A Schiff base fluorescence probe for highly selective turn-on recognition of Zn2+

Article abstract of DOI:10.1016/j.tetlet.2016.12.041

A simple Schiff base CTS, synthesized between 2-hydroxy-1-naphthaldehyde and 2-benzylthio-ethanamine, was found to be a good turn-on fluorescence probe for the detection of Zn²⁺, due to the restriction of the rotation of the bond between C[dbnd]N and naphthalene ring and/or the blocking of the photo-induced electron transfer (PET) mechanism of the nitrogen atom to naphthalene ring. Excellent selectivity for Zn²⁺was evidenced, over many other competing ions, including Fe³⁺, Cr³⁺, Ni²⁺, Co²⁺, Fe²⁺,Mn²⁺, Ca²⁺, Hg²⁺, Pb²⁺, Cu²⁺, Mg²⁺, Ba²⁺, Cd²⁺, Ag⁺, Li⁺, K⁺, and Na⁺, in EtOH/HEPES buffer (95:5, v/v, pH?=?7.4). It was noteworthy that Cd²⁺had no interference with Zn²⁺. The stoichiometric complex of CTS-Zn²⁺was determined to be 2:1 for CTS and Zn²⁺in molar, based on the Job plot and single crystal X-ray diffraction data. The binding constant of the complex was 85.7?M^?2with a detection limit of 5.03?×?10^?7?M. The fluorescence bio-imaging capability of CTS to detect Zn²⁺in live cells was also studied. These results indicated that CTS could serve as a favorable probe for Zn²⁺.

Full text of DOI:10.1016/j.tetlet.2016.12.041

Accepted Manuscript
A Schiff base fluorescence probe for highly selective turn-on recognition of
2
Zn
+
Jinli Zhu, Yuhuan Zhang, Yihan Chen, Tongming Sun, Yanfeng Tang, Yang
Huang, Qingqing Yang, Danyang Ma, Yipu Wang, Miao Wang
PII:
S0040-4039(16)31684-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.12.041
TETL 48453
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
10 November 2016
13 December 2016
16 December 2016
Please cite this article as: Zhu, J., Zhang, Y., Chen, Y., Sun, T., Tang, Y., Huang, Y., Yang, Q., Ma, D., Wang, Y.,
2
Wang, M., A Schiff base fluorescence probe for highly selective turn-on recognition of Zn , Tetrahedron Letters
+
(
2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.12.041
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2
+
A Schiff base fluorescence probe for highly selective turn-on recognition of Zn
a
b
a
a
a,*
b
Jinli Zhu , Yuhuan Zhang , Yihan Chen , Tongming Sun , Yanfeng Tang , Yang Huang ,
a
a
a
a,
Qingqing Yang , Danyang Ma , Yipu Wang and Miao Wang
a. School of Chemistry and Chemical Engineering, Nantong University, Nantong 226019, P.R.
China
b. School of Textiles, Nantong University, Nantong 226019, P.R. China
Abstract: A simple Schiff base CTS, synthesized between 2-hydroxy-1-naphthaldehyde and
2
-benzylthio-ethanamine, was found to be a good turn-on fluorescence probe for the detection
2+
of Zn , due to the restriction of the rotation of the bond between C=N and naphthalene ring
and/or the blocking of the photo-induced electron transfer (PET) mechanism of the nitrogen
2
+
atom to naphthalene ring. Excellent selectivity for Zn was evidenced, over many other
3
+
3+
2+
2+
2+
2+
2+
2+
2+
2+
2+
2+
competing ions, including Fe , Cr , Ni , Co , Fe ,Mn , Ca , Hg , Pb , Cu , Mg , Ba ,
2
+
+
+
+
+
Cd , Ag , Li , K , and Na , in EtOH/HEPES buffer (95:5, v/v, pH = 7.4). It was noteworthy
2+
2+
2+
that Cd had no interference with Zn . The stoichiometric complex of CTS-Zn was
2+
determined to be 2:1 for CTS and Zn in molar, based on the Job plot and single crystal X-
-2
ray diffraction data. The binding constant of the complex was 85.7 M with a detection limit
-7
2+
of 5.03×10 M. The fluorescence bio-imaging capability of CTS to detect Zn in live cells
was also studied. These results indicated that CTS could serve as a favorable probe for Zn .
2+
2+
Keywords: Zn detection, Schiff base, turn-on fluorescence, live cells
Introduction
Currently, a number of metal ions have been verified to be crucial in living organisms,
1
-4
playing irreplaceable roles in a variety of physiological and biochemical processes.
2
+
Among them, Zn , the second most abundant metal ion in the human body, likewise
participates in many biochemical and physiological processes such as: metabolism of
5
6
7
8
DNA, gene expression, signal transduction, immune function, etc. Modern medical
2
+
research shows that the imbalance of Zn in human bodies can result in numerous
9
10
11
serious diseases, including diabetes types I and II, neural dysfunction, Alzheimer,

Corresponding author
1

1
2
and even certain cancers. Therefore, a method to sensitively and selectively detect
2
+
Zn is of great importance, not only in living systems, but also in environmental
waters. Consequently, several detection methods, including atomic absorption
1
3
14
15
spectrometry (AAS),
atomic emission spectrometry (AES),
voltammetry,
16
17-19
electrochemical method, and fluorescent sensors,
have been developed. Among
2
+
these various methods, fluorescence chemosensors that detect Zn have attracted
enormous interest because of their high sensitivity, good selectivity, simplicity and
2
+
quick-response abilities. To date, most reported fluorescence chemosensors for Zn
2
0-22
23,24
25,26
detection have been designed based on quinolone,
anthracene,
They exhibited good performance for
the detection of Zn . However, some of them require a complicated synthesis
coumarin,
2
7,28
29,30
BODIPY,
and fluorescein fluorophores.
2
+
2
+
2+
protocol. Most of them suffer from the interference of Cd with Zn . In this regard,
developing an easily prepared, highly sensitive, and excellently selective fluorescence
2
+
sensor for recognizing Zn still remains a challenge.
Taking this into account, Sinha et al., synthesized a series of cysteamine-based
2
+
31
fluorescence sensors for Zn in pure DMF. In this study, a sensor synthesized
between 2-hydroxy-1-naphthaldehyde and 2-benzylthio-ethanamine (Scheme 1) could
2
+
not detect Zn in DMF. However, by coincidence, this compound (abbreviated as
2
+
-7
CTS) was an excellent Zn sensor with a detection limit of 5.03×10 M in
2
+
2+
EtOH/HEPES buffer (95:5, v/v, pH = 7.4), while Cd had no interference with Zn . We
2
+
also obtained a single crystal of the complex of CTS with Zn . Moreover, CTS has
2
+
the potential use of detecting Zn in living cells.
2

o
Scheme 1. Synthesis of CTS. (i) NaH, dioxane, 50 C; (ii) ethanol, reflux.
Results and Discussion
Fig. 1 showed the UV-Vis spectra of CTS in EtOH/HEPES buffer (95: 5, v/v, pH
7
.4). It displayed two weak absorption peaks at 204 nm and 232 nm. Upon the gradual
2
+
addition of Zn , the absorption peak at 204 nm slightly red-shifted to 218 nm with
increasing absorption intensities, and the absorption peak at 232 nm disappeared
gradually. These changes, to some extent, indicated the coordinated interaction
2
+
between Zn and CTS.
Fig. 1. UV-Vis absorption spectra of CTS solution (10 μM, EtOH/HEPES, 95:5, v/v, pH 7.4)
2+
upon the addition of different amounts of Zn (0–25 equivalents).
2
+
To further corroborate the selective complexation of CTS with Zn , the fluorescence
response behavior of CTS to various metal ions was systematically investigated in
3

EtOH/HEPES buffer (95:5, v/v, pH 7.4) (Fig. 2A). Pure CTS solution (10 μM)
exhibited hardly detectable fluorescence emission at 450 nm at excitation of 242 nm.
2
+
Upon the addition of Zn (100 μM), a significant fluorescence enhancement (19 fold)
2
+
at 450 nm was observed, demonstrating a Zn -selective “off-on” fluorescent
signaling behavior of CTS. This enhancement directly indicated that the complex of
2
+
CTS with Zn was formed. As expected, there was no obvious change in the
fluorescence intensity after adding other metal ions to the CTS solution, including
3
+
3+
2+
2+
2+
2+
2+
2+
3+
2+
2+
2+
2+
2+
+
Fe , Cr , Mn , Hg , Pb , Cu , Ba , Cd , Al , Ni , Co , Fe , Ca , Mg , Ag ,
+
+
+
Li , K , and Na (100 μM) (Fig. S5). To further display that the selectivity was not
affected by the metal ions concentrations, the fluorescence intensities of CTS added
with these metal ions at different concentrations were investigated (Fig. S6). It was
clearly seen that the fluorescence intensities of CTS were only sensitive to the
2
+
2+
concentration of Zn . It is worth mentioning that there was no interference of Cd
2
+
with Zn . Among these CTS solutions excited at 254 nm after addition of the certain
2
+
metal ion, only the solution containing Zn exhibited a noticeable color change from
green to fluorescent blue, which was easily observed by the naked-eye (Fig. S7). In
addition, the fluorescence intensity of CTS at different concentrations were
investigated. As shown in Fig. S8, the fluorescence intensity of CTS decreased with
increasing of its concentration, suggesting that CTS has the aggregation-caused
3
2-33
quenching (ACQ) property
. The higher concentration of CTS used, the higher
times of fluorescence enhancement in the presence of given was observed (Fig. 2B).
2
+
This result indicated that the binding of Zn to CTS could induce the disaggregation
of CTS to further produce turn-on fluorescence response. Compared with DMF in
2
+
which CTS shows no response to Zn , the EtOH/HEPES buffer is an ideal sensing
2
+
2+
condition for Zn . The binding of CTS with Zn formed a rigid framework
4

inhibiting the rotation of the bond between C=N group and naphthalene ring. And at
the same time the photoinduced electron transfer (PET) process was blocked and CTS
2
+
was disaggregated after complexation of N with Zn . These cooperative interactions
are presumed to trigger the turn-on fluorescence response. These three main reasons
3
4-35
could be employed to explain this fluorescence enhancement (Scheme 2).
Fig. 2. (A) Fluorescence spectra of CTS (10 μM) upon the addition of various metal ions (100
μM) in EtOH/HEPES buffer (95:5, v/v, pH 7.4) at 450 nm. λex = 242 nm. (B) The fluorescence
2+
intensity multiple changes of CTS ( 10, 30, 50 μM) versus the concentrations of Zn ( 5, 10, 20,
0, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150 μM ) in EtOH/HEPES buffer (95:5, v/v,
pH 7.4) with the excitation at 242 nm and the emission at 450 nm. I stands for the fluorescence
3
2+
intensity of CTS solution sample (10，30，50 μM) upon addition of different amount of Zn ( 5,
0
10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150 μM ) ; I stands for the
2
+
fluorescence intensity of pure CTS (10, 30, 50 μM) solution without Zn .
5

2+
Scheme 2. Proposed binding mechanism between CTS and Zn .
The competitive experiments were carried out to further confirm the unique
2
+
selectivity of CTS to Zn . As shown in Fig. 3, it was clear that the fluorescence
2
+
intensities at 450 nm of the CTS-Zn solutions did not significantly change after the
+
2+
2+
2+
3+
+
+
addition of any one of following metal ions: Ag , Ba , Ca , Cd , Cr , K , Li ,
2
+
+
2+
Mg , and Na . Moreover, it was exciting that there were no interferences of Cd and
3
+
2+
2+
Cr with Zn due to the highly selective coordination sites of CTS for Zn . In
2
+
2+
2+
2+
another case, after the addition of other metal ions, such as Mn , Ni , Pb , Fe ,
3
+
2+
3+
2+
2+
Fe , Hg , Al , Co , and Cu , the fluorescence intensities decreased to some
2
+
degree compared to that of the CTS-Zn solution. However, they still displayed
2
+
strong turn-on signals for the recognition of Zn . Therefore, CTS had an excellent
2
+
selectivity for Zn in the presence of other competing metal ions.
6

Fig. 3. Fluorescence intensities of CTS (10 μM) upon addition of various metal ions (100 μM)
2+
3+
+
2+
2+
+
2+
+
2+
+
2+
2+
2+
3+
2+
2+
3+
(
Zn , Al , Ag , Cd , Co , Li , Mn , Na , Pb , K , Ca , Mg , Ba , Cr , Cu , Fe , Fe ,
2+
2+
2+
Hg , Ni ) and that of the respective solution added Zn (100 μM). EtOH/HEPES buffer (95:5,
v/v, pH 7.4), λem=450 nm, λex = 242 nm.
To further understand the detecting properties of CTS, its fluorescence titration was
2
+
carried out by increasing the concentration of Zn . As calculated from the
fluorescence titration spectra shown in Fig. 4A, the fluorescence quantum yield of
2
+
CTS increased from 0.0028 to 0.0595 with increasing Zn concentration. A strong
3
6-38
linear relationship was obtained using the Benesi–Hildebrand analysis
of the
titration profiles based on a 2:1 binding model (Fig. 4D). The binding stoichiometric
2
+
ratio of CTS to Zn was 2:1. The 2:1 binding ratio was also confirmed by Job’s plot
2
+
study (Fig. 5). In addition, this 2:1 composition of CTS-Zn complex was further
corroborated by the single crystal structure (Fig. 6). Based on the linear relationship
2
+
-7
shown in Fig. 4C, the detection limit of CTS for Zn was found to be 5.034×10 M,
2
+
which was low enough to detect a submicromolar concentration of Zn .
7

Fig. 4. (A) Fluorescence emission spectra of CTS (10 μM) upon the addition of different amount
2
+
2+
of Zn . (B) A plot of fluorescence intensity changes versus the concentrations of Zn . (C)
2+
Calculation of detection limit of CTS （10 μM） for Zn （5, 10, 20, 30, 40, 50, 60, 70 μM）.
2+
(
D) Calculation of binding constant between CTS and Zn . I stands for the fluorescence intensity
2
+
of CTS solution sample (10 μM) upon addition of different amount of Zn ; I
0
stands for the
fluorescence intensity of pure CTS solution. All these data were recorded in EtOH/HEPES buffer
(
95:5, v/v, pH 7.4) with the excitation at 242 nm and the emission at 450 nm.
8

2+
Fig. 5. The Job's plot of fluorescence intensity response of CTS to the mole fraction of Zn in
EtOH/HEPES buffer (95:5, v/v, pH = 7.4) , λem=450 nm, λex=242 nm.
2
+
To understand the binding mode of CTS with Zn , an expected coordination
complex was obtained and its structure was shown in Fig. 6. The crystal geometrical
2
+
parameters of the complex CTS-Zn and CTS were listed in the table S1. The single
2
+
crystal structure clearly displayed that one Zn ion coordinated with two nitrogen
atoms and two oxygen atoms of CTS, and it was the tetracoordinated metal centre
possessing a distorted tetrahedral geometry. The bond distances of Zn–N and Zn–O
were in the range of 1.960–1.970 and 1.935-1.945 Å, respectively (table 1). Upon
2
+
complexation, some C–N and C-O bond distances in CTS-Zn changed as shown in
2
+
Table 2. This crystal structure of CTS-Zn strongly confirmed that the stoichiometric
2
+
ratio of CTS to Zn was 2:1, which was consistent with the Job’s plot result.
Furthermore, it also confirmed what was previously speculated, namely the restriction
2
+
of bond rotation by the rigid formation of CTS-Zn and the PET blocking process
2
+
through the coordination of N with Zn after complexation.
9

2+
Fig. 6. Crystal structures of CTS–Zn and CTS. H atoms were omitted for clarity
Table 1 Selected bond lengths (Å) and bond angles (°) for compound CTS around the Zinc (1)
center
Bond length (Å)
Zn(1)-O(1)
Zn(1)-O(1)a
1.940(5)
1.940(5)
Zn(1)-N(1)
Zn(1)-N(1)a
1.965(5)
1.965(5)
Bond angles (°)
O(1)-Zn(1)-N(1)
O(1)-Zn(1)-N(1)a
N(1)-Zn(1)-N(1)a
C(13)-S(1)-C(14)
Zn(1)-N(1)-C(1)
94.6(2)
O(1)-Zn(1)-O(1)a
N(1)-Zn(1)-O(1)a
O(1)a-Zn(1)-N(1)a
Zn(1)-O(1)-C(11)
Zn(1)-N(1)-C(12)
104.7(2)
123.8(2)
94.6(2)
125.0(5)
118.3(4)
123.8(2)
117.3(2)
102.7(5)
124.4(4)
2
+
Table 2 Change in bond lengths for CTS-Zn compared to free CTS
2+
Bond length (Å)
C(12)-N(1)
Free ligand (CTS)
1.458(4)
Complex(CTS-Zn )
1.487(9)
N(1)-C(1)
1.316(3)
1.290(8)
1
0

O(1)-C(11)
1.256(3)
1.294(8)
For a practical application of CTS under physiological conditions, it is necessary to
study its pH-stability. As shown in Fig. 7, no noticeable fluorescence emission of pure
CTS was observed in a wide range of pH values, which suggested that CTS can work
2
+
well under physiological conditions. In the presence of a selective guest like Zn ion,
2
+
the fluorescence intensity of the CTS-Zn was almost constant in the range of pH 6.0
to 10.0, which clearly indicates the compatibility of CTS for biological applications
under physiological conditions (Fig. 7). When pH was below 6, the fluorescence
2
+
intensity of the CTS-Zn decreased due to the combination of N in imidogen group
+
with H .
2+
Fig. 7. The fluorescence intensity response of CTS (10 μM) and CTS with 10 eq of Zn to
different pH values in Ethanol/H O (95:5, V/V), λem=450 nm, λex=242 nm.
2
Before investigating CTS acting as a bio-imaging probe, it was necessary to evaluate
its cytotoxicity. For this purpose, cultured HeLa cells were incubated with different
concentrations of CTS (from 0 to 500 μg/mL) for 24 h. Subsequently, MTT assay was
1
1

3
9-42
carried out according to the reported literature.
Fig. 8A displayed that, even when
treated at a high concentration of CTS at 500 μg/mL, over 85% of cells were alive.
This result indicates that CTS has a low cytotoxicity to cells and is suitable for
intracellular imaging.
Bio-imaging experiments were then performed to study the application of CTS to
2
+
recognize Zn in the Hela cells. As illustrated in Fig. 8B, a barely luminescent signal
2
+
was observed inside the Hela cells only treated with CTS in the absence of Zn .
However, a bright blue fluorescence was observed inside the Hela cells, after
2
+
pretreating with CTS and incubated with Zn (1.0 μM, for 15 min) (Fig. 8C). This
result provided visual evidence that CTS was cell permeable and capable of
2
+
intracellular detection of Zn .
Fig. 8. (A) Cell viability of HeLa cells treated with different concentrations of CTS. Confocal
2
+
fluorescence micrograph of CTS loaded HeLa cells (B) without and (C) with Zn .
Conclusions
1
2

In conclusion, a Schiff base CTS was synthesized between 2-hydroxy-1-
naphthaldehyde and 2-benzylthio-ethanamine, and was found to be a highly selective
2
+
fluorescent sensor for the recognition of Zn even in the presence of many other
metal ions in EtOH/HEPES buffer (95:5, v/v, pH 7.4).This result is different from that
tested in DMF depicted in ref. 31, and the poor performance in DMF may be due to
the N atoms in DMF structure inhibiting the coordination. This fluorescence turn-on
mechanism can be attributed to three main reasons, namely, hindering rotation of
2
+
C=N group, PET, and disaggregation of CTS induced by Zn - binding. Most notably,
2
+
2+
CTS exhibited no interference of Cd to Zn . The composition of the complex
2
+
formed by the coordination of CTS with Zn was determined to be 2:1 by the Job
plot, which was consistent with the analysis of its single crystal structure. The
-7
detection limit of CTS was estimated to be 5.03×10 M based on fluorescence
-2
titration with a binding constant of 85.7 M . Furthermore, biological application of
2
+
CTS was evaluated for the detection of Zn in live cells. The results showed that it
was of low cytotoxicity and excellent cell membrane permeability, and can recognize
2
+
the intracellular Zn .
Acknowledgements
This work was supported by National Natural Science Foundation of China
(
No. 21376124, 21476117, 21501100) and Qing Lan Project 2014. We also
thanked Analysis and Testing Center of Nantong University for their testing
support.
Supporting information
Detailed the experimental methods and characterizations can be found in the
supporting information.
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Graphical Abstract

2
+
1
. A simple Schiff-based fluorescence sensor for Zn , was synthesized.
2
+
2
. This sensor was of good selectivity and sensitivity for Zn , especially without the
2
+
interference of Cd .
3. This sensor can be used in live cells.
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