Deferasirox (ExJade): An FDA-Approved AIEgen Platform with Unique Photophysical Properties

Article abstract of DOI:10.1021/jacs.0c11641

Deferasirox, ExJade, is an FDA-approved iron chelator used for the treatment of iron overload. In this work, we report several fluorescent deferasirox derivatives that display unique photophysical properties, i.e., aggregation-induced emission (AIE), excited state intramolecular proton transfer, charge transfer, and through-bond and through-space conjugation characteristics in aqueous media. Functionalization of the phenol units on the deferasirox scaffold afforded the fluorescent responsive pro-chelator ExPhos, which enabled the detection of the disease-based biomarker alkaline phosphatase (ALP). The diagnostic potential of these deferasirox derivatives was supported by bacterial biofilm studies.

Full text of DOI:10.1021/jacs.0c11641

pubs.acs.org/JACS
Communication
Deferasirox (ExJade): An FDA-Approved AIEgen Platform with
Unique Photophysical Properties
§
§
§
Adam C. Sedgwick, Kai-Cheng Yan, Daniel N. Mangel, Ying Shang, Axel Steinbrueck, Hai-Hao Han,
James T. Brewster, II, Xi-Le Hu, Dylan W. Snelson, Vincent M. Lynch, He Tian, Xiao-Peng He,*
and Jonathan L. Sessler*
Cite This: J. Am. Chem. Soc. 2021, 143, 1278−1283
Read Online
ACCESS
Metrics & More
Article Recommendations
*
sı Supporting Information
ABSTRACT: Deferasirox, ExJade, is an FDA-approved iron chelator used for the treatment of iron overload. In this work, we report
several fluorescent deferasirox derivatives that display unique photophysical properties, i.e., aggregation-induced emission (AIE),
excited state intramolecular proton transfer, charge transfer, and through-bond and through-space conjugation characteristics in
aqueous media. Functionalization of the phenol units on the deferasirox scaffold afforded the fluorescent responsive pro-chelator
ExPhos, which enabled the detection of the disease-based biomarker alkaline phosphatase (ALP). The diagnostic potential of these
deferasirox derivatives was supported by bacterial biofilm studies.
15−17
eferasirox (ExJade) is an FDA-approved iron(III)
chelator used for the treatment of iron overload.
can rotate freely in solution.
share this structural motif.
Neither ExPh nor ExBT
1
−3
18
D
Iron is essential for most living organisms and plays a critical
role in numerous human physiological and pathological
Single-crystal X-ray diffraction analyses of ExPh and ExBT
revealed intramolecular and intermolecular hydrogen-bonding
interactions in the solid state (Figure 2; Figures S2−S5).
Analysis of the packing diagrams for ExPh and ExBT revealed a
slip-stack orientation. These findings led us to consider that an
excited state intramolecular proton transfer combined with an
AIE effect (ESIPT+AIE) might be responsible for the
4
processes, including bacterial growth and biofilm forma-
5
−7
tion.
This has led to explorations of deferasirox in the
context of new therapeutic applications. Recent studies have
demonstrated the utility of deferasirox as chemotherapeutic,
antifungal, and antimicrobial agents.
8
,9
1
0
11−13
However, defer-
19
enhanced emission seen in aqueous media. However, AIE
ESIPT fluorophores can display fluorescence emission in
asirox is not inherently luminescent and, to our knowledge, has
not been extensively explored as a potential diagnostic. Here,
we report that the deferasirox scaffold acts as an aggregation-
induced emission luminogen (AIEgen) with certain derivatives
displaying a seemingly unique combination of aggregation-
induced emission (AIE), excited state intramolecular proton
transfer (ESIPT), charge transfer (TICT), and through-bond
and through-space conjugation characteristics. The diagnostic
potential of several new deferasirox derivatives was shown in
bacterial biofilm studies, which revealed antibiofilm activity
equal to the nonemissive deferasirox parent.
Deferasirox and its derivatives used in this study, ExPh,
ExPh-OMe, ExBT, ExBT-OMe, and the fluorescent responsive
pro-chelator ExPhos, are shown in Scheme 1. Initially, our
focus was on the synthesis of deferasirox derivatives as
chemotherapeutics. Unexpectedly, ExPh and ExBT proved
emissive in aqueous media; however, in organic solution, they
were found to be nonfluorescent. This observation is attributed
to the fluorescence phenomenon known as AIE, wherein ExPh
and ExBT form insoluble fluorescent aggregates in water
+
19−21
both organic and aqueous solvents.
In contrast, ExPh and
ExBT displayed no appreciable fluorescence intensity in
organic solution (cf. Figure 2c and d; Figures S8−S11). This
finding and the different fluorescent maxima seen for ExPh
(
λmax = 480 nm) and ExBT (λmax = 530 nm) in aqueous media
led us to consider a more complex mechanism.
Toward this end, we studied the fluorescent properties of
22,23
the previously reported phenyl-free ExH.
In contrast to
ExPh and ExBT, ExH was found to be strongly fluorescent in
both aqueous and organic media (see SI Figures S12 and S13).
It is thus not an AIEgen. Next, the phenol units present in
ExPh and ExBT were blocked with methyl groups to give
ExPh-OMe and ExBT-OMe. This modification produced a
significant blue-shift in the emission maxima (cf. SI Figures
S14−S17). However, it also led to a loss in the AIE-like
properties. We thus conclude that hydrogen-bonding inter-
actions play a role in promoting the formation of fluorescent
14
Received: November 5, 2020
Published: January 11, 2021
(Figure 1a and b and confirmed by DLS; cf. SI Figure S1).
Studies in mixed MeCN−aqueous media revealed appreciable
emission when the water fraction was >80% (Figure 1c and d).
Most reported AIEgens (systems giving rise to AIE) are
propeller-like analogues of tetraphenylethylene (TPE) or that
©
2021 American Chemical Society
https://dx.doi.org/10.1021/jacs.0c11641
J. Am. Chem. Soc. 2021, 143, 1278−1283
1
278

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
Scheme 1. (a) Chemical Structures of Deferasirox (ExJade)
and the Derivatives Used in This Study; (b) Basic
Schematic of the Alkaline Phosphatase (ALP)-Mediated
Hydrolysis of ExPhos to AIE-Active ExBT Followed by Its
Fluorescence Quenching Mediated by Fe(III) Chelation
Figure 2. (a) Ball and stick view of the X-ray diffraction structures of
ExPh. (b, c, and d) Molecular stacking of ExPh shown in different
views. CCDC no. 1967984 ExPh.
aggregates in the case of ExPh and ExBT. In contrast to ExPh
and ExBT, solvent-dependent behavior was seen for both
ExPh-OMe and ExBT-OMe. On this basis we suggest that
intramolecular charge transfer/twisted intramolecular charge
24,25
transfer (ICT/TICT)
processes modulate the fluorescence
features of the deferasirox core.
Next, ground and excited state calculations were carried out
using DFT and time-dependent density functional theory (TD-
DFT), respectively. Several functionals were screened in the
case of ExPh. The long-range corrected potentials CAM-
B3LYP and ωB97XD best matched the experimental UV−vis
spectral data and were thus chosen for subsequent calculations.
(
See SI Figures S18 and S19.) Excited state natural transition
orbital (NTO) calculations were performed on the electroni-
cally excited singlet state (S ). Vertical excitation of the
1
deferasirox derivatives, ExPh, ExBT, ExPh-OMe, and ExBT-
OMe, results in a change in the electron density consistent
with charge transfer (see SI Figure S20). Geometry
optimization of the S excited state revealed a planarization
1
between the phenyl substituent and the triazole core, as
expected for systems subject to TICT. Subsequent calculations
on the keto tautomers were performed to determine the
propensity to undergo ESIPT. In the case of ExPh, the excited
keto form lies at higher energy (+9.6 eV) than the more stable
TICT enol form. In contrast, ExH, a reported ESIPT system,
was characterized by an excited keto form that was more stable
22
(
−0.8 eV) than the corresponding enol form. This is
consistent with ExH being fluorescent in both polar and apolar
solution in contrast to ExPh, which favors TICT. More
nuanced behavior was seen in the case of ExBT; here a small
energy difference (+0.14 eV) between the excited keto and
TICT enol tautomers was seen, presumably as the result of the
benzothiazole unit. Thus, both TICT and ESIPT mechanisms
need to be considered. NTO calculations revealed additional
through-space conjugation (TSC) between the phenol and
phenyl unit in ExPh, ExPh-OMe, and ExBT, an effect that can
be enhanced through aggregation (Figure 3; SI Figures S21−
Figure 1. Fluorescence spectra of (a) ExPh and (b) ExBT (10 μM) in
MeCN and H O; λ = 310 and 350 nm, respectively (slit widths ex =
2
ex
5
nm, em = 5 nm). (c) Change in normalized emission intensity of
ExPh (10 μM) at 480 nm with increasing water fractions (f , H O/
W
2
MeCN) (λex = 310 nm, slit widths ex = 5 nm, em = 5 nm). (d)
Change in normalized emission intensity of ExBT (10 μM) at 530 nm
with increasing water fractions (f , H O/MeCN) (λ = 350 nm, slit
W
2
ex
26−28
S23).
widths ex = 5 nm, em = 5 nm). Relative quantum yields (Φ ) of ExPh
F
The Fe(III) chelation properties of ExBT were then
evaluated. Evidence of interaction with Fe(III) first came
from UV−visible spectral studies. These initial experiments
were performed in an organic solvent (DMSO) as this facilities
rapid Fe(III) chelation. As seen previously for deferasirox, the
and ExBT in water (reference: quinine sulfate, 0.1 M H SO ) were
2
4
determined as 0.082 and 0.13, respectively (MeCN: ExPh Φ
=
F
−
0.0011, ExBT Φ = 0.0037).
F
1
279
https://dx.doi.org/10.1021/jacs.0c11641
J. Am. Chem. Soc. 2021, 143, 1278−1283

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
Figure 3. Top and side views of geometry-optimized structures of
ExPh and the corresponding natural transition orbitals (NTOs). (a)
Ground state and (b) excited state relaxed geometries.
Figure 4. Fluorescence spectra of (a) ExBT (15 μM), (b) ExBT-OMe
15 μM), and (c) ExPhos (15 μM) recorded upon exposure to
(
Fe(III) (0−300 μM as the FeCl3 salt). (d) Fluorescence spectra of
ExPhos (15 μM) preincubated with 64 U of ALP followed by
exposure to Fe(III) (0−300 μM). (e) Fluorescence changes of
ExPhos (15 μM) with increasing alkaline phosphatase (ALP, 0−64
U). (f) Time-dependent change in the fluorescence-emission intensity
addition of increasing concentrations of Fe(III) (as the FeCl3
salt) to both ExBT (15 μM) and deferasirox (15 μM) resulted
in an increase in their respective UV−vis absorption intensities,
along with a color change from clear to reddish/purple (SI
(
505 nm) of ExPhos (15 μM) when exposed to ALP (two
2
9
Figure S24). No change in UV−vis absorption/color was
seen when Fe(III) was added to ExBT-OMe (SI Figure S24).
We thus conclude that a free phenol is needed to chelate
concentrations, 32 U and 64 U). All measurements were carried
out in deionized water and excited at 320 nm.
2
9
Fe(III). A concentration-dependent quenching of the ExBT
fluorescence was also seen (Figure 4a), as would be expected
for Fe(III) chelation (paramagnetic metal fluorescence
Both Fe(III) concentration and ALP activity are key to the
growth of pathogenic bacteria including biofilm formation and
3
0
13,36−40
quenching).
development.
Biofilms are complex bacterial commun-
Recently, protected versions of known metal chelators (“pro-
chelators”) have been explored in an effort to avoid premature
ities enclosed by extracellular polymeric substances (EPS),
41,42
which provide protection against antibiotics.
biofilms can rapidly adapt to their environments. These
In addition,
41
3
1
metal chelation. We thus prepared the bis-phosphate ester
ExPhos as a phosphatase-responsive fluorescent pro-chelator
that would permit detection of a disease-based biomarker (i.e.,
characteristics result in hard-to-treat infections, promote
43
antibiotic resistance, and lead to patient complications.
32−35
alkaline phosphatase, ALP).
As true for the protected
This provides an incentive to develop fluorescent tools to
image biofilms and visualize biomarkers associated with their
formation and survival.
system, ExBT-OMe, minimal Fe(III) quenching or change in
the UV-Vis absorption was seen for ExPhos (Figure 4c, See SI
Figure S24). However, in the presence of ALP a dose
dependent change in the fluorescence emission was observed
To date, several AIEgens have been reported for bacteria-
44
based imaging applications. For instance, Tang and co-
workers reported an AIEgen that can discriminate between
(
0−64 U), with a final fluorescence emission profile analogous
45
to that of ExBT being seen (Figures 4e and S25). Time-
dependent changes in fluorescence emission intensity were also
seen (see SI Figure S4f). The limit of detection (LoD) was
calculated to be 0.016 75 U (measurements performed after 5
min of incubation; see SI Figure S26). The ratiometric change
in the fluorescence emission was ascribed to the gradual and
stepwise (bis-phosphate ester to monophosphate ester to bis-
phenol) dephosphorylation of ExPhos (as confirmed by LC-
MS analyses; see SI Figures S27−S33). This sequential
conversion leads to a rapid decrease in the blue emission
and a slow increase in the green emission. ExPhos solutions
exposed to ALP (64 U ALP) were subsequently treated with
Gram-positive bacteria, Gram-negative bacteria, and fungi,
while Liu and co-workers detailed a dual-functional TPE-based
antibiotic AIEgen that allows for the intracellular imaging of
46
bacteria in living host cells. However, little attention has been
paid to imaging biofilms. We thus sought to evaluate the
diagnostic and antibiofilm potential of ExBT and ExPhos.
Biofilm experiments were carried out on glass slides with
both Pseudomonas aeruginosa and MRSA. The therapeutic
performance of the broad-spectrum antibiotic cefoperazone-
47
sulbactam (CFP-SUL) was evaluated on its own and in
combination with deferasirox, ExBT, and ExPhos using the
live/dead biofilm caption viability assay (propidium iodide
(PI): dead, red; Syto9: live, green). As shown in the processed
3D images (Figure 5), the use of just CFP-SUL led to a partial
increasing concentrations of Fe(III) (as FeCl ). Quenching of
3
the fluorescence intensity was observed (Figure 4d).
1
280
https://dx.doi.org/10.1021/jacs.0c11641
J. Am. Chem. Soc. 2021, 143, 1278−1283

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
antibiofilm effect that was enhanced in the presence of ExBT,
ExPhos, or deferasirox.
Figure 5. Biofilm experiments. (a) Evaluation of CFP-SUL
(cefoperazone-sulbactam; 16 μg/mL), CFP-SUL@ExBT (16 μg/
mL@64 μg/mL), CFP-SUL@deferasirox (16 μg/mL@64 μg/mL),
and CFP-SUL@ExPhos (16 μg/mL@64 μg/mL) for the treatment of
P. aeruginosa and MRSA biofilms. Processed 3D images of P.
aeruginosa and MRSA biofilms on glass slides using the live/dead
biofilm viability assay. Distributions of PI-stained (red, dead bacteria)
and Syto9-stained (green, live bacteria) (b) P. aeruginosa and (c)
MRSA biovolumes and CFU counts (purple dots) for the above
groups. Biovolume data are mean values of three independent
replicates.
Figure 6. (a) Confocal laser-scanning microscope (CLSM) images of
ExBT (15 μM) and ExPhos (15 μM) associated with treatment of P.
aeruginosa and MRSA biofilms at different times. (b) Normalized
intensities of the fluorescent images.
ASSOCIATED CONTENT
■
*
sı Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c11641.
Subsequent confocal fluorescence imaging experiments were
performed using both P. aeruginosa and MRSA biofilms with
ExBT and ExPhos (Figure 6; see SI Figure S34 for planktonic
bacteria). The green fluorescence emission seen in Figures 5
and 6 arises from Syto9 and ExBT, respectively. Thus, to avoid
interference, the development of fluorescent deferasirox
derivatives with long-wavelength excitation/emission profiles
would be desirable for biological applications. In both the P.
aeruginosa and MRSA biofilms, ExBT gives rise to a strong
fluorescence emission, which gradually diminished with time.
In contrast, ExPhos displayed an initial weak fluorescence
emission, whose intensity gradually increased but then
decreased at later times. A phosphatase-dependent fluores-
cence turn-on response was observed for MRSA (ATCC
Additional information (PDF)
X-ray data (CIF)
X-ray data (CIF)
X-ray data (CIF)
X-ray data (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
Jonathan L. Sessler − Department of Chemistry, The
University of Texas at Austin, Austin, Texas 78712-1224,
United States; orcid.org/0000-0002-9576-1325;
Email: Sessler@cm.utexas.edu
Xiao-Peng He − Key Laboratory for Advanced Materials and
Joint International Research Laboratory of Precision
Chemistry and Molecular Engineering, Feringa Nobel Prize
Scientist Joint Research Center, Frontiers Center for
Materiobiology and Dynamic Chemistry, School of Chemistry
and Molecular Engineering, East China University of Science
and Technology, Shanghai 200237, China; orcid.org/
4
3300) (SI Figure S34). These evolving spectral features are
interpreted in terms of direct Fe(III) chelation vs initial
dephosphorylation followed by Fe(III) chelation in the case of
ExBT and ExPhos, respectively.
In summary, new analogues of the FDA-approved iron
chelator deferasirox have been prepared that display unique
AIE, charge transfer, and through-space conjugation character-
istics in aqueous media. This platform allowed development of
a stimulus-responsive fluorescent pro-chelator, ExPhos, which
was designed to prevent premature Fe(III) chelation while
enabling the detection of the bacteria-based biomarker alkaline
phosphatase. We thus suggest that modified deferasirox
derivatives can be used for cellular imaging applications
including the detection of disease-based biomarkers.
0
000-0002-8736-3511; Email: Xphe@ecust.edu.cn
Authors
Adam C. Sedgwick − Department of Chemistry, The
University of Texas at Austin, Austin, Texas 78712-1224,
United States; orcid.org/0000-0002-3132-2913
Kai-Cheng Yan − Key Laboratory for Advanced Materials and
Joint International Research Laboratory of Precision
Chemistry and Molecular Engineering, Feringa Nobel Prize
1
281
https://dx.doi.org/10.1021/jacs.0c11641
J. Am. Chem. Soc. 2021, 143, 1278−1283

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
Scientist Joint Research Center, Frontiers Center for
Materiobiology and Dynamic Chemistry, School of Chemistry
and Molecular Engineering, East China University of Science
and Technology, Shanghai 200237, China
Central Universities (222201717003) for financial support.
Initial work in Austin was supported by the National Institutes
of Health (R01 GM103790 to J.L.S.) and subsequently by the
Robert A. Welch Foundation (F-0018).
Daniel N. Mangel − Department of Chemistry, The University
of Texas at Austin, Austin, Texas 78712-1224, United States
Ying Shang − Key Laboratory for Advanced Materials and
Joint International Research Laboratory of Precision
Chemistry and Molecular Engineering, Feringa Nobel Prize
Scientist Joint Research Center, Frontiers Center for
Materiobiology and Dynamic Chemistry, School of Chemistry
and Molecular Engineering, East China University of Science
and Technology, Shanghai 200237, China
Axel Steinbrueck − Department of Chemistry, The University
of Texas at Austin, Austin, Texas 78712-1224, United States
Hai-Hao Han − Key Laboratory for Advanced Materials and
Joint International Research Laboratory of Precision
Chemistry and Molecular Engineering, Feringa Nobel Prize
Scientist Joint Research Center, Frontiers Center for
Materiobiology and Dynamic Chemistry, School of Chemistry
and Molecular Engineering, East China University of Science
and Technology, Shanghai 200237, China
James T. Brewster, II − Department of Chemistry, The
University of Texas at Austin, Austin, Texas 78712-1224,
United States; orcid.org/0000-0002-4579-8074
Xi-Le Hu − Key Laboratory for Advanced Materials and Joint
International Research Laboratory of Precision Chemistry
and Molecular Engineering, Feringa Nobel Prize Scientist
Joint Research Center, Frontiers Center for Materiobiology
and Dynamic Chemistry, School of Chemistry and Molecular
Engineering, East China University of Science and
REFERENCES
■
(
1) Moukalled, N. M.; Bou-Fakhredin, R.; Taher, A. T. Deferasirox:
Over a Decade of Experience in Thalassemia. Mediterr. J. Hematol.
Infect. Dis. 2017, 10, e2018066.
(
2) Shirley, M.; Plosker, G. L. Deferasirox: A Review of Its Use for
Chronic Iron Overload in Patients with Non-Transfusion-Dependent
Thalassaemia. Drugs 2014, 74 (9), 1017−1027.
(3) Yang, L. P. H.; Keam, S. J.; Keating, G. M. Deferasirox - A review
of its use in the management of transfusional chronic iron overload.
Drugs 2007, 67 (15), 2211−2230.
(
4) Jung, M.; Mertens, C.; Tomat, E.; Brune, B. Iron as a Central
Player and Promising Target in Cancer Progression. Int. J. Mol. Sci.
019, 20 (2), 273.
5) Oh, E.; Andrews, K. J.; Jeon, B. Enhanced Biofilm Formation by
Ferrous and Ferric Iron Through Oxidative Stress in Campylobacter
jejuni. Front. Microbiol. 2018, 9, DOI: 10.3389/fmicb.2018.01204.
2
(
(
6) Cassat, J. E.; Skaar, E. P. Iron in Infection and Immunity. Cell
Host Microbe 2013, 13 (5), 510−520.
(7) Lin, M. H.; Shu, J. C.; Huang, H. Y.; Cheng, Y. C. Involvement
of Iron in Biofilm Formation by Staphylococcus aureus. PLoS One
2012, 7 (3), e34388.
(
8) Tury, S.; Assayag, F.; Bonin, F.; Chateau-Joubert, S.; Servely, J.
L.; Vacher, S.; Becette, V.; Caly, M.; Rapinat, A.; Gentien, D.; de la
Grange, P.; Schnitzler, A.; Lallemand, F.; Marangoni, E.; Bieche, I.;
Callens, C. The iron chelator deferasirox synergises with chemo-
therapy to treat triple-negative breast cancers. J. Pathol. 2018, 246 (1),
1
(
03−114.
9) Kielar, F.; Wang, Q.; Boyle, P. D.; Franz, K. J. A boronate
Technology, Shanghai 200237, China
prochelator built on a triazole framework for peroxide-triggered
tridentate metal binding. Inorg. Chim. Acta 2012, 393, 294−303.
(10) Puri, S.; Kumar, R.; Rojas, I. G.; Salvatori, O.; Edgerton, M.
Iron Chelator Deferasirox Reduces Candida albicans Invasion of Oral
Epithelial Cells and Infection Levels in Murine Oropharyngeal
Candidiasis. Antimicrob. Agents Chemother. 2019, 63 (4),
DOI: 10.1128/AAC.02152-18.
11) Moon, J. H.; Kim, C.; Lee, H. S.; Kim, S. W.; Lee, J. Y.
Antibacterial and antibiofilm effects of iron chelators against
Prevotella intermedia. J. Med. Microbiol. 2013, 62, 1307−1316.
12) Moreau-Marquis, S.; O’Toole, G. A.; Stanton, B. A.
Dylan W. Snelson − Department of Chemistry, The University
of Texas at Austin, Austin, Texas 78712-1224, United States
Vincent M. Lynch − Department of Chemistry, The University
of Texas at Austin, Austin, Texas 78712-1224, United States
He Tian − Key Laboratory for Advanced Materials and Joint
International Research Laboratory of Precision Chemistry
and Molecular Engineering, Feringa Nobel Prize Scientist
Joint Research Center, Frontiers Center for Materiobiology
and Dynamic Chemistry, School of Chemistry and Molecular
Engineering, East China University of Science and
(
(
Tobramycin and FDA-Approved Iron Chelators Eliminate Pseudo-
monas aeruginosa Biofilms on Cystic Fibrosis Cells. Am. J. Respir. Cell
Mol. Biol. 2009, 41 (3), 305−313.
Technology, Shanghai 200237, China; orcid.org/0000-
0
003-3547-7485
(
13) Post, S. J.; Shapiro, J. A.; Wuest, W. M. Connecting iron
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c11641
acquisition and biofilm formation in the ESKAPE pathogens as a
strategy for combatting antibiotic resistance. MedChemComm 2019,
1
(
0 (4), 505−512.
Author Contributions
A. C. Sedgwick, K.-C. Yan, and D. N. Mangel contributed
equally.
14) Steinbrueck, A.; Sedgwick, A. C.; Brewster, J. T.; Yan, K. C.;
§
Shang, Y.; Knoll, D. M.; Vargas-Zuniga, G. I.; He, X. P.; Tian, H.;
Sessler, J. L. Transition metal chelators, pro-chelators, and ionophores
as small molecule cancer chemotherapeutic agents. Chem. Soc. Rev.
2
(
Notes
020, 49 (12), 3726−3747.
15) Yang, Z. Y.; Chi, Z. H.; Mao, Z.; Zhang, Y.; Liu, S. W.; Zhao, J.;
The authors declare no competing financial interest.
Aldred, M. P.; Chi, Z. G. Recent advances in mechano-responsive
luminescence of tetraphenylethylene derivatives with aggregation-
induced emission properties. Mater. Chem. Front. 2018, 2 (5), 861−
ACKNOWLEDGMENTS
■
The authors thank the National Natural Science Foundation of
China (Nos. 21788102, 91853201, 21722801, 81673489, and
1871414), the National Science and Technology Major
Project of China (No. 2018ZX10732202), the Shanghai
Municipal Science and Technology Major Project (No.
018SHZDZX03), the International Cooperation Program of
Shanghai Science and Technology Committee (No.
7520750100), and the Fundamental Research Funds for the
890.
(16) Chen, Y. C.; Lam, J. W. Y.; Kwok, R. T. K.; Liu, B.; Tang, B. Z.
3
Aggregation-induced emission: fundamental understanding and future
developments. Mater. Horiz. 2019, 6 (3), 428−433.
(17) Dou, W. T.; Qin, Z. Y.; Li, J.; Zhou, D. M.; He, X. P. Self-
2
assembled sialyllactosyl probes with aggregation-enhanced properties
for ratiometric detection and blocking of influenza viruses. Sci. Bull.
2019, 64 (24), 1902−1909.
1
1
282
https://dx.doi.org/10.1021/jacs.0c11641
J. Am. Chem. Soc. 2021, 143, 1278−1283

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
(
18) The solid state fluorescence of deferasirox has been previously
cardiovascular disease in CKD. Nat. Rev. Nephrol. 2017, 13 (7), 429−
442.
reported; however, it is nonemissive in aqueous solution, presumably
as the result of not forming insoluble aggregates. See: Zhang, Y. J.;
Yang, H. Y.; Ma, H. L.; Bian, G. F.; Zang, Q. G.; Sun, J. W.; Zhang,
C.; An, Z. F.; Wong, W. Y. Excitation Wavelength Dependent
Fluorescence of an ESIPT Triazole Derivative for Amine Sensing and
Anti-Counterfeiting Applications. Angew. Chem., Int. Ed. 2019, 58
(35) Gwynne, L.; Sedgwick, A. C.; Gardiner, J. E.; Williams, G. T.;
Kim, G.; Lowe, J. P.; Maillard, J. Y.; Jenkins, A. T. A.; Bull, S. D.;
Sessler, J. L.; Yoon, J.; James, T. D. Long Wavelength TCF-Based
Fluorescent Probe for the Detection of Alkaline Phosphatase in Live
Cells. Front. Chem. 2019, 7, DOI: 10.3389/fchem.2019.00255.
(36) Huang, C. T.; Xu, K. D.; McFeters, G. A.; Stewart, P. S. Spatial
patterns of alkaline phosphatase expression within bacterial colonies
and biofilms in response to phosphate starvation. Appl. Environ.
Microbiol. 1998, 64 (4), 1526−1531.
(
26), 8773−8778.
(
19) Sedgwick, A. C.; Wu, L. L.; Han, H. H.; Bull, S. D.; He, X. P.;
James, T. D.; Sessler, J. L.; Tang, B. Z.; Tian, H.; Yoon, J. Excited-
state intramolecular proton-transfer (ESIPT) based fluorescence
sensors and imaging agents. Chem. Soc. Rev. 2018, 47 (23), 8842−
(37) Danikowsk, K. M.; Cheng, T. Alkaline Phosphatase Activity of
Staphylococcus aureus Grown in Biofilm and Suspension Cultures.
Curr. Microbiol. 2018, 75 (9), 1226−1230.
8
(
880.
20) Liu, H. W.; Li, K.; Hu, X. X.; Zhu, L. M.; Rong, Q. M.; Liu, Y.
C.; Zhang, X. B.; Hasserodt, J.; Qu, F. L.; Tan, W. H. In Situ
Localization of Enzyme Activity in Live Cells by a Molecular Probe
Releasing a Precipitating Fluorochrome. Angew. Chem., Int. Ed. 2017,
(38) Katsipis, G.; Tsalouxidou, V.; Halevas, E.; Geromichalou, E.;
Geromichalos, G.; Pantazaki, A. A. In vitro and in silico evaluation of
the inhibitory effect of a curcumin-based oxovanadium (IV) complex
on alkaline phosphatase activity and bacterial biofilm formation. Appl.
Microbiol. Biotechnol. 2021, 105, 147.
5
(
6 (39), 11788−11792.
21) Peng, L.; Xu, S. D.; Zheng, X. K.; Cheng, X. M.; Zhang, R. Y.;
(39) O’May, C. Y.; Sanderson, K.; Roddam, L. F.; Kirov, S. M.; Reid,
Liu, J.; Liu, B.; Tong, A. J. Rational Design of a Red-Emissive
Fluorophore with AIE and ESIPT Characteristics and Its Application
in Light-Up Sensing of Esterase. Anal. Chem. 2017, 89 (5), 3162−
D. W. Iron-binding compounds impair Pseudomonas aeruginosa
biofilm formation, especially under anaerobic conditions. J. Med.
Microbiol. 2009, 58 (6), 765−773.
3
(
168.
(40) Rao, N. N.; Torriani, A. Molecular aspects of phosphate-
22) Sahu, S.; Das, M.; Bharti, A. K.; Krishnamoorthy, G. Proton
transport in Escherichia-Coli. Mol. Microbiol. 1990, 4 (7), 1083−
090.
41) Hall, C. W.; Mah, T. F. Molecular mechanisms of biofilm-based
transfer triggered proton transfer: a self-assisted twin excited state
intramolecular proton transfer. Phys. Chem. Chem. Phys. 2018, 20
1
(
(
42), 27131−27139.
23) Das, M.; Sahu, S.; Krishnamoorthy, G. Tweaking the proton
transfer triggered proton transfer of 3,5-bis(2-hydroxyphenyl)-1H-
,2,4-triazole. Phys. Chem. Chem. Phys. 2019, 21 (28), 15669−15677.
24) Sasaki, S.; Drummen, G. P. C.; Konishi, G. Recent advances in
antibiotic resistance and tolerance in pathogenic bacteria. FEMS
microbiol. Rev. 2017, 41 (3), 276−301.
(
(42) Stephens, L. J.; Werrett, M. V.; Sedgwick, A. C.; Bull, S. D.;
1
(
Andrews, P. C. Antimicrobial innovation: a current update and
perspective on the antibiotic drug development pipeline. Future Med.
Chem. 2020, 12 (22), 2035−2065.
twisted intramolecular charge transfer (TICT) fluorescence and
related phenomena in materials chemistry. J. Mater. Chem. C 2016, 4
(43) Sharma, D.; Misba, L.; Khan, A. U. Antibiotics versus biofilm:
(
14), 2731−2743.
an emerging battleground in microbial communities. Antimicrob.
Resist. Infect. Control 2019, 8, DOI: 10.1186/s13756-019-0533-3.
(
25) Tian, H.; Sedgwick, A. C.; Han, H. H.; Sen, S.; Chen, G. R.;
Zang, Y.; Sessler, J. L.; James, T. D.; Li, J.; He, X. P. Fluorescent
probes for the imaging of lipid droplets in live cells. Coord. Chem. Rev.
(44) Feng, X.; Tong, B.; Shi, J.; Zhao, C.; Cai, Z.; Dong, Y. Recent
progress of aggregation-induced emission luminogens (AIEgens) for
bacterial detection and theranostics. Mater. Chem. Front. 2021,
DOI: 10.1039/D0QM00753F.
2
(
021, 427, 213577.
26) He, B. R.; Nie, H.; Luo, W. W.; Hu, R. R.; Qin, A. J.; Zhao, Z.
J.; Tang, B. Z. Synthesis, structure and optical properties of
tetraphenylethene derivatives with through-space conjugation be-
tween benzene and various planar chromophores. Org. Chem. Front.
(45) Zhou, C. C.; Jiang, M. J.; Du, J.; Bai, H. T.; Shan, G. G.; Kwok,
R. T. K.; Chau, J. H. C.; Zhang, J.; Lam, J. W. Y.; Huang, P.; Tang, B.
One stone, three birds: one AIEgen with three colors for fast
differentiation of three pathogens. Chem. Sci. 2020, 11 (18), 4730−
2
016, 3 (9), 1091−1095.
27) Wang, H.; Zhao, E. G.; Lam, J. W. Y.; Tang, B. Z. AIE
luminogens: emission brightened by aggregation. Mater. Today 2015,
8 (7), 365−377.
28) Shen, P. C.; Zhuang, Z. Y.; Jiang, X. F.; Li, J. S.; Yao, S. N.;
(
4
(
740.
46) Hu, F.; Qi, G. B.; Mao; Zhou, S. W.; Wu, M.; Wu, W. B.; Liu,
1
(
B. Visualization and In Situ Ablation of Intracellular Bacterial
Pathogens through Metabolic Labeling. Angew. Chem., Int. Ed. 2020,
Zhao, Z. J.; Tang, B. Through-Space Conjugation: An Effective
Strategy for Stabilizing Intramolecular Charge-Transfer States. J. Phys.
Chem. Lett. 2019, 10 (11), 2648−2656.
5
(
9 (24), 9288−9292.
47) Sheu, M. J.; Chen, C. C.; Lu, Y. C.; Su, B. A.; Zhang, C. C.;
Wang, S. S.; Chuang, Y. C.; Tang, H. J.; Lai, C. C. In Vitro
Antimicrobial Activity of Various Cefoperazone/Sulbactam Products.
Antibiotics 2020, 9 (2), 77.
(29) Steinhauser, S.; Heinz, U.; Bartholoma, M.; Weyhermuller, T.;
Nick, H.; Hegetschweiler, K. Complex formation of ICL670 and
related ligands with Fe-III and Fe-II. Eur. J. Inorg. Chem. 2004, 2004
(
21), 4177−4192.
(
30) Yang, W. J.; Chen, X. B.; Su, H. Z.; Fang, W. H.; Zhang, Y. The
fluorescence regulation mechanism of the paramagnetic metal in a
biological HNO sensor. Chem. Commun. 2015, 51 (47), 9616−9619.
(31) Wang, Q.; Franz, K. J. Stimulus-Responsive Prochelators for
Manipulating Cellular Metals. Acc. Chem. Res. 2016, 49 (11), 2468−
477.
32) Zhang, X.; Ren, C. H.; Hu, F.; Gao, Y.; Wang, Z. Y.; Li, H. Q.;
2
(
Liu, J. F.; Liu, B.; Yang, C. H. Detection of Bacterial Alkaline
Phosphatase Activity by Enzymatic In Situ Self-Assembly of the
AIEgen-Peptide Conjugate. Anal. Chem. 2020, 92 (7), 5185−5190.
(33) McCullough, B. S.; Barrios, A. M. Fluorogenic probes for
imaging cellular phosphatase activity. Curr. Opin. Chem. Biol. 2020,
7, 34−40.
34) Haarhaus, M.; Brandenburg, V.; Kalantar-Zadeh, K.; Stenvinkel,
P.; Magnusson, P. Alkaline phosphatase: a novel treatment target for
5
(
1
283
https://dx.doi.org/10.1021/jacs.0c11641
J. Am. Chem. Soc. 2021, 143, 1278−1283