A Rhodamine‐based Fluorescent Chemodosimeter for Au3+ in Aqueous Solution and Living Cells

Article abstract of DOI:10.1007/s10895-021-02725-0

A highly selective rhodamine hydrazide-based fluorescent chemosensor for Au³⁺ detection was developed. The aqueous solution of rhodamine N-hydroxysemicarbazide (RHS), in the presence of Au³⁺, exhibited a significant 55-fold turn-on fluorescence response at 591 nm and a colorimetric change from colorless to pink. Other interested ions including Li⁺, Na⁺, K⁺, Cs⁺, Mg²⁺, Ca²⁺, Ba²⁺, Pb²⁺, Mn²⁺, Co²⁺, Ni²⁺, Ag⁺, Cd²⁺, Cu²⁺, Hg²⁺, Zn²⁺, Sn²⁺, Fe²⁺, Fe³⁺, Cr³⁺, Ce³⁺ did not induce any distinct color/spectral changes. The irreversible detection mechanism occurred via Au³⁺-promoted 5-exo-trig ring closure to yield 1,3,4-oxadiazole-2-one product. The RHS probe is non-responsive to other biologically relevant metal ions and the limit of detection for Au³⁺ was calculated to be 0.5 μM with a linear range of 0 to 90 μM. Fluorescence bioimaging of Au³⁺ in HepG2 cells was also successfully demonstrated.

Full text of DOI:10.1007/s10895-021-02725-0

Journal of Fluorescence (2021) 31:1211–1218
https://doi.org/10.1007/s10895-021-02725-0
ORIGINAL ARTICLE
A Rhodamine‐based Fluorescent Chemodosimeter for Au3+
in Aqueous Solution and Living Cells
Chariwat Pitsanuwong1 & Juthamanee Boonwan1 & Sinchai Chomngam2,3 & Kanokorn Wechakorn4
&
Phongthon Kanjanasirirat5 & Yongyut Pewkliang5 & Suparerk Borwornpinyo5,6 & Palangpon Kongsaeree2,3
Received: 28 August 2020 /Accepted: 17 March 2021
/ Published online: 27 May 2021
#
The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021
Abstract
A highly selective rhodamine hydrazide-based fluorescent chemosensor for Au3+ detection was developed. The aqueous solution
of rhodamine N-hydroxysemicarbazide (RHS), in the presence of Au3+, exhibited a significant 55-fold turn-on fluorescence
response at 591 nm and a colorimetric change from colorless to pink. Other interested ions including Li+, Na+, K+, Cs+, Mg2+,
Ca2+, Ba2+, Pb2+, Mn2+, Co2+, Ni2+, Ag+, Cd2+, Cu2+, Hg2+, Zn2+, Sn2+, Fe2+, Fe3+, Cr3+, Ce3+ did not induce any distinct color/
spectral changes. The irreversible detection mechanism occurred via Au3+-promoted 5-exo-trig ring closure to yield 1,3,4-
oxadiazole-2-one product. The RHS probe is non-responsive to other biologically relevant metal ions and the limit of detection
for Au3+ was calculated to be 0.5 µM with a linear range of 0 to 90 µM. Fluorescence bioimaging of Au3+ in HepG2 cells was
also successfully demonstrated.
3+
.
.
.
.
Keywords Au -selective chemosensor N-hydroxysemicarbazide Rhodamine Fluorescence detection Bioimaging
Introduction
of chemical transformations to construct complex molecular
structures [5–8]. Gold-based compounds are also beneficial
for the treatment of various diseases including rheumatic ar-
thritis, tuberculosis, asthma, malaria, cancer, brain lesions and
HIV [9–11]. Gold nanoparticles have been applied for drug
delivery into cells and for sensors in biological processes
[12–15]. Nonetheless, gold salts can damage liver, kidneys,
and peripheral nervous system. Strong affinity of Au3+ to
enzyme and DNA could lead to DNA damage by a catalytic
cleavage [16, 17]. Therefore, it is highly attractive to develop
efficient methods to detect gold species in both biological and
environmental settings. The traditional analytical methods
have been used to detect gold ions including electrochemistry,
atomic absorption and ICP mass spectrometry [18]. Because
of these typical methods are unsuitable for detecting biologi-
cal samples, sensitive and efficient fluorescent chemosensors
are useful for monitoring biologically relevant species.
Fluorescent chemosensors for Au3+ have been reported with
rhodamine, naphthalimide, rhodol, fluorescein, BODIPY and
calixarene as reporter units [19–23]. Several Au3+-selective
fluorescent probes were designed based on the alkynophilicity
of gold ions [24–31]. For example, Au3+ reacted with a pro-
pargyl rhodamine conjugate, followed by intramolecular cy-
clization to form an oxazolecarbaldehyde moiety, resulting in
a turn-on fluorescence emission of the rhodamine probe [32].
Gold has attracted a great deal of scientific attention due to
their potential in catalysis and biomedical applications [1–4].
The characteristic alkynophilicity of gold ions leads to a series
* Chariwat Pitsanuwong
chariwat.ph@ssru.ac.th
* Palangpon Kongsaeree
palangpon.kon@mahidol.ac.th
1
Department of Chemistry, Faculty of Science and Technology, Suan
Sunandha Rajabhat University, Bangkok 10400, Thailand
2
Department of Chemistry, Center of Excellence for Innovation in
Chemistry, Faculty of Science, Mahidol University,
10400 Bangkok, Thailand
3
Center for Excellence in Protein and Enzyme Technology, Faculty of
Science, Mahidol University, 10400 Bangkok, Thailand
4
Department of Chemistry, Faculty of Science and Technology,
Rajamangala University of Technology Thanyaburi,
12110 Pathumthani, Thailand
5
Excellent Center for Drug Discovery, Faculty of Science, Mahidol
University, 10400 Bangkok, Thailand
6
Department of Biotechnology, Faculty of Science, Mahidol
University, 10400 Bangkok, Thailand

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Scheme 1 The synthesis of RHS probe
Noteworthy, for rhodamine hydrazides, different alkyl substit-
uents in N-alkyl semicarbazide analogs, possessed different
specificity toward metal ions including Cu2+ and Hg2+
[33–38]. Herein, we report a rhodamine hydrazide appended
with N-hydroxysemicarbazide RHS as a highly selective turn-
on fluorescent chemodosimeter for Au3+ but not Cu2+ or
Hg2+. RHS reacted with Au3+ and underwent a cyclization
reaction to give a fluorescent product.
10-mm quartz cuvette. Fluorescence spectra were mea-
sured on an Agilent Cary Eclipse fluorescence spectro-
1
photometer. H Nuclear magnetic resonance (NMR) and
13
C NMR spectra were obtained from a Bruker AV-400
spectrometer in CDCl3 with tetramethylsilane (TMS) as
an internal standard. High-resolution electrospray ioniza-
tion (ESI) mass spectrometric data were measured a
Bruker MicrOTOF mass spectrometer. Cell imaging ex-
periments were carried out on an Operetta high-content
imaging system (PerkinElmer).
The Experimental Section
Chemicals and Instrumentations
Preparation and Characterization of Rhodamine N-
hydroxysemicarbazide
All chemicals used in this study were obtained from com-
mercial suppliers and used without further purification.
Common solvents including hexane, CH2Cl2, EtOAc,
MeOH, and acetone were distilled prior to use. Sodium
phosphate buffer (10 mM, pH 7.4) was prepared from
Na2HPO4·12H2O and NaH2PO4·2H2O. Column chro-
matographic purification was performed on silica gel 60
(70–230 mesh, Merck). UV-Vis absorption spectra were
recorded on an Agilent 89090A spectrophotometer with a
Rhodamine B hydrazide was prepared by using the modified
method [39]. Rhodamine (1.92 g, 4.0 mmol) was dissolved in
EtOH (40 mL) and hydrazine hydrate (640 µL, 3.3 equiv.)
was added dropwise. The reaction mixture was refluxed for
12 h under argon atmosphere. The reaction was monitored by
silica gel TLC. The solvent was removed under reduced pres-
sure, extracted with EtOAc (3 ⋅ 100 mL), dried over anhy-
drous MgSO4, and the solvent was removed under reduced

J Fluoresc (2021) 31:1211–1218
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pressure. After recrystallized from EtOH, rhodamine hydra-
zide was obtained in 76.7 % yield (1.39 g).
Mg2+, Ca2+, Ba2+, Pb2+, Mn2+, Co2+, Ni2+, Ag+, Cd2+, Cu2+,
Hg2+, Zn2+, Sn2+, Fe2+, Fe3+, Cr3+, Ce3+, and Au3+) were
prepared in 10 mM phosphate buffer, pH 7.4. All measure-
ments were carried out in aqueous EtOH (1:1 v/v, 10 mM
phosphate buffer, pH 7.4) at room temperature. The samples
were excited at 535 nm and the emission spectrum was
scanned from 545 nm to 745 nm.
The synthesis of the RHS probe was carried out using
rhodamine hydrazide, 4-nitrobenzoyl chloride and hydroxyl-
amine (Scheme 1). Rhodamine hydrazide (456 mg, 1.0 mmol)
was dissolved in MeCN (30 mL) and 4-nitrobenzoyl chloride
(241 mg, 1.2 equiv.) was added to the solution and subse-
quently with hydroxylamine (210 µL, 1.2 equiv.) at room
temperature. After 24 h, the solvent was removed under re-
duced pressure and the crude mixture was purified by silica
Determination of the Binding Stoichiometry and the
Quantum Yield
gel column chromatography (EtOAc as an eluent) to give
1
RHS as a pale magenta solid in 35 %yield (180.6 mg).
H
The binding stoichiometry of RHS and Au3+ was
established by a Job plot. The fluorescence intensity data
were plotted against the mole fractions of Au3+. The total
concentration of RHS and Au3+ was kept constant at 10.0
µM. The stock solution of RHS (1 mM) and stock solu-
tion of Au3+ (10 mM) were prepared in EtOH-phosphate
buffer (1:1 v/v, 10 mM, pH 7.4). Dilutions of the RHS (1
equiv.) and Au3+ (10 equiv.) solutions were prepared in
various RHS concentrations in the range of 0.1–0.6 mM.
The fluorescence intensity data for each concentration
were plotted against the absorbance then the linear fitting
of the positive slope was calculated. The fluorescence
quantum yield (ΦF) was evaluated by using rhodamine B
as a standard in the range of 5–50 µM EtOH-phosphate
buffer (1:1 v/v, 10 mM, pH 7.4). The quantum yield of
NMR (400 MHz, CDCl3) δ (ppm): 7.8 (d, J = 7.0 Hz, 1 H),
7.4–7.6 (m, 2 H), 6.9–7.2 (d, J = 7.5 Hz, 1 H), 6.6 (d, J =
9.0 Hz, 2 H), 6.4 (s, 2 H), 6.3 (dd, J = 8.9, 2.6 Hz, 2 H), 3.3
13
(q, J = 7.2 Hz, 8 H), 1.25 (t, J = 7.0 Hz, 12 H). C NMR
(100 MHz, CDCl3) δ (ppm): 166.5, 159.3, 153.9, 152.2,
149.2, 133.8, 129.4, 128.8, 128.4, 124.3, 123.7, 108.1,
104.0, 98.0, 66.9, 44.5, 12.8. HRMS (ESI) m/z calcd. for
C29H34N5O4 [M + H]+: 516.2605, found 516.2584.
General Procedure for Spectroscopic Studies
RHS was dissolved in aqueous EtOH (1:1 v/v, 10 mM phos-
phate buffer, pH 7.4) to provide the test solution (10 µM). All
stock solutions (10 mM) of metal cations (Li+, Na+, K+, Cs+,
Fig. 1 Chromogenic and fluorogenic response of the RHS solution with
Au3+ (above). (a) Absorption and fluorescence spectra of RHS (10 µM)
with Au3+ (1 equiv.) in aqueous EtOH (1:1 v/v, 10 mM phosphate buffer,
pH 7.4) (b) fluorescence responses of RHS (10 µM) to Au3+ and other
interested metal ions (10 equiv.)

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DMEM at 37 °C for 1 h. Subsequently, the treated cells were
washed with the culture medium to remove excess Au3+ prior
to incubation with RHS (20 µM) for 1 h, followed by Hoechst
33342 (20 µM) as a nuclear staining dye. Cells were imaged in
DMEM culture medium at 37 °C under 5 % CO2 with an
Operetta high-content imaging system (PerkinElmer) using a
40× objective lens and the Harmony® software. For the fluo-
rescence bioimaging of RHS, the emission wavelength was
collected a 560–630 nm and the excitation wavelength was set
at 520–550 nm. For Hoechst-stained nuclei, the emission
wavelength was collected at 410–480 nm and the excitation
wavelength was set at 360–400 nm.
Microculture Tetrazolium (MTT) Cell Viability Assays
Fig. 2 Fluorescence titration of RHS (10 µM) and Au3+ (0–20 equiv.) in
in aqueous EtOH (1:1 v/v, 10 mM phosphate buffer, pH 7.4). Inset;
changes of emission intensity at 591 nm (λex = 535 nm)
HepG2 cells (1 × 104 cells/well) were incubated with 0–40
µM RHS for 24 h in modified Eagle’s medium at 37 °C under
humidified 5 % CO2 atmosphere. Subsequently, the cells were
incubated with 0.5 mg/ml MTT (3-(4,5-dimethylthiazol-2-yl)-
2,5-diphenyltetrazolium bromide) for 4 h at 37 °C under hu-
midified 5 % CO2 in an air incubator, followed by adding
100 % DMSO (100 µL) to solubilize the crystals before mea-
surement of absorbance at 570 nm by an EnVision multilabel
plate reader (PerkinElmer, Germany). Error bars denote stan-
dard error of the mean (SEM), n = 3. Hep-G2 cells maintained
the cell viability in the presence of RHS, revealed by standard
MTT assays. Data are reported as percentages of the negative
control (Fig. S13).
RHS was determined according to the following equation:
GradX η2X
ΦX ¼ ΦST
Á
Á
η2ST
GradST
where the subscripts ST and X denote standard and sam-
ple, respectively. Φ is the quantum yield. Grad is the
slope from the plot of integrated fluorescence intensity
and absorbance, and η is the refractive index of the
solvent.
Cell Culture and Fluorescence Imaging
HepG2 cells were grown in Dulbecco’s modified Eagle’s me-
dium (DMEM) with 10 % fetal bovine serum (FBS), 100 µg/
ml streptomycin and 100 U/ml penicillin at 37 °C in 5 % CO2
atmosphere. The cells (3 × 104 cells well) were seeded on
sterile glass coverslips in a 96-well plate in culture medium.
After 24 h, the cells were treated with HAuCl4 (200 µM) in
Results and Discussion
Synthesis of the Prob RHS
The RHS chemical probe was prepared in a moderate
yield from rhodamine hydrazide, hydroxylamine and 4-
Fig. 3 Fluorescence changes
(F/F0) of RHS in various metal
ions (3 equiv., red), and in the
presence of Au3+ (3 equiv., blue)
(1:1 v/v, EtOH-phosphate buffer,
10 mM, pH 7.4, λex = 535 nm,
λem = 591 nm)

J Fluoresc (2021) 31:1211–1218
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Fig. 4 Fluorescence intensity of
RHS (10 µM, blue) and in the
presence of Au3+ (10 equiv., red)
in different pH values (λem = 591
nm)
nitrobenzoyl chloride as shown in Scheme 1. The struc-
The characteristic peak of the spirolactam carbon of
1
13
ture of RHS was spectroscopically established by
H
RHS appeared at δ 66.9 ppm in the
C NMR spectra
13
NMR,
C NMR and ESI-HRMS data (Fig. S1-S3).
indicating the closed spirolactam ring [33].
Scheme 2 The proposed sensing mechanism of RHS induced by Au3+ in aqueous EtOH (1:1 v/v, 10 mM phosphate buffer, pH 7.4) to yield 1,3,4-
oxadiazole-2-one product (λem = 591 nm)

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J Fluoresc (2021) 31:1211–1218
Photophysical Property and Selectivity of RHS
(98 ppb) ( σ/N = 3). In addition, the binding stoichiometry of
RHS and Au3+ was found to be 1:1 based on a Job plot analysis
with the maximum fluorescence intensity at the mole fraction of
0.5 (Fig. S10). For a competitive experiment, other metal ions,
including Li+, Na+, K+, Cs+, Mg2+, Ca2+, Ba2+, Pb2+, Mn2+,
Co2+, Ni2+, Ag+, Cd2+, Cu2+, Hg2+, Zn2+, Sn2+, Fe2+, Fe3+,
Cr3+, and Ce3+, did not affect the sensing of RHS to Au3+
(Fig. 3).
The effect of pH values in fluorescence sensing of RHS
and the RHS-Au3+ was investigated in a pH range from 1 to
13 (Fig. 4). Without Au3+, RHS did not give a clear fluores-
cence enhancement except in pH 1–3, and with Au3+, en-
hanced emission was strongly observed in a pH range of 4–
7, rendering its possibility to apply RHS to monitor Au3+
under physiological conditions. Upon the addition of Au3+, a
time-course study of the fluorescence enhancement of RHS
showed the reaction was completed within 12 min (Fig. S11).
The solution of RHS displayed almost no fluorescence in
aqueous EtOH (1:1 v/v, 10 mM phosphate buffer, pH 7.4).
Preliminarily, the probe solutions were tested with various
metal ions and the colorless RHS solution changed to pink
only in the presence of Au3+. UV-Vis spectral data of the
colorless RHS solution had no absorption band in the visible
region (400–700 nm), indicating the structure existed predom-
inantly in the spirolactam form.
Upon the addition of Au3+, the colorless solution of RHS
displayed a new absorption spectrum centered at 564 nm. Its
fluorescence spectrum revealed a maximum emission band at
591 nm (Fig. 1a) with a 55-fold increase (Φ = 0.50). These data
indicated that Au3+ promoted the ring opening of the spirolactam
unit. To investigate the selectivity of the chemical probe, the
fluorescence responses of RHS toward other metal ions, includ-
ing Li+, Na+, K+, Cs+, Mg2+, Ca2+, Ba2+, Pb2+, Mn2+, Co2+, Ni2+,
Ag+, Cd2+, Cu2+, Hg2+, Zn2+, Sn2+, Fe2+, Fe3+, Cr3+, Ce3+, and
Au3+, were recorded in EtOH-phosphate buffer (1:1 v/v, 10 mM,
pH 7.4) (Fig. 1b and S9). The fluorescence emission, due to the
ring-opening reaction of the spirocyclic moiety of RHS, was
clearly observed only in the presence of Au3+, but not with
Cu2+ or Hg2+ like in previously reported N-alkylsemicarbazide
rhodamine derivatives [33–37]. These results supported that
RHS can serve as a highly selective fluorescent probe for Au3+
detection. In the fluorescence titration of RHS and Au3+ (0–20
equiv.) in aqueous EtOH (1:1 v/v, 10 mM phosphate buffer, pH
7.4), the fluorescence of RHS was linearly enhanced with Au3+
concentrations in a range of 0–90 µM (Fig. 2). The limit of
detection (LOD) of RHS for Au3+ was calculated to be 0.5 µM
Response Mechanism
The signaling mechanism of RHS for Au3+ was investigated by
mixing RHS (50 mM) with Au3+ (1 equiv.) in aqueous EtOH
[32]. In silica gel TLC analysis, upon the disappearance of the
RHS probe, a less polar spot was observed (Fig. S8). The prod-
uct was subsequently purified by silica gel PLC and character-
ized by 1 H NMR and 13 C NMR and ESI-HRMS analysis (Fig.
S4-S7). The MS data displayed an intense peak at m/z 483.2401,
suggesting the cyclized 1,3,4-oxadiazole-2-one rhodamine deriv-
13
ative (calcd. 483.2391 for C29H31N4O3). The C NMR data
revealed two new signals at δ 166.1 and 157.4 ppm, correspond-
ing to the two carbon atoms of the oxadiazolone [40–43]. A
Fig. 5 Confocal fluorescence images of RHS in HepG2 cells. The
cultured cells were incubated with Au3+ in DMEM medium for 1 h (a-
h) and then incubated (a-d) without or (e-h) with RHS (20 µM) for 1 h at
37 °C. (a, e) bright-field images; (b, f) fluorescence images of nuclei
counterstained with Hoechst 33,342; (c, g) fluorescence images; (d)
merged images of (b-c) and (h) merged images of (f-g), respectively

J Fluoresc (2021) 31:1211–1218
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previous versions of the manuscript, read and approved the final
manuscript.
plausible reaction mechanism was therefore proposed as shown
Scheme 2. Upon the binding of Au3+, the ring opening process
was induced, followed by a 5-exo-trig ring closure of N-
hydroxysemicarbazide to form 1,3,4-oxadiazole-2-one unit
[44]. Notably, the N-arylsemicarbazide rhodamine hydrazide an-
alog was also sensitive to Au3+ but led to the hydrolysis reaction
[44] not the cyclization product.
Funding Suan Sunandha Rajabhat University, Center for Innovation in
Chemistry (PERCH-CIC) and Office of National Higher Education
Science Research and Innovation Policy Council (PMU-C).
Data Availability All the data and materials from this manuscript will be
made available on request.
Confocal Bioimaging
Declarations
To further demonstrate its biological applications of RHS as a
highly selective probe for Au3+, it was applied in cultured HepG2
cells to monitor Au3+ (Fig. 5). HepG2 cells were washed with
Dulbecco’s phosphate-buffered saline buffer (DPBS, pH 7.4),
and fixed by using MeOH for 20 min at − 20 °C.
Subsequently, the cells were treated with HAuCl4 (200 µM)
for 1 h and the excess Au3+ was removed before incubating with
RHS (20 µM) at 37 °C for 1 h. The treated cells were stained
with Hoechst 33342 nuclear staining dye (20 µM) and the fluo-
rescence imaging was observed by excitation at 515 nm. Bright-
field images indicated the cell morphology was not damaged.
Cells incubated with both RHS and Au3+ exhibited a distinctive
fluorescence emission, whereas cells treated with only RHS
remained non‐emissive.
Ethics Declarations Not applicable.
Conflict of Interest Authors declare that they have no conflict of
interest.
References
1. Bertelsen S, Jørgensen KA (2009) Organocatalysis - After the gold
rush. Chem Soc Rev 38(8):2178–2189. https://doi.org/10.1039/
b903816g
2. Liu G, Li G, Song H (2009) Direct synthesis of methyl propionate
from n-propyl alcohol and methanol using gold catalysts. Catal Lett
128(3–4):493–501. https://doi.org/10.1007/s10562-008-9782-0
3. Sardar R, Funston AM, Mulvaney P, Murray RW (2009) Gold
nanoparticles: Past, present, and future. Langmuir 25(24):13840–
13851. https://doi.org/10.1021/la9019475
4. Yamamoto Y, Gridnev ID, Patil NT, Jin T (2009) Alkyne activation
with Brønsted acids, iodine, or gold complexes, and its fate leading
to synthetic application. ChemComm (34):5075–5087. https://doi.
org/10.1039/b909978f
Conclusions
5. Arcadi A (2008) Alternative synthetic methods through new devel-
opments in catalysis by gold. Chem Rev 108(8):3266–3325. https://
doi.org/10.1021/cr068435d
In summary, a new rhodamine N-hydroxysemicarbazide RHS
as the Au3+-sensitive fluorescent chemodosimeter was devel-
oped. The fluorescent probe is highly selective to Au3+ with
the LOD value of 0.5 µM (98 ppb) based on a 1:1 binding
ratio in aqueous EtOH. The irreversible sensing mechanism of
RHS occurred via the ring-opening spirolactam and a subse-
quent intramolecular 5-exo-trig cyclization to form the 1,3,4-
oxdiazole-2-one fluorescent product. The confocal fluores-
cence bioimaging of RHS in monitoring Au3+ was success-
fully demonstrated in cultured HepG2 cells.
6. Hashmi ASK, Rudolph M (2008) Gold catalysis in total synthesis.
Chem Soc Rev 37(9):1766–1775. https://doi.org/10.1039/b615629k
7. Jiménez-Núñez E, Echavarren AM (2008) Gold-catalyzed
cycloisomerizations of enynes: A mechanistic perspective. Chem
Rev 108(8):3326–3350. https://doi.org/10.1021/cr0684319
8. Li Z, Brouwer C, He C (2008) Gold-catalyzed organic transforma-
tions. Chem Rev 108(8):3239–3265. https://doi.org/10.1021/
cr068434l
9. Sannella AR, Casini A, Gabbiani C, Messori L, Bilia AR, Vincieri
FF, Majori G, Severini C (2008) New uses for old drugs.
Auranofin, a clinically established antiarthritic metallodrug, ex-
hibits potent antimalarial effects in vitro: Mechanistic and pharma-
cological implications. FEBS Lett 582(6):844–847. https://doi.org/
10.1016/j.febslet.2008.02.028
10. Nobili S, Mini E, Landini I, Gabbiani C, Casini A, Messori L
(2010) Gold compounds as anticancer agents: Chemistry, cellular
pharmacology, and preclinical studies. Med Res Rev 30(3):550–
580. https://doi.org/10.1002/med.20168
11. Berners-Price SJ, Filipovska A (2011) Gold compounds as thera-
peutic agents for human diseases. Metallomics 3(9):863–873.
https://doi.org/10.1039/c1mt00062d
Supplementary Information The online version contains supplementary
material available at https://doi.org/10.1007/s10895-021-02725-0.
Acknowledgements The authors acknowledge Suan Sunandha Rajabhat
University, Center for Innovation in Chemistry (PERCH-CIC) and Office
of National Higher Education Science Research and Innovation Policy
Council (PMU-C) for financial support.
12. Ghosh P, Han G, De M, Kim CK, Rotello VM (2008) Gold nano-
particles in delivery applications. Adv Drug Deliv Rev 60(11):
1307–1315. https://doi.org/10.1016/j.addr.2008.03.016
13. Boisselier E, Astruc D (2009) Gold nanoparticles in nanomedicine:
Preparations, imaging, diagnostics, therapies and toxicity. Chem
Soc Rev 38(6):1759–1782. https://doi.org/10.1039/b806051g
Author Contributions All authors contributed to the study conception
and design. Material preparation, data collection and analysis were per-
formed by C. Pitsanuwong, J. Boonwan, S. Chomngam, K. Wechakorn,
P. Kanjanasirirat, and Y. Pewkliang. The first draft of the manuscript was
written by C. Pitsanuwong and S. Chomngam. All authors commented on

1218
J Fluoresc (2021) 31:1211–1218
14. Giljohann DA, Seferos DS, Daniel WL, Massich MD, Patel PC,
Mirkin CA (2010) Gold nanoparticles for biology and medicine.
Angew Chem Int Ed 49(19):3280–3294. https://doi.org/10.1002/anie.
200904359
15. Dykman L, Khlebtsov N (2012) Gold nanoparticles in biomedical
applications: Recent advances and perspectives. Chem Soc Rev
41(6):2256–2282. https://doi.org/10.1039/c1cs15166e
16. Connor EE, Mwamuka J, Gole A, Murphy CJ, Wyatt MD (2005) Gold
nanoparticles are taken up by human cells but do not cause acute
cytotoxicity. Small 1(3):325–327. https://doi.org/10.1002/smll.
200400093
17. Pedersen DS, Locht LJ, Tran TP, Markholt S, Rungby J, Larsen A
(2014) Toxicological aspects of injectable gold-hyaluronan combi-
nation as a treatment for neuroinflammation. Histol Histopathol
29(4):447–456
29. Lee H, Park HY, Jeon K, Jeong BH, Hwang JW, Lee J, Cha HS,
Koh EM, Kang ES, Koh WJ (2015) PLoS One 10:1
30. Srisuratsiri P, Kanjanasirirat P, Chairongdua A, Kongsaeree P
(2017) Reversible rhodamine-alkyne Au3+-selective chemosensor
and its bioimaging application. Tet Lett 58(32):3194–3199. https://
doi.org/10.1016/j.tetlet.2017.07.014
31. Li Z, Xu Y, Fu J, Zhu H, Qian Y (2018) Monitoring of Au(III)
species in plants using a selective fluorescent probe. ChemComm
54(8):888–891. https://doi.org/10.1039/c7cc08333e
32. Egorova OA, Seo H, Chatterjee A, Ahn KH (2010) Reaction-based
fluorescent sensing of Au(I)/Au(III) species: Mechanistic implica-
tions on vinylgold intermediates. Org Lett 12(3):401–403
33. Saleem M, Lee K-H (2014) Selective fluorescence detection of
Cu2+ in aqueous solution and living cells. J Lumin 145:843–848.
https://doi.org/10.1016/j.jlumin.2013.08.044
34. Yang J-p, Fei L, Jing C, Yang J-d (2015) Sensing and magnetic
removal of Hg(II) using core-shell structured nanocomposite
grafted with fluorescence “Off-On” probe. Microporous
Mesoporous Mater 202:175–182. https://doi.org/10.1016/j.
micromeso.2014.09.054
35. Zhao Y-C, Chen C, Chen B, Wang P-Y, Wu Z-B, Li H, Song B-A,
Yang S (2017) Tunable fluorescent probes for selective detection of
copper(II) and sulfide with completely different modes. Sens
Actuators B Chem 241:168–173. https://doi.org/10.1016/j.snb.
2016.10.071
18. Kocúrová L, Balogh IS, Şkrlíková J, Posta J, Andruch V (2010) A
novel approach in dispersive liquid-liquid microextraction based on
the use of an auxiliary solvent for adjustment of density: UV-VIS
spectrophotometric and graphite furnace atomic absorption spectro-
metric determination of gold based on ion pair formation. Talanta
82(5):1958–1964. https://doi.org/10.1016/j.talanta.2010.08.028
19. Young Choi J, Kim GH, Guo Z, Yeon Lee H, Swamy KMK, Pai J,
Shin S, Shin I, Yoon J (2013) Highly selective ratiometric fluorescent
probe for Au3+ and its application to bioimaging. Biosens Bioelectron
49:438–441. https://doi.org/10.1016/j.bios.2013.05.033
36. Hu JH, Long C, Fu QQ, Ni PW, Yin ZY (2019) A novel highly
selective colorimetric and “turn-on” fluorimetric chemosensor for
detecting Hg2+ based on Rhodamine B hydrazide derivatives in
aqueous media. J Photochem Photobiol A 379:105–111. https://
doi.org/10.1016/j.jphotochem.2019.04.031
37. Long C, Hu JH, Fu QQ, Ni PW (2019) A new colorimetric and
fluorescent probe based on Rhodamine B hydrazone derivatives for
cyanide and Cu2+ in aqueous media and its application in real life.
Spectrochim Acta A Mol Biomol Spectrosc 219:297–306. https://
doi.org/10.1016/j.saa.2019.04.052
38. Deepa A, Srinivasadesikan V, Lee SL, Padmini V (2020) Highly se-
lective and sensitive colorimetric and Fluorimetric sensor for Cu2+. J
Fluoresc 30(1):3–10. https://doi.org/10.1007/s10895-019-02450-9
39. Dujols V, Ford F, Czarnik AW (1997) A long-wavelength fluores-
cent chemodosimeter selective for Cu(II) ion in water. J Am Chem
Soc 119(31):7386–7387. https://doi.org/10.1021/ja971221g
40. Young JR, DeVita RJ (1998) Novel synthesis of Oxadiazoles via
palladium catalysis. Tet Lett 39(23):3931–3934. https://doi.org/10.
1016/S0040-4039(98)00719-9
41. Aljaar N, Conrad J, Beifuss U (2013) Synthesis of 2-aryl-1,2-
dihydrophthalazines via reaction of 2-(bromomethyl)benzaldehydes
with arylhydrazines. J Org Chem 78(3):1045–1053. https://doi.org/
10.1021/jo302491x
20. Song F, Ning H, She H, Wang J, Peng X (2014) A turn-on fluores-
cent probe for Au3+ based on rodamine derivative and its
bioimaging application. Sci China Chem 57(7):1043–1047.
https://doi.org/10.1007/s11426-014-5107-x
21. Üçüncü M, Emrullahoǧlu M (2014) A BODIPY-based reactive
probe for the detection of Au(iii) species and its application to cell
imaging. Chem Commun 50(44):5884–5886. https://doi.org/10.
1039/c4cc01958j
22. Memon S, Bhatti AA, Bhatti AA, Ocak Ü, Ocak M (2015)
Calix[4]arene based highly efficient fluorescent sensor for Au3+
and I. J Fluoresc 25(5):1507–1515. https://doi.org/10.1007/
s10895-015-1642-x
23. Wechakorn K, Prabpai S, Suksen K, Piyachaturawat P, Kongsaeree
P (2016) Rhodol-based fluorescent probe for Au3+ detection and its
application in bioimaging. RSC Adv 6(29):24752–24755. https://
doi.org/10.1039/c6ra02342h
24. Liu Y, Song F, Guo S (2006) Cleavage of a carbon-carbon triple
bond via gold-catalyzed cascade cyclization/oxidative cleavage re-
actions of (2)-enynols with molecular oxygen. J Am Chem Soc
128(35):11332–11333. https://doi.org/10.1021/ja062610q
25. Lee JH, Park J, Lah MS, Chin J, Hong JI (2007) High-affinity
pyrophosphate receptor by a synergistic effect between metal coor-
dination and hydrogen bonding in water. Org Lett 9(19):3729–
3731. https://doi.org/10.1021/ol071306e
26. Zhang JF, Zhou Y, Yoon J, Kim JS (2011) Recent progress in
fluorescent and colorimetric chemosensors for detection of precious
metal ions (silver, gold and platinum ions). Chem Soc Rev 40(7):
3416–3429. https://doi.org/10.1039/c1cs15028f
27. Duman N, Ersoy-Evans S, Karadağ Ö, Aşçioğlu S, Şener B, Kiraz
S, Şahin S (2014) Screening for latent tuberculosis infection in
psoriasis and psoriatic arthritis patients in a tuberculosis-endemic
country: A comparison of the QuantiFERON®-TB Gold In-Tube
test and tuberculin skin test. Int J Dermatol 53(10):1286–1292
28. Seo H, Jun ME, Ranganathan K, Lee KH, Kim KT, Lim W, Rhee
YM, Ahn KH (2014) Ground-state elevation approach to suppress
side reactions in gold-sensing systems based on alkyne activation.
Org Lett 16(5):1374–1377. https://doi.org/10.1021/ol5001389
42. Vodela S, Mekala RVR, Danda RR, Kodhati V (2013) Design,
synthesis and screening of some novel benzoxazole based 1,3,4-
oxadiazoles as potential antimicrobial agents. Chin Chem Lett
24(7):625–628. https://doi.org/10.1016/j.cclet.2013.04.005
43. Brahmayya M, Dai SA, Suen SY (2015) Synthesis of 5-substituted-
3H-[1,3,4]-oxadiazol-2-one derivatives: A carbon dioxide route
(CDR). RSC Adv 5(80):65351–65357. https://doi.org/10.1039/
c5ra08910g
44. Patel KD, Prajapati SM, Panchal SN, Patel HD (2014) Review of
synthesis of 1,3,4-oxadiazole derivatives. Synth Commun 44(13):
1859–1875. https://doi.org/10.1080/00397911.2013.879901
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