Synthesis and evaluation of two novel rhodamine-based fluorescence probes for specific recognition of Fec+ ion

Article abstract of DOI:10.1016/j.tetlet.2017.05.052

Two low cytotoxic fluorescence probes Rb1 and Rb2 detecting Fe³⁺ were synthesized and evaluated. Rb1 and Rb2 exhibited an excellent selectivity to Fe³⁺, which was not disturbed by Ag⁺, Li⁺, K⁺, Na⁺, NH₄⁺, Fe²⁺, Pb²⁺, Ba²⁺, Cd²⁺, Ni²⁺, Co²⁺, Mn²⁺, Zn²⁺, Mg²⁺, Hg²⁺, Ca²⁺, Cu²⁺, Ce³⁺, AcO^?, Br^?, Cl^?, HPO₄^2?, HSO₃^?, I^?, NO₃^?, S₂O₃^2?, SO₃^2? and SO₄^2? ions. The detection limits were 1.87?×?10^?7?M for Rb1 and 5.60?×?10^?7?M for Rb2, respectively. 1:1 stoichiometry and 1:2 stoichiometry were the most likely recognition mode of Rb1 or Rb2 towards Fe³⁺, and the corresponding OFF–ON fluorescence mechanisms of Rb1 and Rb2 were proposed.

Full text of DOI:10.1016/j.tetlet.2017.05.052

Accepted Manuscript
Synthesis and evaluation of two novel rhodamine-based fluorescence probes for
c+
specific recognition of Fe ion
Cuicui Jiang, Mian Wang, Yanxiu Wang, Xiuneng Tang, Yamin Zhang, Hui
Zhang, Lin Ma, Jianyi Wang
PII:
S0040-4039(17)30630-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.05.052
TETL 48945
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
15 March 2017
14 May 2017
15 May 2017
Please cite this article as: Jiang, C., Wang, M., Wang, Y., Tang, X., Zhang, Y., Zhang, H., Ma, L., Wang, J., Synthesis
c+
and evaluation of two novel rhodamine-based fluorescence probes for specific recognition of Fe ion, Tetrahedron
Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.05.052
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Synthesis and evaluation of two novel rhodamine-based fluorescence
3+
probes for specific recognition of Fe ion
1
Cuicui Jiang , Mian Wang , Yanxiu Wang , Xiuneng Tang , Yamin Zhang , Hui Zhang , Lin Ma ,
2
3
3
1
1
1
1
,*
Jianyi Wang
1
School of Chemistry and Chemical Engineering, Guangxi University, Nanning 530004, P. R.
2
China. College of Life Science and Technology, Guangxi University, Nanning
3
5
30004, P. R. China. Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine,
Nanning 530011, P. R. China
Corresponding author, E-mail: jianyiwang@gxu.edu.cn
*
Abstract
Two low cytotoxic fluorescence probes Rb1 and Rb2 detecting Fe
synthesized and evaluated. Rb1 and Rb2 exhibited an excellent selectivity to Fe ,
3
+
were
3
+
+
+
+
+
+
2+
2+
2+
2+
2+
2+
4
which was not disturbed by Ag , Li , K , Na , NH , Fe , Pb , Ba , Cd , Ni , Co ,
2
+
2+
2+
2+
2+
2+
3+
-
-
-
2-
-
-
-
Mn , Zn , Mg , Hg , Ca , Cu , Ce , AcO , Br , Cl , HPO
4
, HSO
3
, I , NO
ions. The detection limits were 1.87×10 M for Rb1 and
.60×10 M for Rb2, respectively. 1:1 stoichiometry and 1:2 stoichiometry were the
3
,
2
-
2-
2-
-7
S
2
O
3
, SO
3
and SO
4
−
7
5
3
+
most likely recognition mode of Rb1 or Rb2 towards Fe , and the corresponding
OFF–ON fluorescence mechanisms of Rb1 and Rb2 were proposed.
3
Keywords: rhodamine B; fluorescence probe; Fe ; low cytotoxicity
+
1. Introduction
Iron plays a key role in many biochemical processes involving oxygen transport,
exotic metabolism mediated by P450 (oxido-reduction), gene expression and signal
1
transduction etc . The overload of iron (especially Fe ) in the body would cause
, 2
3+
many severe diseases including hepatitis, cancers, dysfunction of pancreas, livers and
3
heart . While the deficiency of Fe might induce anemia , fatigue and decreased
-5
3+
6
7
immunity. It is worthwhile to note that ferroptosis was recently deemed to be a new
8
strategy for cancer therapy . Also, Fe is important pollutant source of the
-10
3+
environment. Therefore, the effective monitoring and detecting iron ions is very
1

significant. Atomic absorption spectroscopy, spectrophotometry, and voltammetry
inductively coupled plasma mass spectroscopy were familiar identification method of
3
Fe , but limiting their application due to high cost, time-consuming and complex
+
11
3+
samples . Thus, the fluorescence probe technique for detecting Fe ions, as a highly
1
efficient, rapid and convenient technique , has emerged and drawn tremendous
2
attention from academia and industrial circles.
3
Up to date, various fluorescence probes for selective sensing of Fe have been
+
1
3
developed, such as fluorescein , quinazolinone, pyrene, rhodamine, coumarin,
1
4, 15
naphthalimide, boron dipyrromethene difluoride (BODIPY) etc
. Among these
probes, the fluorescence probes based on rhodamine were the most ideal chemosensor
for the detection of iron ions because of their large extinction coefficient, long
wavelength absorption and emission, high fluorescence quantum yield and low
1
6-22
3+
. However, few rhodamine-based Fe fluorescence probes were reported
toxicity
because the rhodamine probes were easily quenched by the paramagnetism of iron
2
+
2+
and iron ions were easily interfered by other metal ions such as Cu and Hg ions
23,
2
4
.
Therefore, the development of a high selective and sensitive sensor for iron ions is
still an important challenge. In this work, two novel probes (Rb1 and Rb2) for
detecting iron ions were designed and synthesized. The obtained target compounds
(
Rb1 and Rb2) were correspondingly characterized and evaluated.
2. Results and discussion
The synthetic routes of probes Rb1 and Rb2 were shown in Scheme 1 and Scheme
. A strong fluorescent rhodamine B, which was used as starting material, first
2
underwent a cyclization process with the ethylenediamine to give a non-fluorescent
2
5
compound Rh-NH
Rh-NH then reacted with dimethylcarbamoyl chloride to provide the probe Rb1.
Similarly, rhodamine B was cyclized by 2-aminoethanol to give a non-fluorescent
2
. In the presence of triethylamine and dry dichloromethane,
2
2
compound Rh-OH . Under the promotion of DIPEA and triphosgene, Rh-OH then
6
reacted with 2-morpholinoethan-1-amine to provide probe Rb2. The obtained
1 13
products were characterized by H NMR, C NMR spectroscopy, and HRMS
2

spectrometry (Figure S1-S10).
Scheme 1 Synthetic route of Rb1. Reagents and conditions: (a) ethylenediamine,
o
o
anhydrous ethanol, 100 C reflux; (b) dimethylcarbamoyl chloride, triethylamine, 0 C,
rt, 84.59%.
Scheme 2 Synthetic route of Rb2. Reagents and conditions: (a) 2-aminoethanol,
o
o
methanol, 78 C, reflux; (b, c) 2-morpholinoethan-1-amine, DIPEA, triphosgene, 0
C to rt, overnight, 76.17%.
2
Figure 1 Absorbance spectra of Rb1 (a) and Rb2 (b) (50 µM) in EtOH/H O (8:2, v/v)
3

+
upon addition of 10 equiv Ag , Li , K , Fe , Pb , Ba , Cd , Ce , Ni , Co , Mn ,
+
+
2+
2+
2+
2+
3+
2+
2+
2+
3
+
2+
2+
2+
Fe , Zn , Mg , Hg , NH
+
2+
2+
+
4
, Ca , Cu , Na . (c) The color changes of Rb1 and Rb2
(
100 µM) in the presence of different metal ions (2 eq) under daylight.
3
+
A strong UV absorption at 564 nm was observed after addition of Fe into the
solution of Rb1 or Rb2 in EtOH/H O (8:2, v/v) (50 µM). However, no clear
absorption in the range of 500-650 nm was observed upon addition of Ag , Li , K ,
2
+
+
+
+
+
2+
2+
2+
2+
2+
2+
2+
2+
2+
2+
2+
3+
4
Na , NH , Fe , Ba , Cd , Ni , Co , Mn , Zn , Mg , Hg , Ca , Cu and Ce
2
+
ions into the Rb1 solution, and the addition of Pb only showed a weak UV
absorption (Figure 1a). The addition of these metal ions into the Rb2 solution did not
even lead to any absorption in the range of 500-650 nm (Figure 1b). Fascinatingly,
under daylight lamp, the orange red color could be observed for the probe (Rb1 or
3
+
Rb2) and Fe solution with the naked-eye (Figure 1c), no clear color variation could
be observed for the probe (Rb1 or Rb2) and other metal ions solution. It is worth
2
noting that Fe ions often coexist with Fe ions as an oxidation-reduction pair.
+
3+
2
However, Fe did not interfere with the selective identification of Rb1 and Rb2 for
+
3
+
3+
Fe . Clearly, both Rb1 and Rb2 have good sensitive to Fe compared with the other
cations above.
2
Figure 2 Fluorescence spectra of Rb1 (a) and Rb2 (b) (10 µM) in EtOH/H O (8:2,
+
+
+
2+
2+
2+
2+
3+
2+
2+
v/v) upon addition of 10 equiv Ag , Li , K , Fe , Pb , Ba , Cd , Ce , Ni , Co ,
2
+
3+
2+
2+
2+
Mn , Fe , Zn , Mg , Hg , NH
+
2+
2+
+
, Ca , Cu , Na ; (c) The color changes of Rb1
4
4

and Rb2 (100 µM) in the presence of different metal cations (2 eq) under UV light
(
365 nm).
The fluorescence spectra of probes were explored upon addition of different cations
2
into the Rb1 or Rb2 solution (10 µM) in EtOH/H O (8:2, v/v). The Rb1 solution
3
showed a strong fluorescence emission at 580 nm upon addition of Fe ions, and no
+
+
+
+
clear fluorescence emission at 580 nm was observed upon addition of Ag , Li , K ,
+
2+
2+
2+
2+
2+
2+
2+
2+
2+
+
2+
2+
3+
4
Na , Fe , Ba , Cd , Ni , Co , Mn , Zn , Mg , Hg , NH , Ca , Cu and Ce
2
+
ions into the Rb1 solution. The addition of Pb showed a weak fluorescence emission
at 580 nm (λexc = 530 nm) (Figure 2a). These mean that the fluorescence probe Rb1
3
could be ‘turn-on’ by Fe ions but was slightly disturbed by Pb . The addition of
+
2+
these metal ions into the Rb2 solution did not even lead to any fluorescence emission
3
+
in the range of 500-650 nm (Figure 2b), only Fe gave significant fluorescence
3
response, indicating that probe Rb2 was a ‘turn-on’ fluorescence probe for Fe .
+
Under the irradiation of ultraviolet lamp (365 nm), the orange red color could be
3
observed for the probe (Rb1 or Rb2) and Fe solution with the naked-eye (Figure
+
2
c), no clear color variation could be observed for the probe (Rb1 or Rb2) and other
2
metal ions solution. It is exciting that the addition of Fe could not cause
+
fluorescence enhancement on Rb1 and Rb2 solutions. Therefore, both Rb1 and Rb2
3
in solution could be recognized by Fe and rather than other cations above.
+
2
Figure 3 Fluorescence spectra of Rb1 (a) and Rb2 (b) (10 µM) in EtOH/H O (8:2,
-
-
-
-
-
2-
-
-
-
3 4 3 3
v/v) upon addition of 10 equiv AcO , Br , Cl , F , HCO , HPO , HSO , I , NO ,
2
-
2-
2-
2 3 3 4
S O , SO and SO .
-
To explore whether the probes (Rb1 and Rb2) could be recognize by anions AcO ,
5

-
-
-
-
2-
-
-
-
2-
2-
2-
Br , Cl , F , HCO
spectra of Rb1 and Rb2 detecting anions were also analyzed. As shown in Figure 3,
the Rb1 and Rb2 solution showed a strong fluorescence emission at 580 nm (λexc
3 4 3 3 2 3 3 4
, HPO , HSO , I , NO , S O , SO , SO , the fluorescence
=
3
30 nm) upon addition of Fe ions, and no clear fluorescence emission at 580 nm was
+
5
-
observed upon addition of AcO , Br , Cl , F , HCO
-
-
-
-
2-
-
-
-
2-
3
, HPO
4 3 3 2 3
, HSO , I , NO , S O ,
2
-
2-
SO
3 4
, SO
ions into the probe solution. The result indicated that both Rb1 and Rb2
3
in solution could be recognized by Fe rather than the above anions.
+
Figure 4 Fluorescence intensity of Rb1 (a) and Rb2 (b) (10 µM) in EtOH/H
2
O (8:2,
3
v/v) in the presence of Fe (10 eq) and other metal ions (10 eq). Insets: 1, Blank; 2,
+
3
+
2+
+
2+
2+
2+
3+
2+
2+
Fe ; 3, Zn ; 4, Ag ; 5, Ba ; 6, Ca ; 7, Cd ; 8, Ce ; 9, Co ; 10, Cu ; 11, Hg ; 12,
2+
+
+
2+
2+
+
+
2+
2+
2+
4
K ; 13, Li ; 14, Mg ; 15, Mn ; 16, Na ; 17, NH ; 18, Ni ; 19, Pb ; 20, Fe .
3
To explore the practical application of Rb1 and Rb2 for the detection of Fe in
+
the solution, the competitive experiments were carried out for Rb1 and Rb2 (10 µM)
+
+
+
in the solution. As shown in Figure 4, when Ag , Li , K , Na , NH
+
+
2+
, Fe , Pb , Ba ,
2+
2+
4
2
+
2+
2+
2+
2+
2+
2+
2+
2+
3+
Cd , Ni , Co , Mn , Zn , Mg , Hg , Ca , Cu , Ce ions (100 µM) were added
3
+
into the test solution with Fe ions, no obvious changes in the fluorescence spectra at
3
80 nm could be observed. Conversely, when the same amount of Fe ions were
+
5
+
+
+
+
2+
added into the test solution with Ag , Li , K , Na , Fe , Pb , Ba , Cd , Ni , Co ,
2+
2+
2+
2+
2+
2
+
2+
2+
2+
Mn , Zn , Mg , Hg , NH
+
2+
2+
3+
4
, Ca , Cu , Ce ions, the fluorescent intensity of test
-
-
solution was dramatically enhanced. When AcO , Br , Cl , HCO
-
-
2-
- -
, I ,
3
, HPO
4
, HSO
3
-
2-
, SO
2-
2-
3+
NO
3
, S
2
O
3
3
, SO
4
ions (100 µM) were added into the test solution with Fe
ions, no obvious variations in the fluorescence intensity 580 nm were observed except
-
-
3+
3 3
HCO (Figure S11). When HCO was added into the test solution with Fe ions, a
3
double hydrolysis would occur to provide Fe(OH) precipitation, which clearly
6

3
decreased the fluorescence intensity of the test solution with Fe ions. Therefore,
+
3
Rb1 and Rb2 can be independently used to detect Fe in the solution through judging
+
the color change, absorption and fluorescence, and be not disturbed by the ions listed
-
above except for HCO
3
.
Figure 5 Fluorescence spectra of Rb1 (a) and Rb2 (b) (10 µM) upon addition
different amounts of Fe (0-18 eq).
3
+
3
To further understand sensibility of Rb1 and Rb2 on Fe ions, the fluorescence
+
titration experiments were carried out. As shown in Figure 5, with the increasing
3
+
amount of Fe ions, the fluorescence intensity at 580 nm gradually increased. In the
3
+
range of 0-60 µM of Fe , the fluorescence intensity of test solution (Rb1 and Rb2)
3
+
2
1
and Fe concentration showed an excellent linear correlation with R = 0.987
2
2
(
Figure S12a) and R
= 0.994 (Figure S12b). The detection limits of Rb1 and Rb2
3
+
-7
−7
for Fe were calculated to be 1.87×10 M and 5.24×10 M, respectively, which were
3
low enough to detect a submicromolar concentration of Fe . The detection limit is
+
equal to 3S/K, where S is the standard deviation of the blank solution, K is the slope
2
of the curve of the fluorescence intensity versus the sample concentration .
7
7

Figure 6 Cell viability of HepG2 cell treated with different concentrations of Rb1 and
Rb2.
To evaluate the cytotoxicity of Rb1 and Rb2, cell viability was determined by an
2
8, 29
MTT method
, where probes Rb1 and Rb2 were incubated with HepG2 cells for
24 h. In Figure 6, Rb1 and Rb2 did not show any toxicity to HepG2 cells in 10 µM.
When the concentrations of Rb1 and Rb2 were 20 µM, Rb1 slightly showed low
toxicity to the cells, and Rb2 did not still show any toxicity to the cells. Clearly, these
3
+
two probes could be safely used to detect Fe ions in biological system.
2
Figure 7 Fluorescence spectra of Rb1 (a) and Rb2 (b) (50 µM) in EtOH/H O (8:2,
3
v/v) in the presence of Fe (1 eq) and F (12 eq).
+
-
3
+
To explore whether the binding of Rb1 or Rb2 (50 µM) to Fe (50 µM) was
-
reversible, we chose F to perform the reversible experiments according to the
3
0, 31
-
. When F ions (12 eq of Fe ) were added to the test solution (Rb1 or
3+
references
3
+
Rb2) with Fe ions, the fluorescent intensity of the test solution (Rb1 or Rb2) with
3
Fe ions was greatly reduced (Figure 7). A possible explanation was that Fe could
+
3+
-
34
3 6
be adequately bound by high concentrations of F to form Na [FeF ] complex ,
inducing that the ring-opening form of Rb1 or Rb2 recyclized to give a
8

non-fluorescent spirocyclic Rb1 or Rb2. The fluorescence intensity of the test
3
solution was quickly revived when further Fe (0.5 eq) was added to the above
+
3
solutions. Therefore, Rb1 or Rb2 response to Fe was reversible, and these two
+
3
probes could be revived and reused to detect Fe ions.
+
3
Figure 8 Job’s plot for Rb1-Fe complex (a) and Rb2-Fe complex (b) (the total
+
3+
3
+
3+
concentration of Rb1 and Fe or Rb2 and Fe was 100 µM).
3
To explore the binding mode of Rb1 or Rb2 towards Fe , the Job’s plot for the
+
3
fluorescence was outlined with the mole fraction of Fe towards Fe and probe
+
3+
3
+
changing from 0.1 to 0.9, and the total concentration of the Rb1 or Rb2 and Fe
being maintained 100 µM. 1:1 stoichiometry was the most likely recognition mode of
3
Rb1 on Fe ions (Figure 8a), and 2:1 stoichiometry was the most likely recognition
+
3
+
mode of Rb2 on Fe ions (Figure 8b). The binding process between Rb1 or Rb2 and
3
Fe was further proven by HRMS spectroscopy of the complex (Figure S13-Figure
+
3
S14). The mass data for Rb1-Fe solution showed peaks at 735.23; calcd for
+
3
+
- +
3+
C
33
H41FeN
7
O
9
[Rb1+Fe +2NO
one peak at 1153.61; calcd for C37
153.61108. Based on the results above, the possible recognition mechanism of Rb1
3
] , 735.23096. The mass data for Rb2-Fe showed
3
+
-
+
H
2 10 3 2
57Fe N O25 [Rb2+2Fe +5NO +5H O] ,
1
3
or Rb2 towards Fe was proposed.
+
9

3
Scheme 3 Proposed recognition mechanism of Rb1, Rb2 towards Fe .
+
As shown in Scheme 3, Rb1 and Rb2 were remained as non-fluorescent
3
+
2
spironolactone form in EtOH/H O (8:2, v/v). When Fe ions were added into the Rb1
3
+
or Rb2 solution, Fe bound to the spirocyclic oxygen and the side-chain oxygen or
nitrogen of the probes Rb1 or Rb2, causing that the spirocyclic form were opened and
-
emitted strong fluorescence. When a large amount of F ions were added into the Rb1
3
or Rb2 solution with Fe , the ring-opening form of Rb1 or Rb2 recyclized to give a
+
non-fluorescent spirocyclic Rb1 or Rb2, which could be ascribed to strong affinity of
-
3+
high concentrations of F ions on Fe ions, resulting in the formation of species
3
-
[
FeF
6
] and the release of free Rb1 or Rb2. Therefore, the identification of Rb1 or
3
+
Rb2 towards Fe was driven by the coordinating effect rather than the catalytic
3
2, 33
reaction
.
3. Conclusions
In summary, we designed and prepared two novel fluorescence chemosensors Rb1
3
+
and Rb2, which exhibited high selectivity and sensitivity towards Fe . The detection
3
+
of Rb1 and Rb2 towards Fe could be judged by the color change, UV absorption
+
+
+
+
2+
2+
2+
and fluorescence and free from the interference of Ag , Li , K , Na , Fe , Pb , Ba ,
2
+
2+
2+
2+
2+
2+
2+
Cd , Ni , Co , Mn , Zn , Mg , Hg , NH
+
2+
2+
, Ca , Cu , Ce , AcO , Br , Cl ,
3+
-
-
-
4
2
-
-
-
-
2-
2-
2-
HPO , HSO , I , NO , S O , SO , SO ions. The detection limits of these two
4 3 3 2 3 3 4
10

3
probes towards Fe reached submicromolar level where Rb1 was 1.87×10 M and
+
-7
−7
Rb2 was 5.60×10 M. Further, cell viability experiments showed that Rb1 and Rb2
3
was low cytotoxicity at low doses and safe enough to detect Fe ions in biological
+
3
system and environment. Rb1 was bound by Fe with a ratio of 1:1, and Rb2 was
+
3
recognized by Fe with a ratio of 1:2, which was confirmed by Job’s plot and HRMS
+
spectroscopy. At last, the corresponding OFF–ON fluorescence mechanisms of Rb1
3
and Rb2 towards Fe ions were proposed.
+
Acknowledgments
W. J. Y. thanks the support of the National Natural Science Foundation of China
(
No.21262004) and Guangxi Key Laboratory of Traditional Chinese Medicine Quality
Standards(No.201602), and W. M. thanks the support of Study Abroad Program for
Excellent Ph.D Students of Guangxi Zhuang Autonomous Region.
A. Supplementary material
Supplementary data associated with this article can be found, in the online version, at
http://.
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3
13

14

High light
3
. Rb1 and Rb2 show high selectivity and sensitivity toward Fe .
3
. Rb1 and Rb2 show low detection limits for Fe .
+
1
2
3
4
+
. Rb1 and Rb2 present low cytotoxicity.
3
. Rb1 and Rb2 response to Fe was reversible, and reused to detect Fe ion.
+
3+
15