Reversible Fluorescent Turn-on Sensors for Fe3+ based on a Receptor Composed of Tri-oxygen Atoms of Amide Groups in Water

Jiaoliang Wang; Liping Long; Guing Xiao; Fang Fang

doi:10.1515/chem-2018-0140

Article Open Access

Reversible Fluorescent Turn-on Sensors for Fe³⁺ based on a Receptor Composed of Tri-oxygen Atoms of Amide Groups in Water

Jiaoliang Wang , Liping Long , Guing Xiao and Fang Fang

Published/Copyright: December 21, 2018

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From the journal Open Chemistry Volume 16 Issue 1

Abstract

Compounds Rh6G-1 and RhB-2 with a novel receptor composed of tri-oxygen atoms of amide groups were designed and synthesized as new reversible fluorescent sensors for Fe³⁺. The prominent features of the novel sensor Rh6G-1 include a large fluorescence turn-on response in essentially pure water at room temperature, high sensitivity, high selectivity, a limit of detection, cell membrane permeability, and low cytotoxicity. These desirable attributes enable us to successfully employ the new sensor Rh6G-1 for Fe³⁺ bioimaging in living cells.

Keywords: Sensor; Reversibility; Fe3+; tri-oxygen

1 Introduction

Iron is an essential trace element with significant roles in chemical and biological processes [1]. As iron transporting, storage, and balance are tightly regulated in an organism [2], iron deficiency or overload may induce various diseases [1,3]. Thus, the detection of iron ions is highly important. Many sophisticated analytical techniques, including atomic absorption, ICP-AES, and voltammetry have been used to detect Fe³⁺ ions in environment [4, 5, 6]. However, there is a high demand to develop inexpensive and real-time monitoring methods for the detection of Fe³⁺ in biosystems.

Recently, a number of fluorescence-enhanced Fe³⁺ sensors based on reversible Fe³⁺ coordination or Fe³⁺- mediated reactions have been reported [7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18]. However, some of them could only function in organic solvents or aqueous-organic media. This incompatibility with water may restrict their potential bio-applications. Therefore, the design of new reversible fluorescent turn-on Fe³⁺ sensors with high selectivity, high sensitivity, rapid response, and good water solubility for bio-applications remains demanding.

Herein, the choice of rhodamine derivatives as the fluorophore is based on the excellent photophysical properties of rhodamine derivatives, which have been extensively employed as a sensing platform for diverse arrays of metal ions, neutral bio-molecules (e.g. NO, HClO, Cys, etc), and anions [19, 20, 21]. Furthermore, inspired by the prior report that Fe³⁺ strongly complexes with the tri-oxygen atoms of the amide groups in the bioactive ferrichromes [22], we further select the similar tri-oxygen atoms of the amide groups as the candidate recognition unit for Fe³⁺. To our best knowledge, this recognition unit has not been previously exploited in design of reversible fluorescent Fe³⁺ sensors. Notably, the novel recognition unit is distinct from the existing N, S, O or N, O atoms as the Fe³⁺ receptors [7].

In this work, we report the synthesis of new reversible fluorescent turn-on sensors Rh6G-1 for Fe³⁺ in essentially pure water. The sensors of Rh6G-1 and RhB-2 have been synthesized in one step by condensation of rhodamine 6G/B hydrazides with excess isocyanatobenzene (PhNCO), and find that sensors Rh6G-1demonstrate high selectivity toward Fe³⁺ over a wide range of tested metal ions in almost pure water. More importantly, the sensor Rh6G-1 is a reversible turn-on sensor for Fe³⁺, and could effectively work at cellular level.

2 Materials and Methods

2.1 Materials and instruments

Unless otherwise stated, all reagents were purchased from commercial suppliers and used without further purification. Solvents used were purified by standard methods prior to use. Twice-distilled water was used throughout all experiments. The salts used in the stock solutions of metal ions were NaCl, KCl, NiCl₂·6H₂O, AgNO₃, MnCl₂·4H₂O, ZnCl₂, MgCl₂·6H₂O, CaCl₂, CdCl₂·2.5H₂O, CuCl₂·2H₂O, FeCl₂·4H₂O, CoCl₂·6H₂O, HgCl₂, Pd(C₂H₃O₂)₂, PbCl₂, AuCl₃ and FeCl₃·6H₂O. Melting points of compounds were measured on a Beijing Taike XT-4 microscopy melting point apparatus, all melting points were uncorrected; Low resolution mass spectra were performed using an LCQ Advantage ion trap mass spectrometer from Thermo Finnigan or Agilent 1100 HPLC/MSD spectrometer; High resolution mass spectrometric (HRMS) analyses were measured on a Finnigan MAT 95 XP spectrometer. NMR spectra were recorded on an INOVA-400 spectrometer, using TMS as an internal standard; Electronic absorption spectra were obtained on a LabTech UV Power spectrometer; Photoluminescent spectra were recorded with a HITACHI F4600 fluorescence spectrophotometer; Cell imaging was performed with a Nikon eclipse TE300 inverted fluorescence microscopy; TLC analyses were performed on silica gel plates and column chromatography was conducted over silica gel (mesh 200–300), both of which were obtained from the Qingdao Ocean Chemicals.

2.2 HeLa cell incubation and imaging using sensor Rh6G-1

HeLa cells were grown in MEM (modified Eagle’s medium) supplemented with 10% FBS (fetal bovine serum) in an atmosphere of 5% CO₂ and 95% air at 37°C. The cells were plated on 6-well plates and allowed to adhere for 24 hours. Immediately before the experiments, the cells were washed with PBS buffer, and then the cells were incubated with sensor Rh6G-1 (10 μM) and Hoechst 33258 (4.5 μM) for 30 min at 37ºC in PBS buffer (containing 1% DMSO as a cosolvent), and then washed with PBS three times. After incubating with ferric citrate (10 equiv.) for another 30 min at 37 ºC, the HeLa cells were rinsed with PBS three times, and the fluorescence images were acquired through a Nikon eclipse TE300 inverted fluorescence microscopy equipped with a cooled CCD camera.

2.3 Cytotoxicity assays

HeLa cells were grown in the modified Eagle’s medium (MEM) supplemented with 10% FBS (fetal bovine serum) in an atmosphere of 5% CO₂ and 95% air at 37°C. Immediately before the experiments, the cells were placed in a 96-well plate, followed by addition of increasing concentrations of sensor Rh6G-1 (99% MEM and 1% DMSO). The final concentrations of the sensor were kept from 5 to 200 μM (n = 3). The cells were then incubated at 37°C in an atmosphere of 5% CO₂ and 95% air at 37_oC for 24 hours, respectively, followed by the standard MTT assays. An untreated assay with MEM (n = 3) was also conducted under the same conditions.

2.4 Synthesis of Compound Rh6G-1

The starting material, Rhodamine 6G hydrazide 1, is a known compound [23] . Rhodamine 6G hydrazide 1 (800.5 mg, 1.9 mmol) and PhNCO (1200.1 mg, 10.0 mmol) in anhydrous toluene (75 mL) were heated to reflux for 1 hour. The hot solution was cooled to room temperature, and the solvent was removed under reduced pressure. The resulting residue was purified on a silica gel column (CH₂Cl₂ / petroleum = 1 : 2) to produce compound Rh6G-1 as a white powder (249.6 mg, isolated yield: 19.7%). mp 157-159_oC; ₁H NMR (400 MHz, CDCl₃): δ = 1.13-1.16 (t, 6H), 1.84 (s, 6H), 2.87-2.95 (m, 2H), 3.01-3.09 (m, 2H), 3.34 (bs, 2H), 6.26 (s, 2H), 6.38 (s, 2H), 6.95-7.01 (m, 6H), 7.12-7.16 (t, J = 7.8 Hz, 4H), 7.39-7.41 (d, J = 7.6 Hz, 1H), 7.66-7.69 (t, J = 7.4 Hz, 4H), 7.74-7.77 (d, J = 7.4 Hz, 1H), 8.09-8.11 (d, J = 7.2 Hz, 1H), 8.67 (bs, 2H); 13C NMR (100 MHz, CDCl₃):14.54, 16.70, 38.17, 68.85, 96.59, 105.59, 117.57, 120.33, 123.75, 124.53, 125.05, 128.34, 129.07, 129.29, 130.39, 134.08, 137.13, 148.10, 148.57, 151.29, 153.60, 166.88; ESI-MS m/z 667.3 [M+H]₊; HRMS (ESI) m/z calcd for C₄₀H₃₉N₆O₄ [M+H]⁺: 667.3027. Found 667.3013.

Synthesis of Compound RhB-2: The starting material, Rhodamine B hydrazide 2, is a known compound [24]. Rhodamine B hydrazide 2 (100.0 mg, 0.22 mmol) and PhNCO (157.1 mg, 1.32 mmol) in anhydrous toluene (60 mL) were heated to 60 C for 2 hours. Subsequently, the reaction mixture was heated to 110 °C and further stirred for 10 hours. The hot solution was cooled to room temperature, and the solvent was removed under reduced pressure. The resulting residue was purified on a silica gel column (petroleum ether/ CH₂Cl₂ / ethyl acetate = 3 : 2: 1) to produce compound RhB-2 as a white powder (111.0 mg, 72.6%). mp 170-172 ^oC; ¹H NMR (400 MHz, CDCl₃): δ = 0.981.01 (t, J = 7.0, 12H), 3.16-3.21 (q, 8H), 6.23-6.26 (dd, J = 8.8, 2.4 Hz, 2H), 6.32 (d, J = 2.4 Hz, 2H), 6.59-6.61 (d, J = 8.8 Hz, 2H), 6.92-6.96 (t, J = 7.6 Hz, 2H), 7.03-7.05 (d, J = 7.6 Hz, 4H), 7.09-7.13 (t, 4H), 7.42-7.44 (d, J = 7.6 Hz, 1H), 7.53-7.66 (t, J = 7.6 Hz, 1H), 7.72-7.60 (t, J = 7.6 Hz, 1H), 8.03-8.05 (d, J = 7.6 Hz, 1H), 8.76 (bs, 2H); ¹³C NMR (100 MHz, CDCl₃): 12.39, 44.32, 97.75, 107.59, 120.82, 123.89, 124.56, 125.00, 128.36, 129.00, 129.47, 130.50, 133.90, 136.96, 148.21, 149.24, 151.39, 155.21, 166.92; ESI-MS m/z 695.1 [M+H]⁺; HRMS (ESI) m/z calcd for C₄₂H₄₃N₆O₄ [M+H]⁺: 695.3340. Found 695.3328.

Scheme 1

Synthesis of the compounds Rh6G-1 and RhB-2. Reagent and experimental condition: anhydrous toluene, reflux.

Ethical approval: The conducted research is not related to either human or animal use.

3 Results and discussion

3.1 UV–vis and fluorescence spectra of sensor Rh6G-1 titrated with Fe³⁺

Fluorescence titrations of Fe³⁺ to sensor Rh6G-1 (10 μM) were conducted in almost pure water (containing 1% DMSO) with excitation at 500 nm at room temperature. Sensor Rh6G-1 exhibited almost no fluorescence in water, indicating that Rh6G-1 exists predominantly as the spirocyclic form. However, upon addition of Fe³⁺ from FeCl₃, the fluorescence intensity at around 556 nm significantly increases (Figure 1), and an 82-fold fluorescence enhancement was observed. The absorption titration studies are in good agreement with the turn-on fluorescence response (Figure 2). Treatment of Fe³⁺ elicited formation of an intense absorption peak at around 542 nm, indicating that sensor Rh6G-1 is in the ring-opening form in the presence of Fe³⁺. Notably, the sensor showed an excellent linear relationship between the fluorescence intensity at 556 nm and the concentrations of Fe³⁺ from 1 to 170 μM (Figure 3), suggesting that the sensor is potentially useful for quantitative determination of Fe³⁺. The detection limit (S/N = 3) of sensor Rh6G-1 was determined to be 1.2 μM in water (containing 1% DMSO) (Figure S1).

Figure 1

Fluorescence spectra of sensor Rh6G-1 (10 μM) in the presence of increasing concentrations of Fe³⁺ (0-50 equiv.) in water (containing 1% DMSO as a cosolvent) with excitation at 500 nm. Inset: Fluorescent intensity at 556 nm of sensor Rh6G-1 (10 μM) upon addition of Fe³⁺ (0-50 equiv.) excited at 500 nm, and the visual fluorescence color changes of the solutions a, b: a, sensor Rh6G-1 (10 μM); b, sensor Rh6G-1 (10 μM) + Fe³⁺ (50 eq).

Figure 2

Absorption spectra of sensor Rh6G-1 (10 μM) in the presence of increasing concentrations of Fe³⁺ (0 - 50 equiv.) in water (containing 1% DMSO as a cosolvent).

Figure 3

Plot of fluorescence intensity of sensor Rh6G-1 (10 μM) at 556 nm vs. Fe³⁺ concentration (1 - 170 μM) in water (containing 1% DMSO as a cosolvent) excited at 500 nm.

Although compound RhB-2 may also operate as a novel fluorescent Fe³⁺ sensor in water containing 20% CH₃CN (Figure S2A), it is inferior to compound Rh6G-1 in terms of sensitivity in water containing 1% DMSO. The fluorescence intensity of compound RhB-2 increased from 2.7 in the absence of Fe³⁺ to 17.7 in the presence of 100 equiv. of Fe³⁺ in water (containing 1% DMSO) (Figure S2B), only a 6.6-fold fluorescence enhancement, which is much less than that (82-fold fluorescence enhancement) of compound Rh6G-1 under the same solvent system (water containing 1% DMSO). Thus, in this work, we focused on sensor Rh6G-1 for further studies.

3.2 Binding mode of sensor Rh6G-1 with Fe³⁺

Job’s plot according to the method for continuous variations [25] shows a 1:1 binding stoichiometry between sensor Rh6G-1 and Fe³⁺ (Figure S3A). Based on the 1: 1 binding mode, the binding constant of sensor Rh6G-1 in water (containing 1% DMSO as a cosolvent) was calculated as Log K_a = 3.34 from the results of the fluorescence titration experiments (Figure S3B) [26]. Importantly, the formation of sensor Rh6G-1/Fe³⁺ complex is prompt and reversible. The reversible nature of the interactions between Rh6G-1 and Fe³⁺ was tested with TPEN (N, N, N’, N’-Tetrakis(2-pyridylmethyl)-1, 2- ethylenediamine) which is known to bind strongly with various metal ions including Fe³⁺. A solution of sensor Rh6G-1 (10 μM) incubated with Fe³⁺ (10 equiv.) in water (containing 1% DMSO as a cosolvent) exhibited a strong fluorescence at around 556 nm. However, upon further titration with TPEN (0 - 60 equiv.), the fluorescence was gradually quenched (Figure 4), indicating the reversible character of the binding of sensor Rh6G-1 with Fe³⁺. To further test the reversible character, we carried out the cyclic tests for the reversibility of the fluorescent turn-on behavior with quenching by TPEN and followed by adding Fe³⁺ (Figure S4), the result showed that fluorescence enhancement can still be recovered after four cycles. Thus, based on these studies and the interaction mode of Fe³⁺ with the bioactive

Figure 4

Fluorescence titration spectra of a solution of sensor Rh6G-1 (10 μM) + Fe³⁺ (10 equiv.) with TPEN (0 - 60 equiv.) in water (containing 1% DMSO as a cosolvent). Inset: Fluorescent intensity at 556 nm of a solution of sensor Rh6G-1 (10 μM) + Fe³⁺ (10 equiv.) upon addition of TPEN (0 - 60 equiv.). Excitation at 500 nm.

ferrichromes [22], a likely binding mode of sensor Rh6G-1 with Fe³⁺ was proposed (Scheme 2).

Scheme 2

The possible binding mode of sensor Rh6G-1 with FeCl₃.

To further understand the nature of interaction between sensor Rh6G-1 and Fe³⁺, the ESI-MS spectrum (positive ion mode) was carried out. The peak at m/z 667.3 (calcd 666.3) corresponded to [Rh6G-1+H] ⁺, when excess Fe³⁺ was added, the new highest peak was obtained at m/z 740.4 corresponded to [Rh6G-1+ Fe³⁺+H₃O⁺] (Figure S5), which indicated that sensor Rh6G-1 have coordinated with Fe³⁺. The possibility reaction mechanism was depicted in Scheme 2.

3.3 Selectivity studies

We then examined the selectivity of sensor Rh6G-1 towards other metal species. The fluorescence titration experiment was carried out in water (containing 1% DMSO as a cosolvent) with a diverse array of metal species. Fluorescence data reveal that sensor Rh6G-1 selectively responds to Fe³⁺ over various metal species tested (Figure 5). Other metal species such as Pd²⁺, Ca²⁺, Cd²⁺, Co²⁺, Zn²⁺, Cu²⁺, Hg²⁺, Mg²⁺, Mn²⁺, Ag⁺, Au³⁺, Ni²⁺, Pb²⁺, Na⁺, and K⁺ displayed very slighted fluorescence variations. Notably, sensor Rh6G-1 has a high selectivity for Fe³⁺ over Fe²⁺. We further investigated the fluorescent turn-on response of sensor Rh6G-1 toward Fe³⁺ in the presence of other potentially competing species. The other species only exhibited minimum interference (Figure S6). This indicates that sensor Rh6G-1 is useful to detect Fe³⁺ in the presence of other related species. Compound RhB-2 also exhibited the high selectivity for Fe³⁺ in water containing 20% CH₃CN (Figures S7-8).

3.4 Effect of pH

To study the practical applicability, the effect of pH on the fluorescence response of sensor Rh6G-1 to Fe³⁺ was investigated. As shown in Figure 6, in the absence of Fe³⁺, almost no change in fluorescence intensity was observed in the free sensor Rh6G-1 over a wide pH range of 4.5 - 9.0, indicating that the free sensor was stable across a wide pH range. Upon treatment with Fe³⁺, the maximal fluorescence signal was observed in the pH range of 5.5 - 8.5. Thus, the observation that sensor Rh6G-1 had the maximal sensing response at physiological pH, suggests that sensor Rh6G-1 was promising for biological applications.

Figure 5

Fluorescence intensity changes of sensor Rh6G-1 (10 μM) in response to various metal species (20 equiv.) in water (containing 1 % DMSO as a cosolvent). 1. none; 2. Pd²⁺; 3. Ca²⁺; 4. Cd²⁺; 5. Co²⁺; 6. Zn²⁺; 7. Cu²⁺; 8. Fe²⁺; 9. Fe³⁺; 10. Hg²⁺; 11. Mg²⁺; 12. Mn²⁺; 13, Ag⁺, 14, Au³⁺, 15. Ni²⁺; 16. Pb²⁺; 17. Na⁺, 18. K⁺. Excitation at 500 nm; emission at 556 nm.

Figure 6

The fluorescence responses (at 556 nm) of free sensor Rh6G-1 (10 μM) (■) and Rh6G-1 (10 μM) + 20 equiv Fe³⁺ (●) in water (containing 1 % DMSO as a cosolvent) as a function of different pH values.

3.5 Fluorescence Image in Living Cells

The potential toxicity is a concern for any fluorescent sensors intended as molecular imaging agents. Thus, we set out to examine the potential toxicity of sensor Rh6G-1 against the representative cell line, Hela cells. The living cells were incubated with various concentrations (0 - 200 μM) of the sensor for 24 h, and then the cell viability was determined by the standard 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays [27]. Almost 90% of the cells were still alive after treatment with 50 μM sensor Rh6G-1 for 24 h (Figure 7), suggesting that sensor Rh6G-1 has low cytotoxicity [28].

Figure 7

Cytotoxicity assay of sensor Rh6G-1 at different concentrations (a: 0 μΜ; b: 5 μΜ; c: 10 μΜ; d: 20 μΜ; e: 50 μΜ; f: 100 μΜ; g: 200 μΜ) for HeLa cells.

The observation that sensor Rh6G-1 can function very well in essentially pure water renders it desirable for imaging of Fe³⁺ in living cells. To test this possibility, sensor Rh6G-1 was incubated with the living HeLa cells. As shown in Figure 8b, the cells treated with only sensor Rh6G-1 exhibited almost no fluorescence. However, the cells pre-loaded with sensor Rh6G-1 and further incubated with Fe³⁺ displayed intense orange fluorescence (Figure 8e), consistent with the emission profiles of sensor Rh6G-1 incubated with Fe³⁺ (Figure 1). Furthermore, the nuclear staining with Hoechst 33258 revealed that sensor Rh6G-1 associates with the cytoplasm of HeLa cells (Figures 8d-f).

Figure 8

Bright-field and fluorescence images of HeLa cells. (a) Brightfield image of the cells treated with sensor Rh6G-1 (10 μM) for 30 min; (b) Fluorescence image of panel (a) from the red channel; (c) Bright-field image of the cells pre-treated with sensor Rh6G-1 (10 μM) and Hoechst 33258 (4.5 μM) for 30 min, and then incubated with Fe³⁺ (10 equiv.) for 30 min; (d) Fluorescence image of panel (c) from the blue channel; (e) Fluorescence image of panel (c) from the green/red channel; (f) Overlay of panels (d) and (e). Scale bar: 30 μm.

4 Conclusions

In conclusion, compounds Rh6G-1 and RhB-2 containing tri-oxygen atoms of the amide groups were designed and synthesized as new reversible fluorescent sensors for Fe³⁺. The favorable features of the novel sensor Rh6G-1 include a big fluorescent turn-on response in almost pure water at room temperature, high sensitivity, high selectivity, cell membrane permeability, and low cytotoxicity. These desirable attributes enable us to successfully employ the new sensor Rh6G-1 for Fe³⁺ bioimaging in living cells. We expect that the new Fe³⁺ ligand composed of tri-oxygen atoms of the amide groups will be useful for development of a wide variety of reversible fluorescent Fe³⁺ sensors based on distinct dyes.

Acknowledgments

This work was financially supported by Hunan Provincial Key Lab of Dark Tea and Jin-hua (2016TP1022), NSFC (21502048), the Natural Science Foundation of Hunan Province (2016JJ3102), Science and Technology Innovative Research Team in Higher Educational Institutions of Hunan Province. There is no any conflict of interest in connection with this articleand no portion of it has been published or under consideration of publication by another journal

Conflict of interest: Authors declare no conflict of interest.
Supplemental Material: The online version of this article offers supplementary material (https://doi.org/10.1515/chem-2018-0140).

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Received: 2018-04-22

Accepted: 2018-09-12

Published Online: 2018-12-21

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License.

Articles in the same Issue

https://doi.org/10.1515/chem-2018-0140

Keywords for this article

Sensor; Reversibility; Fe3+; tri-oxygen

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Reversible Fluorescent Turn-on Sensors for Fe3+ based on a Receptor Composed of Tri-oxygen Atoms of Amide Groups in Water

Article

Abstract

1 Introduction

2 Materials and Methods

2.1 Materials and instruments

2.2 HeLa cell incubation and imaging using sensor Rh6G-1

2.3 Cytotoxicity assays

2.4 Synthesis of Compound Rh6G-1

3 Results and discussion

3.1 UV–vis and fluorescence spectra of sensor Rh6G-1 titrated with Fe3+

3.2 Binding mode of sensor Rh6G-1 with Fe3+

3.3 Selectivity studies

3.4 Effect of pH

3.5 Fluorescence Image in Living Cells

4 Conclusions

Acknowledgments

References

Articles in the same Issue

Articles in the same Issue

Articles in the same Issue

Reversible Fluorescent Turn-on Sensors for Fe³⁺ based on a Receptor Composed of Tri-oxygen Atoms of Amide Groups in Water

3.1 UV–vis and fluorescence spectra of sensor Rh6G-1 titrated with Fe³⁺

3.2 Binding mode of sensor Rh6G-1 with Fe³⁺