decrease in
19.
20.
21.
22.
mitochondrial membrane potential and lysosomal damage, and
finally induced apoptosis.
10.1021/acs.organomet.8b00402.
All the results appear that phenoxide chelated IrIII-NHC complexes
[(η5-Cpx)Ir(C^O)Cl] have well anti-cancer effects. It is hoped that
these type complexes will continue to be studied and become
effective human anti-cancer drugs.
Z. Xu, D. Kong, X. He, L. Guo, X. Ge, X. Liu, H. Zhang, J. Li, Y.
Yang and Z. Liu, Inorg. Chem. Front., 2018, DOI:
10.1039/C8QI00476E.
Z. Tian, J. Li, S. Zhang, Z. Xu, Y. Yang, D. Kong, H. Zhang, X.
Ge, J. Zhang and Z. Liu, Inorg. Chem., 2018, DOI:
10.1021/acs.inorgchem.8b01944.
E. Z. Jahromi, A. Divsalar, A. A. Saboury, S. Khaleghizadeh,
H. Mansouri-Torshizi and I. Kostova, J. Iran. Chem. Soc.,
2016, 13, 967-989.
Conflicts of interest
There are no conflicts to declare.
23.
24.
T. Zou, C.-N. Lok, P.-K. Wan, Z.-F. Zhang, S.-K. Fung and C.-
M. Che, Curr. Opin. Chem. Biol., 2018, 43, 30-36.
M. Z. Ghdhayeb, R. A. Haque, S. Budagumpi, M. B.
Khadeer Ahamed and A. M. S. A. Majid, Inorg. Chem.
Commun., 2017, 75, 41-45.
R. J. Needham, C. Sanchez-Cano, X. Zhang, I. Romero-
Canelón, A. Habtemariam, M. S. Cooper, L. Meszaros, G. J.
Clarkson, P. J. Blower and P. J. Sadler, Angew. Chem. Int.
Ed., 2017, 56, 1017-1020.
Acknowledgements
We thank the National Natural Science Foundation of China
(21671118), the Taishan Scholars Program and Shandong
Provincial Natural Science Foundation (ZR2018LB007) for
support.
25.
26.
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C. Sanchez-Cano, I. Romero-Canelón, Y. Yang, I. J. Hands-
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