Release of Amino- or Carboxy-Containing Compounds Triggered by HOCl: Application for Imaging and Drug Design

Article abstract of DOI:10.1002/anie.201813648

The overproduction of HOCl is highly correlated with diseases such as atherosclerosis, rheumatoid arthritis, and cancer. Whilst acting as a marker of these diseases, HOCl might also be used as an activator of prodrugs or drug delivery systems for the treatment of the corresponding disease. In this work, a new platform of HOCl probes has been developed that integrates detection, imaging, and therapeutic functions. The probes can detect HOCl, using both NIR emission and the naked eye in vitro, with high sensitivity and selectivity at ultralow concentrations (the detection limit is at the nanomolar level). Basal levels of HOCl can be imaged in HL-60 cells without special stimulation. Moreover, the probes provided by this platform can rapidly release either amino- or carboxy-containing compounds from prodrugs, during HOCl detection and imaging, to realize a therapeutic effect.

Full text of DOI:10.1002/anie.201813648

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: HOCl-triggered amino or carboxyl uncaging platform and its
application for imaging and drug design
Authors: Peng Wei, Lingyan Liu, Ying Wen, Guilong Zhao, Fengfeng
Xue, Wei Yuan, Ruohan Li, Yaping Zhong, Mengfan Zhang,
and Tao Yi
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201813648
Angew. Chem. 10.1002/ange.201813648
Link to VoR: http://dx.doi.org/10.1002/anie.201813648
http://dx.doi.org/10.1002/ange.201813648

10.1002/anie.201813648
Angewandte Chemie International Edition
COMMUNICATION
HOCl-triggered amino or carboxyl uncaging platform and its
application for imaging and drug design
Peng Wei,[a] [b] Lingyan Liu,[a] Ying Wen, [c] Guilong Zhao,[d] Fengfeng Xue,[a] Wei Yuan,[a] Ruohan
Li,[a] Yaping Zhong,[a] Mengfan Zhang[a] and Tao Yi* [a] [b]
Abstract: The overproduction of hypochlorous acid (HOCl) is highly
correlated with diseases such as atherosclerosis, rheumatoid arthritis
and cancer. Whilst acting as a marker of these diseases, HOCl might
also be used as an activator of prodrugs or drug delivery systems for
the treatment of the corresponding disease, an area that is so far
unexplored. In this work, a new platform has been developed that can
be used to design and synthesize HOCl probes that integrate
detection, imaging and therapeutic functions. The probes derived from
this platform can be used to detect HOCl using both NIR emission and
the naked eye in vitro, with high sensitivity and selectivity at ultralow
concentrations (the detection limit is at the nM level). Basal levels of
HOCl can be imaged in HL-60 cells without special stimulation.
Moreover, the probes provided by this platform can rapidly uncage
amino or carboxyl groups from prodrugs during HOCl detection and
imaging to realize a therapeutic effect. This platform thus provides
new opportunities for the design of multifunctional probes that
integrate detection, imaging and therapeutic functions.
bactericidal oxidant in vivo that plays a protective role in human
health.[9] However, overproduction of HOCl has been implicated
in an array of pathological disorders, such as atherosclerosis,
rheumatoid arthritis and cancer.[10] Whilst acting as a marker for
these diseases, HOCl might also be exploited as an activator of
prodrugs or drug delivery systems to treat them. However, until
now, most chemical tools related to HOCl have focused only on
the identification of HOCl in vitro or ex vivo.[11] Thus a special
fluorophore was generally selected as the released model
molecule. None of the methods are able to uncaging functional
groups such as amino or carboxyl derivatives for activation of
prodrugs or drug release systems. It is therefore of vital
importance to develop an HOCl stimulus-responsive platform that
can be easily used to integrate detection, imaging and therapy of
HOCl-related disease.
a
> 10min
< 30s
Stimuli-responsive ‘smart’ prodrugs have recently attracted
increasing attention because of their ability to improve efficacy
and avoid severe side effects.[1] Such prodrugs could be activated
by pH and/or redox,[2] ATP,[3] enzyme,[4] reactive oxygen species
(ROS),[1c, 5] etc.[1b, 1d] In past few years, we have developed some
stimuli-responsive systems[6] and built ROS-identifying
fluorescent probes for the detection of biomarkers (e.g. H2O2 and
•OH) in biological systems.[7] Recently, we paid high attention on
ROS-triggered prodrugs and found that although most reported
ROS-triggered prodrugs or drug release systems could be used
to uncage/release drugs in vitro or in vivo, low reactivity and
sensitivity (typically requiring hours or molar levels of ROS to
trigger drug release) limited their biological application.[1a, 8]
b
Among the various ROS, hypochlorous acid (HOCl), generated
via peroxidation of chloride ions (Cl−) by hydrogen peroxide (H2O2)
catalyzed by myeloperoxidase (MPO), is an extremely important
Figure 1. (a) Our previous work and (b) the design strategy of this work
We recently reported a new deformylation reaction-based
probe by delivering methylene blue (MB) (FDOCl-1 in Figure 1)
for rapid detection of HOCl in vivo, in which, near infrared
[a]
P. Wei, L. Liu, Dr. F. Xue, Dr. W. Yuan, R. Li, Y. Zhong, M. Zhang,
Prof. T. Yi
Department of Chemistry, Fudan University,
2005 Songhu Road, Shanghai 200438, China
E-mail: yitao@fudan.edu.cn
College of Chemistry, Chemical Engineering and Biotechnology,
Donghua University, Shanghai 201620, China
Dr. Y. Wen
Institute of Molecular Science, Shanxi University, Taiyuan 030006,
China
fluorescence was switched on when a leucomethylene (LMB)
[12]
derivative was converted to MB in the presence of HOCl.
To
further develop this system into a HOCl responsive drug delivery
system, we therefore compared the reaction efficiency and
products of different derivatives of LMB. We found that the
reaction time of dimethylamino carbamide derivative (FDOCl-4)
with HOCl was > 10 min, much slower than that of FDOCl-1
(Figure 1a), however, when the dimethylamino group of FDOCl-
4 was replaced by NH2 or NHR, or the outer amide group was
replaced by alkyl group, the reaction with HOCl became much
faster. Inspired by this observation, herein, an HOCl-triggered
[b]
[c]
[b]
Dr. G. Zhao
Division of Drug Discovery at Hangzhou Dingzhi Pharmaceuticals,
Inc, 1900 Wenyixi Road, Hangzhou 311132, China
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201813648
Angewandte Chemie International Edition
COMMUNICATION
release platform was developed. In the presence of HOCl, this
platform can not only produce NIR emissive MB fluorophore for
detecting HOCl level, but also release amino or carboxyl group
with high release efficiency (Figure 1). Since amino and carboxyl
groups are functional sites in many anticancer or antiphlogistic
drugs, this platform can be developed as an HOCl-triggered drug
uncaging system that integrates imaging and therapeutic
functions. As proof of concept, a model molecule was designed to
illustrate the synergistic effect of imaging, delivery and therapeutic
functions in this system.
naked eye (Figures 2e and S1g). However, the reaction of
FDOCl-5 with HOCl was so slow that equilibrium was not reached
even after two hours (Figure S4). These results showed that the
sensitivity of these compounds towards HOCl was clearly
increased when the outer amide of the urea bond not fully
substituted (series-I).
To confirm the amino uncaging capability of the series, a further
four analogues containing different functional groups on the outer
amide were designed and synthesized (FDOCl-8–FDOCl-11,
Figure 2a and S5, crystallographic data for FDOCl-11 was shown
in Table S1). All of these compounds reacted rapidly with HOCl
(typically < 60 s) with high sensitivity (typically > 100-fold increase
of fluorescence intensity after treatment with 3.0 equiv of HOCl;
Figures S6–S9) and selectivity. Moreover, both MB and
phenylethylamine were observed in the reaction of FDOCl-8 with
HOCl, which was demonstrated by HRMS analysis (Figure S10).
This demonstrated that series-I could uncage amino derivatives
after reaction with HOCl.
a
25
20
15
10
5
b
0.4
0.3
0.2
0.1
0.0
c
FDOCl-7 + HOCl
15 M
HOCl
0 M
FDOCl-7 only
600 700
a
b
0
650 Wa7v0e0leng7th50(nm8)00
Wavelength (nm)
500
10
8
d
e
Blank
5 M HOCl
HOCl
5
4
3
2
1
0
FI
NO
ed
−
O2
H2O2
iz
6
mal
•OH
ROO•
4
Nor
TBHP
t-BuOO• ONOO−
HOCl
< 30 s
2
0.
0
J
I
H
G
F
3
1
-
l
C
E
D
O
0
D
F
C
B
20 Time4(0s)
0
60
A
B
C
D
E
F
G
H
I
J
A
Figure 2. (a) Chemical structure of the compounds in series-I. (b) Fluorescent
spectra of FDOCl-7 (5 μM) before/after addition of different concentration of
HOCl (0, 5, 10 and 15 μM). (c) Absorption spectra of FDOCl-7 (5 μM)
before/after addition of 15 μM HOCl. (d) Time-dependent changes in fluorescent
intensity of FDOCl-7 (5 μM) at 686 nm after adding HOCl (15 μM). (e)
Fluorescent intensity of FDOCl-7 (5 μM) at 686 nm after adding different
ROS/RNS (20 μM) (from A to J: Blank, O2−, NO, H2O2, t-BuOOH, •OH, t-BuOO•,
ROO•, ONOO− and HOCl); inset in e is the color changes of FDOCl-7 (5 μM)
after adding HOCl (15 μM) and other different ROS/RNS (20 μM). Time range
0–70 s; λex = 620 nm. The data was recorded in PBS (10 mM, 0.5% EtOH)
Figure 3. (a) Chemical structure of the compounds in series-II. (b)
Fluorescence intensity of different probes (FDOCl-12 ~ FDOCl-17, 5 μM) at 686
nm after adding various ROS/RNS. From A to J: Blank, O2−, NO, H2O2, t-BuOOH,
•OH, t-BuOO•, ROO•, ONOO− and HOCl (5 μM HOCl were used for FDOCl-13
and 1 μM HOCl were used for other probes; other ROS/RNS were 20 μM). The
data was recorded in PBS (10 mM, 0.5% EtOH), λex = 620 nm.
In addition to changing the type of amino group in series I, we
also tried to replace the urea bond with other functional groups to
scale the HOCl responsive platform. FDOCl-12–FDOCl-17,
replacing the urea group with amide group of different outer alkyl
or aryl derivatives were therefore designed and synthesized
(series-II, Figure 3a, crystallographic data for FDOCl-16 was
shown in Table S1). All of these compounds reacted rapidly with
HOCl (typically < 60 s, Figures S11–S16). Further studies
showed that changing the length of the carbon chain (e.g. FDOCl-
16) or steric hindrance (e.g. FDOCl-13 and FDOCl-17) had little
influence on the reaction sensitivity even though the selectivity for
HOCl slightly decreased when the position ortho to the carbonyl
was saturated (FDOCl-12 and FDOCl-13) (Figure 3b). However,
even with high steric hindrance, the fluorescence intensity
increase of FDOCl-13 caused by 1 μM HOCl was 22.6–fold higher
than that produced by 20 μM ONOO− (Figure S12). These data
showed that the series-II compounds could react rapidly with
HOCl with high sensitivity and selectivity. In addition to MB,
reaction of FDOCl-12 with HOCl also generated the carboxyl
compound, benzoic acid, which was confirmed by HPLC (Figure
Given that primary, secondary and tertiary amines may have
different steric hindrance or electrical properties, compounds
FDOCl-5–FDOCl-7 were synthesized by changing the substituent
attached to the N1 atom of the urea bond of FDOCl-4 to enhance
HOCl sensitivity (Figure 2a). The ability of these three
compounds to detect HOCl was then evaluated by spectroscopy
under simulated physiological conditions (sodium phosphate
buffer (PBS), 10 mM, pH 7.2, 0.5% EtOH). As shown in Figures
S1 and 2, the fluorescence intensities of FDOCl-6 and FDOCl-7
at 686 nm both increased > 100-fold after treatment with HOCl
(15 μM, 3.0 equiv), combined with increased absorption at 664
nm, indicating the production of MB (further confirmed by HRMS
as shown in Figure S2). Further selectivity studies of FDOCl-6
and FDOCl-7 for HOCl found that similar ROS/RNS, including
−
H2O2, O2 , t-BuOOH, NO, ROO•, ONOO−, •OH and t-BuOO•, did
not induce noticeable enhancement of the fluorescence intensity
or absorption (Figures S1e, S1f, 2e and S3b). Notably, only HOCl
induced a blue color change that could be clearly observed by the
This article is protected by copyright. All rights reserved.

10.1002/anie.201813648
Angewandte Chemie International Edition
COMMUNICATION
S17). Moreover, further quantitative analysis by HPLC found that
the release efficiency of FDOCl-12 was over 70%.
in the red channel in the presence of ABAH was clearly decreased,
confirming that the red fluorescence in the cells was induced by
HOCl. Cells with low MPO expression, such as HeLa cells, were
also used to study the performance of FDOCl-18. As shown in
Figure S27, although the probe was able to penetrate the cell (the
fluorescence in the green channel), no significant fluorescence
enhancement was observed in the red channel until treatment
with HOCl. However, there was a remarkable increase in red
fluorescence intensity after treatment with HOCl. The results
demonstrated that the probe was able to distinguish cells with
high and low expression of HOCl. To confirm the universality of
this platform, a further two compounds, FDOCl-8 (series-I,
Figure S28) and FDOCl-12 (series-II, Figure S29), were also
studied in live cells. As expected, both compounds were able to
detect basal HOCl in HL-60 cells. These data illustrated that both
series have good sensitivity to HOCl in cells.
Different compounds from the two series were chosen to study
the detection limits of this platform for HOCl (Table S2). As shown
in Figures S18 and S19, the detection limit of all those
compounds could reach to nM level (1.46 ~ 14.23 nM), confirming
the high sensitivity of these two series derived from the HOCl
detecting platform. Meanwhile, as shown in Figures S18, S20
and S21, both series were stable in the pH range of 3–10 in the
absence of HOCl, and remarkable fluorescence intensity
enhancement was observed after addition of HOCl. Notably, the
series-II probes maintained remarkable selectivity even under
acidic (pH = 4.52) and alkaline (pH = 9.00) conditions (Figures
S18 and S21). Moreover, some cellular reductants such as
formaldehyde and glucose, had very little impact on the reaction
of the two series towards HOCl (Figures S22–S25). Meanwhile,
even in the presence of 10 equiv of sulfhydryl compounds (50 μM),
such as glutathione (GSH) and N-acetyl cysteine (NAC), HOCl
(3.0 equiv) induced increased fluorescence intensity of these
FDOCl-n probes. It should be noted that the ability of the probes
to overcome interference decreased as steric hindrance
increased in series-II. All these data illustrate that both of the two
series could be used in complex cellular media.
1.2
0.9
0.6
0.3
0.0
1.2
0.9
0.6
0.3
0.0
a
b
c

= 460 nm

= 620 nm
ex
ex
FDOCl-18 + HOCl
FDOCl-18
FDOCl-18 + HOCl
FDOCl-18
Solvent
FDOCl-18
700
400
500
700
500
600
800
Waveleng6th00(nm)
Wavelength (nm)
Green Channel
Merge
d2
Red Channel
By comparing the reaction efficiencies and products, we
propose that reaction of compounds from both series with HOCl
occurs via nucleophilic oxidation, as shown in Figure S26. The
first step could be nucleophilic attack by HOCl on the electron-
deficient carbon atom in amide carbonyl, followed by oxidation to
cleave the amide. This would generate MB and release either a
carboxyl derivative or an unstable carbamic acid that would
rapidly hydrolyze in aqueous solution to form the amino derivative.
This reaction mechanism is consistent with the observation that
greater steric hindrance resulted in slower reaction, since
nucleophilic attack by HOCl would be more difficult.
d1
e1
f1
d3
e2
e3
A
Since compounds from both series were remarkably effective
in vitro, we then studied the application of the two series for HOCl
detection in living cells and in vivo. The above FDOCl series
compounds are not fluorescent until reaction with HOCl, so to
enable visualization of cellular membrane transport of the probe,
FDOCl-18, containing an additional green emissive naphthalene
fluorophore to determine the distribution of the probe, was
designed and synthesized (Figure 4a). After reaction with HOCl,
both the absorption and fluorescence of MB were activated
(Figures 4b and 4c), while the fluorescence signal of the
naphthalene was unchanged (Figure 4c).
f2
f3
B
1.2
0.9
0.6
0.3
0.0
***
A
B
Human promyelocytic leukemia (HL-60) cells, blood cancer
cells that contain an abundance of MPO for endogenic generation
of HOCl, were chosen as the cell model in this study.[13] As shown
in Figure 4d1, HL-60 cells incubated in cell medium displayed no
fluorescence, while those incubated with FDOCl-18 showed
remarkable fluorescence in both the green (Figure 4e1) and red
channels (Figure 4e3). The fluorescence in the green channel
indicates that the probe has good cell membrane permeability. To
confirm the fluorescence in the red channel coming from
intracellular basal HOCl, 4-aminobenzoic acid hydrazide (ABAH),
an MPO inhibitor that should decrease the level of HOCl, was also
added (Figure 4f1-4f3). As expected, the fluorescence intensity
g
A
B
Figure 4. (a) Chemical structure of FDOCl-18. (b) Fluorescent spectra and (c)
absorption spectra of FDOCl-18 (5 μM in THF-PBS solution (1/1, v/v, 10 mM,
pH = 7.2)) before/after addition of 15 μM HOCl. CLSM images of HL-60 cells
(d1, d2, d3) without any treatment; (e1, e2, e3) incubated with FDOCl-18 (10
μM) for 12 h; (f1, f2, f3) preincubated with ABAH (200 μM) for 1 h then incubated
with ABAH (200 μM) and FDOCl-18 (10 μM) for 12 h. (h) The fluorescence
intensity within square A and B in e3 and f3, respectively. Red channel: 700 ±
50 nm, λex = 633 nm; Green channel: 535 ± 25 nm, λex = 488 nm, ***P < 0.001.
This article is protected by copyright. All rights reserved.

10.1002/anie.201813648
Angewandte Chemie International Edition
COMMUNICATION
In vivo studies were then carried on using mouse model of
arthritis generated according to our reported method (details in
supporting information).[12] The three typical probes FDOCl-12
(series II), FDOCl-6 and FDOCl-8 (series I) were selected for the
in vivo detection. As shown in Figure S32, after injected with the
same amount of probes (100 μL, 1 mM), only the arthritic paw
area displayed remarkable fluorescent signal (Figure S32). In the
control paws, without λ-carrageenan-induced arthritis, no
fluorescent signal was observed (Figures S33 and S34). These
data illustrated that all the two series could be used to identify
HOCl in vivo.
selectivity at ultralow concentrations (the detection limit is at the
nM level) and image basal levels of HOCl in HL-60 cells without
special stimulation. Moreover, the probes in this platform can
release amino or carboxyl groups, which are ubiquitously present
in drugs, both in vitro and during cell imaging in the presence of
HOCl. This may enable the design of multifunctional probes that
integrate imaging and therapeutic functions. This utility was
confirmed using a ROS-related prodrug as an example to treat
HL-60 cancer cells expressing high levels of HOCl. Further in vivo
exploration of probes derived from this platform is ongoing.
150
a
b
Acknowledgements
HGF-1
HEK 293
Hela
HL-60
120
90
60
30
0
The authors are grateful for the financial support from NNSFC
(21877013, 21671043).
Keywords: hypochlorous acid • methylene blue • amino and
carboxyl uncaging• bioimaging • therapy
0
5
10
15
20
Concentration(M)
Figure 5. (a) Chemical structure of FDOCl-19. (b) The cell viability of FDOCl-
19 at different concentrations (0, 5, 10, 15 and 20 µM) in different cell lines for
12 h. The toxicity of the compounds was measured by CCK-8 assay.
[1]
a) J. Liang, B. Liu, Bioeng. Transl. Med. 2016, 1, 239-251; b) Y. Lu, A. A.
Aimetti, R. Langer, Z. Gu, Nat. Rev. Mater. 2017, 2, 16075; c) H.-W. Liu,
X.-X. Hu, K. Li, Y. Liu, Q. Rong, L. Zhu, L. Yuan, F.-L. Qu, X.-B. Zhang,
W. Tan, Chem. Sci. 2017, 8, 7689-7695; d) O. K. Nag, L. D. Field, Y.
Chen, A. Sangtani, J. C. Breger, J. B. Delehanty, Ther. Delivery 2016, 7,
335-352;
Compared with other HOCl probes, the most obvious
advantage of this platform is the uncaging of amino or carboxyl
groups when imaging HOCl. Considering that amino and carboxyl
groups are present in many organic compounds and medicines,
this platform may enable construction of multifunctional probes
that integrate imaging and therapeutic functions.[14] To exemplify
the concept, an HOCl-triggered prodrug (FDOCl-19) was
synthesized using a marketed drug melphalan (a kind of
anticancer drug for treating multiple myeloma) as the parent drug
since the amide derivatives of melphalan are generally less
cytotoxic than the parent drug (Figure 5).[15] When treated with
HOCl, both the fluorescence intensity and absorbance of FDOCl-
19 increased a lot coupled with the release of melphalan with high
release efficiency (> 70%) (Figures S35 and S36). The bioactivity
studies in cells shown that FDOCl-19 was highly cytotoxic toward
HL-60 cells, reducing cell viability to < 30% after incubation with
10 M FDOCl-19 for 12 h (Figure 5b). Meanwhile, the prodrug
was found to be non-toxic toward cell lines that had low MPO
expression, such as human gingival fibroblasts (HGF-1), HeLa
and human embryonic kidney (HEK 293) cell lines. CLSM studies
shown that only HL-60 cells treated with FDOCl-19 shown
remarkable fluorescence in the red channel, indicating that only
HL-60 cells could active the prodrug and uncage the toxic drug
melphalan when imaging (Figures S37 and S38). The toxicity of
the uncaged drug caused the morphology of fluorescent HL-60
cells quite different from those with low or none fluorescence
(Figure S37b).
[2]
a) B. J. Hong, A. J. Chipre, S. T. Nguyen, J. Am. Chem. Soc. 2013, 135,
17655-17658; b) S. Maiti, N. Park, J. H. Han, H. M. Jeon, J. H. Lee, S.
Bhuniya, C. Kang, J. S. Kim, J. Am. Chem. Soc. 2013, 135, 4567-4572;
c) D. Spitzer, L. L. Rodrigues, D. Straburger, M. Mezger, P. Besenius,
Angew. Chem. Int. Ed. 2017, 56, 15461–15465; Angew. Chem. 2017,
129, 15664-15669.
[3]
[4]
R. Mo, T. Jiang, R. DiSanto, W. Tai, Z. Gu, Nat. Commun. 2014, 5, 3364.
a) K. Y. Choi, M. Swierczewska, S. Lee, X. Chen, Theranostics 2012, 2,
156; b) M. Xiao, W. Sun, J. Fan, J. Cao, Y. Li, K. Shao, M. Li, X. Li, Y.
Kang, W. Zhang, S. Long, J. Du, X. Peng, Adv. Funct. Mater. 2018, 28,
1805128.
[5]
[6]
F. Muhammad, W. Qi, A. Wang, J. Gu, G. Zhu, J. Mater. Chem. B 2015,
3, 5711-5719.
a) G. Lv, B. Cui, H. Lan, Y. Wen, A. Sun, T. Yi, Chem. Commun. 2015,
51, 125-128; b) G. Lv, A. Sun, P. Wei, N. Zhang, H. Lan, T. Yi, Chem.
Commun. 2016, 52, 8865-8868; c) Y. Zou, T. Yi, S. Xiao, F. Li, C. Li, X.
Gao, J. Wu, M. Yu, C. Huang, J. Am. Chem. Soc. 2008, 130, 15750-
15751; d) S. Mo, Y. Wen, F. Xue, H. Lan, Y. Mao, G. Lv, T. Yi, Sci. Bull.
2016, 61, 459-467; e) P. Wei, F. Xue, Y. Shi, R. Strand, H. Chen, T. Yi,
Chem. Commun. 2018, 54, 13115-13118.
[7]
a) L. Meng, Y. Wu, T. Yi, Chem. Commun. 2014, 50, 4843-4845; b) Y.
Wen, K. Liu, H. Yang, Y. Li, H. Lan, Y. Liu, X. Zhang, T. Yi, Anal. Chem.
2014, 86, 9970-9976; c) Y. Wen, K. Liu, H. Yang, Y. Liu, L. Chen, Z. Liu,
C. Huang, T. Yi, Anal. Chem. 2015, 87, 10579-10584; d) Y. Wen, F. Xue,
H. Lan, Z. Li, S. Xiao, T. Yi, Biosens. Bioelectron. 2017, 91, 115-121.
a) G. Saravanakumar, J. Kim, W. J. Kim, Adv. Sci. 2017, 4, 1600124; b)
C.-C. Song, F.-S. Du, Z.-C. Li, J. Mater. Chem. B 2014, 2, 3413-3426.
M. B. Hampton, A. J. Kettle, C. C. Winterbourn, Blood 1998, 92, 3007-
3017.
[8]
[9]
[10] a) L. Gebicka, E. Banasiak, Toxicol. In Vitro. 2012, 26, 924-929; b) S. J.
Weiss New Eng. J. Med. 1989, 320, 365-376; c) C. L. Hawkins, M. J.
Davies, Chem. Res. Toxicol. 2005, 18, 1600-1610; d) C. L. Hawkins, D.
I. Pattison, M. J. Davies, Amino Acids 2003, 25, 259-274
In conclusion, we have developed a new HOCl-responsive
platform for the design and synthesis of probes that can integrate
detection, imaging and therapeutic functions. The probes derived
from this platform can be used to detect HOCl using both NIR
emission and the naked eye in vitro, with high sensitivity and
[11] a) J. J. Hu, N.-K. Wong, Q. Gu, X. Bai, S. Ye, D. Yang, Org. Lett. 2014,
16, 3544-3547; b) J. J. Hu, N.-K. Wong, M.-Y. Lu, X. Chen, S. Ye, A. Q.
Zhao, P. Gao, R. Yi-Tsun Kao, J. Shen, D. Yang, Chem. Sci. 2016, 7,
This article is protected by copyright. All rights reserved.

10.1002/anie.201813648
Angewandte Chemie International Edition
COMMUNICATION
2094-2099; c) C. Zhang, Q. Nie, I. Ismail, Z. Xi, L. Yi, Chem. Commun.
2018, 54, 3835-3838; d) X. Cheng, H. Jia, T. Long, J. Feng, J. Qin, Z. Li,
Chem. Commun. 2011, 47, 11978-11980; e) W. Lin, L. Long, B. Chen,
W. Tan, Chem. – Eur. J. 2009, 15, 2305-2309; f) G. Cheng, J. Fan, W.
Sun, J. Cao, C. Hu, X. Peng, Chem. Commun. 2014, 50, 1018-1020; g)
S. Kenmoku, Y. Urano, H. Kojima, T. Nagano, J. Am. Chem. Soc. 2007,
129, 7313-7318; h) Y. Koide, Y. Urano, K. Hanaoka, T. Terai, T. Nagano,
J. Am. Chem. Soc. 2011, 133, 5680-5682; i) L. Wu, I. C. Wu, C. C. DuFort,
M. A. Carlson, X. Wu, L. Chen, C.-T. Kuo, Y. Qin, J. Yu, S. R. Hingorani,
D. T. Chiu, J. Am. Chem. Soc. 2017, 139, 6911-6918; j) Q. Xu, C. H. Heo,
G. Kim, H. W. Lee, H. M. Kim, J. Yoon, Angew. Chem. Int. Ed. 2015, 54,
4890-4894; Angew. Chem. 2015, 127, 4972-4976; k) L. Yuan, L. Wang,
B. K. Agrawalla, S.-J. Park, H. Zhu, B. Sivaraman, J. Peng, Q.-H. Xu, Y.-
T. Chang, J. Am. Chem. Soc. 2015, 137, 5930-5938; l) W. Zhang, W. Liu,
P. Li, J. kang, J. Wang, H. Wang, B. Tang, Chem. Commun. 2015, 51,
10150-10153; m) Z. Mao, M. Ye, W. Hu, X. Ye, Y. Wang, H. Zhang, C.
Li, Z. Liu, Chem. Sci. 2018, 9, 6035-6040; n) L. Cao, R. Zhang, W. Zhang,
Z. Du, C. Liu, Z. Ye, B. Song, J. Yuan, Biomaterials 2015, 68, 21-31; o)
X. Chen, K.-A. Lee, X. Ren, J.-C. Ryu, G. Kim, J.-H. Ryu, W.-J. Lee, J.
Yoon, Nat. Protocols 2016, 11, 1219-1228; p) Q. Xu, K.-A. Lee, S. Lee,
K. M. Lee, W.-J. Lee, J. Yoon, J. Am. Chem. Soc. 2013, 135, 9944-9949;
r) S. Chen, J. Lu, C. Sun, H. Ma, Analyst 2010, 135, 577-582; q) H. Feng,
Z. Zhang, Q. Meng, H. Jia, Y. Wang, R. Zhang, Adv. Sci. 2018, 1800397;
r) Y. Jiang, G. Zheng, Q. Duan, L. Yang, J. Zhang, H. Zhang, J. He, H.
Sun, D. Ho, Chem. Commun. 2018, 54, 7967-7970; s) Y. L. Pak, S. J.
Park, D. Wu, B. Cheon, H. M. Kim, J. Bouffard, J. Yoon, Angew. Chem.
Int. Ed. 2018, 57, 1567–1571; Angew. Chem. 2018, 130, 1583-1587.
[12] P. Wei, W. Yuan, F. Xue, W. Zhou, R. Li, D. Zhang, T. Yi, Chem. Sci.
2018, 9, 495-501.
[13] W. M. Nauseef, Blood 1986, 67, 865-872.
[14] a) N. A. Elsharif, Res. Rev.: J. Pharm. Sci. 2018, 9, 22-28; b) K. Hajnal,
H. Gabriel, R. Aura, V. Erzsébet, S. S. Blanka, Acta Med. Marisiensis
2016, 62, 356-362; c) C. Ballatore, D. M. Huryn, A. B. Smith III,
ChemMedChem 2013, 8, 385-395.
[15] a) D. E. Kerr, Z. Li, N. O. Siemers, P. D. Senter, V. M. Vrudhula,
Bioconjugate Chem. 1998, 9, 255-259; b) A. Palumbo, S. V. Rajkumar,
Eur. J. Haematol. 2010, 84, 379-390.
This article is protected by copyright. All rights reserved.

10.1002/anie.201813648
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
An HOCl responsive platform has
been developed that can integrate
detection, imaging and therapeutic
Peng Wei, Lingyan Liu, Ying Wen
Guilong Zhao, Fengfeng Xue, Wei Yuan,
Ruohan Li, Yaping Zhong, Mengfan
Zhang and Tao Yi*
HOCl
functions. The probes derived from
this platform can not only detect HOCl
Methylene Blue
Fluorescence ON
Page No. – Page No.
by using NIR emission in vitro and in
vivo, with high sensitivity and
selectivity, but also rapidly uncage
amino or carboxyl groups from
prodrugs during HOCl detection and
imaging to realize a therapeutic effect
HOCl-triggered amino or carboxyl
uncaging platform and its application
for imaging and drug design
Prodrug
Fluorescence OFF
Drug release for therapy
This article is protected by copyright. All rights reserved.