CO release with ratiometric fluorescence changes: A promising visible-light-triggered metal-free CO-releasing molecule

Article abstract of DOI:10.1039/c9cc04026a

The first visible-light-triggered metal-free and ratiometric fluorescent CORM is reported. This CORM can be used to release CO with distinct ratiometric fluorescence changes in aqueous solution, living cells, zebrafish, and mice, which provided an excelle

Full text of DOI:10.1039/c9cc04026a

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CO release with ratiometric fluorescence changes: A promising
visible-light-triggered metal-free CO-releasing molecule†
Weiyong Feng, Shumin Feng and Guoqiang Feng*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
The first visible-light-triggered metal-free and ratiometric water solubility or turn-off fluorescence signal changes, which
fluorescent CORM was reported. This CORM can be used to release are not desirable for the applications and fluorescence tracking
CO with distinct ratiometric fluorescence changes in aqueous in living systems.
solution, living cells, zebrafish, and mice, which provided an
excellent controllable and trackable CORM for living systems.
Herein, we report a visible-light-triggered metal-free and
ratiometric fluorescent CORM (Cou-Flavone in Scheme 1) for
releasing of CO both in vitro and in vivo. This new CORM is based
on a coumarin-flavonol hybrid structure, which can release CO
upon visible light irradiation and displays distinct ratiometric
fluorescence changes during CO releasing. Ratiometric
fluorescence changes are known particularly useful because
they can provide precise and quantitative analyses owing to
their inherent reliability by the self-calibration and self-
correction by monitoring two emissions.34 Moreover, Cou-
Flavone is easy to prepare and preserve, and shows desirable
properties for CO releasing including rapid releasing speed,
controllable release behavior, low cytotoxicity, and applicable
in both living cells and living animals. To the best of our
knowledge, Cou-Flavone is the first metal-free and ratiometric
fluorescent CORM reported to date (Table S1, ESI).
Carbon monoxide (CO) has been recognized as a fatal toxic gas
for a long time.1 However, recent studies revealed that CO is an
endogenously produced gasotransmitter in our human body
and plays vital roles in a vast number of physiological and
pathological processes.2 Moreover, CO shows great therapeutic
potential for various diseases such as vascular, inflammatory,
hypertension, and even cancer.3 However, many problems exist
in the treatment of disease by direct inhalation of CO gas due to
its toxicity, uncontrollable issues and difficulties in targeted
delivery.4 As such, great attention has been given to the
development of suitable CO-releasing molecules (CORMs) to
replace the direct use of CO gas for disease treatment in the
past decades.5
Many CORMs have been developed based on transition metal-
carbonyl complexes.6 Although CO can be liberated from these
transition metal CORMs, a big problem exists in their medical
applications owing to the potential cytotoxicity of heavy metals.
To sort out this problem, much effort has been devoted recently
to develop metal-free CORMs and many metal-free CORMs
were developed with promising results.7-23 Among them,
visible-light-triggered metal-free CORMs with fluorescence
properties are particularly attractive because they not only can
be used to release CO in a biocompatible and controllable way
but also show an outstanding advantage, that is the capability
to track and monitor the process of CO releasing through their
own fluorescence signal changes.24-33 However, almost all of the
developed fluorescent metal-free CORMs showed either poor
visible
light
O
CO
COOH
OH
O
O
O
O
O
N
O
O
N
Cou-Carboxylate
Em: 475 nm
Cou-Flavone
Em: 555 nm
Scheme 1. A metal-free and ratiometric fluorescent CORM (Cou-Flavone) for CO
releasing.
Cou-Flavone was designed to contain a coumarin fluorophore
and a 3-hydroxy flavonoids fluorophore (Scheme 1). Coumarin
is one of the most common fluorophores with readily
availability and excellent fluorescence properties. 3-hydroxy
flavonoids also shows excellent fluorescent properties due to its
excited state intramolecular proton transfer (ESIPT) nature,35
and more importantly, these compounds were reported
recently to be excellent visible light-triggered CORMs.24-33 In this
work, we combined these two fluorophores so that a light-
Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, Chemical
Biology Center, College of Chemistry, Central China Normal University,152 Luoyu
Road, Wuhan 430079, PR China. Email: gf256@mail.ccnu.edu.cn
†Electronic Supplementary Information (ESI) available: [Experimental details, Table
S1, structure characterizations, and additional data]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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triggered CORM with ratiometric fluorescence changes can be release from Cou-Flavone is light-triggered, which allows for a
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DOI: 10.1039/C9CC04026A
achieved. Before irradiation, Cou-Flavone was expected to precise spatial and temporal control over the CO release.
show yellow fluorescence due to the ESIPT process of flavone
Recently, we reported an effective near-infrared (NIR)
unit, however, once the flavone unit of Cou-Flavone is broken fluorescent turn-on probe system (Probe 1 + PdCl2 in Fig. S4) for
to release CO upon irradiation, Cou-Carboxylate will be selective and sensitive detection of CO.36 The release of CO from
generated, which shows the blue-green fluorescence of the Cou-Flavone was directly proved by this probe system. As
coumarin unit, thus offering a novel metal-free and visible light- shown in the Fig. S5, a big NIR fluorescence enhancement can
triggered ratiometric fluorescent CORM.
be observed when the probe 1 system was used to probe the
Cou-Flavone can be easily prepared via two steps of reaction light irradiated Cou-Flavone solution, indicating CO was
from commercially available 2-hydroxy acetophenone and released. Moreover, the CO release with Cou-Flavone was also
readily available coumarin
1 (Scheme S1, ESI†). Cou- confirmed and quantified by GC analysis (Fig. S6). The
Carboxylate, the photolysis product of Cou-Flavone was also quantitative analysis of the released CO is indeed proportional
synthesized by irradiation of Cou-Flavone under a 460 nm light. to the wavelength changes as shown in Fig. 1 and Fig. S2.
The structures of Cou-Flavone and Cou-Carboxylate were
characterized by NMR, MS, and HRMS (ESI).
In addition, according to the previous reports,27-31 Cou-
Carboxylate should be formed after CO release. Thus, the light
The capacity of Cou-Flavone for CO-releasing was irradiated Cou-Flavone solution was subjected to LC-MS
investigated in HEPES buffer (10 mM, pH 7.4, with 10% DMSO, analysis (Fig. S7). The results showed that Cou-Carboxylate was
v/v) at room temperature under a light irradiation (460 nm, 7 produced in the reaction mixture and increased over the
w, 12 mW /cm2). As shown in Fig. 1, the Cou-Flavone (10 µM) irradiation time. The peak with mass of 381.12342 and
solution before irradiation shows a strong yellow fluorescence 404.11056 in the high resolution spectrometric analysis further
around 555 nm with excitation at 420 nm (Ф = 0.03) and a major proved the formation of Cou-Carboxylate (Fig. S8), which match
absorption peak at 445 nm. However, upon irradiation, the well with the exact mass of Cou-Carboxylate (calcd for
solution showed a dramatic decrease of fluorescence intensity 381.12124 and 404.11046). In addition, Cou-Carboxylate can be
at 555 nm and a concomitant increase in a new emission band isolated and characterized by NMR and Mass analyses from the
at 475 nm (Ф = 0.02) with an apparent isoemissive point at 510 light irradiated Cou-Flavone solution (ESI). The resulting optical
nm, indicating a typical ratiometric fluorescence change (Fig. spectra of the Cou-Flavone solution after irradiation were also
1a). Meanwhile, a distinct emission color change from yellow to found almost the same to that of Cou-Carboxylate (Fig. S9).
blue-green was observed. In the absorption spectra (Fig. 1b), a Based on these results, the mechanism for CO-releasing from
new peak at 433 nm formed and gradually enhanced to Cou-Flavone is proposed to be a process as shown in Scheme 1.
saturation over time after irradiation, accompanied by a color
change from yellow to yellow-green.
CO has been reported to exhibit anti-proliferative effects to
living cells. Thus, we investigated the anti-proliferative effect of
CO released from Cou-Flavone. As shown in Fig. S10, the Cou-
Flavone and Cou-Carboxylate shows almost no cytotoxicity to
both HeLa and MCF-7 cells even they are present up to 50 μM.
The irradiation at 460 nm also shows no influence to the cells
viability (Fig. S11a). However, when the cells were incubated
with different concentrations of Cou-Flavone with an
irradiation for 15 min and then cultured for 24 h, the cell
viability showed a decrease over the loaded amount of Cou-
Flavone (Fig. S11b). These results indicate that the released CO
from the Cou-Flavone showed some anti-proliferative effect.
The release of CO with Cou-Flavone in living cells was then
investigated by fluorescence imaging technique. As shown in
Fig. 2, the blank cells and the cells costained with our probe 1
system (10 μM Probe 1 + 10 μM Pd2+) showed almost no
fluorescence in three channels (blue, yellow, and red channels,
images A1-A3 and B1-B3). When MCF-7 cells were incubated
with Cou-Flavone for 15 min at 37 °C without irradiation, strong
yellow fluorescence was observed in the yellow channel, which
can be ascribed to the fluorescence of itself. However, when the
cells were incubated with Cou-Flavone with an irradiation (460
nm, 7w, 12 mW/cm2) for 5, 10, and 15 min, respectively, the
cells started to show a gradual fluorescence decrease in the
yellow channel (D2, E2, and F2) and an obvious increase in the
blue channel (D1, E1, and F1) as the time of irradiation
increases. This is in good agreement with the ratiometric
fluorescence responses observed in the solution, indicating the
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Fig.1. (a) Fluorescence and (b) UV-vis spectral changes of Cou-Flavone (10 µM)
with irradiation (460 nm, 7w, 12 mW/cm2) in HEPES buffer (10 mM, pH 7.4, 10%
DMSO, v/v) at 25 ℃ . Each data was collected after 1 min of irradiation. For
fluorescent measurements, λex = 420 nm, slit width: dex = dem = 5 nm. Inset in (a)
and (b): fluorescent and color changes, respectively.
Kinetic studies of Cou-Flavone under irradiation showed that
the fluorescence and absorption signal changes at the
corresponding wavelengths gradually changed until
a
saturation was reached at about 15 min (Fig. S1). The half-life
(t1/2) was calculated to be about 130 s (Fig. S2), indicating Cou-
Flavone shows a relatively fast CO-releasing process in aqueous
solution under the irradiation conditions. It should be noted
that Cou-Flavone is stable in the absence of irradiation (Fig.
S3a), and in fact, Cou-Flavone can be well preserved under light-
shielded conditions. In addition, a periodic illumination of the
Cou-Flavone solution resulted in
a
time-dependent
fluorescence change as shown in Fig. S3b, indicating the CO
2 | J. Name., 2012, 00, 1-3
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CO-releasing process of Cou-Flavone in living cells can be strong yellow fluorescence was observed in the yeVllioewwArctihclaenOnnleinle.
DOI: 10.1039/C9CC04026A
tracked by its own fluorescence changes. Moreover, this CO- When the zebrafish was incubated with Cou-Flavone and
releasing process was also proved with probe 1, as can be seen irradiated with a 460 nm light for a period of time (5 and 15
in Figure 2, an obvious fluorescence increase in the red channel min), a dramatic decrease fluorescence in yellow channel
(images D3, E3, and F3) can be clearly observed if using probe 1 (images D2 and E2) and an increase fluorescence in blue
as the indicator. All these results indicate that Cou-Flavone can channel (images D1 and E1) over time can be clearly observed,
be applied to release CO with trackable releasing process with indicating a CO-releasing process happened. This CO-releasing
its own ratiometric fluorescence changes in living cells.
process can be also proved by probe 1 in the red channel
(images D3 and E3). These results demonstrated that Cou-
Flavone could be used to release CO in living zebrafish with
trackable ratiometric fluorescence changes.
A
B
C
D
E
F
Fig. 4 shows the capacity of Cou-Flavone for releasing of CO
in living mice. As shown in Fig. 4, when the mouse was injected
only with saline (100 μL with 5 % DMSO, v/v) in the blank group
and injected with the probe 1 system (10 μM Probe 1 + 10 μM
Pd2+, in 100 μL saline with 5 % DMSO, v/v) in the control group,
almost no fluorescence in three channels (blue, yellow, and red)
can be observed around the injection area. However, when the
mouse was given an intraperitoneal injection of Cou-Flavone
(20 μM, in 100 μL saline with 5% DMSO, v/v) and followed with
an irradiation (460 nm, 7w, 12 mW/cm2) for 0, 5, and 20 min
around the injection area, a gradual decrease of fluorescence in
the yellow channel (images C1, D1 and E1) along with a gradual
increase of fluorescence in the blue channel (images C, D and E)
A1
B1
C1
D1
E1
F1
A2
A3
B2
B3
C2
C3
D2
D3
E2
E3
F2
F3
Fig. 2. Fluorescent imaging of CO-releasing with Cou-Flavone in living MCF-7 cells. Row
A-F: bright field images. Row A1-F1: blue channel images with emissions collected at 420-
500 nm (λex = 405 nm). Row A2-F2: yellow channel images with emissions collected at
520-600 nm (λex = 458 nm). Row A3-F3: red channel images with emissions collected at
670-750 nm (λex = 670 nm). (A and A1-A3) blank group. (B and B1-B3) the probe 1 system
treated group. (C and C1-C3) Cou-Flavone (10 μM) and the probe 1 system treated group
without irradiation. (D and D1-D3) Cou-Flavone (10 μM) with irradiation for 5 min and can be clearly observed over the irradiation time, indicating a
the probe 1 system treated group. (E and E1-E3) Cou-Flavone (10 μM) with irradiation
CO-releasing process occurred with ratiometric fluorescence
for 10 min and the probe 1 system treated group. (F and F1-F3) Cou-Flavone (10 μM)
changes. Meanwhile, probed with the probe 1 system, an
with irradiation for 15 min and the probe 1 system treated group. Irradiation light source:
460 nm, 7 w, 12 mW /cm2.
obvious NIR fluorescence enhancement was also observed
(images C2, D2 and E2), further proving the CO-releasing
process. In addition, the level of blood carboxy-hemoglobin
(COHb) after Cou-Flavone treatment was found to show an
enhancement over the irradiation time (Fig. S12). All these
results indicate that Cou-Flavone can be used as a photo-
controllable CORM for releasing of CO with ratiometric
fluorescent signal changes in living animals.
A
B
C
D
E
A1
A2
A3
B1
B2
B3
C1
C2
C3
D1
D2
D3
E1
E2
E3
1600
Blue channel
A
B
C
D
E
F
**
1200
800
400
0
**
D
**
B
**
A
C
E
Yellow channel
**
A1
A2
B1
B2
C1
C2
D1
D2
E1
E2
G
H
1600
1200
800
400
0
**
D1
**
E1
**
Fig. 3. Fluorescence confocal images of CO-releasing in living wild zebrafish with Cou-
Flavone. For images of A-E were bright fields. For images of A1-E1, emissions were
collected at 420-500 nm (λex = 405 nm). For images of A2-E2, emissions were collected at
520-600 nm (λex = 458 nm). For images of A3-E3, emissions were collected at 670-750 nm
(λex = 670 nm). (A, A1, A2 and A3) blank group. (B, B1, B2 and B3) the probe 1 system
treated group. (C, C1, C2 and C3) Cou-Flavone without irradiation and the probe 1
system treated group. (D, D1, D2 and D3) Cou-Flavone with irradiation for 5 min and the
probe 1 system treated group. (E, E1, E2 and E3) Cou-Flavone with irradiation for 15 min
and the probe 1 system treated group. Irradiation light source: 460 nm, 7 w, 12 mW
/cm2.
A1
B1
C1
Red channel
1600
1200
800
400
0
**
**
D2
**
C2
**
A2
B2
E2
Fig. 4. Fluorescent images of CO-releasing in mice with Cou-Flavone. TOP A-E: blue
channel (λex/λem = 420/470 nm). Middle A1-E1: yellow channel (λex/λem = 460/550 nm).
Bottom A2-E2: red channel (λex/λem = 670/710 nm). (A, A1 and A2) blank group. (B, B1
and B2) control group injected with the probe 1 system. (C, C1 and C2) Cou-Flavone (100
µL, 20 µM, without irradiation) and the probe 1 system treated group. (D, D1 and D2)
Cou-Flavone (100 µL, 20 µM) with irradiation for 5 min and the probe 1 system treated
group. (E, E1 and E2) Cou-Flavone (100 µL, 20 µM) with irradiation for 15 min and the
probe 1 system treated group. The yellow squares in D1 and E1 indicate the irradiation
areas. (F, G, H) quantification of fluorescent intensity from the abdominal area of the
mice at three channels, respectively. Irradiation light source: 460 nm, 7 w, 12 mW /cm2.
Results are presented as meanꢀ±ꢀs.d. nꢀ=ꢀ3 per group. **Pꢀ<ꢀ0.05, versus group A.
The release of CO with Cou-Flavone in living zebrafish and
mice was also investigated. As illustrated in Fig. 3, the blank
zebrafish and zebrafish costained with the probe 1 system (10
μM Probe 1 + 10 μM Pd2+) showed almost no fluorescence in
three channels (blue, yellow and red). However, when the
zebrafish was costained with Cou-Flavone (10 μM), an obvious
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9
M. Devillard, d. B. Bas, M. A. Siegler and J. I. V.VViewluAgrtti,clCe hOenlmine.
Eur. J., 2017, 23, 13628–13632.
In summary, we have developed a metal-free ratiometric
fluorescent CO-releasing molecule, Cou-Flavone, based on a
coumarin-flavone hybrid structure. Cou-Flavone not only can
be easily prepared, but also can be used to release CO in
aqueous solution, living cells and animals under a visible light
irradiation with low cytotoxicity and distinct ratiometric
fluorescent signal changes, which provided a very promising
CORM for living systems with controllable and trackable
properties. The investigation of the therapy potential of this
CORM is currently ongoing in our laboratory.
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Acknowledgements
This work was financially supported by National Natural Science
Foundation of China (Grant Nos. 21672080 and 21472066) and
the Fundamental Research Funds for the Central Universities
(CCNU19TS007).
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DOI: 10.1039/C9CC04026A
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Graphical abstract for contents page:
A visible-light-triggered metal-free CO-releasing molecule with distinct ratiometric fluorescence
changes was reported for CO release in living systems.
visible
light
CO
O
O
COOH
Ratiometric
fluorescence
changes
OH
O
CO release
O
living systems
O
O
N
O
O
N
Em 555 nm
Em 475 nm