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

X-ray intensity data were measured at room temperature (298 K) were observed under the confocal microscope (Olympus
on a Bruker AXS Kappa ApexII Duo diffractometer using FV1000). QPA was excited at 405 nm with a diode laser and
frames of oscillation range 0.3u, with 2u , h , 28u. The pH the emitted fluorescent signals at 500–600 nm were collected.
measurements were performed on a Orion 420A pH mV Images were processed and analyzed using the FV10-ASW
temperature meter with a combined glass-calomel electrode. software (Olympus).
Double-distilled water was used throughout. The excitation
wavelength was 330 nm. Single-crystal structure determination
All regents for synthesis were obtained commercially and were
X-ray intensity data were measured at room temperature (298 K)
used without further purification. Solvents such as dimethylfor-
on a Bruker AXS Kappa ApexII Duo diffractometer using frames
mamide (DMF), acetonitrile (ACN) and tetrahydrofuran (THF)
of oscillation range 0.3u, with 2u , h , 28u. The structures were
were purchased from commercial sources and were the highest
solved by the direct method and refined by full-matrix least-
grade, dry dichloromethane (DCM) was distilled in calcium
squares on F2 using the SHELXTL program package.
hydride. Silica gel (200–300 mesh, MACHEREY-NAGEL
GmbH & Co. KG) was used for column chromatography.
Synthesis
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Analytical thin-layer chromatography was performed using TLC

silica gel 60 F254 (aluminium sheets, Merck KGaA). In titration 2-bromo-N-(quinolin-8-yl)acetamide (1). 8-Aminoquinoline (0.5
experiments, all the cations in the form of perchlorate or chloride g, 3.46 mmol) was dissolved in dry dichloromethane (20 mL) and
and other substrates were purchased from Sigma-Aldrich, USA, triethylamine (0.35 g, 3.46 mmol) was added into this solution.
and stored in a vacuum desiccator. After the mixture was stirred at 0 uC for 10 min, bromoacetyl
bromide (0.84 g, 4.16 mmol) was introduced dropwise to the
Sample preparation stirred solution over a period of 20 min. The reaction mixture was
The probe was dissolved in ACN as a stock solution (1 mM). then stirred at room temperature for 3 hours. After removal of
Buffer solution was prepared by dissolving HEPES in water (100 solvent, the crude product was purified by column chromato-
mM). Slight variations in the pH of the solution were achieved graphy on silica gel (petroleum ether : ethyl acetate = 6 : 1) as the
by adding the minimum volumes of NaOH or HCl. 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 =
Absorption and fluorescence analysis 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);
Absorption spectra and fluorescence emission spectra were 13
C-NMR(100 MHz, CDCl3): 164.0, 148.6, 138.7, 136.3, 133.8,
obtained with 1.0 cm quartz cells. The detection procedures 127.9, 127.2, 122.5, 121.8, 116.6, 29.7. HRMS(ESI): m/z calcd for
were as follows: in 25% ACN-HEPES (100 mM, pH = 7.0) buffer C11H10N2OBr: [M + H+] 264.9976, found: 264.9957.
solution containing 10 mM QPA, a Zn2+ sample was gradually
titrated into the solution, the mixture was equilibrated for 2 min N-(quinolin-8-yl)-2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-
before measurement. The fluorescence intensity was measured 1H-pyrazol-4-yl-amino)-acetamide (QPA). A mixture of
simultaneously at lex/em = 330/550 nm. The excitation and 2-bromo-N-(quinolin-8-yl)acetamide (0.265 g, 1.0 mmol), 4-ami-
emission slits were set to 5.0 nm and 5.0 nm, respectively. 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
Cell culture reaction mixture was poured into 30 mL of water, the aqueous
Human nasopharyngeal carcinoma cells (HK-1) were cultured in phase was extracted with ethyl acetate (3 6 30 mL), the organic
RPMI 1640 (Gibco) supplemented with 10% FBS (Gibco) and phases were combined and washed with H2O (2 6 20 mL) and
antibiotics (penicillin 50 U/mL; streptomycin 50 mg/ml). The cells brine (20 mL) successively, and dried over Na2SO4. After
were incubated at 37 uC in a humidified CO2 (5%) incubator. removal of solvent, the crude product was purified by column
chromatography on silica gel (petroleum ether : ethyl acetate =
Confocal fluorescence imaging 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
HK-1 cells (1 6 105 cells) were grown onto a glass coverslip in (1H, br. s), 8.88 (1H, dd, J = 4.2 Hz, J = 1.6 Hz), 8.82 (1H, dd, J
35 mm culture dish overnight. The Zinc sensor QPA and the zinc = 7.4 Hz, J = 1.5 Hz), 8.33 (1H, dd, J = 8.3 Hz, J = 1.6 Hz), 7.67–
chelator N,N,N9,N9-tetrakis(2-pyridylmethyl)ethylene diamine 7.56 (4H, m), 7.51–7.43 (4H, m), 7.33–7.28 (1H, m), 3.98 (2H, s),
(TPEN) were dissolved in DMSO while the zinc perchlorate 3.75 (1H, br. s), 2.90 (3H, s), 2.29 (3H, s); 13C-NMR (100 MHz,
and the zinc carrier pyrithione were dissolved in H2O. All CDCl3): 170.30, 162.53, 148.52, 142.65, 138.91, 136.21, 135.16,
compounds were prepared at a stock concentration of 10 mM 134.15, 129.14, 128.06, 127.32, 126.21, 123.15, 121.92, 121.63,
and then diluted in culture medium for incubation with cells. The 120.86, 116.67, 52.79, 37.35, 10.73. HRMS(ESI): m/z calcd for
cells were incubated with the zinc sensor QPA (10 mM) for C22H21N5O2: [M+H+] = 388.1773, found: 388.4032, [M+Na+] =
30 min at 37 uC. Additional zinc ions were introduced by 410.1593, found: 410.3490.
incubating the cells with a mixture of zinc perchlorate (5 mM)
and zinc ion carrier pyrithione (5 mM) for 15 min at room
Results and discussion
temperature. In order to remove the zinc ion, the cells were
further incubated with the zinc chelator TPEN (20 mM) for Fluorescent Zn2+ sensors bearing 2-amino-N-(quinolin-8-yl)ace-
15 min at room temperature. The fluorescence images of the cells tamide (AQA) moiety have been reported.22–32,34–35 The

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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. View Article Online

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+
Fig. 3 (a) Fluorescence titration of QPA (10 mM) in 25% ACN-HEPES induced a slight enhancement of the probe, and Cu2+ quenched
(100 mM, pH = 7.0) with addition of Zn2+. Inset: visible emission the fluorescence completely because of its paramagnetic property
(irradiated by 365 nm light) observed from QPA in the absence and (Fig. 6a). When 10 equiv. of these competing metal ions were
presence of Zn2+ (10 equiv.); (b) fluorescence intensity at 500 nm of QPA added to a mixture of QPA with 10 equiv. of Zn2+, only Fe3+,
(10 mM) in 25% ACN-HEPES buffer (100 mM, pH = 7.0) as a function
Hg2+ and Co2+ can quench the fluorescence to a small extent and
of concentration of free Zn2+ and the probe.

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+,
Fig. 4 Job’s plot by fluorescence method of the complex between QPA Cu2+, Co2+, Ni2+, Pb2+, Hg2+, Ag+, Li+, Mg2+, and 5 mM of Na+, Ca2+,
and Zn2+ in 25% ACN-HEPES (100 mM, pH = 7.0). Total concentration K+). The response is normalized to the integrated fluorescence intensity
of QPA and Zn2+ is 50 mM. of free dye (F0).

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 View Article Online

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

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