Quinazoline copper(II) ensemble as turn-on fluorescence sensor for cysteine and chemodosimeter for NO

Article abstract of DOI:10.1016/j.jphotochem.2014.02.015

A fluorescent quinazoline based chemosensor QHYN had been designed and synthesized. It exhibits high sensitivity and selectivity towards Cu ²⁺ over other metal ions in DMSO:H₂O (1:9, v/v) at pH = 7.4 [HEPES buffer] by fluorescence quenching. Addition of nitric oxide to a solution of this QHYN·Cu(II) restores the fluorescence. This is attributed to the reduction of the Cu(II) centre by nitric oxide to diamagnetic Cu(I). The fluorescence response of QHYN·Cu(II) to NO is direct and specific, which is a significant improvement over commercially available small molecule-based chemodosimeter probe that are capable of detecting NO. The QHYN·Cu(II) also acts as an efficient off-on fluorescent sensor for cysteine with high sensitivity.

Full text of DOI:10.1016/j.jphotochem.2014.02.015

Journal of Photochemistry and Photobiology A: Chemistry 281 (2014) 47–52
Contents lists available at ScienceDirect
Journal of Photochemistry and Photobiology A:
Chemistry
journal homepage: www.elsevier.com/locate/jphotochem
Quinazoline copper(II) ensemble as turn-on fluorescence sensor for
cysteine and chemodosimeter for NO
∗
Thangaraj Anand, Gandhi Sivaraman, Duraisamy Chellappa
School of Chemistry, Madurai Kamaraj University, Madurai 625021, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A fluorescent quinazoline based chemosensor QHYN had been designed and synthesized. It exhibits high
sensitivity and selectivity towards Cu over other metal ions in DMSO:H2O (1:9, v/v) at pH = 7.4 [HEPES
Received 17 December 2013
Received in revised form 18 February 2014
Accepted 19 February 2014
Available online 12 March 2014
2+
buffer] by fluorescence quenching. Addition of nitric oxide to a solution of this QHYN·Cu(II) restores the
fluorescence. This is attributed to the reduction of the Cu(II) centre by nitric oxide to diamagnetic Cu(I).
The fluorescence response of QHYN·Cu(II) to NO is direct and specific, which is a significant improvement
over commercially available small molecule-based chemodosimeter probe that are capable of detecting
NO. The QHYN·Cu(II) also acts as an efficient “off–on” fluorescent sensor for cysteine with high sensitivity.
Keywords:
Quinazoline
Copper(II)
Cysteine
©
2014 Elsevier B.V. All rights reserved.
Nitric oxide
Off–On
TD-DFT
1
. Introduction
Many fluorescent probes for copper revealing either fluorescence
On–Off or Off–On types have been developed [13–15].
The development of fluorescent molecules for the photophys-
In recent years, metal analyte bound fluorescent receptor are
being developed as sensors for detection of small molecules like
NO, cysteine [16,17]. Nitric oxide is a neutral molecule with one
unpaired electron, and it is a signal transduction molecule in the
physiological and biological systems. It plays major role in the
cardiovascular system as well as in the central and peripheral ner-
vous systems [18]. Elevated levels of NO production are implicated
with various diseases, while minimum level of NO is necessary
for protecting liver from ischaemia disease [19]. In earlier days,
small-molecule fluorescent probes reported for NO detection such
as o-diaminonaphthalene and o-diaminofluorescein respond only
ical detection of cations [1,2], anions [3], sugars and proteins [4,5]
has attracted considerable attention due to their prime impor-
tance for biological and environmental applications [6]. After zinc
and iron, copper is the significant metal pollutant and also the
third most abundant essential trace element in the human biol-
ogy. Nevertheless copper(II) metabolically requires homeostasis for
its inadequacy results in anaemia, and irregularity in glucose and
cholesterol metabolism [7] while its surplus in the body leads to
Menkes disease, Wilson disease [8,9] and so on. So it is necessary to
observe copper levels in biological systems and in the environment.
Various analytical methods such as photometric methods,
atomic absorption spectroscopy (AAS), inductively coupled plasma
emission or mass spectrometry (ICP-ES, ICP-MS), total reflection X-
ray fluorimetry (TXRF) and anodic stripping voltammetry [10–12]
−
to NO2 , N O , the oxidized products of NO, rather than NO directly
2
3
[20,21]. Transition-metal complexes had been investigated as plat-
forms for NO detection. Number of iron complexes, which can
act as sensors for NO in aqueous medium, exhibit only modest
turn-on emission with NO and these are air sensitive [22]. Nowa-
days the reduction of Cu(II) to Cu(I) by nitric oxide can offer
a good methodology for nitric oxide detection but many of the
reported fluorescence probes for NO involves complicated proce-
dures. Besides they display a decrease in fluorescence after reaction
with NO [23] and are pH-sensitive. In our case the QHYN prepa-
ration is very easy and the method offers excellent yield. The
molecule QHYN is not pH/air sensitive in nature. Of the twenty
amino acids cysteine (Cys), an important and essential amino acid,
plays crucial role in the biological systems because of its thiol group
(
ASV), though provide good detection limit for detection of cop-
per ions, involve high cost instrumentation and tedious procedure.
Among these methods photophysical methods are widely used
due to its high selectivity, simplicity and sensitivity. In addition
the photophysical methods make feasible bio-imaging of analytes.
∗ Corresponding author. Tel.: +91 452 2456614; fax: +91 452 2459181.
E-mail address: dcmku123@gmail.com (D. Chellappa).
http://dx.doi.org/10.1016/j.jphotochem.2014.02.015
1
010-6030/© 2014 Elsevier B.V. All rights reserved.

4
8
T. Anand et al. / Journal of Photochemistry and Photobiology A: Chemistry 281 (2014) 47–52
Scheme 1. Synthesis of probe (QHYN).
[
24,25]. In addition Cys is a building block of proteins and key
absorbance at the excitation wavelength, S refers to the integrated
emission band areas and nD is the solvent refractive index.
factor in enzyme reaction. It can also be used as radio-protective
agent, cancer indicator and connected to Alzheimer, Parkinson and
autoimmune syndrome, etc. [26,27]. Hence the quantitative detec-
tion of NO/cysteine is of immense value.
SS Ar n2
DS
˚S = ˚r SR AS
2
n
Dr
In continuation of our ongoing research for the development of
fluorescent chemosensors [28–30] here in we report simple rapid
and easily synthesizable QHYN Schiff base derivative [31] as a fluo-
3
. Results and discussion
rescent probe for Cu ions. Subsequent investigation of Cu2+ bound
QHYN reveals its capability to sense NO as well as cysteine inde-
pendently. To the best of our knowledge this is the simple molecule
based fluorescent sensor that allows the detection of both nitric
oxide (NO) and cysteine (Cys) independently.
2+
The receptor QHYN was synthesized by reported procedure
(Scheme 1). Initially the binding behaviour of QHYN towards dif-
2+
3+
2+
ferent biologically relevant metal cations such as Co , Fe , Ni
,
2+
2+
2+
2+
+
2+
3+
2+
3+
+
+
Mn , Zn , Cd , Hg , Ag , Ba , Al , Ca , Cr , K and Na using
their chloride salts was carried out by using UV–vis absorption
method as illustrated in (Fig. 1). The QHYN shows three absorp-
2
. Materials and methods
-Aminobenzohydrazide, 2-hydroxy-1-naphthaldehyde and
tion bands at 246, 278, 324 nm in DMSO:H O (1:9, v/v) at pH = 7.4
2
[
HEPES buffer]. During the addition of Cu(II) ions to the solution of
2
QHYN the absorbance of QHYN at 246 nm increased gradually and
the peak at 328 nm decreased. Moreover a new absorption band
at 397 nm emerged gradually along with the addition of increased
amounts of copper(II) ions, accompanied by a clear colour change
from yellow to green (Fig. 2); interestingly there is no significant
colour change nor any spectral change of QHYN upon addition of
amino acids were purchased from Sigma–Aldrich. Carbon disul-
phide and metal chloride salts were obtained from Merck. All the
solvents were of analytical grade. UV–vis spectra were recorded
on a JASCO V-550 spectrophotometer, fluorescence analysis were
done by using JASCO spectrofluorimeter. Cyclic voltammograms
were recorded in Bio-Analytical system (BAS-model-CV-50W) elec-
trochemical analyser consisting of an Ag/AgCl reference electrode,
a platinum wire as counter electrode, and a platinum working
electrode. The supporting electrolyte was 0.5 M (Bu N) (PF ) in
4
6
CH CN. IR spectra in solutions were recorded using JASCO FT-IR
3
Spectrophotometer. Electro spray ionization mass spectral stud-
ies were carried out by using LCQ fleet thermo fisher instruments
limited, US. Electron spin resonance recorded from a Jeol model FA
3
00. ESR was recorded on a JEOL FA-300 spectrophotometer with
X-band micro web unit.
2.1. Quantum yield calculation procedure
The recognition properties of QHYN towards cations were
investigated in DMSO/H O (1:9, v/v) system through UV–vis
2
and fluorescence measurements. The solutions of metal ions
−
3
(
1 × 10 mol/L) were prepared in distilled water. A solution of
−5
QHYN (1 × 10 mol/L) was made up with DMSO/H O solvent.
2
Different ion solutions were added in portions to QHYN and
absorption/fluorescent intensity changes were recorded at room
temperature after each addition. The fluorescence quantum yield
˚S was estimated from the absorption and fluorescence spectra of
probe according to the equation, where the subscript s and r stand
2
+
Fig. 1. UV–vis spectra of probe QHYN upon addition of Cu ion and other transition
for the sample and reference (quininine sulphate in 0.1 M H SO ,
2+
3+
2+
2+
2+
2+
2+
+
2+
3+
2+
3+
2
4
metal ions such as Co , Fe , Ni , Mn , Zn , Cd , Hg , Ag , Ba , Al , Ca , Cr ,
+
+
˚f = 0.54), respectively. ˚ is the quantum yields, A represent the
K and Na (0–1 equiv.) in DMSO:H2O (1:9, v/v) at pH = 7.4 [HEPES buffer].

T. Anand et al. / Journal of Photochemistry and Photobiology A: Chemistry 281 (2014) 47–52
49
Fig. 2. UV–vis spectra of probe QHYN upon addition of Cu2+ ion (0–1 equiv.) in
DMSO:H2O (1:9, v/v) at pH = 7.4 [HEPES buffer].
Fig. 4. Fluorescence emission spectra of QHYN (10 ␮m) upon addition of Cu2+
ion (0–1 equiv.) in DMSO:H2O (1:9, v/v) at pH = 7.4 [HEPES buffer] (ꢀex = 325 nm,
ꢀ
em = 434, 494 nm, (slit: 5 nm/5 nm).
other metal ions. Hence the receptor QHYN is a selective and sen-
sitive sensor probe for copper (II) ions.
2+
3+
miscellaneous metal ions. The other metal ions such as Co , Fe
,
The fluorescence spectra of QHYN in DMSO:H O (1:9, v/v) at
Ni , Mn , Zn , Cd , Hg , Ag , Ba , Al , Ca , Cr , K and Na+
exhibit almost no fluorescence quenching under the same condi-
tion (Fig. S4). Hence it is obvious that the receptor QHYN is highly
selective fluorescent sensor for Cu ions. To investigate the influ-
ence of various metal ions the experiment was carried out by adding
equivalent of copper(II) to the solution of QHYN in the presence
of one equivalence of other metal ions. The result shows there is no
significant change in the fluorescence quenching compared with
2+
2+
2+
2+
2+
+
2+
3+
2+
3+
+
2
pH = 7.4 [HEPES buffer] exhibited a strong green emission band at
4
34 and 494 nm with the quantum yield value being 0.48, when
excited at 325 nm. The fluorescence of QHYN is almost completely
2+
quenched with the addition of Cu2+ ions. No obvious changes in
2
+
3+
2+
emission spectra were observed upon addition of Co , Fe , Ni
,
1
Mn , Zn , Cd , Hg , Ag , Ba , Al , Ca , Cr3+, K+ and Na+
2+
2+
2+
2+
+
2+
3+
2+
ions (Fig. 3). The green fluorescent QHYN when titrated with the
2+
addition of increasing concentration of Cu undergoes a gradual
decrease in the emission bands at 434 and 494 nm. The fluorescence
of QHYN was completely quenched after 1 equivalent addition of
copper ions (Fig. 4). These results summarize the formation of well-
2+
that observed by the addition of Cu alone to the probe QHYN
2+
solution (Fig. S5). So it exhibits excellent selectivity for Cu over
other cations. Further to confirm the paramagnetic nature of cop-
per (II) and geometry of complex, we have recorded EPR spectra at
liquid nitrogen temperature (Fig. 5).
2+
defined complex between receptor QHYN and Cu ions.
The selectivity of QHYN towards Cu2+ was examined by the flu-
orescence titration experiments of QHYN with biologically relevant
The QHYN·Cu (II) exhibited the characteristic four line pattern of
2+
Cu with the g|| = 2.212, g⊥ = 1.998 and A|| = 197.2. g|| > g⊥ indicates
2
2
Cu(II) complex is had unpaired electron in the dx –y orbital. The
g||/A|| value of 112 cm is consistent with the square planar geom-
etry [32,33]. The electrochemical behaviour of copper complex
2+
Fig. 3. Fluorescence emission spectra of QHYN upon addition of Cu ion and other
2
+
3+
2+
2+
2+
2+
2+
+
2+
3+
transition metal ions such as Co , Fe , Ni , Mn , Zn , Cd , Hg , Ag , Ba , Al
,
2+
3+
+
+
Ca , Cr , K and Na (0–1 equiv.) in DMSO:H2O (1:9, v/v) at pH = 7.4 [HEPES buffer]
ꢀex = 325 nm, ꢀem = 434, 494 nm, slit: 5 nm/5 nm).
(
Fig. 5. EPR spectra of QHYN with the addition of Cu2+
.

5
0
T. Anand et al. / Journal of Photochemistry and Photobiology A: Chemistry 281 (2014) 47–52
Fig. 7. The photoluminescence spectra of QHYN + Cu2+ (125 ␮M) DMSO:H2O (1:9,
v/v) at pH = 7.4 [HEPES buffer] in the presence of increasing concentration of Nitric
oxide (0–100 ␮M). (ꢀex = 325 nm, ꢀem = 434, 494 nm, slit: 5 nm/5 nm).
Fig. 6. Fluorescence intensity of a solution of QHYN (5 ␮M) with different concen-
trations of Cu2+ at ꢀem = 434 nm.
was studied in acetonitrile solvent. Cyclic voltammetric studies
revealed reduction potential of 340 mV for Cu(II)/Cu(I) couple with
−
OH , t-BuOOH and O was added and fluorescence monitored. No
2-
+
detectable fluorescence responses appeared, whereas the fluores-
cence intensity increased only when treated with NO solution (Fig.
S12).
respect to Ag/Ag reference electrode (Fig. S6).
The stoichiometry of the complex between QHYN and Cu2+
is found to be 1:1 by using jobs plot method (Fig. S7). It was
further confirmed by ESI-MS wherein the molecular ion peak
2+
+
at m/z = 429 corresponds to (QHYN-2H + Cu + H) (Fig. S8). The
fluorimetric titration profile shows a steady quenching of green
3
.2. Detection of cysteine (Cys)
2+
fluorescence with increase in concentration of Cu (Fig. 6). The
association constant [34] and the detection limit [35] were found
From the above studies it could be concluded that the displace-
5
−1
to be 5.91 × 10 M , 20.0 nM respectively.
2+
ment of Cu(II) from the ensemble QHYN + Cu would restore the
emission property of receptor [41]. To investigate the ability of
ensemble QHYN + Cu2+ as sensor for amino acids, the fluorescence
changes of solution were analyzed with various amino acids. Emis-
sion was changed only with the addition of Cys, whereas other
amino acids produce negligible changes in the fluorescence spectra.
To further explore the selectivity for cysteine, fluorescence experi-
ments were carried out with solution of ensemble (125 ␮M) in the
presence of other amino acids such as Ala, Thr, Ser, Gly, Glu, Arg,
Val, Trp, Lys, Pro, Ile, Leu, Asp, Met, Tyr, Phe, His, and GSH (500 ␮M)
3.1. Nitric oxide detection (NO)
The emission spectra of QHYN showed typical green fluores-
cence at 434 and 494 nm. When 100 ␮M of Cu2+ was added to the
buffer solution of receptor QHYN (25 ␮M), the fluorescence was
drastically quenched. This could be attributed to the paramagnetic
nature of Cu(II). On the other hand addition of NO (50 ␮M) to the
2+
Cu bound QHYN ensemble solution was found to restore the
emission intensity [36,37]. On the basis of fluorescence titration
the fluorescence intensity was found to be steadily increasing with
increasing concentration of NO (Fig. 7). Upon interaction of nitric
(Fig. S13). The fluorescence results show no obvious changes in
the emission spectra even under higher concentration (Fig. S14).
Subsequent addition of cysteine (Cys) (50 ␮M) restored the flu-
orescence (Fig. 8). The change in the position and shapes of the
cathodic and anodic peaks of the ensemble QHYN + Cu with the
addition of cysteine displays the change in the environment around
copper centre (Fig. S15). Yu et al. reports the same observation in
the presence of amino acid in copper ensemble [42]. It suggests
the cysteine coordinates to the copper. Obviously these results
show that the QHYN + Cu2+ were working as a selective and sen-
sitive detector of cysteine. To find the binding constant, first Cu2+
2
+
2+
oxide to the QHYN + Cu ensemble, Cu is reduced to Cu(I) with
2
+
+
concomitant conversion of NO to NO ion. The complete reduc-
tion of Cu to Cu was evident from the EPR silent nature [38] of
2
+
+
2
+
the QHYN + Cu ensemble after treatment with NO (Fig. S9). This
resembles the earlier report of Lippardetal.[39] In the cyclic voltam-
metric studies, both cathodic and anodic peaks, present initially
in the QHYN + Cu ensemble, disappeared with nitric oxide addi-
tion (Fig. S10). This further substantiates that Cu(II) is completely
reduced to Cu(I). Probably the affinity of Cu(I) towards the ligand
QHYN ion is lesser than those of Cu(II) and the complex dissocia-
2
+
(100 mM) was added to QHYN (25 mM) to effect, complete fluores-
2+
cence quenching. Then to the QHYN + Cu ensembles cysteine was
gradually added to perform fluorescence titration (Fig. S16). From
−
1
tes. The observation of a new peak at 1373 cm in the IR spectra
40] of ensemble after the addition of NO solution clearly shows
4
−2
the titration association constant was calculated as 1.54 × 10 M
[
−
7
and the detection limit was found to be 5.41 × 10 M. Job’s plot
constructed from fluorescence titration data suggest 2:1 bind-
ing between Cys and Cu2+. It was further supported by ESI-MS
wherein the molecular ion peak at m/z = 327 corresponds to (2Cys-
2H + Cu2+) + Na (Figs. S17 and S18).
that the NO was incorporated in the freed probe QHYN. Hence it
is obvious that this sensor has the potential of being a fluores-
cent chemodosimeter for NO (Fig. S11). To check the selectivity and
chemodosimetric response of the probe, 100 equiv. of reactive oxy-
−
−
−
−
gen and nitrogen species such as ClO , NO2 , NO3 , H O , ONOO ,
2
2

T. Anand et al. / Journal of Photochemistry and Photobiology A: Chemistry 281 (2014) 47–52
51
Acknowledgements
T.A, G.S. thanks DST-PURSE and UGC for research fellowship
respectively. T.A., G.S. and D.C. also acknowledge DST-IRHPA, FIST
and PURSE for funding and instrumental facilities. We thank Prof.
S. Krishnaswamy, School of Biotechnology, for providing access to
the spectrofluorimeter facility.
Appendix A. Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.jphotochem.
2
014.02.015.
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