A new dual-channel ratiometric fluorescent chemodosimeter for Cu2+and its imaging in living cells

Article abstract of DOI:10.1016/j.tetlet.2016.10.050

A new BODIPY derivative bearing hydrazone and hydrazide moieties was developed as an efficient dual-channel ratiometric fluorescence chemodosimeter 1 for Cu²⁺in neutral aqueous medium via Cu²⁺-mediated hydrolysis of C[dbnd]N bond in hydrazone unit. Confocal microscopy experiments have demonstrated that chemodosimeter 1 could also be used in live cells for the fast detection of Cu²⁺.

Full text of DOI:10.1016/j.tetlet.2016.10.050

Accepted Manuscript
2
A new dual-channel ratiometric fluorescent chemodosimeter for Cu and its
+
imaging in living cells
Zheng Fan, Jia-Hai Ye, Yang Bai, Song Bian, Xiaolong Wang, Wenchao Zhang,
Weijiang He
PII:
S0040-4039(16)31364-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.10.050
TETL 48220
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
14 August 2016
4 October 2016
14 October 2016
Please cite this article as: Fan, Z., Ye, J-H., Bai, Y., Bian, S., Wang, X., Zhang, W., He, W., A new dual-channel
2
ratiometric fluorescent chemodosimeter for Cu and its imaging in living cells, Tetrahedron Letters (2016), doi:
+
http://dx.doi.org/10.1016/j.tetlet.2016.10.050
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Graphical Abstract
A new dual-channel ratiometric fluorescent
2
+
chemodosimeter for Cu and its imaging in
living cells
Zheng Fan, Jia-Hai Ye, Yang Bai, Song Bian, Xiaolong Wang, Wenchao Zhang, and Weijiang He
OMe
OMe
5
55 nm
5
25 nm
450 nm
5
05 nm
O
Cu2+
O
H
N
NH
1
HO
2
N
F
N
F
N
F
N
F
B
B
H

1
Tetrahedron Letters
2
+
A new dual-channel ratiometric fluorescent chemodosimeter for Cu and its imaging
in living cells
a
a,
b
a
c,
a
Zheng Fan , Jia-Hai Ye *, Yang Bai , Song Bian , Xiaolong Wang * Wenchao Zhang , and Weijiang
He *
b,
a
School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing 210094, China
State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210093, China
College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210046, China
b
c
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A new BODIPY derivative bearing hydrazone and hydrazide moieties was developed as an
2
+
efficient dual-channel ratiometric fluorescence chemodosimter 1 for Cu in neutral aqueous
2
+
medium via Cu -mediated hydrolsis of C=N bond in hydrazone unit. Confocal microscopy
experiments have demonstrated that chemodosimter 1 could also be used in live cells for the fast
2
+
Available online
detection of Cu .
2
016 Elsevier Ltd. All rights reserved.
Keywords:
ratiometric
BODIPY
Chemodosimeter
2+
Cu
Fluorescence
Living cell imaging
reactions
including
oxidations,
dethioacetalizations,
10
1
. Introduction
Ratiometric fluorescent technique, which provides built-in
rearrangements, and oxidative cyclizations. The method of
copper induced reactions has been an excellent approach for the
development of selective chemodosimeters for these ions.
Nevertheless, only few of ratiometric chemodosimeters for Cu
detection have been reported.
ratiometric chemodosimeters based on Cu -selective reaction in
aqueous medium is still challenging and very attractive for the
demand of the diversified and complicated biological systems.
correction by simultaneously measuring two different emission
signals to minimize or even eliminate these interferences and
provide higher analytical accuracy than conventional single-
intensity probes, has attracted increasing attention among the
various analysis and detection methods in recent years. As far as
we know, ratiometric fluorescent detection method has been
being utilized for chemo/bio sensing recently. On the other hand,
as the third most abundant transition essential element after zinc
and iron in the human body, Cu plays vital roles in multiple
physiological processes dependent on the copper homeostasis in
the living organisms. Excess copper intake can result in cancers
of the breast, lung, prostate, pancreas, and kidney, and disturbs
the cellular homeostasis that will cause Wilson’s disease,
Alzheimer’s disease, and Menkes syndrome owing to the
aberrant oxidative and nitrosative stress induced by Cu .
According to the U.S. Environmental Protection Agency (EPA),
2
+
9g,10f,g,j,11
Thus the design of new
2+
1
2
Recently, we reported a highly sensitive and selective turn-on
chemodosimeter for Cu based on 4,4-difluoro-4-bora-3a,4a-
diaza-s-indacene (BODIPY) containing hydrazone moiety.
2
+
2
+
1
0m
Encouraged by this interesting result, we try to design new
system for the ratiometric fluorescence detection to the metal
ions. In this communication, we describe a new ratiometric
chemodosimeter for Cu based on the metal ions promoted
hydrolysis of C=N bond in hydrazone unit. In this compound 1, a
fluorophore, BODIPY core, was conjugated with hydrazone and
hydrazide units. As shown in scheme 1, compound 1 was
prepared facilely from condensation of formyl BODIPY 2 with
salicylic hydrazide 3 in the yield of 30 % and characterized by
3
4
5
2
+
6
7
2
+
2
+
the maximum acceptable level of Cu in drinking water is 1.3
ppm (～20 µM). Therefore, there is considerable interest in
8
2
+
1
13
developing specific fluorescent sensors for sensitive Cu
detection, especially in environmental and physiological
conditions. Even though fluorescent probes for Cu have been
extensively explored owing to biological significance of this
metal ion, there are still only a few examples of ratiometric
ESI-MS, H- NMR, C-NMR, and elemental analysis.
2
+
9
fluorescent probes available in aqueous systems.
2
+
It is well known that Cu , being of a catalytic nature, can
promote the hydrolysis of amides, esters, lactones and hydrazide,

2
Tetrahedron Letters
OMe
OMe
CHO
N
N
O
B
F
F
N
NH
2
HO
N
N
B
H2NHN
O
F
F
1
Fig.2 Fluorescence spectra of chemodosimeter 1 (10 μM) towards
OH
2+
Cu (0，0.02，0.04，0.08，0.1，0.3，0.5，0.8，1，2，3，4，
，6，7，8，9，10，11，12，13，14，15，18，23，30，40
equiv) in DMF:H O (7:3, v:v) medium, (a) λ = 450 nm, (b) λex
5
3
=
2
ex
Scheme 1 Synthesis of chemodosimeter 1.
5
25 nm.
We then proceeded to examine the selectivity of the probe.
2
. Results and discussion
The ratiometric fluorescent response of probe 1 (10 µM) to other
metal cations of interest has also been determined (Fig. S2b,S2b),
and the results showed that other tested metal ions (400 µM, 40
The absorption spectra of probe 1 in the presence of varying
2
+
Cu concentrations were recorded first in DMF-H O (7:3, v:v)
solution. As shown in Figure 1, the solution of probe 1 alone
2
+
+
+
2+
2+
2+
3+
2+
3+
equiv.) including Li , Na , K , Mg , Ca , Ba , Al , Pb , Cr ,
2
+
3+
2+
2+
2+
3+
+
2+
2+
2+
2+
-
5
Mn , Bi , Ni , Sn , Fe , Fe , Ag , Zn , Cd , Hg and Co ,
did not induce any distinct change of F505, and F555. Furthermore,
the examination of the fluorescence response of probe 1 toward
(1.0×10 M) exhibits a maximum absorption peak at 526 nm,
consistent with the pink coloration of the solution. Upon addition
2
+
of Cu , the probe 1 solution showed a new maximum absorption
wavelength at 495 nm, which can be ascribed to the fluorophore
containing the moieties of BODIPY hydrazone and salicylic
hydrazide. Meanwhile, the absorption band centered at 526 nm
decreased gradually was observed (Fig. S3). In addition, the
absorption behavior changes the color of the resultant solution
from pink into pale yellow, allowing “naked-eye” detection (Fig.
S7). The addition of various other transition and alkali metal ions
did not alter the absorption spectrum of receptor 1 and the color
of the metal ions solution, initially indicating the special
2
+
Cu in the presence of other potentially competing ions was
carried out to investigate the applicability of the developed
ratiometric chemodosimeter 1 to the analysis of Cu ions in a
2
+
practical sample (Fig. 3; Fig. S5a-5c). As shown in Fig. 3, the
2
+
ratiometric response induced by Cu was almost intact even in
the presence of various competitive metal ions. This is also
supported by the absorption spectra which showed the similar
selectivity to the species. All these results indicate that probe 1 is
2
+
able to sense Cu in a ratiometric manner in aqueous media with
high selectivity. Moreover, the detection limit of this sensor was
2
+
selectivity towards Cu .
1
2
determined to be 0.2 µM (Fig. S6), much lower than the
2
+
allowable Cu
level in drinking water and the typical
concentration of blood copper (11.8-23.6 µM) in normal
8,13
individuals.
2
+
Fig.1 Absorption spectra of chemodosimeter 1 (10 μM) with Cu or
+
+
other different metal ions (100 μM, 10 equiv.) including Li , Na ,
+
2+
2+
2+
3+
2+
3+
2+
3+
2+
2+
2+
K , Mg , Ca , Ba , Al , Pb , Cr , Mn , Bi , Ni , Sn , Fe ,
3
+
+
2+
2+
2+
2+
Fe , Ag , Zn , Cd , Hg and Co in DMF:H O (7:3, v:v) medium.
2
Fig.3 Ratio of emission at 505 nm to that at 555 nm for 1 (10 μM) in
in DMF:H O (7:3, v:v) medium, F505/F , determined in the absence
Next, the titrations of the novel ratiometric probe 1 (10 µM)
2
555
+
+
+
2
+
and presence of different metal ions: 1, none; 2, Li ; 3, Na ; 4, K ; 5,
with Cu were conducted in DMF-H O (7:3, v:v) solution. In a
2
2
+
2+
2+
3+
2+
3+
2+
3+
Mg ; 6, Ca ; 7, Ba ; 8, Al ; 9, Pb ; 10, Cr ; 11, Mn ; 12, Fe ;
solution of probe 1, very weakly fluorescent emission was
observed around 505 nm in the featured emission of formyl-
BODIPY under the excitation in 450 nm. Upon the increasing
3
+
2+
2+
2+
2+
+
2+
1
3, Bi ; 14, Co ; 15, Ni ; 16, Sn ; 17, Fe ; 18, Ag ; 19, Zn ; 20,
2
+
2+
2+
Cd ; 21, Hg ; 22, Cu . 100 μM. Black bars: free sensor, or sensor
2
+
treated with the marked metal ions. Red bars: sensor treated with the
addition of Cu , a drastic increase in the featured emission of
formyl-BODIPY around 505 nm was observed, and the
fluorescence intensity enhancement was up to 8-fold (Fig. 2a; Fig.
S2b). Interestingly, as shown in Figure 1b, upon excitation at 525
nm, the free probe 1 displays a single emission band centered at
2+
marked metal cations (100 μM, 10 equiv.) followed by Cu (100 μM,
1
0 equiv).
The effect of pH on the fluorescence of the probe was
evaluated due to the great importance of the probe solution for
the practical application. As shown in Fig. S4, the pH value of
the solution has a great influence on the free probe 1 in the range
of 4.0-10.0 for the two emission channels. However, no
remarkable change of two emission fluorescence intensities of
5
55 nm and the fluorescence intensity decreases smoothly upon
2+
the addition of Cu (Fig. 2b; Fig. S2c).
2
+
probe 1 upon the addition of Cu was observed from about 5.0 to
.0 pH range. That is to say, the ratiometric probe works well
8

3
under physiological conditions. Moreover, to understand the
2
+
sensing mechanism of the chemodosimeter 1 toward Cu , we
1
carried out the H NMR experiments for the probe 1 solution
2+
followed by the addition of Cu . As shown in Fig. 4, two singlet
peaks at 8.46 ppm (H ) and 12.01 ppm (H ) corresponding to the
a
b
protons on the hydrazone (H C=N)and hydrazide (CONH )
a
b
moieties in probe 1 respectively disappeared upon the addition of
2
+
Cu . Meanwhile, the singlet peak at 9.96 ppm (Hc)
corresponding to the proton of the CHO moiety in the major
hydrolysis products fomyl-BODIPY was observed. This result
integrated with significant emission enhancement around 505 nm,
the featured fluorescence emission band, confirms that the C=N
bond in the hydrazone unit of probe 1 was hydrolyzed effectively
Fig.5 Confocal fluorescence images of living Hela cells: Hela cells
incubated with compound 1 (5 μM) for 15 min (a, b, c, d) at 37 ℃.
The stained cells were exposed to 30 μM Cu solution for 30min (e,
2
+
in the presence of Cu to generate the green fluorescence
product fomyl-BODIPY.
2+
OMe
f, g, h). (a, e) Bright-field transmission images. (b, f) Fluorescence
images obtained according to the emission collected by the green
OMe
H
Cu
5
25 nm
5
55 nm
N
O
O
channel (λ : 488 nm, band path 491-540 nm). (c, g) Fluorescence
ex
O
Cu2+
N
images obtained from the red channel (λ : 543 nm, band path 546-
ex
NHb
N
HO
N
F
N
F
H
650 nm). (d, h) Ratiometric images generated from (b, f) and (c, g).
N
F
N
F
B
B
Ha
1
OMe
3
. Conclusion
In conclusion,
hydrolysis
5
05 nm
the
new
fluorescent
ratiometric
2+
4
50 nm
O
2+
2
chemodosimeter 1 for Cu sensing exhibits a specific Cu -
induced blue shift from 555 to 505 nm. The key point is that the
N
F
N
B
F
Hc
2
+
ratiometric sensing is conducted through Cu -promoted
hydrolysis of the C=N bond in the hydrazone unit in aqueous
medium. Moreover, the emissive blue shifting comes from dual
excitation channels (λem = 505 nm, λex = 450 nm; λem = 555 nm,
λex = 525 nm). Further, chemodosimeter 1 can also be used as a
2
+
ratiometric fluorescent probe for intracellular imaging of Cu
ions with tunable emission (green and red) which will help in the
understanding of biological processes at the molecular level. This
study displays also an effective rationale to design ratiometric
2
+
chemodosimeters for rapid Cu sensing and bioimaging.
Acknowledgments
1
Fig.4 Proposed sensing mechanism and partial H NMR spectra of 1
2+
(
1 mM) in DMSO -D O upon addition of (a) 0, (b) 1 equiv. of Cu .
d6 2
We thank the National Natural Science Foundation of China
(
No. 211571099) and Priority Academic Program Development
Finally, The ratiometric imaging ability of probe 1 for
intracellular Cu has been confirmed in HeLa cells by confocal
fluorescence imaging with a dual channel mode (green channel,
of Jiangsu Higher Education Institutions (PAPD) for financial
support.
2
+
4
91–540 nm, λex = 488 nm; red channel, 546–650 nm, λex = 543
Supplementary data
nm) and the ratiometric image was obtained via mediating the red
channel image with the related green channel image (Fig. 5, Fig.
S9). After HeLa cells were incubated with 5 µM Probe 1 (15
min), the ratiometric image displayed a deep blue color in the
Supplementary material associated with this article can be
found, in the online version, at doi:
2
+
cytosol, indicating the low intracellular chelatable Cu level (Fig.
d). After the probe 1-stained cells were incubated with a 30 µM
References and notes
5
2
+
Cu solution (15 min), the related ratiometric image showed a
remarkable ratio enhancement in the cytosol (Fig. 5h), implying
that the chelatable cytosolic Cu level can be effectively
1
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5
Highlights
·
·
·
·
A new ratiometric chemodosimeter 1 was
2
+
developed for recognizing Cu efficiently;
Chemodosimeter 1 works well within a wide
range pH and physiological conditions;
1 shows high selectivity and low detection
limitation (0.2 μM) in aqueous medium;
1 can be successfully utilized in fluorescent
2
+
imaging in living cells for the Cu detecting.