Triethylene glycol-modified iridium(III) complexes for fluorescence imaging of: Schistosoma japonicum

Article abstract of DOI:10.1039/c7tb00662d

Schistosomiasis, an infectious disease caused by the Schistosoma parasitic worm, presents a serious public health issue. To date, investigation of anti-Schistosomiasis drug mechanisms through fluorescence imaging remains challenging due to the lack of appropriate dyes as fluorescent probes. Phosphorescent Ir(iii) complexes have been attracting substantial attention among various classes of fluorophores given their excellent photophysical properties. Herein, four phosphorescent Ir(iii) complexes were synthesized, two of which contained a triethylene glycol (TEG) hydrophilic group. The phosphorescent emission range of the four complexes lay between 500 and 750 nm, and their quantum yields ranged from 0.031 to 0.146. Furthermore, under the experimental concentration conditions, the TEG-modified complexes had low cytotoxicity. Cell fluorescence labeling experiments indicated that the TEG-modified complexes had good membrane permeability. Finally, the TEG-modified complexes showed remarkable labeling effects in adult Schistosoma fluorescence imaging. Thus, TEG-modified Ir(iii) complexes could be used as a new class of bilharzial fluorescent probes.

Full text of DOI:10.1039/c7tb00662d

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Triethylene glycol-modified iridium(III) complexes for
fluorescence imaging of Schistosoma japonicum
Received 00th January 20xx,
Accepted 00th January 20xx
Yongquan Wu, Guanjie Zeng, Nannan Lvyue, Weihua Wu, Tianyu Jiang, Rongle Wu, Wei Guo, Xun
Li*, and Xiaolin Fan*
DOI: 10.1039/x0xx00000x
Schistosomiasis, an infectious disease caused by the Schistosoma parasitic worm, presents a serious public health issue. To
date, investigation of anti-Schistosomiasis drug mechanisms through fluorescence imaging remains challenging due to the
lack of appropriate dyes as fluorescent probes. Phosphorescent Ir(III) complexes have been attracted substantial attention
among various classes of fluorophores given their excellent photophysical properties. Herein, four phosphorescent Ir(III)
complexes were synthesized, two of which contained a triethylene glycol (TEG) hydrophilic group. The phosphorescent
emission range of the four complexes lay between 500 and 750 nm, and their quantum yields ranged from 0.031 to 0.146.
Further, under the experimental concentration conditions, the TEG-modified complexes had a low cytotoxicity. Cell
fluorescence labeling experiments indicated that the TEG-modified complexes had good membrane permeability. Finally,
the TEG-modified complexes showed remarkable labeling effects in adult Schistosoma fluorescence imaging. Thus, TEG-
modified Ir(III) complexes could be used as a new type of bilharzial fluorescent probe.
www.rsc.org/
death Schistosoma) to assess drug activity mechanisms,
fluorescence imaging can directly monitor the target both in
situ and in vivo, thus providing more reliable data. With the
1
. Introduction
Schistosomiasis, an infectious disease caused by the
Schistosoma parasitic worm, has a serious impact on human
health, being the second largest tropical parasitic disease. To
date, 600 million people are threatened by the disease and
development of fluorescence probes, fluorescence imaging has
been applied in biology and medicine, including in the study of
5
-6
7
Schistosomiasis. Kohn et al. used the fluorescent probe 4,5-
diaminofluorescein-2 to detect the nitric oxide content in the
body of Schistosoma, and suggested that the release of nitric
oxide in the body of the worm was dependent on nitric oxide
synthase, which played an important role in Schistosoma
1
approximately 200 million are currently infected worldwide.
The adult Schistosoma worm, resident mainly in the
parasitifer’s liver and the intestinal wall of the colon, can lead
2
-3
to vascular granuloma and fibrosis, including hepatomegaly
and splenomegaly. Furthermore, the deposition of metabolites,
secretions, and excretions of the adult worms can result in
inflammation, finally leading to acute or chronic
Schistosomiasis. Praziquantel is the most commonly used drug
against adult Schistosoma; however, given its broad and long-
8
physiology. Further, Sato et al. observed the excretory system
of the adult worm of Schistosoma mansoni by fluorescence
imaging, and provided useful information for the
understanding of the physiological function of the parasite
kidney. Unfortunately, the fluorescent probes used thus far in
Schistosomiasis research have been traditional organic
fluorescent dyes, which have several inherent limitations,
4
term use, drug resistance has emerged. Yet, the exact
mechanism of adult worm death by praziquantel remains
unknown. Therefore, a study of the drug’s underlying
mechanisms is necessary for new drug development.
9
-10
including poor photobleaching and small Stokes shifts.
Therefore, the design of a novel fluorescent probe for
fluorescence imaging in Schistosomiasis research is warranted.
Phosphorescent iridium (Ir) complexes have advantages over
traditional organic fluorescent dyes, including a large Stoke
shift, good light stability, long emission lifetime, and an
adjustable emission wavelength resulting from the metal–
In contrast to traditional research methods (for example,
immunohistochemical staining methods to detect signals from
School of Chemistry and Chemical Engineering & Key Laboratory of Organo-
pharmaceutical Chemistry of Jiangxi Province, Gannan Normal University,
Ganzhou Jiangxi 341000, P. R. China. E-mail: fanxl2013@gnnu.cn;
gnsylixun@163.com; Fax: +86 797 8393 536; Tel: +86 797 8393 536
Electronic Supplementary Information (ESI) available: synthesis of ligands L1 and L2
1
1
ligand charge transfer (MLCT) excited state. Recently,
luminescent materials composed of phosphorescent Ir
complexes have been widely used in electroluminescent
(
Scheme S1), synthesis of ligands L3 and L4 (Scheme S2), synthesis of complexes devices, chemical sensors, and bioimaging due to their
A1, A2, B1 and B2 (Scheme S3), summary of frontier MOs obtained the
PBE/(DSPP/DNP) level (Figure S1 and Table S1), cytotoxicity of A1 and B1 (Figure
S2), photobleaching curves of A2 and B2 (Figure S3), emission spectra of four Ir
complexes at different pH values (Figure S4 and Figure S5).See
DOI: 10.1039/x0xx00000x
12-14
excellent optical properties.
The adult Schistosoma worm lives in direct contact with the
blood of the parasitifer and therefore its body is covered with
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an ab antigen sugar derived from the parasitifer’s cells, leading 2.2 Photophysical properties
it to be hydrophilic. Additionally, the skin of Schistosoma
The UV–Vis absorption and emission spectra of A1, A2, B1, and
B2 in ethanol at room temperature are shown in Figure 1. With
reference to previous photophysical studies on related Ir(III)
systems, all complexes had intense absorption bands in the UV
1
5
worms is negatively charged. Thus, interaction with Ir
complexes for adult Schistosoma labeling will depend on the
amphiphilic and charge properties of Ir complexes. Further, in
order to ensure efficient Schistosoma fluorescent labeling,
complexes must be hydrophilic. Yet, most of the reported
4
region under 400 nm, with an extinction coefficient ε of 10 –
5
–1 –1
L mol cm , assigned to spin-allowed singlet ligand-
1
0
1
6
phosphorescent Ir complexes have poor water solubility.
centered transitions. The weaker band at above 400 nm with ε
20
Herein, an increase in the hydrophilicity of the fluorescence
probe was addressed through the synthesis of cationic Ir
complexes, two of these complexes were modified by
triethylene glycol (TEG) (Scheme 1), offering good lipid
3
4
–1
of 10 –10 L mol cm was assigned to a MLCT transition.
–1
In ethanol or water solution, all complexes showed a
structured emission band at a wavelength range of ~500 to
7
5
5
50 nm. Complex A1 displayed a maximum emission band at
73 nm, and A2 showed intense emission band at 519 nm and
58 nm. Complexes B1 and B2 showed a similar maximum
1
7
solubility, water solubility, and biological compatibility. The
photophysical properties of the Ir complexes were investigated
by UV-vis absorption and emission spectroscopy, and their
cytotoxicity was tested by the MTT assay. Finally, fluorescence
imaging microscopy was successfully applied to investigate the
luminescence labeling relationship between Ir complexes and
living adult Schistosoma japonicum.
emission band. With reference to [Ru(bpy)
3
]Cl
Φ = 0.063 in DMF), the quantum efficiencies (Φ) of A1, A2,
B1, and B2 in the corresponding solution were 0.054, 0.146,
.031, and 0.98, respectively (Table 1). The results indicate
2
as a standard
21
(
0
that the quantum yields of complexes A2 and B2 were higher
than those of A1 and B1.
Scheme 1. Molecular structures of the iridium(III) complexes
2
. Results and discussion
2.1 Synthesis of Ir(III) complexes
The synthesis procedure for all ligands and complexes are
outlined in Schemes S1–3. TEG-OTs was prepared according to
1
8-19
the literature.
The ligands L1 and L2 were easily obtained
by the Suzuki coupling reaction of aryl halides with
phenylboronic acid. Ligands L3 and L4 were synthesized by the
crosslinking of L1 or L2 with TEG-OTs in alkaline anhydrous
acetonitrile, at 80 °C. The four cationic Ir(III) complexes
2 6
([Ir(N^C) (phen)](PF ), where N^C = bt-OH (A1), bt-TEG (A2),
pq-OH (B1), or pq-TEG (B2)) were obtained via treatment of
the chloro-bridged dimer precursor with the corresponding
ancillary ligands (1,10-phenanthroline) in moderate yields,
−
−
6
followed by a counter ion exchange reaction from Cl to PF .
The –OH and TEG group containing N^C ligands acted as the
hydrophilic groups. The structure of all four complexes was
1
characterized by H NMR and mass spectroscopy. The cationic
character of the complexes was beneficial to permeate the
Figure 1. Absorption (a) and emission (b) spectra of complex A1, B1 in ethanol
and A2, B2 in water solution
epidermis of Schistosoma japonicum.
Table 1. Photophysical properties of complexes A1, B1 in ethanol and A2, B2 in water solution
4
3
-1
-1
Complex
Solvent
λ
abs/nm(ε(×10 dm mol cm ))
λem (nm)
τ (ns)
Φ
em
A1
A2
B1
B2
ethanol
water
264(3.47), 273(2.77), 368(1.81), 404(1.35)
273(5.44), 325(4.32), 370(2.43), 407(1.51)
268(3.60), 322(1.84), 362(1.28), 436(0.58)
272(4.71), 321(2.59), 357(2.08), 433(0.79)
573
69.3
635.9
101.5
582.3
0.054
0.143
0.031
0.096
519,558
567
ethanol
water
561
To further shed light on the photophysical characteristics of
these complexes, theoretical calculations of electronic
2.3 Theoretical calculations
2
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structures were performed using density functional theory
DFT). The distributions of molecular orbitals (HOMO-2,
(
Table 2. Octanol/water partition coefficients of complexes A1, A2, B1 and B2
HOMO-1, HOMO, LUMO, LUMO+1, and LUMO+2) are shown in
Figure 2 and Figure S1. The HOMO, HOMO-1, and HOMO-2 of
A1 and B1 were seen to reside primarily at the Ir center and at
the phenyl part of the cyclometalated ligands, similar to most
Complex
A1
C
o
(µg/mL)
26.97
30.66
18.42
24.02
C
w
(µg/mL)
6.23
Log Po/w
0.636
A2
16.08
1.85
0.280
2
2
B1
0.999
Ir(III) complexes. However, for A2 and B2, HOMO and
HOMO-1 were partially located at a chain end in the
cyclometalated ligand, whereas HOMO-2 was seen to reside
on the Ir center and the cyclometalated ligands. Finally, the
LUMO and LUMO+1 of all complexes resided primarily on the
phenanthroline ligand, while LUMO+2 was localized mainly on
the C^N ligand. Therefore, for complexes A1 and B1, the
B2
24.32
-0.005
2
.5 Cytotoxicity
The MTT assay was used to determine the effect of the A2 and
B2 complexes on HeLa cell proliferation (Figure 3). At A2 and
B2 concentrations of 20 and 15 μM, respectively, cell viability
remained above 80% for A2 and at approximately 80% for B2.
Yet, at the concentration required for cell imaging (5 μM), the
cell viability of both complexes remained above 98%, even
after 24 h incubation. Therefore, the two complexes show
relatively low cytotoxicity in the concentration range and
incubation times examined required for fluorescence imaging
applications.
HOMO (HOMO-1 and HOMO-2)
→ LUMO (LUMO+1)
3
transitions could contribute to the [dπ(Ir)-πN^N*] MLCT or
3
πC^N-πN^N*] LLCT excited state, with mixing of a small
3
quantity of IL(π-π*)(C^N) (HOMO to LUMO). Similarly, for A2
[
and B2, the HOMO (HOMO-1 and HOMO-2) → LUMO
(
LUMO+1, LUMO+2) transitions could contribute to the [dπ(Ir)-
3
3
πN^N*] MLCT or [πC^N-πN^N*] LLCT. Furthermore, the
corresponding energy gaps between HOMO and LUMO were
calculated to be 1.57, 1.36, 1.53, and 1.47 eV for A1, A2, B1,
and B2, respectively (Table S1).
Additionally, A1 and B1 were used as control samples and
the effect of the A1 and B1 samples on HeLa cell proliferation
was also assessed. Due to the relatively poor water-solubility
of A1 and B1, the incubation concentration was 2.5 to 10 µM.
Upon incubation with A1 and B1 (10 µM) for 24 h, the cell
viability remained above 85% and 88%(Figure S2), respectively.
Figure 3. Cell viability values (%) estimated by an MTT proliferation test versus
incubation concentrations of HeLa cells were cultured in the presence of 5~20
0
μM A2 and B2 at 37 C for 24 h
2
.6 Luminescent imaging of Ir(III) complex-treated cells
Firstly, to determine whether A2 and B2 were photo-stable for
biological imaging, their photostability in an aqueous solution
was assessed. As shown in Figure S3, the photoluminescence
intensity of A2 and B2 was maintained > 95% of its initial value
when monitored over a period of 1 hour under excitation at
Figure 2. Representations of the frontier molecular orbitals (MOs) for ground
state geometry of four iridium complexes as determined at the PBE/(DSPP/DNP)
level of theory
2.4 Measurement of amphiphilicity
3
65 nm. This observation indicated that A2 and B2 are
Lipophilicity is a key characteristic indicating the ability of a
responsible for bioimaging with no obvious photobleaching.
Next, we selected cells as a biological model to evaluate the
biocompatibility for imaging and the application of the four
Ir(III) complexes in luminescence imaging of living HeLa cells
was investigated by confocal laser scanning microscopy. HeLa
cells were incubated with 5 μM of complex A1, B1 in
2
3
fluorescent probe to permeate biological membranes.
Complexes A1 and B1 had a higher lipophilicity than A2 and B2
log Po/w of 0.999, 0.636, 0.280, and –0.005, respectively; Table
), which could be attributed to the significantly enhanced
(
2
hydrophilic nature of the ether chain in the main ligand (TEG).
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DMSO/PBS (pH 7, 1/99, v/v) and A2, B2 in pure PBS (pH 7) for
0 min at 37 °C, respectively. Luminescence signals with a high
2
signal to noise to ratio (S/N > 10) were detected for complexes
A2 and B2 at 510–610 nm following excitation at 405 nm
(Figure 4A2, B2). Overlay of confocal luminescence and bright-
field images for A2 and B2 demonstrated that luminescence
was evident in the cytoplasm over the nucleus and membrane.
In contrast, weaker luminescence was measured when cells
were incubated in the presence of complexes A1 and B1
(Figure 4A1, B1), mainly due to their lower quantum yields and
emission intensity, influenced by pH values. As shown in Figure
S4, the emission intensity of A1 and B1 were obviously
influenced by solution pH values. Under physiological
conditions (pH= 7 or 7.4), the luminescence intensity for A1
and B1 was weaker than that in acid solution (pH= 3 or 5).
However, A2 and B2 exhibited a similar intensity at various pH
values (pH= 3, 7, 12) (Figure S5), which revealed that A2 and
B2 are stable within the pH range from 3 to 12. Further, the
cell imaging results indicated that the complexes A2 and B2
had good membrane permeability.
2.7 Luminescent imaging of Schistosoma japonicum
Considering the significant fluorescence labeling properties of
complexes A2 or B2 as fluorescent probes, imaging of
Schistosoma japonicum was performed. Following treatment
with 5 μM of A2 or B2 in PBS (pH 7) for 15 min at 37 °C, intense
luminescence was observed from adult Schistosoma
japonicum. Additionally, bright-field images of Schistosoma
japonicum showed an intact skin surface structure and good
survival, indicating low injury to Schistosoma japonicum 5 μM
concentrations of A2 or B2 (Figure 5). Moreover, with A2
treatment, strong fluorescence was also observed within the
internal body; this was further confirmed by Z-scan confocal
microscopy (Figure 6, 3D image). As a control experiment,
complexes A1 and B1 were used to label the adult Schistosoma
in DMSO/PBS (pH 7, 1/99, v/v) for 3 h (Figure 7), showing
much weaker labelling than A2 and B2.
Figure 4. The luminescence, bright-field, and overlay images of HeLa cells
incubated with 5 μM complex A1, B1 in DMSO/PBS (pH 7, 1/99, v/v) and A2, B2
in PBS (pH 7) for 20 min, λex=405 nm, λem=560±50 nm
Considering the negatively charged, hydrophilic nature of
1
5
the skin of adult Schistosoma worms, it is logical that water-
soluble cationic Ir(III) complexes would improve the probe
labeling effects. Indeed, complexes A2 and B2 were able to
enter within the body of adult Schistosoma at low
concentrations, with a remarkable fluorescence labeling effect,
and had an excellent biological compatibility. Additionally, the
ability of A2 and B2 complexes to directly dissolve at low
concentrations in PBS, without the need for dissolution in
DMSO, avoids organism damage caused by organic solvents.
Therefore, complexes A2 and B2 could be used as a new type
of bilharzial fluorescent probe.
The above experimental results prove that the TEG-
modified, hydrophilic complexes A2 and B2 are outstanding
Schistosoma fluorescence labeling probes. To the best of our
knowledge, this is the first case of cationic Ir(III) complexes
used as luminescent probes for Schistosoma japonicum
imaging applications.
4
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3
. Conclusions
In summary, four luminescent Ir(III) complexes were designed
and synthesized, of which the TEG-modified, hydrophilic
complexes A2 and B2 could be used as phosphorescent probes
for fluorescence imaging of living Schistosoma japonicum.
Compared to the hydrophobic A1 and B1, complexes A2 and
B2 exhibited a higher phosphorescent quantum yield and
better water solubility. Moreover, at 20 μM concentration, A2
and B2 had low cytotoxicity. In addition, cell imaging
experiments indicated that A2 and B2 had good cell membrane
permeability. Finally, luminescent imaging experiments
demonstrated that the labeling effects of complexes A2 and B2
were remarkable for adult Schistosoma, and could be used for
fluorescence imaging of Schistosoma japonicum. Thus, TEG-
modified Ir(III) complexes will be helpful in the design of
fluorescent probes for parasitic research. Further studies
should focus on assessing the functional mechanisms of anti-
Schistosomiasis drugs using Ir(III) complexes. The results
described herein may well be of interest to others working in
the areas of phosphorescent metal complexes, bioimaging,
and Schistosomiasis.
4
. Experimental section
Figure 5. Confocal luminescence, bright-field, and overlay images of living
Schistosoma japonicum treated with 5 μM complex A2 and B2 in PBS (pH 7) for
4
.1 Characterization and Materials
1
5 min, λex= 405 nm, λem= 560±50 nm
1
13
H NMR and C NMR spectra were recorded on Bruker DRX-
4
00 NMR spectrometers with tetramethylsilane as the internal
standard. Mass spectra were collected with an AB SCIEX mass
spectrometer. The UV-visible spectra were recorded on a
Shimadzu UV-2007 spectrometer. Steady-state emission
experiments at room temperature were measured on a
PerkinElmer LS-55 spectrometer. The fluorescence imaging
experiment was taken using an Olympus FV1000 confocal laser
scanning microscope. The absorbance value was measured
using a KBH ST-360 micro-plate reader (China) in the MTT
assay.
All solvents, unless specified, were purchased from Shanghai
Titan Scientific Co., Ltd (China), and were used without further
purification. 2-Chlorobenzothiazole and 2-Chloroquinoline
were purchased from Energy Chemical Co., Ltd (China). 4-
Hydroxyphenylboronic acid was purchased from Soochiral
Chemical Science & Technology Co., Ltd (China). Triethylene
Figure 6. 3D luminescence imaging of Schistosoma japonicum incubated with A2
for 15 min
glycol, Tosyl chloride, 1,10-phenanthroline, Pd[P(Ph)
and KPF were purchased from Aladdin Technology Co., Ltd
China). Tetrabutyl ammonium bromide was purchased from
Comio Chemical Reagent Co., Ltd (China). IrCl ·3H O was
purchased from Rock New Material Co., Ltd (China), All
procedures involving IrCl ·3H O were carried out under a
3 4 2 3
] , K CO ,
6
(
3
2
3
2
nitrogen atmosphere. MTT and PBS were purchased from
Beyotime Biotechnology Co., Ltd (China). DMEM, RPMI 1640,
and FBS were purchased from Thermo Fisher Scientific Co., Ltd.
4
.2 Synthesis of L1 and L2
Synthetic route of ligands L3 and L4 was shown in the Scheme
Figure 7. Confocal luminescence, bright-field, and overlay images of Schistosoma
japonicum treated with 5 μM complex A1 and B1 in DMSO/PBS (pH 7, 1/99, v/v) S1 (see SI). A mixture of 2-Chlorobenzothiazole or 2-
for 3 h, λex=405 nm, λem=560±50 nm
Chloroquinoline (3 mmol), 4-Hydroxyphenylboronic acid (3
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mmol),
K
2
CO
3
(9 mmol), Terakis (triphenylphosphine) intermediate with 1,10-phenanthroline (phen) as the diimine
O (V/V=1:1, 30 mL) was ligand, according the literature methods.
palladium (0) (0.24 mmol) and THF: H
refluxed with stirring for 10 h under a N
2
0
atmosphere at 70 C.
1
6
A1: yellow solid, yield 40%. H NMR (400 MHz, d -DMSO): δ
2
After it was cooled, the mixture was poured into water and 9.90 (s, 2H), 8.92 (dd, J = 8.3, 1.2 Hz, 2H), 8.47 (d, J=1.2 Hz, 2H),
extracted with dichloromethane (20 mL×3). The combined 8.31 (d, J = 3.4 Hz, 2H), 8.15 (dd, J = 8.3, 5.1 Hz, 2H), 8.04 (d, J =
organic phases were dried over anhydrous Na
2 4
SO , filtered and 7.8 Hz, 2H), 7.88 (d, J = 8.4 Hz, 2H), 7.17 (t, J = 7.5 Hz, 2H), 6.82
evaporated to dryness. The crude product was purified using (t, J = 7.9 Hz, 2H), 6.59 (dd, J = 8.4, 2.3 Hz, 2H), 5.86 (d, J = 2.2
1
column chromatography with petroleum ether/ethyl acetate Hz, 2H), 5.60 (d, J = 8.4 Hz, 2H). C NMR (100 MHz, d -DMSO)
3
6
(
2:1) as the eluent.
δ 180.88, 161.14, 153.58, 151.63, 149.21, 147.30, 139.76,
1
L1: gray solid, yield 33%. H NMR (400 MHz, DMSO): δ6.90- 136.63, 131.07, 129.49, 128.92, 127.86, 125.37, 124.61, 119.82,
6
7
1
.97 (m, 2H), 7.36-7.43 (m, 1H), 7.49 (m, 1H), 7.90-7.95 (m, 2H), 116.10, 111.64. MS Calcd. for A1 (m/z): 824.9698; found: 824.6.
1
A2: yellow solid, yield 35%. H NMR (400 MHz, CDCl
.97 (dd, J = 8.1, 0.4 Hz, 1H), 8.07 (dd, J = 7.9, 0.6 Hz, 1H),
3
): δ 8.95
0.21 (s, 1H). MS Calcd. for L1 (m/z): 227.0405; found: 227.2.
1
(d, J = 8.1 Hz, 2H), 8.46 (dd, J = 5.0, 1.1 Hz, 2H), 8.32 (s, 2H),
L2: white solid, yield 35%. H NMR (400 MHz, DMSO): δ 8.03 (dd, J = 8.2, 5.1 Hz, 2H), 7.70-7.87 (m, 4H), 7.16 (t, J = 7.4
.96-6.87 (m, 2H), 7.49-7.57 (m, 1H), 7.73 (m, 1H), 7.91-7.96 Hz, 2H), 6.74 - 6.84 (m, 2H), 6.70 (dd, J = 8.6, 2.4 Hz, 2H), 5.98
6
(m, 1H), 7.99 (d, J = 8.5 Hz, 1H), 8.04 (d, J = 8.7 Hz, 1H), 8.09- (d, J = 2.3 Hz, 2H), 5.66 (d, J = 8.4 Hz, 2H), 3.81-3.89 (m, 2H),
8
.18 (m, 2H), 8.36 (d, J = 8.6 Hz, 1H), 9.86 (s, 1H). MS Calcd. for 3.76 (dt, J = 7.3, 3.9 Hz, 2H), 3.61-3.68 (m, 8H), 3.57 (s, 8H),
1
3.49-3.55 (m, 4H). C NMR (100 MHz, d -DMSO) δ 180.93,
3
6
L1 (m/z): 221.0842; found: 221.2.
1
1
61.45, 152.46, 151.86, 148.99, 147.29, 139.88, 133.64, 131.12,
29.59, 128.82, 128.10, 125.81, 124.90, 119.32, 116.33, 109.30,
4.3 Synthesis of L3 and L4
Synthetic route of ligands L3 and L4 was shown in the Scheme 72.74, 70.22, 70.09, 68.90, 67.26, 60.63. MS Calcd. For A2
S2 (see SI). TEG-OTs was prepared according to the literature (m/z): 1089.2851; found: 1089.5.
1
9
1
6
methods. And then, the obtained TEG-OTs (1 mmol) was
mixed with L1 (1 mmol) or L2 (1 mmol), Tetrabutyl ammonium 9.49 (s, 2H), 8.71 (dd, J = 8.2, 1.2 Hz, 2H), 8.53 (d, J = 5.1 Hz,
bromide (0.1 mmol), K CO (2 mmol) and acetonitrile (30 mL). 2H), 8.34 (q, J = 9.0 Hz, 4H), 8.18 (t, J = 13.3 Hz, 2H), 7.99-8.11
B1: orange solid, yield 25%. H NMR (400 MHz, d -DMSO): δ
2
3
0
This reaction was refluxed with stirring for 10 h at 80 C. After (m, 4H), 7.65-7.76 (m, 2H), 7.14 (t, J = 7.5 Hz, 2H), 7.01 (d, J =
being cooled, the mixture was evaporated to dry (removal the 8.9 Hz, 2H), 6.68-6.79 (m, 2H), 6.63 (dd, J = 8.6, 2.3 Hz, 2H),
1
3
6
acetonitrile), and added deionized water then extracted with 5.98 (d, J = 2.2 Hz, 2H). C NMR (100 MHz, d -DMSO) δ 169.99,
dichloromethane (15 mL×3). The combined organic phases 159.80, 154.03, 148.93, 147.33, 146.32, 139.85, 139.10, 137.44,
were dried over anhydrous Na
concentration under vacuum. The crude residue was purified 121.02, 118.21, 111.38. MS Calcd. for B1 (m/z): 813.1842;
using column chromatography with petroleum found: 814.6 (M+1).
ether/ethyl acetate (6:1) as the eluent. B2: orange solid, yield 32%. H NMR (400 MHz, CDCl
2 4
SO , filtered, and followed by 130.59, 130.14, 129.39, 128.28, 127.34, 126.94, 126.08, 123.62,
1
3
): δ
1
TEG-OTs: white transparent liquid, yield 55%. H NMR (400 8.61 (d, J = 7.4 Hz, 2H), 8.50 (dd, J = 5.1, 1.0 Hz, 2H), 8.09 (q, J =
6
MHz, d -DMSO): δ 7.76 (dd, J = 8.3, 1.8 Hz, 2H), 7.31 (d, J = 8.1 8.9 Hz, 4H), 7.99 (d, J = 8.8 Hz, 2H), 7.94 (s, 2H), 7.87 (dd, J =
Hz, 2H), 4.12 (m, 2H), 3.62-3.72 (m, 4H), 3.49-3.61 (m, 6H), 8.2, 5.2 Hz, 2H), 7.52 (dd, J = 7.9, 3.6 Hz, 2H), 7.06 (tt, J = 7.1,
2
.41 (s, 3H).
3.6 Hz, 4H), 6.78 (dd, J = 8.7, 2.4 Hz, 2H), 6.63-6.72 (m, 2H),
1
L3: light yellow solid, yield 85%. H NMR (400 MHz, CDCl3): δ 6.16 (d, J = 2.4 Hz, 2H), 3.75-3.84 (m, 2H), 3.63-3.70 (m, 2H),
1
.09 (t, J = 5.7 Hz, 2H), 8.04-8.08 (m, 1H), 7.89 (dd, J = 8.0, 0.5 3.61 (dd, J = 6.1, 3.2 Hz, 4H), 3.44-3.56 (m, 16H). C NMR (100
3
8
6
Hz, 1H), 7.47-7.54 (m, 1H), 7.35-7.43 (m, 1H), 7.01-7.08 (m, 2H), MHz, d -DMSO) δ 169.85, 160.32, 152.88, 149.06, 147.18,
.92 (dd, J = 5.4, 4.1 Hz, 2H), 3.74-3.78 (m, 4H), 3.72 (d, J = 3.0 146.27, 140.34, 139.29, 130.86, 130.67, 130.22, 129.61, 128.34,
Hz, 4H), 3.64 (d, J = 1.6 Hz, 2H). 127.45, 127.11, 126.48, 123.59, 120.31, 118.49, 109.13, 72.71,
3
1
6
L4: light yellow solid, yield 80%. H NMR (400 MHz, d - 70.15, 70.05, 68.93, 67.00, 60.61. MS Calcd. for B2 (m/z):
DMSO): δ 8.39 (d, J = 8.6 Hz, 1H), 8.27-8.21 (m, 2H), 8.10 (d, J = 1077.3414; found: 1077.6.
8
.7 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 7.4 Hz, 1H), 7.75
4
.5 Measurement of photophysical properties
(m, 1H), 7.52-7.60 (m, 1H), 7.11 (t, J = 5.9 Hz, 2H), 4.19 (dd, J =
1
5
5
0.6, 6.1 Hz, 2H), 3.79 (dd, J = 10.6, 6.0 Hz, 2H), 3.61 (dd, J = UV-visible spectra were recorded on Shimadzu UV-2007
.8, 3.2 Hz, 2H), 3.55 (dd, J = 5.7, 3.2 Hz, 2H), 3.49 (dd, J = 10.2, spectrometer and emission spectra were recorded on
.2 Hz, 2H), 3.43 (dd, J = 7.7, 3.0 Hz, 2H).
.4 Synthesis of Complexes A1, A2, B1 and B2
PerkinElmer LS-55 spectrometer in ethanol solution at room
temperature. Emission lifetime studies were measured on an
4
Edinburgh Instruments spectrometer (LFS-920) with
a
Synthetic route of complexes A1, A2, B1 and B2 was shown in hydrogen-filled excitation source. The data were analyzed by a
the Scheme S3 (see SI). The cyclometalated iridium(III) chloro- software package provided by Edinburgh Instruments.
bridged dimeric intermediate [Ir(ligand)
2
Cl
2
]
2
was prepared
Quantum yields were calculated according to the literature
24
according to the literature methods. Complexes A1, A2, B1, at room temperature. The samples solution was diluted by
and B2 were synthesized from the reaction of the dimeric aerated ethanol, and the aerated DMF solution of Tris (2,2'-
bipyridyl) ruthenium (II) chloride hexahydrate (Φ= 0.063 in
6
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2
1
DMF) was utilized as the reference. The quantum yields of lens (40X). Excitation of the HeLa cells at 405 nm was carried
the complexes were calculated according to equation out with a laser, and emission was collected between 520 and
2
2
μ s μ s μ s μ s
Φ =Φ I A N /I A N . where, ‘N’ represents the solution’s 620 nm using a PMT detector. Prior to imaging, the medium
refractive index, ‘I’ represents the integrated fluorescence was removed. Cell imaging was carried out after washing cells
intensity, ‘A’ represents the integrated absorbance intensity, with PBS (pH=7, 10 mM) three times.
and the subscripts ‘μ’ and ‘s’ refer to the reference samples
4
.10 Luminescence imaging of Schistosoma japonicum
Schistosoma japonicum infected Oncomelania hupensis
provided by Jiangsu Institute of Parasitic Disease, China)
The geometry and energy optimizations were performed with releasing cercariae was according to routine cercariae shedding
and the samples, respectively.
4.6 Energy optimization
(
3
the DMol package based on the density functional theory method
． The mice (purchased from Gannan Medical
(DFT) method. The generalized-gradient approximation (GGA) University, China) were infected with cercariae of Schistosoma
with the Perdew–Burke–Ernzerhof (PBE) functional was japonicum. Animal procedures were in agreement with the
employed for all the calculations. A DFT-based relativistic semi- guidelines of the Institutional Animal Care and Use Committee.
core pseudopotential (DSPP) and double numerical basis Each mouse was challenged by 40 cercariae. The adult worms
including d- and p-polarization function (DNP) was used. Once were obtained from the liver and mesenteric veins of the mice
an optimized geometry was obtained, imaginary frequencies by perfusion 5 weeks after the infection. The worms were
0
were checked at the same level by vibration analysis to verify cultured in RPMI 1640 supplemented with 10% FBS at 37 C in
2
the genuine minimum on the potential energy surfaces (PES). a humidified atmosphere of 5 % CO and 95 % air incubator.
To understand the nature of the ground state, the orbitals of
2
the complexes were also performed.
Fluorescence imaging studies were performed with an
Olympus FV1000 confocal laser scanning microscope with an
objective lens (10X). Excitation of the Schistosoma japonicum
at 405 nm was carried out with a laser, and emission signal
5
4.7 Amphiphilicity measurement
The measurement of lipophilicity was in the mixed solution of was collected between 520 and 620 nm using a PMT detector.
isometric water and octanol. Dissolved the sample into trace Prior to imaging, the medium was removed. Schistosoma
amounts of ethanol, and then put it into the mixed solution. japonicum was carried out after washing with PBS (pH=7, 10
Oscillated and afterwards left it into settlement lamination. mM) three times.
Finally sample concentration was tested the in water (C
oil (C ), respectively. Lipophilicity was calculated according to
equation logPo/w=log(C /C ). The bigger the number of logPo/w
is, the stronger the hydrophobicity.
w
) and
o
Acknowledgements
o
w
2
3
The authors thanks for the financially support by National
Natural Science Foundation of China (21501031, 51478123,
4.8 Cytotoxicity assays
2
1463003, 21662002), Advanced Innovation Research Teams
The HeLa cell lines were provided by the Institute of
Biochemistry and Cell Biology (Chinese Academy of Sciences).
HeLa human cervical carcinoma cells were cultured in DMEM
Project of Jiangxi Province (20133BCB24011), Key Technology
R&D Program of Jiangxi Province (20143ACG70019), Natural
Science Foundation of Jiangxi Province of China
0
supplemented with 10% fetal bovine serum (FBS) at 37 C in a
(
20151BAB213001, 20141BBG70070), and Training Plan to
Innovation and Enterprise of Gannan Normal University
201510418005).
humidified atmosphere of 5% CO
The in vitro cytotoxicity was measured using the MTT [3-(4, 5-
dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide]
method in HeLa cells. Cells growing in a 96-well flat-bottomed
2
and 95% air incubator 24 h.
(
4
-1
microplate (1×10 cells well ) in complete DMEM Notes and references
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-1
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Novel Iridium(III) Complexes for Fluorescence Imaging of Schistosoma japonicum