Monitoring of Fe (II) ions in living cells using a novel quinoline-derived fluorescent probe

Article abstract of DOI:10.1016/j.saa.2021.119729

Physiologically, Fe(III) and Fe(II) is the most important redox pairs in a variety of biological and environmental procedures with its capability of transition. The detection of physiological iron, especially Fe(II), has become the recent research focus of investigations on revealing the mechanism of iron-related metabolism. In this work, we exploited a novel quinoline-derived fluorescent probe, YTP, for the detection of Fe(II). It could monitor the level of Fe(II) with a linear range of 0–2.0 equivalent and the detection limit of 0.16 μM. High selectivity from other analytes including Fe(III) and steadiness for over 24 h confirmed the practicability of YTP. YTP was further applied in real buffer systems and in cellular imaging. The probe could achieve the semi-quantitative monitoring of Fe(II) in living cells. This work provided a potential implement for the detection of Fe(II), and raised important information for further researches on the redox pairs of iron, in mechanism and in practice.

Full text of DOI:10.1016/j.saa.2021.119729

Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 255 (2021) 119729
Contents lists available at ScienceDirect
Spectrochimica Acta Part A: Molecular and
Biomolecular Spectroscopy
journal homepage: www.elsevier.com/locate/saa
Monitoring of Fe (II) ions in living cells using a novel quinoline-derived
fluorescent probe
Chun-He Cai a,c,d, He-Li Wang a, , Ruo-Jun Man b,
⇑
⇑
a
School of Water Resources and Environment, China University of Geosciences (Beijing), 20 Chengfu Rd., Beijing 100083, PR China
College of Chemistry and Chemical Engineering, Guangxi University for Nationalities, Guangxi Key Laboratory of Polysaccharide Materials and Modifications, Nanning 530006, China
Beijing Kaiheyingran Consulting Co., Ltd., F-101, Fuliaidingbao, Baijiazhuang No.1, Chaoyang Dist, Beijing 100020, China
b
c
d
Nanjing University, School of Life Science, Xianlin Campus, No.163, Xianlin Rd, 210093 Nanjing, China
h i g h l i g h t s
g r a p h i c a l a b s t r a c t
ꢀ
ꢀ
A novel quinoline-derived fluorescent
probe, YTP, for the detection of Fe(II).
High sensitivity, high selectivity from
other analytes including Fe(III) and
steadiness for over 24 h.
ꢀ
ꢀ
Further applied in real buffer systems
and in cellular imaging.
Achieving the semi-quantitative
monitoring of Fe(II) in living cells.
a r t i c l e i n f o
a b s t r a c t
Article history:
Physiologically, Fe(III) and Fe(II) is the most important redox pairs in a variety of biological and environ-
mental procedures with its capability of transition. The detection of physiological iron, especially Fe(II),
has become the recent research focus of investigations on revealing the mechanism of iron-related meta-
bolism. In this work, we exploited a novel quinoline-derived fluorescent probe, YTP, for the detection of
Fe(II). It could monitor the level of Fe(II) with a linear range of 0–2.0 equivalent and the detection limit of
Received 17 January 2021
Received in revised form 10 March 2021
Accepted 16 March 2021
Available online 22 March 2021
0
.16 mM. High selectivity from other analytes including Fe(III) and steadiness for over 24 h confirmed the
Keywords:
practicability of YTP. YTP was further applied in real buffer systems and in cellular imaging. The probe
could achieve the semi-quantitative monitoring of Fe(II) in living cells. This work provided a potential
implement for the detection of Fe(II), and raised important information for further researches on the
redox pairs of iron, in mechanism and in practice.
Monitoring Fe (II)
Rapid response
High selectivity
Practical applications
Cellular imaging
Ó 2021 Elsevier B.V. All rights reserved.
1
. Introduction
Iron, which is the second abundant metal element on earth, act
physiological functions of various pathways, whereas an abnormal
level of iron may cause adverse impact on the health including
aging. neurodegenerative diseases and cardiovascular problems
[6–8]. Physiologically, iron in organisms exists in the oxidative
states including Fe(III) and Fe(II), which acts as one of the most
important redox pairs. Unlike in the environmental conditions, in
human body, the main form is Fe(II) [9–10]. Additionally, the most
recent hotspot, Ferroptosis, relies on the redox pair with Fe(II)
specifically [11–13]. Thus the detection of physiological iron,
especially Fe(II), has become the recent research focus of
investigations on revealing the mechanism of iron-related
metabolism [14–16].
as essential members in a variety of biological and environmental
procedures with its capability of transition [1,2]. For the research-
ers in life sciences, iron is attractive due to its roles in metabolism,
including the maintenance of hematopoietic ability, the trans-
portation of oxygen, the synthesis of coenzymes and nuclein
[
3–5]. Being controlled in a certain level, iron ensures the
⇑
Corresponding authors.
E-mail addresses: wangheli@cugb.edu.cn (H.-L. Wang), manruojun@163.com
(
R.-J. Man).
https://doi.org/10.1016/j.saa.2021.119729
386-1425/Ó 2021 Elsevier B.V. All rights reserved.
1

Chun-He Cai, He-Li Wang and Ruo-Jun Man
Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 255 (2021) 119729
1
Till now, the available monitoring approaches for ferrous ions
mainly involved inductively coupled plasma emission spectrome-
try (ICP-ES) and atomic absorption spectrometry (AAS) [17,18], of
which both needed high cost, complex preparation and specific
operators. Actually, the most troubling thing was lacking the
potential of real-time and in-situ detection. Within one decade,
the springing up of the fluorescent probes brought possibilities of
non-invasion and high selectivity [19,20]. Such technique also led
to the designs of probes for ferrous ions gradually. With a glance
at the differences between Fe(III) and (II), we found that most of
the reported fluorescent probes were for Fe(III), and some of them
chose the quenching signaling method which was not beneficial for
eliminating the background fluorescence [21–29]. However,
reports on monitoring Fe(II) were few, and the mechanisms were
deficient or non-specific [30–37]. The development of Fe(II) probes
was catching up with the requirements of monitoring Fe(II) in
physiological conditions, eagerly but falteringly. Thus, novel
probes with distinguishing mechanisms should be exploited for
monitoring Fe(II).
a sand-brown solid (3.6 g, 52.7%). H NMR (400 MHz, CDCl
3
) d 7.92
(d, J = 9.3 Hz, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.37 (d, J = 2.8 Hz, 1H),
7.19 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 2.8 Hz, 1H), 3.07 (s, 6H), 2.70 (s,
3H). C NMR (100 MHz, CDCl ) d (ppm) 154.46, 148.22, 141.60,
3
1
3
134.68, 128.91, 127.82, 122.16, 119.45, 105.39, 40.83, 24.78.
2.2. Synthesis of 6-(Dimethylamino) quinoline-2-carbaldehyde (3)
A mixture of selenium dioxide (2.8 g, 25.1 mmol, 1.3 equiv) in
dioxane/water (140 mL/14 mL) was heated at 80 ℃ for 30 min,
compound 2 (3.5 g, 18.8 mmol, 1 equiv) was then added and the
mixture was stirred at 80 ℃ for 4 h. After being cooled down to
room temperature, the mixture was filtered through diatomite,
then the filter residue was flushed three times by a small amount
of methylene chloride. The filtrate was concentrated under
reduced pressure to afford crude product which was further puri-
fied by column chromatography on silica gel (PE: EA = 6:1 v/v) to
afford 0.8 g of corresponding aldehyde as a yellow solid (21.3%).
1
H NMR (400 MHz, CDCl ) d 10.14 (s, 1H), 8.07 (d, J = 9.4 Hz,
3
Herein, we designed and tested a novel quinoline-derived fluo-
rescent probe, YTP, for the detection of Fe(II) (Fig. 1). Dimethy-
lamino quinoline was selected as the fluorophore because of its
usual long emission wavelength as well as the charge condition
of the nitrogen on the ring. With the rotation of the double bond
between carbon and nitrogen, the probe YTP itself was quenched.
When reacting with Fe(II), the rotation was blocked and the ben-
zoxazole ring was formed to obtain the product YTP-prod, which
resulted in the fluorescent signals at 560 nm. This mechanism
was quite different with the common one of redox [32,34], and
might show corresponding advantage. In mechanism, it was rapid
and irreversible, thus was less affected by the reaction equilibrium
than usual reaction-based fluorescent probes. Most importantly,
the selectivity and response rate should be better than that of
the redox ones. The comparison of YTP and the above mentioned
probes for Fe(II) in Table SI inferred that this probe might be
promising with its unique mechanism. Therefore we attempted
to evaluate the practical performances of YTP to check its potential
in applications.
1H), 8.02 (d, J = 8.5 Hz, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.43 (dd,
J = 9.4, 2.7 Hz, 1H), 6.80 (d, J = 2.6 Hz, 1H), 3.17 (s, 6H). 13C NMR
(100 MHz, CDCl ) d (ppm) 193.48, 150.20, 148.87, 141.70, 134.25,
3
132.24, 131.29, 119.73, 118.13, 103.86, 40.41.
2.3. (E)-2-(((6-(dimethylamino)quinolin-2-yl)methylene)amino)
phenol(YTP)
Compound 3 (200 mg, 1.0 mmol) was dissolved in dry ethyl
alcohol (10 mL), then added ortho-aminophenol (109 mg,
.0 mmol). The mixture was stirred at 80 ℃ for 8 h. After being
cooled down to room temperature, the pure solid obtained by
1
1
pumping was the final product (YTP). H NMR (600 MHz, CDCl
3
)
d 8.99 (s, 1H), 8.19 (d, J = 8.6 Hz, 1H), 8.07 (d, J = 8.1 Hz, 1H),
7
1
1
1
1
.50–7.37 (m, 2H), 7.24 (d, J = 1.1 Hz, 1H), 7.04 (dd, J = 8.1,
.4 Hz, 1H), 6.93 (ddd, J = 8.3, 7.4, 1.4 Hz, 1H), 6.83 (d, J = 2.8 Hz,
1
3
H), 3.15 (s, 6H). C NMR (151 MHz, DMSO) d 158.74, 150.91,
49.83, 148.58, 140.44, 136.37, 133.30, 129.66, 129.32, 127.40,
18.99, 118.85, 118.82, 118.71, 118.44, 115.59, 103.82.
2
. Experimental section
.1. Synthesis of N,N,2-trimethylquinolin-6-amine (2)
-N,N-Dimethylamino aniline (1) (5 g, 36.7 mmol, 1.0 equiv)
3. Results and discussion
2
3.1. Chemical synthesis
4
The synthesis route of the probe YTP was generated in Fig. 2.
was dissolved in a solution of HCl (6 M, 66 mL), after addition of
crotonaldehyde (6.0 mL, 73.5 mmol, 2 equiv), the result mixture
was stirred at room temperature for 1 h. Then toluene (35 mL)
was added and the reaction was further refluxed at 115 ℃ over-
night. After being cooled down to room temperature, the toluene
layer was removed and saturated sodium hydroxide solution was
added to neutralize the aqueous layer. The solution was extracted
with dichloromethane, washed twice with saturated NaCl solution,
and dried over anhydrous sodium sulfate, filtered and concen-
trated under reduced pressure. The crude product was purified
by column chromatography on silica gel (PE: EA = 4:1 v/v) to obtain
The structure was confirmed by satisfactory spectroscopic data
including H NMR, C NMR and HRMS (Figure S1-S7 in Supporting
Information).
1
13
3.2. Fluorescent performances of the probe YTP
Initially, the fluorescence spectra of the probe YTP were
scanned. As the reporting signals, the fluorescent peak of YTP itself
was at 530 nm, with an obvious enhancement at 560 nm after
reacting with Fe(II). The excitation wavelength was set as
374 nm and the fluorescence quantum yield
u
U was calculated
Fig. 1. The monitoring of Fe(II) with the probe YTP in this work.
2

Chun-He Cai, He-Li Wang and Ruo-Jun Man
Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 255 (2021) 119729
Fig. 2. The synthesis route of the probe YTP.
as 0.045 by the reference method with Rhodamine B as the stan-
dard dye in water (n = 1.333). Additionally, we have checked the
photostability of the probe YTP and the detecting system contain-
ing both YTP and Fe(II) (Figure S8). The fluorescence intensity
could be retained after at least 5 times of excitation at 374 nm.
the probe YTP and gradually increased the concentration of Fe(II)
from 0 to 6.0 equivalent in the detecting system (Fig. 3a). It could
be observed that the fluorescence intensity at 560 nm exhibited a
concentration-dependent enhancement along with the increase of
the Fe(II) concentrations. According to the linear correlation
(Fig. 3b), the probe YTP could monitor Fe(II) linearly within the
In convention, we took 10
lM as the working concentration of
Fig. 3. Significant photophysical characteristics of YTP. (a) Emission spectra of YTP (10 mM) in PBS buffer (10 mM, pH 7.4, containing 1% DMSO, v/v) with different
2
+
concentration of ferrous ion (Fe : 0–6.0 eq). (b) Linear functional relationship between the fluorescence intensity of 560 nm and YTP (10 mM). (c) Time-dependent emission
2
+
fluorescence intensity of YTP (10
lM) at 560 nm with Fe (100 mM). (d) Fluorescence intensity at 560 nm of YTP (10 mM) in various pH values at 37 ℃. kex = 374 nm, slit
width = dex = dem = 10 nm, voltage = 600 V. Data were mean ± SEM, n = 3.
3

Chun-He Cai, He-Li Wang and Ruo-Jun Man
Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 255 (2021) 119729
2
+
+
+
+
Fig. 4. Significant photophysical characteristics of YTP. (a) Fluorescent intensity changes of YTP (10
l
M) with Fe and other analysts (K , Na , Cu , Hg2+, Cu2+, Mg2+, Mn2+
,
2+
2+
2+
2+
2+
2+
3+
3+
3+
3+
ꢁ
ꢁ
ꢁ
–
ꢁ
ꢁ
2ꢁ
ꢁ
2–
ꢁ
2ꢁ
4
Pb , Pd , Pt , Zn , Ni , Ca , Al , Fe , Cr , Au , F , Cl , HSO
3
3
, HCO , HSO
4
, SCN , S , SO
4
, CO
3
, Ac , HPO
, Cys, GSH, 100
l
M) in PBS buffer (10 mM, pH 7.4, containing
2+
1
% DMSO, v/v). (b) Fluorescence intensity at 560 nm of probe YTP (10 mM) in the presence of various relevant analytes (10 eq) and Fe (10 eq) in PBS buffer (10 mM, pH 7.4,
+
+
+
2+
2+
2+
2+
2+
2+
2+
2+
2+
2+
3+
3+
3+
3+
ꢁ
ꢁ
ꢁ
, HCO–
2ꢁ
4
, Cys, GSH, Fe ). (c) Fluorescence intensity at 560 nm of YTP remaining stable in PBS buffer (10 mM, pH 7.4, containing 1% DMSO, v/v) over 24 h at 37 ℃. (d)
ꢁ ꢁ
ꢁ
2ꢁ
2–
containing 1% DMSO, v/v) at 37 ℃. (K , Na , Cu , Hg , Cu , Mg , Mn , Pb , Pd , Pt , Zn , Ni , Ca , Al , Fe , Cr , Au , F , Cl , HSO
3
3 4 4 3
, HSO , SCN , S , SO , CO ,
ꢁ
2+
Ac , HPO
2
+
Fluorescence intensity at 560 nm of YTP (10 mM) upon addition of Fe (100 mM) in different buffer systems, including PBS, Changjiang River, soft drink, and rice water
samples. kex = 374 nm, slit width = dex = dem = 10 nm, voltage = 600 V. Data were mean ± SEM, n = 3.
range of 0–20
formula 3 /slope, the Limit of Detection (LOD) was determined to
be 0.16 M, which was practical for the quantitative measuring of
Fe(II) in living organisms. Subsequently, we took 10 M TYP and
00 M Fe(II) to ensure the saturation of the reaction. and con-
ducted the following experiments. As shown in Fig. 3c, the probe
YTP could complete the reaction with Fe(II) within only 20 s, which
was really a short period among the reported probes. Besides, in
Fig. 3d, we could see that both the probe itself and the detecting
system were stable in various pH conditions. The above-
mentioned performances inferred that YTP was potential for
applications.
l
M (0–2.0 equiv.). One step further, according to the
probe at absence and presence of Fe(II) in 4–24 h. In Fig. 4c, we
could conclude that the detecting system was steady for at least
24 h. Moreover, we prepared different buffer systems to check
the monitoring system. The results in Fig. 4d indicated that no mat-
ter the buffer was river water, soft drink or rice water, the report-
ing fluorescent signals were basically unchanged from that in PBS
buffer.
r
l
l
1
l
3.4. Cellular imaging
Finally, we checked the performance of TYP in cellular imaging
in living HeLa cells. After the incubation of the probe YTP for
2
2
5
0 min at 37 ℃, the subsequent treating with buffer (Fig. 5a-d),
5 mM Fe (Fig. 5e-h) and 50 mM Fe (Fig. 5i-l) for an extra
min led to the does-dependent fluorescent responses. Such a cor-
2
+
2+
3.3. Selectivity and anti-interference ability of the probe YTP
relation could be illustrated with the columns diagram (Fig. 5m)
with variance analysis. Therefore, TYP could be applied in cellular
imaging with the semi-quantitative capability.
Here we evaluated the selectivity of the probe YTP towards Fe
II) from common metallic ions and other analytes. As shown in
(
Fig. 4a, YTP only exhibited fluorescent response to Fe(II), whereas
almost no reporting signals could be observed at 560 nm upon
adding other analytes, including Fe(III). Then we evaluated the
anti-interference ability in the coexistence systems of Fe(II) and
other analytes. In each group, one competing analyte was added
in the system containing both TYP and Fe(II). In Fig. 4b, basically,
no competing analytes could interfere the fluorescence of the
detecting system containing TYP and Fe(II). In consideration of
the steadiness with the time condition, we also compared the
4. Conclusion
In conclusion, we exploited a novel quinoline-derived fluores-
cent probe, YTP, for the detection of Fe(II). YTP could monitor
the level of Fe(II) with a linear range of 0–2.0 equivalent and the
detection limit of 0.16 mM. It also presented high selectivity
towards Fe(II) from other analytes including Fe(III). The detecting
4

Chun-He Cai, He-Li Wang and Ruo-Jun Man
Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 255 (2021) 119729
Fig. 5. Confocal microscopy images of HeLa cells incubated with YTP (10 mM) for 20 min at 37 ℃ (a-d), followed by the addition of 25 mM Fe (e-h), 50 mM Fe2+ (i-l) and
2+
incubated for another 5 min. (a, e, i) Green channel (540–620 nm), (b, f, j) Zoom, (c, g, k) Bright field, (d, h, l) Merge images. kex = 405 nm, Scale bar = 25 mm. (g) Quantification
0
of imaging data (c, f). n = 3, error bars were ± SD. Statistical analysis performed with a two-tailed Student s t-test with unequal variance, ***p value < 0.001.
system was steady in coexistence and in 24 h, respectively. The
applications in real buffer systems and in cellular imaging further
convinced the practicability of TYP. The probe could achieve the
semi-quantitative monitoring of Fe(II) in living cells. This work
provided a potential implement for the detection of Fe(II), and
raised important information for further researches on the redox
pairs of iron, in mechanism and in practice.
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Chun-He Cai: Writing - original draft, Methodology, Formal
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Jun Man: Writing - review & editing, Project administration, Fund-
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