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www.rsc.org/advances PAPER
A quinolinyl antipyrine based fluorescence sensor for Zn2+ and its application
in bioimaging{
Qi-Hua You,a Pui-Shan Chan,b Wing-Hong Chan,*a Sam C. K. Hau,c Albert W. M. Lee,a N. K. Mak,b
Thomas C. W. Makc and Ricky N. S. Wongb
Received 8th August 2012, Accepted 4th September 2012
Published on 17 September 2012. Downloaded on 25/10/2014 04:57:37.

DOI: 10.1039/c2ra21736h

By incorporating 4-aminoantipyrine moiety onto 8-aminoquinoline with a suitable spacer, a highly

selective and sensitive fluorescent Zn2+ sensor, QPA, was designed and constructed. In 25% ACN-
HEPES buffer pH 7.0 solution, QPA exhibited 10.6-fold fluorescence enhancement at 500 nm upon
addition of Zn2+. The limit of detection (LOD) was calculated to be 1.3 6 1027 M according to
fluorescence titration. The 1 : 1 binding mode of the metal complex was established by combined UV-
vis, fluorescence and HRMS spectroscopic method. The membrane permeability of QPA to living
cells and bioimaging of Zn2+ are demonstrated.

Introduction
The development of highly selective and sensitive metal chemo-
sensors is an active field in supramolecular chemistry.1–4 Zinc ion
is the most abundant d-block transition metal essential in the
human body with concentration ranging from sub-nM to
0.3 mM,5,6 playing a pivotal role in physiological processes such
as enzyme regulation, gene expression, catalytic function of
protein, apoptosis and so-forth.7–13 The disorder of zinc
metabolism in biological systems is associated with a variety of
diseases such as Alzheimer’s disease, diabetes, epilepsy.14–20
Therefore, there is a huge demand and potential for exploring
novel development of Zn2+ chemosensors.
Since the first quinoline-based Zn2+ sensor TSQ (N-(6-
methoxyl-8-quinolyl)-p-toluenesulfonamide) was reported,21
many fluorescent sensors based on 8-aminoquinoline structure
have been developed and applied in in vitro and in vivo imaging
Zn2+ in biological samples.22–26 Also, 8-aminoquinoline was
tethered to silica nanoparticles, cyclodextrin or polymers to
improve water solubility so that they can detect Zn2+ in aqueous
solutions.27–30 The signal display mechanisms of these sensors
were mainly based on the photo-induced electron transfer (PET)
a
Department of Chemistry, Hong Kong Baptist University, Hong Kong,
China. E-mail: whchan@hkbu.edu.hk; Fax: +852-3411-7348;
Tel: +852-3411-7076
b
Department of Biology, Hong Kong Baptist University, Hong Kong,
China
c
Department of Chemistry, The Chinese University of Hong Kong,
Hong Kong, China
{ Electronic supplementary information (ESI) available: Supplementary
data contain fluorescence spectra of QPA and 8-NQ-NH2 upon addtion
of Zn2+ and Cd2+, measurement of detection limit, time course of QPA/
Zn2+ complex formation, stepwise complexation/decomplexation cycle of
QPA to Zn2+, MALDI-TOF HRMS of QPA and QPA/Zn2+, 1H, 13C
NMR spectrum of QPA. CCDC reference numbers 892765. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/
c2ra21736h
and internal charge transfer (ICT). However, some of these Zn2+
sensors have undesirable selectivity and are vulnerable to
interference by other metal ions, particularly Cd2+.30–32
Therefore, the design and synthesis of a more versatile and
improved performance Zn2+ fluorescent sensor is still a great
challenge.
Herein, we synthesized 8-aminoquinoline derivative QPA (N-
(quinolin-8-yl)-2-((1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-
pyrazol-4-yl)amino)acetamide) bearing 4-aminoantipyrine moi-
ety as a new chemosensor for the detection of Zn2+, which
showed high selectivity and sensitivity to Zn2+ over other
competitive metal ions, operating on the basis of chelation-
enhanced fluorescence (CHEF) mechanism. The introduction of
4-aminoantipyrine group provides two binding sites for coordi-
nating Zn2+ ion and the enhanced PET effect from the lone pair
of two nitrogen atoms in 4-aminoantipyrine group exerting onto
quinoline moiety endowing the aptosensor with a low fluores-
cence off-state. The complementary ligating properties of the
binding sites of QPA confer the sensor with high selectivity and
sensitivity towards Zn2+ over other metal ions.
Experimental
General
1
H-NMR and 13C-NMR spectra were recorded on a Bruker
Advance-III 400 MHz Spectrometer (at 400 and 100 MHz,
respectively) using trimethylsilane (TMS) as an internal stan-
dard. Low resolution mass spectra were recorded on a Finnigan
MAT SSQ-710 mass spectrometer while high resolution mass
spectra was performed on a Bruker Autoflex mass spectrometer
(MALDI-TOF). Fluorescence emission spectra and UV-vis
spectra were collected on a PE LS50B and a Cary UV-300
spectrometer, respectively. The melting point was determined
with a MEL-TEMPII melting point apparatus (uncorrected).

11078 | RSC Adv., 2012, 2, 11078–11083 This journal is ß The Royal Society of Chemistry 2012

X-ray intensity data were measured at room temperature (298 K)
on a Bruker AXS Kappa ApexII Duo diffractometer using
frames of oscillation range 0.3u, with 2u , h , 28u. The pH
measurements were performed on a Orion 420A pH mV
temperature meter with a combined glass-calomel electrode.
Double-distilled water was used throughout. The excitation
wavelength was 330 nm.
All regents for synthesis were obtained commercially and were
used without further purification. Solvents such as dimethylfor-
mamide (DMF), acetonitrile (ACN) and tetrahydrofuran (THF)
were purchased from commercial sources and were the highest
grade, dry dichloromethane (DCM) was distilled in calcium
hydride. Silica gel (200–300 mesh, MACHEREY-NAGEL
GmbH & Co. KG) was used for column chromatography.
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Analytical thin-layer chromatography was performed using TLC
silica gel 60 F254 (aluminium sheets, Merck KGaA). In titration
experiments, all the cations in the form of perchlorate or chloride
and other substrates were purchased from Sigma-Aldrich, USA,
and stored in a vacuum desiccator.
Sample preparation
The probe was dissolved in ACN as a stock solution (1 mM).
Buffer solution was prepared by dissolving HEPES in water (100
mM). Slight variations in the pH of the solution were achieved
by adding the minimum volumes of NaOH or HCl.
Absorption and fluorescence analysis
Absorption spectra and fluorescence emission spectra were
obtained with 1.0 cm quartz cells. The detection procedures
were as follows: in 25% ACN-HEPES (100 mM, pH = 7.0) buffer
solution containing 10 mM QPA, a Zn2+ sample was gradually
titrated into the solution, the mixture was equilibrated for 2 min
before measurement. The fluorescence intensity was measured
simultaneously at lex/em = 330/550 nm. The excitation and
emission slits were set to 5.0 nm and 5.0 nm, respectively.
Cell culture
Human nasopharyngeal carcinoma cells (HK-1) were cultured in
RPMI 1640 (Gibco) supplemented with 10% FBS (Gibco) and
antibiotics (penicillin 50 U/mL; streptomycin 50 mg/ml). The cells
were incubated at 37 uC in a humidified CO2 (5%) incubator.
Confocal fluorescence imaging
HK-1 cells (1 6 105 cells) were grown onto a glass coverslip in
35 mm culture dish overnight. The Zinc sensor QPA and the zinc
chelator N,N,N9,N9-tetrakis(2-pyridylmethyl)ethylene diamine
(TPEN) were dissolved in DMSO while the zinc perchlorate
and the zinc carrier pyrithione were dissolved in H2O. All
compounds were prepared at a stock concentration of 10 mM
and then diluted in culture medium for incubation with cells. The
cells were incubated with the zinc sensor QPA (10 mM) for
30 min at 37 uC. Additional zinc ions were introduced by
incubating the cells with a mixture of zinc perchlorate (5 mM)
and zinc ion carrier pyrithione (5 mM) for 15 min at room
temperature. In order to remove the zinc ion, the cells were
further incubated with the zinc chelator TPEN (20 mM) for
15 min at room temperature. The fluorescence images of the cells
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were observed under the confocal microscope (Olympus
FV1000). QPA was excited at 405 nm with a diode laser and
the emitted fluorescent signals at 500–600 nm were collected.
Images were processed and analyzed using the FV10-ASW
software (Olympus).
Single-crystal structure determination
X-ray intensity data were measured at room temperature (298 K)
on a Bruker AXS Kappa ApexII Duo diffractometer using frames
of oscillation range 0.3u, with 2u , h , 28u. The structures were
solved by the direct method and refined by full-matrix least-
squares on F2 using the SHELXTL program package.
Synthesis
2-bromo-N-(quinolin-8-yl)acetamide (1). 8-Aminoquinoline (0.5
g, 3.46 mmol) was dissolved in dry dichloromethane (20 mL) and
triethylamine (0.35 g, 3.46 mmol) was added into this solution.
After the mixture was stirred at 0 uC for 10 min, bromoacetyl
bromide (0.84 g, 4.16 mmol) was introduced dropwise to the
stirred solution over a period of 20 min. The reaction mixture was
then stirred at room temperature for 3 hours. After removal of
solvent, the crude product was purified by column chromato-
graphy on silica gel (petroleum ether : ethyl acetate = 6 : 1) as the
eluant to afford 1 as a white solid (0.88 g, 96% yield). m.p.: .300
uC, 1H-NMR (400 MHz, CDCl3): 10.72 (1H, s), 8.86 (1H, dd, J =
4.0, 1.6 Hz), 8.75 (1H, dd, J = 5.6, 3.6 Hz), 8.18 (1H, dd, J = 8.0,
3.6 Hz), 7.57 (2H, m), 7.49 (1H, dd, J =8.4, 4.0Hz), 4.14 (2H, s);
13
C-NMR(100 MHz, CDCl3): 164.0, 148.6, 138.7, 136.3, 133.8,
127.9, 127.2, 122.5, 121.8, 116.6, 29.7. HRMS(ESI): m/z calcd for
C11H10N2OBr: [M + H+] 264.9976, found: 264.9957.
N-(quinolin-8-yl)-2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-
1H-pyrazol-4-yl-amino)-acetamide (QPA). A mixture of
2-bromo-N-(quinolin-8-yl)acetamide (0.265 g, 1.0 mmol), 4-ami-
noantipydine (0.182 g, 0.9 mmol) and K2CO3 (0.276 g, 2.0 mmol)
in DMF (10 mL) was stirred at room temperature overnight. The
reaction mixture was poured into 30 mL of water, the aqueous
phase was extracted with ethyl acetate (3 6 30 mL), the organic
phases were combined and washed with H2O (2 6 20 mL) and
brine (20 mL) successively, and dried over Na2SO4. After
removal of solvent, the crude product was purified by column
chromatography on silica gel (petroleum ether : ethyl acetate =
1 : 4) as the eluant to afford QPA as a yellow solid (0.28 g, 72%
yield). m.p.: 180–181uC, 1H-NMR (400 MHz, ACN-d3): 11.19
(1H, br. s), 8.88 (1H, dd, J = 4.2 Hz, J = 1.6 Hz), 8.82 (1H, dd, J
= 7.4 Hz, J = 1.5 Hz), 8.33 (1H, dd, J = 8.3 Hz, J = 1.6 Hz), 7.67–
7.56 (4H, m), 7.51–7.43 (4H, m), 7.33–7.28 (1H, m), 3.98 (2H, s),
3.75 (1H, br. s), 2.90 (3H, s), 2.29 (3H, s); 13C-NMR (100 MHz,
CDCl3): 170.30, 162.53, 148.52, 142.65, 138.91, 136.21, 135.16,
134.15, 129.14, 128.06, 127.32, 126.21, 123.15, 121.92, 121.63,
120.86, 116.67, 52.79, 37.35, 10.73. HRMS(ESI): m/z calcd for
C22H21N5O2: [M+H+] = 388.1773, found: 388.4032, [M+Na+] =
410.1593, found: 410.3490.
Results and discussion
Fluorescent Zn2+ sensors bearing 2-amino-N-(quinolin-8-yl)ace-
tamide (AQA) moiety have been reported.22–32,34–35 The
RSC Adv., 2012, 2, 11078–11083 | 11079
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preliminary work showed that the fluorescence of AQA was only

turn-on upon either addition of Zn2+ or Cd2+ (Fig. S1, ESI{). To
eliminate the interference of Cd2+ on Zn2+ detection, we called
for the appendage of 4-aminoantipyrine moiety to AQA to form
a new probe, QPA. The binding experiments revealed that the
fluorescence of QPA can be turned on upon addition of Zn2+
and in contrast negligible fluorescent enhancement was observed
in the presence of Cd2+ (Fig. S2, ESI{). Therefore, a highly
selective Zn2+ chemosensor has emerged.
As described in Scheme 1, QPA was synthesized from
substitution reaction of 8-aminoquinoline to 2-bromacetyl
bromide affording compound 1 in 96% yield. Then 1 was
reacted with 4-aminoantipyrine in DMF to give rise to QPA in
72% yield. The control compound AQA was synthesized from 1
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with NaN3, followed by reduction by PPh3 obtained in 65%

overall yield.34 The structure of QPA and AQA was confirmed
by 1H NMR, 13C NMR, HRMS (Supporting information{) and
X-ray diffraction method (Fig. 1). Both AQA and QPA showed
Fig. 1 X-ray crystal structure of QPA. All hydrogen atoms are omitted
good solubility in 25% ACN aqueous solution.
for clarity (30% probability level for the thermal ellipsoids). The green
Initially the binding behavior of QPA towards Zn2+ was
dashed line indicates the internal H-bond between H2 and N3 atoms.
investigated by UV-vis spectroscopy. The absorption spectrum
of QPA exhibited a strong band at 238 nm and also a weak
Job’s plot (Fig. 4). In low Zn2+ concentration (0y9 mM), the
broad band at about 300 nm in 25% ACN-HEPES buffer (100
fluorescence of QPA increased linearly upon addition of Zn2+,
mM, pH = 7.0) solution. Upon addition of Zn2+, the absorbance
and the limit of detection (LOD) for Zn2+ is 1.3 6 1027 M (3s/
at 238 and 300 nm decreased with concomitant formation of new
slope, Fig. S3, ESI{).
peaks at 252 and 350 nm (Fig. 2). Clear isosbestic points at 245,
For practical applications, the sensing ability of QPA towards
275 and 328 nm are apparent, which indicates the formation of
Zn2+ at different pH values was investigated (Fig. 5). As shown
only one active zinc complex with the probe.
in Fig. 5, the fluorescence intensity of the QPA-Zn2+ complex
The fluorescence emission spectrum from 350 to 600 nm was
increases gradually from pH 4.0 to 6.5, reaching a steady high
obtained by exciting QPA at 330 nm. Operating on PET
reading at around pH 6.5. Apparently, in acidic conditions,
mechanism, QPA exhibited very weak fluorescence at 500 nm in
protonation of the amino group in the 4-aminoantipyrine moiety
25% ACN-HEPES buffer (100 mM, pH = 7.0). Addition of Zn2+
would reduce its binding ability to Zn2+ and suppress the
(0y10 equiv.) produces a new emission band centered at 500 nm
formation of the complex.26,35 On the other hand, due to the
with a 10.6-fold increase in fluorescence (Fig. 3a). A greenish
formation of the less soluble Zn(OH)+ or Zn(OH)2 in alkali
fluorescence emission of the solution was observed under UV
conditions, fewer QPA-Zn2+ complexes could be formed at high
lamp irradiation (Fig. 3a, inset). These results may be due to the
breakage of the intramolecular hydrogen bond and electron pH. Thus, fluorescence of the complex decreases with the
transfer from the nitrogen atom of the quinoline moiety to metal increase of pH from 8.0 to 10.0.32 A plateau of stable reading
ion after binding of QPA with Zn2+.33 Another reason for from pH 6.5 to 8.0, covering the physiological pH window, was
fluorescence enhancement could be that the binding of QPA and
Zn2+ formed a more rigid chelating ring.24,35 On the basis of
non-linear fitting of the titration curve of 1 : 1 binding model,
the association constant of QPA-Zn2+ was computed to be (5.85
¡ 0.54) 6 104 M21 (R2 = 0.986) using Benesi-Hildebrand
equation (Fig. 3b).36–38 This binding model is also supported by

Fig. 2 UV-vis spectra of QPA (10 mM) in 25% ACN-HEPES (100 mM,
Scheme 1 Facile synthesis of AQA and QPA. pH = 7.0) upon addition of Zn2+ (1-8 equiv.).

11080 | RSC Adv., 2012, 2, 11078–11083 This journal is ß The Royal Society of Chemistry 2012
Published on 17 September 2012. Downloaded on 25/10/2014 04:57:37.
Fig. 3 (a) Fluorescence titration of QPA (10 mM) in 25% ACN-HEPES
(100 mM, pH = 7.0) with addition of Zn2+. Inset: visible emission
(irradiated by 365 nm light) observed from QPA in the absence and
presence of Zn2+ (10 equiv.); (b) fluorescence intensity at 500 nm of QPA
(10 mM) in 25% ACN-HEPES buffer (100 mM, pH = 7.0) as a function
of concentration of free Zn2+ and the probe.
Fig. 4 Job’s plot by fluorescence method of the complex between QPA
and Zn2+ in 25% ACN-HEPES (100 mM, pH = 7.0). Total concentration
of QPA and Zn2+ is 50 mM.
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Fig. 5 Fluorescence intensity at 500 nm of QPA (10 mM) in 25% ACN-
HEPES (100 mM) with (red) and without (black) addition of Zn2+ (10
equiv.) as a function of pH.
observed. Therefore, subsequent metal binding studies were
carried out in HEPES buffer solution at pH = 7.0.
We also investigated the time course of QPA to different
equivalents of Zn2+ in 25% ACN-HEPES buffer (20 mM, pH =
7.0) (Fig. S4, ESI{). We found that the fluorescence of the probe
became steady within 1 min after addition of Zn2+. Therefore,
this system could be used to detect Zn2+ in real-time.
The selectivity of QPA to various metal ions was examined
systematically. Among the 14 metal ions being studied, upon
excitation at 330 nm, only Zn2+ induced a dramatic fluorescence
enhancement of QPA. On the other hand, Cd2+ and Fe2+
induced a slight enhancement of the probe, and Cu2+ quenched
the fluorescence completely because of its paramagnetic property
(Fig. 6a). When 10 equiv. of these competing metal ions were
added to a mixture of QPA with 10 equiv. of Zn2+, only Fe3+,
Hg2+ and Co2+ can quench the fluorescence to a small extent and
Fig. 6 (a) Fluorescence spectra of QPA (10 mM) in 25% ACN-HEPES
(100 mM, pH = 7.0) upon addition of various metal ions; (b) The
fluorescence response of QPA (10 mM) in 25% ACN-HEPES (100 mM,
pH = 7.0) in the absence (black bars) and presence (red bars) of Zn2+ (10
equiv.) upon addition of various metal ions (0.1 mM of Cd2+, Fe2+, Fe3+,
Cu2+, Co2+, Ni2+, Pb2+, Hg2+, Ag+, Li+, Mg2+, and 5 mM of Na+, Ca2+,
K+). The response is normalized to the integrated fluorescence intensity
of free dye (F0).
RSC Adv., 2012, 2, 11078–11083 | 11081
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Cu2+ quenched completely the fluorescence (Fig. 6b).

Furthermore, to establish the reversibility binding of Zn2+ by
QPA, the fluorescence enhancement of the probe at 500 nm
triggered by 10 equiv. of Zn2+ can be completely switched-off by
the addition of 10 equiv. of EDTA. The same extent of
fluorescence enhancement can be recovered when an additional
10 equiv. of Zn2+ was introduced and this complexation/
decomplexation cycle can be repeated 5 times (Fig. S5, ESI{).
These results show that QPA is suitable to be used as a reversible Fig. 8 Proposed binding mechanism of QPA and Zn2+.
fluorescent chemosensor to detect Zn2+.
The binding mode of the complex was studied by MALDI- this is the first 8-aminoquinoline based Zn2+ sensor which did
TOF HRMS and 1H NMR spectroscopic method. When the not involve quinoline nitrogen atom as a ligating group.
complex was subjected to mass spectral measurement, a clear Therefore, a binding mode between QPA and Zn2+ is proposed
peak of m/z 450.0459 corresponding to [QPA+Zn2+-H+]+ was (Fig. 8).
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observed (Fig. S7, ESI{). However, attempts to prepare a single

A preliminary study on the Zn2+-sensing behaviors of QPA in
crystal of QPA-Zn2+ complex were unsuccessful.
the biological system was carried out by fluorescence microscopy
To evaluate the binding mode of QPA-Zn2+ complex, detailed
1
using HK-1 cells40 as model cells. The results show that QPA-
H NMR titration was carried out (Fig. 7). Upon gradual
stained HK-1 cells exhibited good fluorescence responses for
addition of Zn2+ to the ACN-d3 solution of QPA, with the
Zn2+. After incubation with QPA at 37 uC for 1 hour, the cells
addition of 0.5 equiv. of Zn2+, a large upfield shift of H7 (Dd =
displayed very weak fluorescence (Fig. 9a). Presumably, the
0.64) and H6 (Dd = 0.24), ascribed to the amide proton and the
native Zn2+ concentration in the cell is too low to turn on the
ortho- aromatic proton to the carboxamido group in the
probe. When exogenous Zn2+ is introduced by incubation with
quinoline ring, respectively, was observed. At the same time,
5 mM Zn(ClO4)2/pyrithione (1 : 1), the cells displayed bright
H1 (Dd = 0.06) and H3 (Dd = 0.06), which are ascribed to the
green fluorescence (Fig. 9b). This fluorescence signal can be
ortho- and para-aromatic protons to the quinoline nitrogen,
quenched by subsequent incubation with cell permeable chelator
showed negligible downfield shift. These results confirm that
TPEN (Fig. 9c). Being a strong Zn2+ chleator, TPEN can remove
Zn2+ coordinates to the nitrogen atom of the carboxamido group
Zn2+ completely from its binding to QPA. This finding indicates
and seemingly has no interaction with the nitrogen atom of
that the fluorescence emission is a result of reversible Zn binding
quinoline moiety. Also, a large downfield shift of NCH3 (Dd =
to QPA in the cell environment.
0.38), CLCCH3 (Dd = 0.16) and H8 (Dd = 0.26) adjacent to the
carboxamido group were also observed. These observations
suggest that the metal ion has strong coordination with nitrogen Conclusions
atom in NCH3 and oxygen of carbonyl in the antipyrine By tethering 4-aminoantipyrine moiety onto the molecular
moiety.39 In contrast to other 8-aminoquinoline based Zn2+ platform comprising 8-aminoquinoline as the fluorescent signal
sensors which coordinate with nitrogen atom in quinoline display unit, a highly selective and sensitive fluorescent Zn2+
moiety,23–28,30–35 the contribution of strong ligating groups by sensor, QPA, was designed and constructed. Under physiological
the antipyrine moiety of QPA deprived of the metal binding
affinity of the quinoline nitrogen atom. To our best knowledge,

Fig. 7 Partial 1H NMR spectra (400 MHz) of QPA (20 mM) in ACN- Fig. 9 HK-1 cells were incubated with QPA (10 mM) (a), followed by
d3. (a) Free QPA; (b) QPA + 0.1 equiv. of Zn2+; (c) QPA + 0.3 equiv. of 5 mM Zn(ClO4)2/pyrithione (1 : 1) (b), followed by further incubation
Zn2+; (d) QPA + 0.5 equiv. of Zn2+; (e) QPA + 0.8 equiv. of Zn2+; (f) with TPEN (20 mM) (c). Green dots represent the fluorescence from zinc
QPA + 1.0 equiv. of Zn2+. ions interacting with the QPA. Scale bar: 20 mm.

11082 | RSC Adv., 2012, 2, 11078–11083 This journal is ß The Royal Society of Chemistry 2012
 View Article Online

pH conditions, in vitro detection of Zn2+ at subnanomolar
concentrations can be achieved in aqueous ACN solution. The
binding mode of the metal complex was established by combined
UV-vis, fluorescence and 1H NMR spectroscopic method.
Moreover, QPA can be used as an imaging reagent of Zn2+ in
living cells.
Acknowledgements
The work was supported by a grant from the Research
Committee of Hong Kong Baptist University (FRG2/11-12/121).
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