An ESIPT Probe for the Ratiometric Imaging of Peroxynitrite Facilitated by Binding to Aβ-Aggregates

Article abstract of DOI:10.1021/jacs.8b08457

A series of 3-hydroxyflavone (3-HF) ESIPT (excited-state intramolecular proton transfer) boronate-based fluorescent probes have been developed for the detection of peroxynitrite (ONOO^-). The dyes are environmentally sensitive, and each probe exhibited a ratiometric response toward ONOO^-in a micellar environment. The probes were used to image different aggregation states of amyloid-β (Aβ) in the presence of ONOO^-. The3-HF-OMeprobe was found to produce a ratiometric response toward ONOO^-when bound to Aβ aggregates, resulting in a novel host-guest ensemble, which adds insight into the development of other ESIPT-based probes for the simultaneous sensing of fibrous proteins/peptides and environmental ROS/RNS.

Full text of DOI:10.1021/jacs.8b08457

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Article
An ESIPT Probe for the Ratiometric Imaging of
Peroxynitrite Facilitated by Binding to A#-Aggregates
Adam Sedgwick, Wei-Tao Dou, Jin-Biao Jiao, Luling Wu, George T Williams, A. Toby
A. Jenkins, Steven D. Bull, Jonathan L. Sessler, Xiao-Peng He, and Tony D. James
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b08457 • Publication Date (Web): 02 Oct 2018
Downloaded from http://pubs.acs.org on October 3, 2018
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An ESIPT Probe for the Ratiometric Imaging of Peroxynitrite Faciliꢀ
tated by Binding to AβꢀAggregates
Adam C. Sedgwick,ad‡ WeiꢀTao Dou,b‡ JinꢀBiao Jiao,b Luling Wu,a George T. Williams,a A. Toby A. Jenkins,a Steven D.
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Bull,a Jonathan L. Sessler,d* XiaoꢀPeng He,b* and Tony D. Jamesac*
aDepartment of Chemistry, University of Bath, Bath, BA2 7AY, U.K.
bKey Laboratory for Advanced Materials and Joint International Research Laboratory of Precision Chemistry and Molecu-
lar Engineering, Feringa Nobel Prize Scientist Joint Research Center, School of Chemistry and Molecular Engineering, East
China University of Science and Technology, 130 Meilong Rd., Shanghai 200237, China
cDepartment of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, 7-1 Kioi-cho, Chiyoda-
ku, Tokyo 102-8554 Japan.
dDepartment of Chemistry. University of Texas at Austin, 105 E 24th street A5300, Austin, TX 78712-1224 (USA)
Supporting Information Placeholder
(a)
ABSTRACT: A series of 3ꢀHydroxyflavone (3ꢀHF) ESIPT (exꢀ
citedꢀstate intramolecular proton transfer) boronateꢀbased fluoresꢀ
cence probes have been developed for the detection of peroxyniꢀ
trite (ONOOꢀ). The dyes are environmentally sensitive, and each
probe exhibited a ratiometric response towards ONOOꢀ in a micelꢀ
lar environment. The probes were used to image different aggreꢀ
gation states of amyloidꢀβ (Aβ) in the presence of ONOOꢀ. The 3ꢀ
HFꢀOMe probe was found to produce a ratiometric response toꢀ
wards ONOOꢀ when bound to Aβ aggregates, resulting in a novel
hostꢀguest ensemble, which adds insight into the development of
other ESIPTꢀbased probes for the simultaneous sensing of fibrous
proteins/peptides and environmental ROS/RNS.
ONOOꢀ
S
N
S
N
S
N
H
N
NH
N
O
B
O
(b)
O
B
O
O
O
OH
ONOOꢀ
O
OH
O
O
O
O
X
X
X
N
T*
3-HF-OMe
(X = OMe)
3-HF-PhMe (X = Me)
3-HF-Ph (X = H)
Alzheimer’s disease (AD) is a common neurodegenerative disease
that involves the progressive and gradual decline in cognitive
functions. Selfꢀassociating amyloidꢀβ peptides Aβ1ꢀ42 result in the
buildꢀup of amyloidꢀβ (Aβ) plaques, which are one of the key
factors for this cognitive decline.1ꢀ3 The neurotoxicity of Aβ pepꢀ
tides is believed to alter calcium homeostasis, inducing the inꢀ
flammatory response, and increase the formation of reactive oxyꢀ
gen and nitrogen species (ROS/RNS).4 Furthermore, it has been
shown that Aβ peptides can damage neurons by activating microꢀ
glia, which generate peroxynitrite (ONOOꢀ).5 ONOOꢀ is a RNS
known for its deleterious effects, causing irreversible damage to a
range of biological targets such as lipids, proteins and DNA.6, 7 In
addition, higher levels of nitrated proteins are typically found in
the neurons (ONOOꢀ indicator) of AD victims.8 As a result, a
number of small molecule fluorescent probes have been develꢀ
oped for Aβ detection9ꢀ12 ‘OR’ for ONOOꢀ detection.13ꢀ17 Howevꢀ
er, to date no fluorescenceꢀbased probe has been developed that
can simultaneously detect ONOOꢀ whilst bound to an Aβ peptide.
The development of such a probe would provide a powerful tool
that might enhance the understanding of AD progression and
could potentially be used to evaluate AD therapeutic strategies.
Scheme 1. (a) Our previous work on boronate based ESIPT fluoresꢀ
cence probes for peroxynitrite. (b) Boronate based ESIPT fluorescence
probes for peroxynitrite based on 3ꢀhydroxyflavones (3ꢀHFs) (X = OMe,
Me or H). Also shown are the normal (N) and phototautomeric (T*) forms
of the excitedꢀstate intramolecular proton transfer (ESIPT) process.
Figure 1. Schematic illustration of the proposed interactions of 3ꢀHF
probes with amyloid β (Aβ) aggregates and their use as a new hostꢀguest
system for the ratiometric sensing of peroxynitrite (ONOOꢀ). The 3ꢀHFꢀ
OMe “guest” molecules can associate with the hydrophobic cavity of a
“host” matrix formed by Aβ peptide aggregation. This leads to an enꢀ
hanced fluorescence of the N state of the ESIPT probe. Subsequent reacꢀ
tion of ONOOꢀ with the peptideꢀmatrixꢀbound 3ꢀHFꢀOMe probe activates
the T* fluorescence state of the ESIPT probe, thus enabling the ratiꢀ
ometric detection of RNS.
We have been particularly interested in developing small moleꢀ
cule fluorescenceꢀbased probes owing to their high sensitivity,
selectivity and high spatial and temporal resolution.18ꢀ20 Here we
report the use of 3ꢀhydroxyflavones (3ꢀHF) as fluorescenceꢀbased
reporters for the ratiometric detection of ONOOꢀ when bound to
Aβ aggregates (Scheme 1 and Fig. 1).
3ꢀHFs have been used extensively as fluorescent probes for the
detection of a wide range of analytes.21ꢀ25 The interest in such
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systems arises from the dual fluorescence emission ascribed to the
addition of ONOOꢀ to the 3ꢀHF probes in the presence of CTAB
(hexadecyltrimethylammonium bromide) (2 mM) led to a ratiꢀ
ometric fluorescence change with an increase in fluorescence
intensity of the T* emission peak at 530 nm and a decrease in
fluorescence emission at 425 nm (see ESI Fig. S4–9).The LOD
(limit of detection) for the probes with ONOOꢀ are in the nanomoꢀ
lar range 3ꢀHFꢀOMe (65.5 nM) 3ꢀHFꢀPhMe (21.0 nM) and 3ꢀ
HFꢀPh (255.5 nM) (See ESI Fig. S10). We then evaluated the
selectivity of the 3ꢀHF probes towards other ROS (See ESI Fig.
S11–S19). The probes exhibited an excellent selectivity for
ONOOꢀ against most ROS. However, the addition of ClOꢀ (100
µM) led to the degradation of the probe as a fluorescence decrease
of the N emission intensity and decrease of the initial T* fluoresꢀ
cence emission intensity.31 Even though ClOꢀ is an important ROS
that plays a vital role in immune defence systems due to its miꢀ
crobiocidal properties. It is produced enzymatically, through the
reaction of H2O2 and chloride (Clꢀ) catalysed by myeloperoxiꢀ
dase.29, 32ꢀ33 Therefore, when ONOOꢀ is present in cells the levels
of ClOꢀ are expected to be low.
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normal (N) and photo tautomeric (T*) forms that result from exꢀ
cited state intramolecular proton transfer (ESIPT) (Scheme 1).26
The ratio of the intensity of these two emission peaks is dependent
on the surrounding environment of the molecule, especially the
polarity of the solvent. We have previously shown (Scheme 1)
that the ESIPT process can be blocked using a benzyl boronic
ester protecting group.27 The group can then be selectively reꢀ
moved by ONOOꢀ resulting in a ‘turnꢀon’ fluorescenceꢀbased
probe suitable for the detection of ONOOꢀ. Our work and that of
others has clearly demonstrated that ONOOꢀ has a much greater
reactivity towards boronates than other oxidants including ClOꢀ
and H2O2.13,28,29 Since environmentally sensitive fluorescent dyes
have been used to image amyloidꢀβ plaques (Aβ), taking adꢀ
vantage of the presence of multiple βꢀsheets that entropically form
hydrophobic pockets.12 We believed the development of a 3ꢀHF
ONOOꢀ fluorescence based probe could be used as a diagnostic
tool for AD as it would provide information on the surrounding
environment (hydrophilic or hydrophobic) and simultaneously
detect ONOOꢀ.
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a
b
450
300
150
0
450
300
150
0
Aβ42 (oligo)
ONOOꢀ
+
ꢀ
Aβ42 (aggr)
ONOOꢀ
+
ꢀ
420 480 540 600
Wavelength (nm)
420 480 540 600
Wavelength (nm)
c
d
450
300
150
0
450
300
150
0
Aβ42 (oligo)
ONOOꢀ
+
+
Aβ42 (aggr)
ONOOꢀ
+
+
420 480 540 600
Wavelength (nm)
420 480 540 600
Wavelength (nm)
Figure 3. (a) Plot of the ratiometric change for 3ꢀHFꢀOMe (5 ꢁM) with
Aβ42 with different aggregation states (50 ꢁM) as a function of ONOOꢀ
concentration. The Aβ42 aggregates were produced by incubating the
peptide in TrisꢀHCl at room temperature (pH 8.0) for 2 h, 4 h, 8 h, 16 h, 1
d (24 h), 3 d (72 h), 5 d (120 h) and 7 d (168 h). All measurements were
carried out in TrisꢀHCl (0.01 M, pH 7.4) with excitation at 365 nm. (b)
Circular dichroism spectra of Aβ42 with different aggregation states. (c)
Scanning electron microscopic images of Aβ42 with different aggregation
states (note that when Aβ42 was aggregated for 2ꢀ16 h they are almost
invisible in the images; therefore only those with aggregation times
exceeding 1 d are shown).
Figure 2. Fluorescence emission spectra of 3ꢀHFꢀOMe (5 ꢁM) in the
presence of (a) Aβ42 oligomers (blue arrow (I420) – represent a decrease in
fluorescence intensity : 0ꢀ50 ꢁM, interval: 5 ꢁM), (b) Aβ42 aggregates
(blue arrow (I420) – represents a decrease in fluorescence intensity: 0ꢀ50
ꢁM, interval: 5 ꢁM), (c) Aβ42 oligomers (50 ꢁM) and then ONOOꢀ (red
arrow (I530), represents an increase in fluorescence intensity: 0ꢀ10 ꢁM,
interval: 1 ꢁM) and (d) Aβ42 aggregates (50 ꢁM) and then ONOOꢀ (red
arrow (I530), represents an increase in fluorescence intensity: 0ꢀ10 ꢁM,
interval: 1 ꢁM). All measurements were carried out in TrisꢀHCl (0.01 M,
pH 7.4) with excitation of 365 nm.
We then turned our attention towards the 3ꢀHF ONOOꢀ fluoꢀ
rescence based probes in the presence of oligomeric Aβ42 pepꢀ
tides. The Aβ42 peptide was purchased and used as provided, and
was incubated in TrisꢀHCl buffer at room temperature, pH 8.0 for
2 h, 4 h, 8 h, 16 h, 1 d (24 h), 3 d (72 h), 5 d (120 h) and 7 d (168
h) in order to produce different Aβ42 aggregates.34 The addition
of the oligomeric (oligo) Aβ42 peptides and Aβ42 aggregates
(aggr) to 3ꢀHFꢀOMe led to an increase in N fluorescence intensiꢀ
ty (Fig. 2). However, in the presence of Aβ42, 3ꢀHFꢀPhMe and
3ꢀHFꢀPh only a slight change in fluorescence intensity was obꢀ
served with and without the addition of ONOOꢀ (See ESI – Fig.
S20 and Fig. S21). Interestingly, with 3ꢀHFꢀOMe a larger inꢀ
crease in fluorescence intensity was observed for Aβ42 aggregates
than the oligomeric Aβ42 peptides. This is believed to be due to a
more “compact” matrix enhancing the hydrophobic pockets. We
deduce that the stronger binding of 3ꢀHFꢀOMe with the Aβ42
peptides might be caused by the additional methoxyl group faciliꢀ
Three benzyl boronic ester protected 3ꢀHF fluorescenceꢀbased
probes were developed (3ꢀHFꢀOMe, 3ꢀHFꢀPhMe and 3ꢀHFꢀPh).
The synthesis of 3ꢀHFs fluorophores were achieved using a simꢀ
ple procedure developed by Ozturk et al.26 Subsequently, their
alcohol
functionalities
were
alkylated
with
2ꢀ(4ꢀ
(bromomethyl)phenyl)ꢀ4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolane to
afford the desired 3ꢀHF probes (3ꢀHFꢀOMe, 3ꢀHFꢀPhMe and 3ꢀ
HFꢀPh).
Firstly we evaluated the fluorescence behavior of the 3ꢀHF
probes in aqueous PBS, pH 7.4. The addition of ONOOꢀ (10 µM)
to each 3ꢀHF probe resulted in a decrease in N fluorescence emisꢀ
sion intensity and no T* was observed (see ESI – Fig. S1–S3). It
is known that micelles can create a hydrophobic microenvironꢀ
ment facilitating emission from the T* tautomer.30 Therefore, the
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tating hydrogen bonding interactions within the aggregated pepꢀ
cence imaging. We observed that the Aβ42 aggregates of the brain
sections displayed the Nꢀstate fluorescence of 3ꢀHFꢀOMe (Fig.
4a, blue channel), which accorded well with the fluorescence of
an antiꢀAβ antibody (Fig. 4a, red channel). Then, after treatment
with ONOOꢀ the fluorescence emission of the probe bound to the
peptide aggregates of the brain section switched to the T* state
(Fig. 4b, green channel), which correlated well with the antibody
fluorescence (Fig. 4b, red channel). While the excitation and
emission wavelengths of 3ꢀHFꢀOMe are not long enough for in
vivo staining (ideally NIR is required),35ꢀ37 our concept of using
peptide aggregates as part of a naturally inspired host system for
environmentally sensitive fluorescenceꢀbased probes provides the
basis and motivation for the development of a new generation of
ratiometric probes.
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tide matrix. Moreover, the addition of ONOOꢀ to 3ꢀHFꢀOMe in
the Aβ42 “host matrix” (oligomeric and aggregates) led to a reꢀ
markable ratiometric change in fluorescence intensity (Fig. 2). In
addition, 3ꢀHFꢀOMe bound to oligomeric Aβ42 peptides was
found to have a greater sensitivity towards ONOOꢀ. This is beꢀ
lieved to be due to the compact matrix of the Aβ42 aggregate
providing a protective barrier against ONOOꢀ.
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In summary, we have demonstrated that an ESIPT probe, 3ꢀ
HFꢀOMe, could be used to form a supramolecular hybrid with Aβ
aggregates for the ratiometric detection of ONOOꢀ. Importantly, it
has been reported that the concentration of ONOOꢀ in the brain is
~300 nM,4 which is above the LOD of the hybrid system. Our
novel ESIPT probe/Aβ hybrid system for ratiometric ONOOꢀ
sensing is unprecedented and will pave the way for the
development of supramolecular peptide/probe hybrids for the
simultaneous sensing of fibrous protein/peptides and ‘oxidative
state’.
Figure 4 - Fluorescence imaging of a brain section of a transgenic mouse
treated with 3ꢀHFꢀOMe (20 ꢁM) without (w/o) (a) and with (w/) (b)
ONOOꢀ (30 ꢁM). The excitation/emission wavelengths for the blue (Nꢀ
state fluorescence of 3ꢀHFꢀOMe), green (T*ꢀstate fluorescence of 3ꢀHFꢀ
OMe) and red channel (antiꢀAβ antibody) are 404/425ꢀ475, 404/500ꢀ550
and 561/640ꢀ730 nm, respectively. The white arrows indicate the stained
Aβ aggregates.
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website. Additional figures, experimental secꢀ
tion and spectral copies of new compounds are supplied.
AUTHOR INFORMATION
Corresponding Authors
t.d.james@bath.ac.uk
xphe@ecust.edu.cn
To corroborate further the ratiometric response of our 3ꢀHFꢀ
OMe/Aβ hybrid system for ONOOꢀ, different aggregates of Aβ42
were used. Firstly we determined that the concentrationꢀ
dependent N fluorescence increase of probe 3ꢀHFꢀOMe was
gradually enhanced with Aβ aggregation (Fig. S22). In contrast,
the concentrationꢀdependent T* fluorescence increase of the
probe was gradually reduced at the same level of Aβ42 aggregaꢀ
tion (Fig. S23). Furthermore, plotting the ratio of the fluorescence
intensity of the probe in the Nꢀstate (I420) with that of the T*ꢀstate
(I530) (Fig. 3a) indicates that the decreased ratiometric response of
the probe/Aβ42 hybrid to ONOOꢀ (at low concentrations 0ꢀ2.0
ꢁM) is proportional to the aggregation state of Aβ42 determined
by both circular dichroism spectroscopy (Fig. 3b) and scanning
electron microscopy (Fig. 3c). Furthermore, the ratiometric reꢀ
sponse of 3ꢀHFꢀOMe/Aβ hybrid system was shown to be indeꢀ
pendent of the concentration of 3ꢀHFꢀOMe. (Fig. S24 and S25)
Using the titration data, we have also calculated the LODs for
the different probe/Aβ42 hybrids with ONOOꢀ (Fig. S26). While
the sensitivity of the hybrid system gradually decreases as Aβ
aggregation increases, the LOD of our new hostꢀguest system for
ONOOꢀ is in the nanomolar range (21.7 ± 1.2 nM to 106.9 ± 4.6
nM). We also measured the selectivity of the probe and the
probe/Aβ42 hybrid for a range of other proteins and ROS/RNS,
respectively. (Fig. S27ꢀ28) Supporting the conclusion that this
probe is a selective and effective smallꢀmolecular probe for Aβ
and probe/Aβ42 hybrid sensor for ONOOꢀ. Dynamic light scatterꢀ
ing confirmed the association of 3ꢀHFꢀOMe with Aβ42 through
the increased diameter of the latter (Fig. S29). In addition, the
fluorescence quantum yield of 3ꢀHFꢀOMe was found to increase
when bound to Aβ42 oligomers and aggregates (Fig. S30).
Sessler@cm.utexas.edu
Author Contributions
‡These authors contributed equally
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank the EPSRC and the University of Bath for funding.
ACS. ATAJ thanks the EPSRC for funding EP/R003939/1. TDJ
wishes to thank the Royal Society for a Wolfson Research Merit
Award and Sophia University for a visiting professorship. NMR
characterisation facilities were provided through the Chemical
Characterisation and Analysis Facility (CCAF) at the University
of Bath (www.bath.ac.uk/ccaf). The EPSRC UK National Mass
Spectrometry Facility at Swansea University is thanked for analꢀ
yses. HaiꢀHao Han and JingꢀJing Zhang are thanked for biological
experiments. X.ꢀP. He thanks the National Natural Science Founꢀ
dation of China (21788102, 21722801 and 21572058), the Proꢀ
gramme of Introducing Talents of Discipline to Universities
(B16017) and the Shanghai RisingꢀStar Program (16QA1401400).
JLS thanks The Robert A. Welch Foundation (Fꢀ0018). Prof. He
Tian is warmly thanked for his helpful discussions.
REFERENCES
(1) Greenwald, J.; Riek, R., Structure 2010, 18 (10), 1244ꢀ1260.
(2) RojasꢀGutierrez, E.; MunozꢀArenas, G.; Trevino, S.; Espinosa, B.;
Chavez, R.; Rojas, K.; Flores, G.; Diaz, A.; Guevara, J., Synapse 2017, 71,
e21990.
(3) Lambert, M. P.; Barlow, A. K.; Chromy, B. A.; Edwards, C.; Freed,
R.; Liosatos, M.; Morgan, T. E.; Rozovsky, I.; Trommer, B.; Viola, K. L.;
To investigate the potential of the probe for real world applicaꢀ
tions, we used the brain of an ADꢀtransgenic mouse for fluoresꢀ
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Wals, P. Zhang, C.; Finch, C. E.; Krafft, G. A.; Klein, W. L., Proc. NatL.
Acad. Sci. U.S.A. 1998, 95 (11), 6448ꢀ6453.
(20) Sedgwick, A. C.; Gardiner, J. E.; Kim, G.; Yevglevskis, M.; Lloyd,
M. D.; Jenkins, A. T. A.; Bull, S. D.; Yoon, J.; James, T. D., Chem.
Commun. 2018, 54 (38), 4786ꢀ4789.
(21) Hu, Q. H.; Zeng, F.; Yu, C. M.; Wu, S. Z., Sens. Actuator B-Chem.
2015, 220, 720ꢀ726.
1
2
3
4
5
6
7
8
(4) Malinski, T., J. Alzheimer's Dis. 2007, 11 (2), 207ꢀ218.
(5) Boje, K. M.; Arora, P. K., Brain Res. 1992, 587 (2), 250ꢀ256.
(6) Beckman, J. S.; Koppenol, W. H., Am. J. Physiol. Cell Physiol.
1996, 271 (5), C1424ꢀC1437.
(7) Pacher, P.; Beckman, J. S.; Liaudet, L., Physiol. Rev. 2007, 87 (1),
315ꢀ424.
(8) Smith, M. A.; Harris, P. L. R.; Sayre, L. M.; Beckman, J. S.; Perry,
G., J. Neurosci. 1997, 17 (8), 2653ꢀ2657
(9) Yang, H. Y.; Zhang, J. J.; Zang, Y.; Zhang, H. Y.; Li, J.; Chen, G.
R.; He, X. P., Dyes Pigm. 2017, 136, 224ꢀ228.
(22) Liu, B.; Wang, J. F.; Zhang, G.; Bai, R. K.; Pang, Y. ACS Appl.
Mater. Interfaces 2014, 6 (6), 4402ꢀ4407.
(23) Liu, B.; Wang, H.; Wang, T. S.; Bao, Y. Y.; Du, F. F.; Tian, J.; Li,
Q. B. A.; Bai, R. K., Chem. Commun. 2012, 48 (23), 2867ꢀ2869.
(24) Shynkar, V. V.; Klymchenko, A. S.; Kunzelmann, C.; Duportail,
G.; Muller, C. D.; Demchenko, A. P.; Freyssinet, J. M.; Mely, Y., J. Am.
Chem. Soc. 2007, 129 (7), 2187ꢀ2193.
9
(10) Cui, M. C.; Ono, M.; Watanabe, H.; Kimura, H.; Liu, B. L.; Saji,
H., J. Am. Chem. Soc. 2014, 136 (9), 3388ꢀ3394.
(11) Kim, D.; Moon, H.; Baik, S. H.; Singha, S.; Jun, Y. W.; Wang, T.;
Kim, K. H.; Park, B. S.; Jung, J.; MookꢀJung, I.; Ahn, K. H., J. Am. Chem.
Soc. 2015, 137 (21), 6781ꢀ6789.
(12) Ran, C. Z.; Xu, X. Y.; Raymond, S. B.; Ferrara, B. J.; Neal, K.;
Bacskai, B. J.; Medarova, Z.; Moore, A., J. Am. Chem. Soc. 2009, 131
(42), 15257ꢀ15261.
(13) Kim, J.; Park, J.; Lee, H.; Choi, Y.; Kim, Y., Chem. Commun.
2014, 50 (66), 9353ꢀ9356.
(25) Klymchenko, A. S.; Shvadchak, V. V.; Yushchenko, D. A.; Jain,
N.; Mely, Y., J. Phys. Chem. B. 2008, 112 (38), 12050ꢀ12055.
(26) Gunduz, S.; Goren, A. C.; Ozturk, T., Org. Lett. 2012, 14 (6),
1576ꢀ1579.
(27) Sedgwick, A. C.; Sun, X. L.; Kim, G.; Yoon, J.; Bull, S. D.; James,
T. D., Chem. Commun. 2016, 52 (83), 12350ꢀ12352.
(28) Sedgwick, A. C.; Han, H. H.; Gardiner, J. E.; Bull, S. D.; He, X. P.;
James, T. D., Chem. Commun. 2017, 53 (95), 12822ꢀ12825.
(29) Sikora, A.; Zielonka, J.; Lopez, M.; Joseph, J.; Kalyanaraman, B.,.
Free Radical Biol. Med. 2009, 47 (10), 1401ꢀ1407.
(30) Sarkar, N.; Das, K.; Das, S.; Datta, A.; Nath, D.; Bhattacharyya, K.,
J. Phys. Chem. 1995, 99 (50), 17711ꢀ17714.
(31) Chakrabartty, S. K.; Kretschmer, H. O., J. Chem. Soc., Perkin
Trans. 1, 1974, 0, 222ꢀ228.
(32) van der Veen, B. S.; de Winther, M. P. J.; Heeringa, P., Antioxid
Redox Signal. 2009, 11 (11), 2899ꢀ2937.
(33) Klebanoff, S. J., J. Leukoc. Biol. 2005, 77 (5), 598ꢀ625.
(34) Ishida, Y.; Tanimoto, S.; Takahashi, D.; Toshima, K.,
MedChemComm 2010, 1 (3), 212ꢀ215.
(35) Zhang, X.; Tian, Y.; Yuan, P.; Li, Y.; Yaseen, M. A.; Grutzendler,
J.; Moore, A.; Ran, C. Chem. Commun. 2014, 50, 11550−11553.
(36) Zhang, X.; Tian, Y.; Zhang, C.; Tian, X.; Ross, A. W.; Moir, R. D.;
Sun, H.; Tanzi, R. E.; Moore, A.; Ran, C. Proc. Natl. Acad. Sci. U. S. A.
2015, 112, 9734−9739.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(14) Sun, Z. N.; Wang, H. L.; Liu, F. Q.; Chen, Y.; Tam, P. K. H.;
Yang, D., Org. Lett. 2009, 11 (9), 1887ꢀ1890.
(15) Yu, F. B. A.; Li, P.; Li, G. Y.; Zhao, G. J.; Chu, T. S.; Han, K. L.,
A. J. Am. Chem. Soc. 2011, 133 (29), 11030ꢀ11033.
(16) Li, X.; Tao, R.ꢀR.; Hong, L.ꢀJ.; Cheng, J.; Jiang, Q.; Lu, Y.ꢀM.;
Liao, M.ꢀH.; Ye, W.ꢀF.; Lu, N.ꢀN.; Han, F.; Hu, Y.ꢀZ.; Hu, Y.ꢀH., J. Am.
Chem. Soc. 2015, 137 (38), 12296ꢀ12303.
(17) Sun, X.; Xu, Q.; Kim, G.; Flower, S. E.; Lowe, J. P.; Yoon, J.;
Fossey, J. S.; Qian, X.; Bull, S. D.; James, T. D., Chem. Sci. 2014, 5 (9),
3368ꢀ3373.
(18) Sedgwick, A. C.; Han, H. H.; Gardiner, J. E.; Bull, S. D.; He, X. P.;
James, T. D., Chem. Sci. 2018, 9 (15), 3672ꢀ3676.
(19) Sedgwick, A. C.; Chapman, R. S. L.; Gardiner, J. E.; Peacock, L.
R.; Kim, G.; Yoon, J.; Bull, S. D.; James, T. D., Chem. Commun. 2017, 53
(75), 10441ꢀ10443.
(37) Chen, C.; Liang, Z.; Zhou, B.; Li, X. Lui, C.; Ip, N. Y.; Qu, J. Y.
ACS Chem. Neurosci. DOI: 10.1021/acschemneuro.8b00306.
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