Dithiolane linked thiorhodamine dimer for Hg2+ recognition in living cells

Article abstract of DOI:10.1039/b815956d

Thiorhodamine-based chemodosimeter A, a disulfide linked dimer, was designed for Hg²⁺ recognition by virtue of the strong affinity of mercury for sulfur. Spectroscopic results reveal that chemodosimeter A exhibits real-time responses, and high

Full text of DOI:10.1039/b815956d

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Dithiolane linked thiorhodamine dimer for Hg2+ recognition in living cells†
Weimin Liu,a Liwei Xu,a,c Hongyan Zhang,a Juanjuan You,a,b Xiaoling Zhang,*c Ruilong Sheng,a
Huaping Li,*d Shikang Wua and Pengfei Wang*a
Received 11th September 2008, Accepted 21st November 2008
First published as an Advance Article on the web 6th January 2009
DOI: 10.1039/b815956d
Thiorhodamine-based chemodosimeter A, a disulfide linked dimer, was designed for Hg2+ recognition
by virtue of the strong affinity of mercury for sulfur. Spectroscopic results reveal that chemodosimeter
A exhibits real-time responses, and high sensitivity and selectivity for Hg2+ in comparison to other
cations. These properties are mechanistically ascribed to the transfer from rhodamine spirolactam to
the thiazoline-derived open-ring rhodamine via Hg2+ induced desulfurization. The in vitro recognition
of Hg2+ in living cells pretreated with A was examined, showing that the concentration of Hg2+ that
could be imaged reaches the safety limit for human beings.
small molecules.9 Of these, fluorescence probes derived from bio-
compatible substrates offer a promising approach for the in vitro
Introduction
Mercury is the third most frequently found and second most
and in vivo monitoring of mercury due to their low costs and easy
cellular uptakes.5
common toxic heavy metal in the list of the Agency for Toxic
Substances and Disease Registry (ATSDR) of the U. S. Depart-
ment of Health and Human Services.1,2 The extreme toxicity
of mercury and its derivatives results from its high affinity for
thiol groups in proteins and enzymes, leading to the dysfunction
of cells and consequently causing health problems.3 The health
concerns over exposure to mercury have motivated the exploration
of selective and efficient methods for the monitoring of mercury in
biological and environmental samples.4,5 A number of fluorescent
chemosensors with selectivity for Hg2+ have been reported includ-
ing conjugated polyelectrolytes,6 foldamers,7 biomolecules,8 and
Rhodamine derivatives exhibit high molar absorption coeffi-
cients and high fluorescence quantum yields at longer wavelengths
(>500 nm) when in ring-open conformations, but their spirolactam
structures are colorless and nonfluorescent. More recently, several
rhodamine-based probes were reported, in which the signal was
transduced either through simply opening the spirolactam ring
upon mercury binding10 or through chemodosimetric reactions of
the thiocarbonyl activated by the strong affinity of mercury for
sulfur.11 However, most of them have cross-sensitivities toward
other metal cations or delayed responses. For example, these
chemodosimetric sensors take one minute or several minutes
to complete the ring-opening reaction. In the present work,
a rhodamine-based chemodosimeter A with a disulfide linker
(Scheme 1) was designed on the basis of the extreme affinity of
sulfur for mercury. It shows the features of unique selectivity
and real-time responses to mercury over other cations in aqueous
solution. Compound A was obtained from the reaction of com-
pound B (Scheme 1) and P2S5/HMDO (hexamethyl disiloxane)
in refluxing CHCl3 (yield: 19%). Compound B was synthesized
from the simple reaction of rhodamine B acyl chloride and
cystamine dihydrochloride in a yield of 55.6%. The detailed
synthetic procedures and characterizations are described in the
Experimental Section.
aLaboratory of Organic Optoelectronic Functional Materials and Molec-
ular Engineering, Technical Institute of Physics and Chemistry, the Chi-
nese Academy of Sciences, Beijing, 100190, China. E-mail: wangpf@
mail.ipc.ac.cn; Fax: +86-10-82543512; Tel: +86-10-82543512
bGraduate School of the Chinese Academy of Sciences, Beijing, China
cDepartment of Chemistry, School of Sciences, Beijing Institute of Technol-
ogy, Beijing 100081. E-mail: zhangxl@bit.edu.cn
dCenter for Polymers and Organic Solids, Departments of Materials, Chemi-
stry & Biochemistry, University of California, Santa Barbara, CA 93106.
E-mail: hli@chem.ucsb.edu
† Electronic supplementary information (ESI) available: IR, 1H NMR, 13
C
NMR and HRMS spectra of A, B, and C; the reversibility of compound A
and B with DETA; the effect of different pH on the fluorescence response
of A and A + Hg2+; confocal images of living HK-2 cells in the presence of
compound A. See DOI: 10.1039/b815956d
Scheme 1 The synthesis of compounds A and B.
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Results and discussion
Hg2+ recognition in aqueous solution
Compounds A and B exhibit selectivity for Hg2+ among a series
of metal cations, such as Hg2+, Cu2+, Cd2+, Pb2+, Zn2+, Fe2+, Co2+,
Ni2+, Ca2+, Mg2+, Li+, K+, Na+, Cu+, Ag+ and Fe3+. However, it
takes several hours to observe the fluorescence enhancement for
compound B upon the addition of Hg2+ (Fig. 1a). Additionally, the
fluorescence change of compound B was reversed upon addition
of diethylenetriamine (DETA) (Fig. S1, ESI†). This returning phe-
nomenon elicits that the spectral response of compound B to Hg2+
is likely due to the chelation-induced ring-opening of rhodamine
spirolactam,10,12 rather than other possible reactions. However, the
formation of complex [B-Hg]2+ might decrease the electrophilicity
of Hg2+, which is needed to open the rhodamine spirolactam,
consequently slowing down the fluorescence response.
Fig. 2 UV-Vis absorption (a) and fluorescence emission (b) spectra of A
(5 mM) in an ethanol-water (80/20, v/v) solution upon addition of Hg2+ in
concentrations of 0, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0 mM. Insert:
the plot of fluorescence intensity of compound A (5 mM) upon additions
of Hg2+ from 0.1 to 10 mM in ethanol-water (v/v = 80/20) solution.
lex = 510 nm, lem = 580 nm.
Fig. 1 Time response curves of compound B (10 mM) (a) and compound
A (5 mM) (b) to the addition of 5 equiv. of Hg2+ in an ethanol-water
(v/v = 80/20) solution. lex = 510 nm, lem = 580 nm.
Significantly different from compound B, the solution color and
fluorescence changes of A were observable upon the addition of
Hg2+ within 10 seconds (Fig. 1b). This feature of real-time response
to mercury is particularly important in practical application. In
addition, the solutions of compound A and A + Hg2+ remain stable
in a wide pH range from 4 to 9 (Fig. S2, ESI†).
As shown in Fig. 2, the growth of an absorption peak at 560 nm
and a maximum emission at 580 nm were observed upon gradual
addition of Hg2+. The plot of fluorescence intensity of compound
A against the concentration of added Hg2+ is depicted in Fig. 2b
(insert), and exhibits a good linear correlation in the concentration
range from 0.1 mM to 10 mM (R2 = 0.99875). The fluorescence
intensity of compound A increased with increasing concentration
of Hg2+ to 2 equiv., but remained unchanged with further addition
of Hg2+ (Fig. 3). The Job’s plot (Fig. 3, insert) was conducted when
[A + Hg2+] = 10-5 M, and the turn point clearly appears at 0.66,
indicating the 1:2 stoichiometric ratio of compound A to Hg2+.
In order to evaluate the selectivity of compound A for Hg2+
among a series of metal cations, such as Hg2+, Cu2+, Cd2+, Pb2+,
Zn2+, Fe2+, Co2+, Ni2+, Ca2+, Mg2+, Li+, K+, Na+, Cu+, Ag+ and
Fe3+, the fluorescence spectra of compound A (5 mM) in an
ethanol-water (v/v = 80/20) solution upon addition of various
metal caions are depicted in Fig. 4a. Apparently, a significant
fluorescence enhancement of compound A (~50 times) was
observed only when Hg2+ was added, in comparison to that seen
by adding other cations (<5 times). Moreover, the Hg2+ induced
Fig. 3 The titration curve of A (0.2 mM) upon addition of Hg2+ in an
ethanol-water (v/v: 80/20) solution. Insert: Job’s plot for the complex of
A and Hg2+ in ethanol-water (v/v = 80/20) solution. [A] + [Hg2+] = 10-5 M.
lex = 510 nm, lem = 580 nm.
fluorescence enhancement was not affected by the presence of
alkali or alkaline-earth metals, such as Ca2+, Mg2+, Li+, K+, Na+,
and other transition metals like Cu2+, Cd2+, Pb2+, Zn2+, Fe2+, Co2+,
Ni2+, Cu+, Ag+ and Fe3+. As shown in Fig. 4b, the fluorescence
intensity of compound A in the presence of other cations upon
the addition of Hg2+ was approximately invariant. All together
the results illustrate that the selectivity and responsive time of A
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induced cyclizations,11 a rhodamine derivative with a thiazoline
structure was formed.
Intracellular imaging of Hg2+
Taking into account the advantages of real-time response, ex-
tremely high sensitivity and selectivity of compound A for Hg2+,
compound A was used for in vitro Hg2+ detection in living cells.
After HK-2 cells were incubated with 10 mM of compound A
for 30 min at 37 ◦C, and then treated with different concen-
trations of Hg2+ from 0.1, 1, 10, to 20 mM, their fluorescence
images were taken by confocal microscopy. As shown in Fig. 5,
these confocal images display Hg2+-concentration dependence: the
stronger fluorescence images of HK-2 cells are those treated with
the higher concentrations of Hg2+. The imaged intracellular Hg2+
concentration was as low as 0.1 mM (0.1 ppm) (Fig. 5a), the
limit of safe concentration for human beings. Under the same
experimental conditions, no fluorescence was imaged in HK-2
cells incubated with compound A only (Fig. S4a, ESI†). Based on
these results, any concerns about fluorescence emission possibly
arising from the enzymatic ring-opening of the thiorhodamine
spirolactam in living cells can be ruled out. In addition, the bright
field transmission image of the HK-2 cell was displayed in Fig. S4b
(ESI†).
Fig. 4 (a) The fluorescence spectra of A (5 mM) upon addition of 10 mM
of Hg2+ and 50 mM of various other metal ions in an ethanol-water (v/v =
80/20) solution. (b) Fluorescence response of A (5 mM) to 10 mM of Hg2+
in an ethanol-water (v/v = 80/20) solution containing 50 mM of various
metal ions. lex = 510 nm, lem = 580 nm.
are remarkably improved for Hg2+ recognition in comparison to B
=
=
possibly due to the transformation of the C O in B to C S in A.
Rationalization
To rationalize the sensitivity and selectivity of compound A for
Hg2+, an excess of DETA was added into a compound A solution
in the presence of Hg2+ (Fig. S3, ESI†). Unlike the phenomenon
observed in the same experiment conducted with compound B, the
fluorescence spectra of compound A remained unchanged after the
excellent chelating agent of transition metals (DETA) was added.
The result implies an irreversible nature for the desulfurization,
which was also observed in those chemodosimeters typical for
Hg2+.11,13
Fig. 5 Confocal images of HK-2 cells incubated with A (10 mM) for
30 min at 37 ◦C and then treated with (a) 0.1 mM, (b) 1 mM, (c) 10 mM and
(d) 20 mM of Hg2+ for 30 min.
To characterize the desulfurization induced by Hg2+, the reac-
tion of compound A with Hg2+ in ethanol/CH2Cl2 was conducted.
The molecular structure of the unique reaction product was
characterized by IR, 1H NMR, 13C NMR and HRMS (ESI†) to be
compound C (Scheme 2) with a high fluorescence quantum yield
(Uf = 0.53 in reference to rhodamine B).14 Similarly to other Hg2+
Conclusions
In conclusion, a thiorhodamine-based chemodosimeter A with a
disulfide linker was synthesized and characterized. The experimen-
tal results show that compound A exhibits real-time responses, and
an extremely high sensitivity and unique selectivity for Hg2+, which
are mechanistically ascribed to the transfer from thiorhodamine
spirolactam to the thiazoline-derived open-ring rhodamine C
through Hg2+ induced desulfurization. The utilization of com-
pound A for the monitoring of mercury levels in living cells was
thus examined, and showed that the concentration of Hg2+ that
could be imaged, reached the safety limit for human beings. The
reported chemodosimeter A containing a disulfide linker might
find its application in mercury recognition in biological systems.
Scheme 2 The synthesis of compound C.
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and added dropwise to a solution of cystamine dihydrochloride
(0.3 g, 1.3 mmol) in dry acetonitrile (15 mL) containing 2.0 mL of
triethylamine over 1~1.5 h in an ice bath. After 8 h, the solvent was
removed under reduced pressure and the residue was washed with
water. The purple residue was dried in a vacuum oven and purified
by column chromatography (using CH2Cl2/methanol = 20:1 as
eluent). The first pink band was collected to afford B (0.64 g,
yield: 55.6%). IR (KBr pellet, cm-1): 3078, 2969, 2928, 1693, 1614,
1515, 1229, 1118, 819, 785, 756, 699. 1H NMR (CDCl3, 400 MHz)
d (ppm): 1.17 (24H, t, J = 7.0 Hz), 2.27 (4H, q), 3.29 (4H, m),
3.35 (16H, q, J = 7.0 Hz), 6.28 (4H, d), 6.38 (4H, s), 6.45 (4H,
d), 7.07 (2H, m), 7.43 (4H, m), 7.90 (2H, m). 13C NMR (CDCl3,
100 MHz) d (ppm): 12.7, 35.9, 40.0, 44.4, 65.0, 97.9, 105.5, 108.0,
122.7, 124.0, 128.1, 128.8, 131.8, 132.4, 149.0, 153.7, 167.5. TOF-
HRMS [M]+: m/z, found 1000.4746, calcd 1000.4743.
Experimental section
Materials and methods
UV-vis absorption and fluorescence spectra were recorded in a
Hitachi U-3010 absorption spectrometer and a Hitachi F-4500 flu-
orescence spectrometer, respectively. NMR spectra were recorded
on a Bruker-400 (400 MHz). Mass spectroscopy was measured on
either a Finnigan GC-MS 4021 or a Bruker Paltonics FlexAnlysis
BA060655 MS-spectrometer instrument. Cationic compounds
such as LiClO4, NaClO4, KClO4, AgNO3, CuI, Mg(ClO4)2,
Ca(ClO4)2, Pb(ClO4)2, Fe(ClO4)2, FeCl3, CoCl2, NiCl2, Cu(ClO4)2,
Zn(ClO4)2, Cd(ClO4)2, Hg(ClO4)2 were purchased from Aldrich,
and were used as received. Rhodamine B base was analytical grade,
purchased from Beijing Chemical and recrystallized once before
use. Dry 1,2-dichloroethane and acetonitrile were distilled from
these refluxing solvents with CaH2. Ethanol for spectra detection
was HPLC reagent without fluorescent impurity and H2O was
deionized water. Flash chromatography was carried out on silica
gel 60 (200–300 mesh; Qingdao Haiyang Chemical Co., Ltd).
All experiments were carried out in an ethanol/water (v/v =
80/20) solution except when specifically described. The stock
solution of A or B was prepared in ethanol/CH2Cl2 (v/v =
8/2) (1.0 ¥ 10-3 M), stored at -25 ◦C and thawed in the dark
before use. The cationic solutions were prepared in ethanol/water
(v/v = 80/20) with concentrations of 1.0 ¥ 10-2 M for fluorescence
and UV-vis measurements. To a quartz cell (1 cm of optical
path length) filled with 2 mL of A or B was added the stock
solution of cations dropwise using a micro-syringe. The volume
of these added cationic stock solutions was less than 100 mL to
leave the concentration of A or B unchanged. All fluorescence
Compound A. Compound B (100 mg, 0.1 mmol) was dissolved
in 10 mL of CHCl3 and added to a mixture of P4S10 (32 mg,
0.07 mmol) and HMDO (0.2 mL, 0.94 mmol) in 10 mL of
CHCl3. The reaction mixture was refluxed for 4 hours under a N2
atmosphere. After the removal of CHCl3, the residue was purified
by chromatography (CH2Cl2/petroleum = 4:1 as eluent) to give
A (20 mg, yield: 19%). IR (KBr pellet, cm-1): 2968, 2967, 1615,
1516, 1397, 1220, 1118, 818, 770. 1H NMR (CDCl3, 400 MHz) d
(ppm): 1.12 (24H, t, J = 6.5 Hz), 2.39 (4H, m), 3.28 (16H, m), 3.54
(4H, m), 6.26 (12H, m), 7.09 (2H, m), 7.49 (4H, m), 8.12 (2H, m).
13C NMR (CDCl3, 100 MHz) d (ppm): 12.7, 29.8, 35.0, 44.5, 73.6,
98.1, 103.4, 108.2, 123.5, 124.9, 128.7, 132.4, 138.6, 149.3, 150.1,
153.5, 190.0. MALDI-TOF-MS found [M + H]+: m/z, 1033.462,
calcd 1033.44.
Compound C. Compound A (103 mg, 0.1 mmol) was dissolved
in CH2Cl2/ethanol (1:1, 20 mL). To the solution of A, was
added Hg(ClO4)2·3H2O (227 mg, 0.5 mmol). After stirring for
10 min, the solvent was removed under reduced pressure and
the residue was purified by column chromatography (using ethyl
acetate/ethanol = 3/1 as eluent). The red band was collected and
the solvent was removed under vacuum to afford C (15.6 mg, yield:
16.1%). IR (KBr pellet, cm-1): 2970, 2926, 1589, 1412, 1338, 1181,
1074, 822, 683. 1H NMR (CDCl3, 400 MHz) d (ppm): 1.33 (12H,
t, J = 7.12 Hz), 3.21 (2H, t, J = 8.4 Hz), 3.63 (8H, q, J = 7.16 Hz),
4.00 (2H, t, J= 8.4), 6.80 (2H, m), 6.89 (2H, d), 7.14 (2H, d), 7.27
(1H, m), 7.68 (2H, m), 7.95 (1H, m). 13C NMR (CDCl3, 100 MHz)
d (ppm): 12.8, 34.6, 46.2, 65.5, 96.79, 113.7, 113.9, 130.3, 130.5,
130.7, 130.9, 131.6, 133.4, 155.5, 157.8 166.3. ESI-HRMS [M]+:
m/z, 484.2433 found, calcd 484.2417.
◦
spectra were recorded at 25 C under excitation of 510 nm. The
maximum fluorescence intensities at 580 nm were analyzed against
the concentrations of added cations.
Cell culture
HK-2 cells (gifted from the center of cells, Peking Union Medical
College) were cultured in culture media (DMEM/F12 supple-
mented with 10% FBS, 50 unit/mL penicillin, and 50 mg/mL of
streptomycin) at 37 ◦C in a humidified incubator. HK-2 cells were
seeded in a 6-well plate at a density of 104 cells per well in culture
media. After 24 h, the cells were incubated with 10 mM of A in
culture media for 20–30 min at 37 ◦C. After carefully washing
with PBS to remove free A, the cells pretreated with A were then
incubated with HgCl2 in different concentrations in culture media
for another 30 min at 37 ◦C. These cells were imaged using confocal
fluorescence microscopy (excitation light source: Green; Olympus
IX 71 S 8F-2).
Acknowledgements
This work was supported by NNSF of China (No.20673132), the
Croucher Foundation of Hong Kong, the Chinese Academy of
Sciences “hundred talents program”, the National Basic Research
Program of China (No. 2006CB933000) and the 111 Project
(B07012).
Synthesis
Compound B. To a solution of rhodamine B base (1.0 g,
2.3 mmol) in 1,2-dichloroethane (15 mL), was added phosphorus
oxychloride (0.75 mL, 8.2 mmol) dropwise over 5 min under
stirring. The mixture solution was refluxed for 4 hours. After the
reaction mixture was cooled down to r.t., the solvent was removed
under reduced pressure to obtain rhodamine B acyl chloride,
which was directly used in the next step. The crude rhodamine
B acyl chloride (2.3 mmol) was dissolved in acetonitrile (30 mL)
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