A Water-Soluble, Green-Light Triggered, and Photo-Calibrated Nitric Oxide Donor for Biological Applications

Article abstract of DOI:10.1021/acs.bioconjchem.7b00821

Nitric oxide (NO) is a versatile endogenous molecule, involved in various physiological processes and implicated in the progression of many pathological conditions. Therefore, NO donors are valuable tools in NO related basic and applied applications. The traditional spontaneous NO donors are limited in scenarios where flux, localization, and dose of NO could be monitored. This has promoted the development of novel NO donors, whose NO release is not only under control, but also self-calibrated. Herein, we reported a phototriggered and photocalibrated NO donor (NOD565) with an N-nitroso group on a rhodamine dye. NOD565 is nonfluorescent and could release NO efficiently upon irradiation by green light. A bright rhodamine dye is generated as a side-product and its fluorescence can be used to monitor the NO release. The potentials of NOD565 in practical applications are showcased in in vitro studies, e.g., platelet aggregation inhibition and fungi growth suppression.

Full text of DOI:10.1021/acs.bioconjchem.7b00821

Article
Cite This: Bioconjugate Chem. XXXX, XXX, XXX−XXX
pubs.acs.org/bc
A Water-Soluble, Green-Light Triggered, and Photo-Calibrated Nitric
Oxide Donor for Biological Applications
†
†
†
⊥
†
¶
#
Haihong He, Yang Xia, Yingxue Qi, Hong-Yin Wang, Zhuang Wang, Jianming Bao, Ziqian Zhang,
Fu-Gen Wu,⊥ Haolu Wang, Daijie Chen, Dahai Yang, Xiaowen Liang,* Jinquan Chen,*
Shengmin Zhou,* Xin Liang,* Xuhong Qian, and Youjun Yang*
‡
∥
†
,‡
,§
,†
,†
†
,†
†State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, Shanghai Key
Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
‡Therapeutics Research Centre, The University of Queensland Diamantina Institute, The University of Queensland, Translational
Research Institute, Woolloongabba, QLD 4102, Australia
§
State Key Laboratory of Precision Spectroscopy, East China Normal University, Shanghai, 200062, China
∥
School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
⊥
State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing,
Jiangsu 210096, China
#
Guangxi Scientific Research Center of Traditional Chinese Medicine, Guangxi University of Chinese Medicine, Nanning, Guangxi
5
30200, China
¶
School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
S Supporting Information
*
ABSTRACT: Nitric oxide (NO) is a versatile endogenous molecule,
involved in various physiological processes and implicated in the progression
of many pathological conditions. Therefore, NO donors are valuable tools in
NO related basic and applied applications. The traditional spontaneous NO
donors are limited in scenarios where flux, localization, and dose of NO
could be monitored. This has promoted the development of novel NO
donors, whose NO release is not only under control, but also self-calibrated.
Herein, we reported a phototriggered and photocalibrated NO donor
(
NOD565) with an N-nitroso group on a rhodamine dye. NOD565 is
nonfluorescent and could release NO efficiently upon irradiation by green
light. A bright rhodamine dye is generated as a side-product and its
fluorescence can be used to monitor the NO release. The potentials of
NOD565 in practical applications are showcased in in vitro studies, e.g.,
platelet aggregation inhibition and fungi growth suppression.
INTRODUCTION
Existing NO donors are diverse in structure and mechanism.
Trinitroglycerin, isoamyl nitrite, and sodium nitroprusside
■
24
25
26
The biological implications of nitric oxide (NO) were not
recognized until the 1970s. Murad et al. proved that nitro-based
vasodilators function by production of nitric oxide in vivo,
which induces the formation of cGMP and leads to
are among the oldest nitric oxide donors, which have been used
in treating hypertensive emergencies in the 19th century.
Nitrosothiols, diazeniumdiolates, and (benzo-/)furoxans are
18−23
1
recent additions to the field.
They spontaneously release
vasodilation. Furchgott et al. discovered that endothelial cells
NO in a biological milieu in the presence of various biological
analytes or enzymes without the necessity of external stimuli.
The biological response of NO is profoundly influenced by
could release an unknown substance (EDRF) to induce
2
vasodilation. He further hypothesized that EDRF could be
3
NO and this was confirmed independently by Moncada et al.
27−30
4
where, when, and how much NO is released.
This has
and Ignarro et al. To date, NO has been found to be involved
greatly limited the scope of these spontaneous NO donors in
basic mechanistic studies. The development of the first
phototriggered NO donor (CNOs), i.e., an o-nitrobenzyl
in numerous physiological and pathological processes in
5
,6
7,8
mammalian cells,
isms.
plants cells,
and prokaryotic organ-
9
,10
Recently, Bossy-Wetzel reported that mitochondrial
11
dynamics is also regulated by nitric oxide. NO donors, a
group of chemicals capable of decomposing to release NO, are
sought-after for both basic biological studies and therapeutics
Received: December 25, 2017
Revised: February 8, 2018
1
2−23
applications.
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.bioconjchem.7b00821
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Bioconjugate Chemistry
Article
protected NONOate constructed by protection of a sponta-
neous NO donor with a photolabile group, has been
by alkylation of m-aminophenol (2a) with 1,3-propane sultone
(2a) in acetonitrile at room temperature in quantitative yield.
Subsequent condensation of 1 and 2 in 75% H SO at 100 °C
3
1
enlightening. Another notable group of phototriggered NO
donors involves photoinduced sensitization of an electron-rich
2
4
furnished the rhodamine 3 in a 81% yield. Treatment of 3 with
NaNO in a mixed solvent of dichloromethane and acetic acid
32
N-nitrosamine (NO-Rosa). We have recently proposed to
develop phototriggered NO donors with a concomitant
fluorescent turn-on. Such phototriggered and photocalibrated
NO donors are advantageous because they not only render a
spatiotemporal control over the release of NO, but also offer a
convenient and sensitive method for monitoring. The first
examples of such novel NO donors are a group of N-nitrosated
2
at 0 °C yielded the desired NO donor (NOD565) in a 90%
yield.
The UV−vis absorption and fluorescence spectra of
NOD565 and 3 were acquired in phosphate buffer (50 mM,
pH = 7.4). NOD565 and 3 exhibited a favorable water-
solubility, which was tested to be at least 11 mg/mL, equivalent
to 20 mM. The solution NOD565 has a unique absorption
band from ∼420 to 570 nm. Three peaks were identified to be
33
naphthalimide dyes (NOD545) (Figure 1).
−
1
−1
−1
at 475 nm (ε = 19,900 cm M ), 505 nm (ε = 28,800 cm
−1
−1
−1
M ), and 537 nm (ε = 23,700 cm M ). The fluorescence
emission spectrum of this solution was obtained with an
excitation at 505 nm. Overall, a very low but finite emission
band with a maximum at 565 nm could be observed. The UV−
vis absorption spectrum of 3 is very typical of a rhodamine, an
−1
intense band with a maximum at 540 nm (ε = 70,300 cm
−1
−1
−1
M ) and minor shoulder at 510 nm (ε = 32,300 cm M ).
Upon excitation at 540 nm, an emission band at 565 nm was
observed with a fluorescence quantum yield of 0.14.
Figure 1. Examples of notable photoactivated NO donors.
Photoinduced decomposition of NOD565 and triggered
+
NOD545 have a few limitations yet to be addressed. First, it
requires UV light to trigger NO release. Also, the fluorescence
of naphthalimide dyes is moderate in brightness. Third, their
scaffolds are rather hydrophobic and exhibit limited water-
solubility. Therefore, it is the ambition of this work to develop
highly water-soluble NO donors, which can be triggered to
release NO by a longer-wavelength green light and can release a
brighter fluorophore, i.e., rhodamine.
release of NO was studied. An Ar laser line (532 nm, 200
mW) was used as the light source. The UV−vis absorption and
fluorescence emission of a solution of NOD565 (10 μM) in
aqueous phosphate buffer (50 mM, pH = 7.4) were monitored
before and intermittently after photoirradiation (Figure 2). The
RESULTS AND DISCUSSION
■
We have previously showcased that N-nitrosated push−pull
dyes are viable general strategies for the development of novel
phototriggered and photocalibrated NO donors. We designed
the structure of NOD565 which employed a highly fluorescent
rhodamine scaffold. Also, a sulfonate group is installed to
promote aqueous solubility of the NO donor. It is conveniently
synthesized in 4 steps (Scheme 1). The intermediate 1 was
obtained by condensation of m-N,N-diethylaminophenol (1a)
and stoichiometric phthalide anhydride (1b) upon refluxing in
toluene in a 98% yield. The coupling partner (2) was obtained
Figure 2. (A) UV−vis absorption spectral and fluorescence emission
spectral changes of NOD565 solution upon photoirradiation by 532
nm. Blue lines: the absorption and emission of NOD565. Red lines:
the absorption and emission of 3. (B) The enhancement of emission
intensity at 565 nm of the solution with respect to the duration of
photoirradiation.
Scheme 1. Design of Photo-Triggered and Photo-Calibrated
NO Donors
absorption spectrum has changed dramatically. The absorbance
at 540 nm was enhanced by ∼3-fold before and after complete
photodecomposition. An isosbestic point was found at 503 nm
and the absorbance in the range of 310−503 nm underwent a
drop. An abrupt fluorescence enhancement of 53-fold was seen
at 565 nm. The majority of decomposition and fluorescence
recovery occurred within the first 100 s. Continuous photo-
irridation for 532 nm did not induce further fluorescence
fluctuation.
The phototriggered NO release was verified by a commercial
NO probe (DAN), which reacts with NO in the presence of
34
oxygen to produce NAT (Figure 3A). All three compounds
DAN, NAT and rhodamine 3) are excitable by 300 nm.
Therefore, it is possible to simultaneously monitor the three
species with a three channel ratiometric emission scan (λex
00 nm). A solution containing both NOD565 (10 μM) and
DAN (10 μM) in aqueous phosphate buffer (50 mM, pH =
(
=
3
7
.4) with 5% DMSO was prepared. The use of higher
B
DOI: 10.1021/acs.bioconjchem.7b00821
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Bioconjugate Chemistry
Article
Figure 4. Confocal fluorescence imaging of HeLa cells invubated with
NOD565 (20 μM) for 30 min. (A) Bright-field image. (B)
Fluorescence image before irradiation. (C) Fluorescence image after
irradiation by 532 nm for 60 s. Scale bar: 10 μM.
Figure 3. (A) Capture of NO released from NOD565 upon
photoirradiation. (B) Fluorescence changes of a solution containing
NOD565 (10 μM) and DAN (10 μM) in aqueous phosphate buffer
Inhibition of Platelet Aggregation. NO plays a role in
37,38
platelet aggregation inhibition.
Hence, we evaluated the
potentials of our donors in such an application. The inhibition
percentage of platelet aggregation was measured at different
conditions (Figure 5). First, at the time point indicated by
(
50 mM, pH = 7.4) upon photoirradiation at 532 nm for 80 s, λex =
3
4
00 nm. (C) Gradual change of emission intensity at 390 nm (DAN),
35 nm (NAT), and 565 nm (3) of the solution is plotted with respect
to the duration of photoirradiation.
percentage of DMSO is owing to the poor solubility of both
DAN and NAT in an aqueous medium. The solution was then
irradiated with 532 nm light and the fluorescence emission
spectrum of the solution was collected intermittently. The
fluorescence of 3 gradually increased with respect to the
exposure time (Figure 3B), consistent with Figure 2. At the
same time, the emission band of DAN at 390 nm gradually
decreased and the emission band of NAT at 435 nm increased
(
Figure 3A), essentially at the same kinetic profile (Figure 3C).
The release of NO was also independently verified by EPR
study (Figure S1).
Figure 5. Inhibition effect of NOD565 (in aqueous solvent) toward
platelet aggregation in the presence of ADP (10 μM) and collagen (5
μg/mL). NC: negative control group without 3 or NOD565 or light
irradiation. Light: 3 W green LED light. Light duration: 10 min.
Excellent chemostability of NO donors is desired in
biological studies to avoid unintended NO release and
fluorescence turn-on. Theoretically, N-nitroso compounds
may cause denitrosation in the presence of nucleophiles, e.g.,
3
5
36
thiols, and reducing agents. Hence, the stability of NOD565
was tested in phosphate buffer (50 mM, pH = 7.4) with
cysteine, glutathione, and ascorbic acid in the dark. The
absorbance spectra of these solutions were collected and
plotted in Figure S3. All three agents at very high
concentrations (up to 10 mM) did not induce any spectra
changes at room temperature in 30 min, suggesting competent
chemostability of NOD565. The absorbance values for 24 h
also comfirmed the result except for conditions at 37 °C or with
ascorbic acid, which exhibited an absorbance enhancement by
ca. 5% decomposition of NOD565 (Figure S4). Overall,
NOD565 displayed high chemostability and feasibility for
practical applications.
In vitro NO release of NOD565 was investigated in HeLa
cells. An aqueous solution of NOD565 (20 μM) was added
into the HeLa cell culture and incubated for 30 min. The
fluorescence images were collected before and after irradiation
by 532 nm (Figure 4). As shown in Figure 3B, the cells
exhibited no background as expected. However, upon photo-
irradiation by 532 nm for 60 s, punctate fluorescence was
captured. This highlighted its potentials as an exogenous NO
donor for in vitro NO studies. The feasibility of NOD565 in
zebrafish embryos was also preliminarily tested. An aliquot of
NOD565 solution (1 mM, 3 nL) in DMSO was injected into
the yolk sac region of a zebrafish egg, which we have indicated
in SI. As shown in Figure S7, the fluorescence was turned on
upon green light irradiation, which suggested that NOD565
could release NO and dye 3 in this case.
arrows, adenosine diphosphate (ADP, 10 μM) and collagen (5
μg/mL) were added into the platelet-rich plasma to induce
aggregation. By the end of 3.5 min, platelet aggregation was
nearly 90% (NC). The addition of 3 (100 μM) or NOD565
(100 μM) without photoirradiation did not significantly inhibit
platelet aggregation to any appreciable extent. In the presence
of NOD565 (10 μM) and green light irradiation, aggregation
percentage dropped to ca. 50%, suggesting that NO produced
from photolysis of NOD565 indeed inhibited platelet
aggregation. Platelet aggregation inhibition by NOD565
under photoirradiation was dose dependent. Raising the
concentration of NOD565 (to 100 μM) helped to further
inhibit the platelet aggregation percentage (to below 50%).
Antimicrobial Activity. The immune system harnesses
NO as a defense against infectious microbes and intracellular
39
parasites. To further test the feasibility of our NO donors in
biological applications, we carried on qualitative and
quantitative studies on cytotoxicity of released NO to microbes.
Aspergillus nidulans is one of the model fungi, exhibiting
sensitivity to NO, generated from NO donors, e.g., NOCs (10
40,41
mM) or acidified nitrite (1−40 mM).
First, we examined
the sensitivity of wild type fungus A. nidulans to NO released
from NOD565 on the agar plate. As shown in Figure 6, after
cultivation for 30 h, compared to strains grown under the
control conditions without NOD565, the cell growth was
clearly suppressed by the NO released from NOD565 (3 mM)
triggered by an LED light (532 nm, 16 W). No obvious growth
impairment was observed on the media containing NOD565 (3
C
DOI: 10.1021/acs.bioconjchem.7b00821
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Bioconjugate Chemistry
Article
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.bioconj-
chem.7b00821.
General synthetic methods, experimental, compound
characterizations, photophysical results, chemostability
1
13
study, H NMR, C NMR and HRMS spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
E-mail: youjunyang@ecust.edu.cn (Yang, Y.).
E-mail: x.liang@uq.edu.au (Liang, X).
E-mail: jqchen@lps.ecnu.edu.cn (Chen, J.).
E-mail: zhoushengmin@ecust.edu.cn (Zhou, S.).
E-mail: xin.liang@ecust.edu.cn (Liang, X.).
■
*
*
*
*
*
Figure 6. Sensitivities of fungi to NO, derived from NOD565. Conidia
4
(
2 × 10 ) of wild type and Δfhb A. nidulans were grown on DPY agar
plates. The concentrations of NOD565 and 3 were all 3 mM. The
plates were incubated at 37 °C for 30 h with or without
photoirradiation by 532 nm (16 W LED light) as indicated.
ORCID
Fu-Gen Wu: 0000-0003-1773-2868
Jinquan Chen: 0000-0003-0652-1379
Shengmin Zhou: 0000-0002-9172-3444
Youjun Yang: 0000-0001-7085-6048
mM) in the dark or the photolysis product 3 (3 mM). This
experiment excludes the possibility that NOD565 itself or its
fluorophore product (3) inhibited the cell growth, and verifies
that the cytotoxicity was induced by NO. Furthermore, we
performed the experiment with A. nidulans Δfhb, which is
deficient of flavohemoglobin, a NO detoxifying enzyme.
Similarly to wild type cells, only NO releasing conditions
inhibited the cell growth. Moreover, the NO cytotoxicity
deriving from NOD565 to the mutant was indeed enhanced
compared to the wild type.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The work is supported by the Fundamental Research Funds for
the Central Universities (Nos. WY1514053, WY1516017),
Shanghai Pujiang Program (16PJ1402500) and the National
Natural Science Foundation of China (Nos. 21372080,
It is noteworthy that the dose of NO release is readily
monitored by the fluorescence from the agar media. Also, the
spectroscopic analysis (Figure S8) indicated NOD565 in the
agar media did not decompose without light irradiation, in
agreement with the chemostability study in Figure S3. These
results indicated that 3 mM NO could suppress and abolish the
growth of wild type and Δfhb of this fungus, respectively. As an
important immunological molecule, antimicrobial properties of
NO have been intensively studied. However, most studies
focused on the NO detoxification pathways and resistant
abilities of the microbial enzymes in qualitative levels rather
than quantitative investigations due to the difficulties to
quantify the dose of NO release from the existing NO donors.
Our present NO donor overcame the shortcomings of the
common NO donors. Additionally, being triggered by green-
light rather than the cytotoxic UV-light makes NOD565
potentially suitable for investigation of the physiological or
pathological roles of NO in microorganisms.
2
1572061, 11674101, 21236002, and 81502540).
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DOI: 10.1021/acs.bioconjchem.7b00821
Bioconjugate Chem. XXXX, XXX, XXX−XXX