Phenoxazine-based Near-infrared Fluorescent Probes for the Specific Detection of Copper (II) Ions in Living Cells

Article abstract of DOI:10.1002/asia.202000783

Abstract: It is well known that copper ions play a critical role in various physiological processes. However, a variety of human diseases are tightly correlated with copper overload. Although there are numerous fluorescent probes capable of detecting copper ions, most of them are “turn-off” probes owing to copper (II) ions fluorescence quenching effect, resulting in poor sensitivity. Herein, a novel “turn-on” near-infrared (NIR) fluorescent probe PZ-N based on phenoxazine was designed and synthesized for the selective detection of copper (II) ions (Cu²⁺). Upon the addition of Cu²⁺, the probe could quickly react with Cu²⁺ and emit strong fluorescence, along with colour change from colourless to obvious blue. Moreover, the probe PZ-N showed good water solubility, high selectivity, and excellent sensitivity with low limit of detection (1.93 nM) towards copper (II) ions. More importantly, PZ-N was capable of effectively detecting Cu²⁺ in living cells.

Full text of DOI:10.1002/asia.202000783

CHEMISTRY
AN ASIAN JOURNAL
www.chemasianj.org
Accepted Article
Title: Phenoxazine-based near-infrared fluorescent probes for the
specific detection of copper (II) ion in living cells
Authors: Yang Shen, Wubin Zheng, Yusi Yao, Dongmei Wang,
Guanglei Lv, and Chunxia Li
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Asian J. 10.1002/asia.202000783
Link to VoR: https://doi.org/10.1002/asia.202000783
A Journal of
A sister journal of Angewandte Chemie
and Chemistry – A European Journal

Chemistry - An Asian Journal
10.1002/asia.202000783
COMMUNICATION
Phenoxazine-based near-infrared fluorescent probes for the
specific detection of copper (II) ion in living cells
[
a]
[a]
[a]
[a]
[a]
[a], [b]
Yang Shen⁺, Wubin Zheng⁺, Yusi Yao, Dongmei Wang, Guanglei Lv,* and Chunxia Li*
[
a]
Y. Shen, W. Zheng, Y. Yao, Dr. D. Wang, Dr. G. Lv, Prof. C. Li
Key Laboratory of the Ministry of Education for Advanced Catalysis Materials
Zhejiang Normal University
Jinhua 321004 (P. R. China)
E-mail: guanglei@zjnu.edu.cn
[
b]
Prof. C. Li
Institute of Frontier and Interdisciplinarity Science and Institute of Molecular Sciences and Engineering
Shandong University
Qingdao 266237 (P. R. China)
E-mail: cxli@sdu.edu.cn
[⁺] These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of the document.
2
+
Abstract: It is well known that copper ions play a critical role in
various physiological processes. However, a variety of human
diseases are tightly correlated with copper overload. Although there
are numerous fluorescent probes capable of detecting copper ions,
most of them are ꢀturn-offꢁ probes oꢂing to copper (II) ions
fluorescence quenching effect, resulting in poor sensitivity. Herein, a
novel ꢀturn-onꢁ near-infrared (NIR) fluorescent probe PZ-N based on
phenoxazine was designed and synthesized for the selective
including slow response and low detection sensitivity towards Cu .
Thus, it is of significant importance to develop novel ꢀturn-onꢁ near-
infrared fluorescent probes for the selective, sensitive and rapid
2
+
detection of Cu .
Initially, we focused on methylene blue (MB) scaffold to design
2+
fluorescent probes for the detection of Cu . This mainly attributed to
the significant difference in fluorescence between the reduced and
[
10]
oxidized forms of MB. Therefore, a series of probes (MB-N and
2+
2+
detection of copper (II) ions (Cu ). Upon the addition of Cu , the
MB-C, Scheme S1) based on MB scaffold was synthesized to
2+
2+
probe could quickly react with Cu and emit strong fluorescence,
along with colour change from colourless to obvious blue. Moreover,
the probe PZ-N showed good water solubility, high selectivity, and
excellent sensitivity with low limit of detection (1.93 nM) towards
copper (II) ions. More importantly, PZ-N was capable of effectively
investigate the response to Cu . Unfortunately, none of them
2+
showed quick response or high sensitivity towards Cu (Figure S1).
Subsequently, we turned our attention to the phenoxazine skeleton,
[
11]
which possesses similar photophysical properties to MB.
Its
maꢅimum absorption (ꢆabs = 654 nm) and emission (ꢆem = 669 nm)
peaks both lie in the near-infrared region. In addition, the reduced
form of phenoxazine (ROP) showed rare fluorescence, while the
oxidized form of phenoxazine displayed intensive fluorescence
emission in NIR region. These spurred us to develop novel ꢀturn-onꢁ
2+
detecting Cu in living cells.
Among numerous indispensable trace elements, metal ions play a
vital role in physiological processes, such as cellular energy
production, catalytic cofactor, oxygen delivery and signal
2+
fluorescent probes for the detection of Cu on the basis of
phenoxazine skeleton. Consequently, we for the first time developed
several novel ꢀturn-onꢁ NIR fluorescent probes (PZ-N, PZ-O and PZ-
C, Scheme S1) on the base of phenoxazine skeleton for detecting
[
1]
transduction.
Besides zinc and iron elements, copper also
[
2]
occupies a high proportion in human body. Nevertheless, several
studies reported that the excessive intake of copper contributed to a
large number of diseases, including Menkes syndrome, Alzheimer's
2+
Cu . Interestingly, among them, the probe PZ-N (Scheme 1)
exhibited rapid response and higher sensitivity, along with dramatical
fluorescence intensity increase. Another two fluorescent probes PZ-
O and PZ-C did not exhibit remarkable fluorescence change in the
[
3]
disease, Wilsonꢃs disease, Parkinson's disease and so on. It is well
known that rivers and soil are vulnerable for the pollution of copper
ions due to the discharge of industry sewage, resulting in
a
2+
presence of Cu compared to PZ-N (Figure S1). Compared with
[
4]
significant increase in the risk of illness. Therefore, it is significantly
urgent to realize the specific and sensitive detection of copper ions.
It is well established that the fluorescence technique possesses
several merits, such as high selectivity and sensitivity, real-time and
some reported probes (Table S1), the probe PZ-N showed faster
response, longer emission wavelength, and lower detection limit for
2+
Cu . Apart from dramatic fluorescence intensity increase upon the
[
5]
non-invasive detecting as well as high resolution and so on. So far,
great effort has been made by numerous researchers to develop
[
6]
fluorescent probes for detecting copper ions. However, most of
them are ꢀturn-offꢁ fluorescent sensors oꢂing to the fluorescence
quenching effect of copper ions, which may cause false positive
[
7]
results. Therefore, it is quite important to construct ꢀturn-onꢁ
2+
fluorescent probes for the selective detection of Cu . Furthermore,
NIR, 650ꢄ900 nm) fluorescent probes, possessing high signal-to-
(
noise ratio, deep tissue penetration, and low background
fluorescence interference, have been widely used in living
2+
[
8]
Scheme 1. The structure of PZ-N and the response towards Cu
.
organisms. Although there are some NIR fluorescent probes
2+ [9]
reported to detect Cu , some challenges remain to overcome,
1
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Chemistry - An Asian Journal
10.1002/asia.202000783
COMMUNICATION
2+
addition of Cu , the solution colour remarkably changed from
colourless to blue, which could be directly obserbed by the naked
eye. Moreover, the probe PZ-N exhibited repaid response and high
1
1
0
0
0
0
0
.2
.0
.8
.6
.4
.2
.0
1.2
1.0
0.8
0.6
0.4
0.2
0.0
A
B
2+
sensitivity towards Cu in living cells.
The probe PZ-N was obtained through a two-step reaction, as
shown in Scheme S1. The compounds were characterized by IR
1
H
13
spectroscopy, HR-MS,
NMR, and
C NMR in supporting
A
B
C
D
E
F
G
H
I
A
B
C
D
E
F
G
H
I
J
information. After that, we investigated the fluorescence response of
Anions
ROS/RNS
2+
1.2
1.2
1.0
0.8
0.6
0.4
0.2
0.0
PZ-N towards Cu . The probe PZ-N itself showed relatively weak
fluorescence (ꢆem = 669 nm) and absorption, as shown in Figure S2.
C
D
1
.0
2
+
0.8
The addition of Cu induced remarkable fluorescence intensity
enhancement (Figure 1) in phosphate-buffered saline (PBS, pH =
0
0
.6
.4
7
.4) solution containing PZ-N at 669 nm. The limit of detection (LOD)
2+
0.2
0.0
of the probe PZ-N towards Cu was 1.93 nM, which could enable
2+
PZ-N to detect Cu in vivo. Additionally, the probe PZ-N responded
A B C D E F G H
I
J
K L M N
A
B
C
D
E
F
G
H
I
J
K
L
M
N
O P
Cations
Amino acids
2+
E
rapidly to Cu and the fluorescence intensity significantly increased
within approximately 40 s (Figure S3). More importantly, after the
Cu2+ Fe3+ Ni2+ Mg2+ Fe2+ Al3+ Ca2+ K+ NH Cd2+ Mn2+ Co2+ Zn2+ Na+
+
2+
4
addition of Cu , the colour of the solution changed from colorless to
2+
obvious blue, which made the detection of Cu possible by naked
eyes. These results indicated that the probe PZ-N exhibited fast
2
+
response and high sensitivity towards Cu .
Figure 2. Fluorescence intensity changes of the probe PZ-N (10 ꢇM in PBS,
2+
pH= 7.4) at 669 nm in the addition of 2 ꢇM Cu or other analytes. (A) Various
-
-
-
ROS/RNS (2 ꢇM): from A to H: H
2
O
2
, TBHP, NO, ROOꢈ, HOꢈ, ONOO , O
2
,
-
2-
2-
A
B
and HClO; (B) Some anions (20 ꢇM): from A to I: CH
3
COO , CO
3
, SO
4
, Cl ,
1
0
.1
.9
-
-
-
2-
-
3+
,
1
0
0
0
0
0
.0
.8
.6
.4
.2
.0
F , I , NO
2
, S
2
O
4
2+
, and NO
3
2+
; (C) Several cations (20 ꢇM): from A to M: Fe
0
.0
0.2
.4
0.6
.8
1.0
ꢀM
2+
2+
3+
+
+
2+
2+
2+
2+
+
1
.4 ꢀM
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
M
M
M
M
M
M
M
2
4
Ni , Mg , Fe , Al , Ca , K , NH , Cd , Mn , Co , Zn , and Na ; (D)
R =0.99329
0
0.7
0.4
0.2
Varieties of amino acids (20 ꢇM): from A to O: Pro, Ser, Ala, Gln, Val, Thr, lle,
Gly, Tyr, Met, Trp, Phe, Cys, Glu, and Lys; (E) Picture of PZ-N solutions in the
2+
Cu
0
2+
0
.0 ꢀM
presence of 2 ꢇM Cu or various anions.
1
1
.2
.4
0
.0
6
40 660 680 700 720 740 760 780 800
-0.2 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6
2
+
Wavelength (nm)
Cu
(ꢀM)
mechanism, we performed the HPLC experiment. It can be clearly
seen that the peak of fluorophore phenoxazine emerged after the
Figure 1. (A) Fluorescence spectra of PZ-N (10 ꢇM in PBS, pH = 7.4)
before/after the addition of Cu (0, 0.2, 0.4, 0.6, 0.8, 1.0, 12 and 1.4 ꢇM); (B)
Fluorescence intensities (669 nm) and concentrations of Cu (0-1.4 ꢇM)
showed good linear relationship. ꢆex = 620 nm, ꢆem =669 nm.
2+
2+
reaction of PZ-N with Cu (Figure S9). In addition, the molecular ion
peak of phenoxazine at m/z = 324.2070 was found in HRMS (Figure
S10). These results confirmed that PZ-N yielded the product
2+
2+
phenoxazine after the addition of Cu , further confirming the
mechanism we proposed.
Subsequently, we investigated the selectivity of the probe PZ-N
2+
towards Cu . A variety of analytes, including reactive oxygen
species (ROS)/reactive nitrogen species (RNS) (H , TBHP, NO,
2
O
2
-
-
3+
2+
2
ROOꢈ, HOꢈ, ONOO , O , and HClO), common cations (Al , Ca ,
2
+
2+
2+
3+
+
2+
+
2+
2+
+
2+
Cd , Co , Fe , Fe , K , Mg , Na , Mn , Ni , NH
4
, and Zn ),
-
2-
-
-
-
2-
4
2-
4
-
-
3
anions (CH
3
COO , CO
3
, F , Cl , I , SO
, S
2
O
NO
2
, and NO
),
and amino acids (Ala, Cys, Gln, Glu, Gly, lle, Pro, Lys, Met, Phe, Ser,
Thr, Tyr, Trp, Val, Hcy, GSH, and Cys), were chosen to perform the
experiment. As shown in Figure 2 and S4, there were no remarkable
fluorescence changes in the presence of these analytes except
HClO. Although HClO induced slight fluorescence intensity increase,
2+
the intensity was very lower compared with the addition of Cu . We
2+
found that only the addition of Cu (PBS, pH= 7.4) could trigger
significant fluorescence intensity increase, along with obvious colour
change (Figure S5-8). Overall, the probe PZ-N exhibited high
2
+
Scheme 2. Possible detection mechanism of the probe PZ-N towards Cu
.
2+
selectivity towards Cu .
[
10, 11, 12]
Based on previous literatures,
a possible detection
2+
In order to ensure the effective applications of the probe PZ-N at
the cellular level, the interference of several ubiquitous substances
in living cells, including GSH (glutathione, 0-20 ꢇM), NAC (N-
acetylcysteine, 0-20 ꢇM), aldehꢉde (0-200 ꢇM) and glucose (0-200
ꢇM) was studied. Interestingly, the presence of these species did not
mechanism was proposed. Initially, Cu combined with the amide
moiety from PZ-N to form a highly unstable four-membered ring
(Scheme 2). And then, a water molecule attacked the carbon atom
of carbonyl group, resulting in the cleavage of the four-membered
ring to produce unstable carbamic acid. Finally, the carbamic acid
2+
-
2
cause remarkable interference between PZ-N and Cu (Figure 3A-
D). In addition, we investigated whether different atmospheres,
including air, nitrogen and oxygen, would interfere the detection of
released HCO
to generate an unstable intermediate, which would
quickly produce fluorophore phenoxazine. To confirm the detection
2
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Chemistry - An Asian Journal
10.1002/asia.202000783
COMMUNICATION
2
+
2+
Cu . The fluorescence intensity of probe PZ-N considerably
As expected, no fluorescence was detected in absence of Cu
2+
increased with prolonged time in the presence of Cu under air,
nitrogen and oxygen (Figure S11). It is worth noting that little
fluorescence intensity changed when the PZ-N was only exposed to
(Figure 4, A1-A3), while remarkable intracellular fluorescence signal
could be observed upon the addition of the probe PZ-N and
2+
exogenous Cu (Figure 4, B1-B3) in the fluorescence channel (700
2+
2+
air, nitrogen or oxygen without the presence of Cu , indicating Cu
± 50 nm). Additionally, the probe showed concentration dependent
2+
did induce the fluorescence intensity increase. Moreover, the
stability of the fluorophore phenoxazine was explored in PBS
towards Cu at cellular level and the fluorescence signal became
2+
brighter with higher concentration of Cu (Figure 4, B1-B3 and C1-
2+
solution in the presence of high concentrations of Cu (20 and 50
C3). Taken together, the probe PZ-N was capable of permeating cell
2+
ꢇM, Figure S12). The result displayed that there was rare
membrane and detecting Cu in living cells and showing great
2+
2+
fluorescence change in the presence of 50 ꢇM Cu even though the
reaction time was up to one hour. Importantly, the fluorescence and
absorption intensity of PZ-N showed little change in a wide pH range
potential for detecting Cu in biological system.
2+
from 2 to 10 without the addition of Cu (Figure 3, E and F),
indicating that pH did not trigger the structure change of the probe
PZ-N. Furthermore, the probe PZ-N exhibited the strongest
fluorescence and absorption intensities (Figure 3, E and F) under the
neutral environment (pH = 7.0), which is beneficial for the further
application in living systems. Taken all together, these results
showed that PZ-N exhibited high stability and sensitivity towards
A1
A2
B2
C2
A3
B3
C3
2+
B1
C1
Cu .
1
1
0
0
0
0
0
.2
.0
.8
.6
.4
.2
.0
A
1.2
B
1
0
0
0
.0
.8
.6
.4
0.2
0.0
2+
Cu2+
Cu
2.0
4.0
10.0
20.0
2.0
2.0
4.0
10.0
20.0
M)
2
+
2+
2.0 ꢀM Cu + NAC (ꢀM)
ꢀ
M Cu + GSH (
ꢀ
1
1
0
0
0
0
0
.2
.0
.8
.6
.4
.2
.0
C
1.2
D
1
0
0
0
.0
.8
.6
.4
2
+
Figure 4. Fluorescence images of PZ-N for Cu in HeLa cells. (A1-A3) The
cells were only incubated with probe PZ-N (20 ꢇM) for 20 min. The cells ꢂere
0.2
0.0
2+
preincubated with PZ-N (20 ꢇM), and further cultured ꢂith 20 ꢇM Cu (B1-B3)
and 50 ꢇM Cu (C1-C3) for 20 min, respectively. Images from left to right:
bright field, fluorescence field and merged images, fluorescence channel: 700
2+
2+
Cu
20
40
2
100
200
Cu
20
40
100
200
2+
+
2+
2.0 ꢀM Cu + HCHO (ꢀM)
2.0
ꢀ
M Cu + Glucose (
ꢀ
M)
1
.2
0.6
ꢊ 50 nm, ꢆex = 633 nm.
P N
BC-1
Z-
BC-1
PZ-N
E
2+
F
BC-1+ 4
ꢀ
M Cu2+ 1.0
2+
PZ-N+2 μM Cu
BC-1+ 4 ꢀM Cu2+ 0.5
PZ-N+2 μM Cu
0
.8
.6
.4
.2
.0
0.4
0.3
0.2
0.1
0.0
0
In summary, we designed and synthesized a novel near-infrared
0
fluorescence ꢀturn-onꢁ probe PZ-N based on phenoxazine for
2+
detecting Cu . The probe PZ-N exhibited high selectivity and fast
0
2
+
response to Cu in PBS solution. Furthermore, the probe PZ-N can
0
2+
be used to detect Cu rapidly by the naked eye. More importantly,
the probe showed low cytotoxicity and high specificity towards the
pH
pH
2+
detection of Cu in living cells.
Figure 3. The anti-interference and stability of PZ-N. A series of substances,
including NAC (A), GSH (B), HCHO (C) and Glucose (D), were added into PZ-
N solution (10 ꢇM). The fluorescence (E, ꢆem = 669 nm) and absorption (F, ꢆabs
=
654 nm) intensity changes of PZ-N (10 ꢇM) under different pH.
Acknowledgements
This research was funded by the National Natural Science
Foundation of China (51872263), Taishan Scholars Project
Subsequently, we further studied the practical application of PZ-N
2+
for monitoring Cu in living cells. The cytotoxicity of PZ-N was firstly
examined in living HeLa cells (Figure S13). The result showed that
the probe PZ-N exhibited low cytotoxicity (cell viability > 90 %). And
then the stability of PZ-N was tested under physiological condition
(
ts20190911), and Zhejiang Provincial Natural Science
Foundation of China (LZ19E020001 and LQ19B050003).
(PBS, 37 ℃). As showed in Figure S14, the probe PZ-N did not
Keywords: fluorescent probes ꢈ near-infrared (NIR) ꢈ copper ꢈ
show obvious absorption changes in physiological condition without
phenoxazine
2+
the presence of Cu within 120 minutes, indicating that PZ-N
showed considerable stability. Then we chose HeLa cells to
2+
investigate whether the probe PZ-N could detect Cu in living cells.
3
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Chemistry - An Asian Journal
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COMMUNICATION
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Chemistry - An Asian Journal
10.1002/asia.202000783
COMMUNICATION
No Fluorescence
Fluorescence
high selectivity
rapid response
Cu2+
PZ-N
2
+
We developed a novel ꢀturn-onꢁ near-infrared (NIR) fluorescent probe PZ-N for the selective detection of copper (II) ions (Cu ). The
2
+
2+
probe PZ-N showed quick response and high sensitivity towards Cu . Moreover, the probe PZ-N was also capable of detecting Cu
in living cells.
5
This article is protected by copyright. All rights reserved.