A novel turn-on Schiff-base fluorescent sensor for aluminum(III) ions in living cells

Abstract

(E)-4-Methoxy-N-((8-methylquionline-2yl)methylene)aniline (L) was successfully synthesized and characterized. The complexation behavior of L with different metal ions was studied using UV-Vis absorption spectroscopy and fluorescence spectroscopy. Results showed that the sensor (L) exhibited a 38-fold enhancement in fluorescence at 517 nm after adding 10 equiv. of Al³⁺ ions. Such fluorescent responses could be detected by the naked eye under a UV-lamp at 365 nm. The complex solution (L–Al³⁺) showed reversibility with EDTA and the complex was a 1 : 1 ratio according to Job’s plot and electrospray ionization mass spectroscopy (ESI-MS). A photoinduced electron transfer (PET) mechanism was considered to be operational for fluorescence enhancement. The detection limit of Al³⁺ was calculated to be 1.2 × 10⁻⁷ M, a satisfying level to detect Al³⁺ in the micromolar scale. Importantly, the chemosensor L could be used to detect and quantify Al³⁺ in living cells. Therefore, this sensor has the ability to be a practical system for monitoring Al³⁺ concentrations in biological systems.

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1. Introduction

Aluminum is the third most abundant element in the earth’s crust. Due to acidic rain and human activities, Al³⁺ exists widely in the environment. Al³⁺ affects the activity of gastrointestinal enzymes and excess Al³⁺ is toxic in the central nervous system.^1–3 The World Health Organization (WHO) recommends an average daily human intake of Al³⁺ of around 3–10 mg kg⁻¹ and the tolerable weekly dietary intake as 7 mg kg⁻¹ body weight. Excessive exposure of the human body to Al³⁺ leads to many diseases such as Alzheimer’s disease and Parkinson’s disease, bone softening, smoking related diseases and chronic renal failure.^4–8 Up to now, many measurement technologies have been developed to sensitively and reliably detect Al³⁺ such as atomic absorption spectrometry, inductively coupled plasma-atomic emissions spectrometry and inductively coupled plasma-mass spectrometry.⁹ Compared to these approaches, fluorescent probes for detecting Al ions have attracted great interest from researchers due to their several outstanding advantages such as low cost, simplicity, high sensitivity and selectivity.

Since there is a close association between Al³⁺ and human health, the investigation of Al³⁺ detection has attracted increasing attention.¹⁰ In recent years, data showed that forty percent of children in China had an aluminum intake exceeding the limitation of the WHO recommended allowance.¹¹ Therefore, the development of sensitive molecular signaling systems, especially for aluminum ions, has become increasingly important.^12,13 To date, a good number of Schiff-base compounds have been reported very recently as a sensor for the detection of aluminum metal ions using fluorescence spectroscopy.^14–23 J. Wang et al. reported commercially available compound, 2-hydroxy-1-naphthaldehyde, as a highly sensitive and selective fluorescent sensor for Al³⁺ for the first time in 2012.²⁴ After that, a number of Schiff-bases have been synthesized over the past couple of years employing 2-hydroxy-1-naphthaldehyde as the aldehyde and have been applied as chemosensors for the detection of aluminum ions.^25–29

Based on this knowledge, herein, a simple, high selectivity and high sensitivity Al³⁺ sensor has been designed and synthesized. We report the aluminum(III) sensing behavior of (E)-4-methoxy-N-((8-methylquionline-2yl)methylene)aniline (L) (Scheme 1). It has been prepared from the Schiff-base condensation between 8-hydroxyquinoline-2-carbaldehyde and anisidine. L has been characterized by different spectroscopic techniques.

Scheme 1 The synthetic routes of compound L.

2. Experimental

2.1. Materials and instrumentation

All reagents were purchased commercially of grade quality and used without any further purification. (E)-4-Methoxy-N-((8-methylquionline-2yl)methylene)aniline (L) was synthesized in the laboratory. Double-distilled water was used throughout the experiments. ¹H NMR spectra were measured on a Bruker 500 MHz instrument using TMS as an internal standard. UV-Vis absorption spectra were determined on a U-3900 spectrophotometer. Fluorescence spectra were recorded with a Hitachi F-4600 spectrophotometer equipped with quartz cuvettes of 1 cm path length. MS spectra were measured on a Shimadzu GC-17A, QP-5000 GC/MS spectrometer. FT-IR spectra were recorded with a NICOLET 6700 spectrophotometer.

2.2. Synthesis and characterization

2.2.1. Synthesis of 8-hydroxyquinoline-2-carbaldehyde (L1). 2-methylquinoline-8-ol (3.2 g, 20 mmol) was dissolved in dioxane (90 mL), and SeO₂ (2.8 g, 24.8 mmol) was added to this solution. The mixture was stirred at 80 °C for 24 h and then cooled to room temperature. The precipitate was filtered off. The solvents were evaporated to give the crude product, which was purified by flash chromatography on silica gel (5 : 1 petroleum ether/ethyl acetate as the eluent) to give a yellow solid L1 (3.28 g, 18.96 mmol, 95%). ¹H NMR (500 MHz, CDCl₃) δ 10.23 (s, 1H), 8.33 (d, J = 8.0 Hz, 1H), 8.15 (s, 1H), 8.07 (d, J = 8.3 Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.44 (d, J = 7.4 Hz, 1H).

2.2.2. Synthesis of (E)-4-methoxy-N-((8-methylquionline-2yl)methylene)aniline (L). 8-Hydroxyquinoline-2-carbaldehyde (0.692 g, 4 mmol) was dissolved in ethanol (30 mL); then anisidine (0.492 g, 4 mmol) was added to the solution. The solution was refluxed for 4 h under stirring. The solution was cooled to room temperature and the solvent was evaporated under pressure to obtain a yellow crude product. It was purified by recrystallization in ethanol to give the light yellow solid L (0.689 g, 2.52 mmol, 62%). ¹H NMR (500 MHz, DMSO) δ 9.95 (s, 1H), 8.82 (s, 1H), 8.41 (d, J = 8.6 Hz, 1H), 8.26 (d, J = 8.6 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.45 (d, J = 8.9 Hz, 3H), 7.16 (d, J = 7.5 Hz, 1H), 7.05 (d, J = 8.8 Hz, 2H), 3.81 (s, 3H). ¹³C NMR (126 MHz, DMSO) δ 159.71, 158.98, 154.63, 153.51, 143.89, 139.14, 137.65, 130.24, 129.76, 123.82, 119.15, 118.74, 115.58, 113.04, 56.30. ESI-mass (m/z): [L + H⁺]⁺: calcd: 279.31. Obsd: 279.27. Anal. calcd for C₁₇H₁₄N₂O₂: C, 73.37; H, 5.07; N, 10.07. Found: C, 73.29; H, 4.99; N, 10.01.

2.3. Analysis

The receptor could be dissolved in methanol. The stock solution for the different metal salts of Na⁺, K⁺, Ca²⁺, Mg²⁺, Ba²⁺, Al³⁺, Fe³⁺, Pb²⁺, Mn²⁺, Co²⁺, Ni²⁺, Sr²⁺, Zn²⁺, Sn²⁺, Cd²⁺, Hg²⁺, Cr³⁺, Ce³⁺ and Ag⁺ were prepared in water.

2.4. Job’s plot measurements

Receptor 1 (1.39 mg, 0.005 mmol) was dissolved in methanol (5 mL). 20, 18, 16, 14, 12, 10, 8, 6, 4 and 2 μL of the receptor solution were taken and transferred into vials. Each vial was diluted with methanol to make a total volume of 1.976 mL. AlCl₃·6H₂O (0.005 mmol) was dissolved in water (1 mL). 0, 2, 4, 6, 8, 10, 12, 14, 16, 18 and 20 μL of the Al³⁺ solution were added to each diluted receptor solution. Each vial had a total volume of 2 mL. After shaking the vials for a few minutes, fluorescence spectra were taken at room temperature.

2.5. Benesi–Hildebrand plot

The binding constant value was determined from the fluorescence intensity data using a modified Benesi–Hildebrand equation where F₀, F and F_max are the emission intensities of L in the absence of Al³⁺, intermediate Al³⁺ concentration and concentration of Al³⁺ of complete interaction, respectively; the plot of (F_max − F₀)/(F − F₀) vs. 1/[Al³⁺] (Fig. 5) is the Benesi–Hildebrand plot.

2.6. pH study

pH buffer solution (20 mM) preparation: 2.384 g HEPES and 4.25 g NaNO₃ were dissolved in pure water (500 mL volumetric flask), then 1 mol L⁻¹ HCl and 1 mol L⁻¹ NaOH were used to adjust the pH value to 7. The compound L (10 μM in methanol) and Al³⁺ (10 mM in water) were prepared in a cuvette, then the pH values (3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0, 11.0, 12.0) were adjusted with 1 mol L⁻¹ HCl and 1 mol L⁻¹ NaOH (2 mL, constant volume with buffer).

2.7. Cell imaging studies

The living HeLa cells were provided by XiangYa Central Experiment Laboratory of Central South University (China).

HeLa cells were incubated with 10 μM of L in the culture medium at 37 °C for 30 min and washed with phosphate-buffered saline (PBS), followed by the addition of (0, 5, 10, 20 and 40 μM) Al³⁺ ions. Bright field and fluorescent images were captured at 20× magnification using an Olympus microscope (1 × 70) using Camedia software (Chicago, MI, USA) (E-20P 5.0 Megapixel).

3. Results and discussion

3.1. UV-Vis studies of compound L

The UV-Vis absorption spectra of compound L in the presence of various metal ions Na⁺, K⁺, Ca²⁺, Mg²⁺, Ba²⁺, Al³⁺, Fe³⁺, Pb²⁺, Mn²⁺, Co²⁺, Ni²⁺, Sr²⁺, Zn²⁺, Sn²⁺, Cd²⁺, Hg²⁺, Ag⁺, Cr³⁺ and Ce³⁺ were recorded in an alcoholic medium (CH₃OH) using a U-3900 spectrophotometer. As seen in Fig. 1, the absorption spectrum of compound L exhibited two broad absorption bands at 271 nm and 358 nm. The position of absorption bands remained unchanged over the various metal ions except Sn²⁺ and Al³⁺ ions. Due to the complexation of Al³⁺ and L, a new absorption band at 258 nm was formed with Al³⁺, and the absorption intensity at 358 nm tends to decrease.

Fig. 1 UV-Vis absorption spectra of compound L (10 μM) in the absence and presence of different metal ions (10 equiv.) such as Al³⁺, Fe³⁺, Ba²⁺, Ag⁺, Cd²⁺, Co²⁺, Sr²⁺, Hg²⁺, K⁺, Pb²⁺, Mg²⁺, Na⁺, Ca²⁺, Ni²⁺, Mn²⁺, Sn²⁺, Cr³⁺, Ce³⁺ and Zn²⁺ at room temperature.

The binding properties of L with Al³⁺ were studied using UV-Vis titrations in methanol solution (Fig. 2). Upon addition of increasing amounts of Al³⁺ (0–1.5 equiv.), while the absorption bands at 271 and 358 nm decreased gradually, the absorption band at 271 nm shifted to 258 nm. The blue-shifted absorption indicated that the phenol proton was not deprotonated.³⁰ Moreover, there were clearly two isosbestic points at 256 and 396 nm, and the presence of two different isosbestic points for the sensor L suggested the formation of complex L–Al³⁺.³¹

Fig. 2 UV-Vis absorption spectra of compound L (10 μM) upon the titration of Al³⁺ (0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.2, 1.4 and 1.5 equiv.) at room temperature.

3.2. Fluorescence studies of compound L

3.2.1. Selectivity of compound L for Al³⁺ over other metal ions. For an excellent chemosensor, high selectivity is a matter of necessity. To confirm the selectivity of sensor L, the fluorescence behavior of (E)-4-methoxy-N-((8-methylquionline-2yl)methylene)aniline (L) upon the addition of various metal ions was investigated using a Hitachi F-4600 spectrophotometer. Quinoline Schiff base L did not show any significant emission band alone at 517 nm when the excitation wavelength was at 373 nm. After the addition of Na⁺, K⁺, Ca²⁺, Mg²⁺, Ba²⁺, Fe³⁺, Pb²⁺, Mn²⁺, Co²⁺, Ni²⁺, Sr²⁺, Zn²⁺, Sn²⁺, Cd²⁺, Hg²⁺, Ag⁺, Cr³⁺ and Ce³⁺ (Fig. 3), compound L exhibited no significant fluorescent enhancement. Only in the case of Al³⁺ ions compound L exhibited a more than 38-fold fluorescent enhancement. The quantum yields of L and its metal complex L–Al³⁺ were 0.016 and 0.62, respectively (Fig. 4).

Fig. 3 Fluorescence emission spectra of L (10 μM) in methanol in the presence of different metal ions (10 equiv.) such as Al³⁺, Fe³⁺, Ba²⁺, Ag⁺, Cd²⁺, Co²⁺, Sr²⁺, Hg²⁺, K⁺, Pb²⁺, Mg²⁺, Na⁺, Ca²⁺, Ni²⁺, Mn²⁺, Sn²⁺, Cr³⁺, Ce³⁺ and Zn²⁺. Excitation wavelength was at 373 nm. Inset (left): fluorescence intensity of compound L with Al³⁺ at 517 nm. Inset (right): the fluorescence intensity of different metal ions at 517 nm.

Fig. 4 Selectivity of L for Al³⁺ ions in the presence of other competitive metal ions (10 equiv.) in methanol. Excitation wavelength and emission maximum are 373 nm and 517 nm, respectively. Black bars represent fluorescent intensity after the addition of 10 equiv. of the appropriate metal ions (Fe³⁺, Ba²⁺, Ag⁺, Cd²⁺, Co²⁺, Mn²⁺, Sn²⁺, Hg²⁺, K⁺, Pb²⁺, Mg²⁺, Na⁺, Ca²⁺, Ni²⁺, Sr²⁺, Cr³⁺, Ce³⁺ and Zn²⁺) in a 10 μM solution of L. Red bars represent the subsequent addition of same equiv. of Al³⁺ ions in each of the samples.

Interferences of cations were studied by treating L with 10 equiv. of Al³⁺ in the presence of 10 equiv. of other metal ions. As shown in Fig. 4, the response of compound L for Al³⁺ is not affected by competing metal ions (except Fe³⁺, as L and Fe³⁺ could form a stable chelate complex leading to fluorescence quenching), the fluorescent response of L–Al³⁺ is observed to be relatively reduced in the presence of Ni²⁺ and Sn²⁺ ions but is clearly detectable. From the results above, it was concluded that compound L had high selectivity and specificity for Al³⁺ over other metal ions.

3.2.2. Fluorescence titration of compound L with Al³⁺. The sensitivity of L for aluminum ions was examined with the fluorescence titration of different concentrations of Al³⁺ ions (0.0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.2 and 1.5 equiv.) at 517 nm (Fig. 5); the point which primarily indicates 1 : 1 stoichiometric complexation between compound L and Al³⁺ ions. The detection limit of L in recognizing Al³⁺ was found to be 1.2 × 10⁻⁷ M with the fluorescence titration spectra, which was lower than some reported Al³⁺ selective fluorescent sensors.^32–36 It demonstrated that the detection limit was low enough for this sensor to detect and control Al³⁺ in environmental and biological systems (Table S1†).^37–41

Fig. 5 Fluorescence emission spectra at 517 nm of L upon addition of Al³⁺ (0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.2 and 1.5 equiv.) with an excitation of 373 nm, inset: fluorescence emission spectra of L upon addition of Al³⁺ (0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.2 and 1.5 equiv.) with an excitation of 373 nm and an emission of 517 nm.

3.3. Binding mode of compound L and Al³⁺

A proposed binding mode of L with Al³⁺ ions has been shown in Fig. 5 (inset), which primarily demonstrates a 1 : 1 stoichiometric complexation between sensor L and Al³⁺. These results are further confirmed by applying the emission Job’s plot method. The maximum fluorescence intensity appears at 0.5 mole fraction of Al³⁺ which indicates a 1 : 1 complexation between quinoline Schiff base L and Al³⁺ ions (Fig. 6). Furthermore, from the electrospray ionization mass spectra (ESI-MS) (Fig. S4†), a peak was observed at 335.59 [L + Al³⁺ + CH₃OH − 2H⁺]⁺, which further supports a 1 : 1 binding stoichiometry between L and Al³⁺.

Fig. 6 Job’s plot of L according to the method for continuous variations, indicating the 1 : 1 stoichiometry for L–Al³⁺ (the total concentration of L and Al³⁺ is 20 μM).

3.3.1. ¹H NMR titration. In order to determine the coordination site, ¹H NMR spectroscopy experiments were performed in the presence of Al³⁺ ions, with 0 to 2 equivalents of Al³⁺ added to compound L. As shown in Fig. 7, chemical shift changes were observed in the spectrum as the HC=N proton signal of L at 8.82 ppm shifted downfield to 8.86 ppm. Meanwhile, the hydroxyl hydrogen at 9.96 ppm shifted downfield to 10.16 ppm with the proton signal almost disappearing. The proton signals of the quinoline and benzene groups have been shifted, while a significant shift has been observed for the para-position hydrogen of nitrogen in the quinoline group. These spectrum changes demonstrated that nitrogen in the imine group, oxygen in the hydroxyl group and nitrogen in the quinoline group participated in the complexation with Al³⁺ ions.

Fig. 7 ¹H NMR (500 MHz) spectra of L with Al³⁺ (0.0–2.0 equiv.) in DMSO.

3.3.2. Calculations of association constants and detection limit. Association constants of L–Al³⁺ were calculated with the Benesi–Hildebrand equation through fluorescence titration:^42–44 (Fig. S5†).

In this equation F is the fluorescence intensity at 517 nm at any given Al³⁺ concentration, F₀ is the fluorescence intensity at 517 nm in the absence of Al³⁺, and F_max is the maximal fluorescence intensity at 517 nm in the presence of Al³⁺ in solution. Data were fitted linearly as shown in Fig. 8. The association constant (K_a) for Al³⁺ binding in sensor L was determined to be 2.4 × 10⁴ M⁻¹. The detection limit (DL) of Al³⁺ using L was determined from the following equation: DL = K × SD/S, where K = 3; SD is the standard deviation of the blank solution; S is the slope of the calibration curve. DL = 1.2 × 10⁻⁷ M, which exhibits good selectivity of L with aluminum ions.

Fig. 8 Plot of fluorescence intensity variation upon varying the concentration of Al³⁺ ion from 2–20 μM with an excitation of 373 nm and an emission of 517 nm.

3.3.3. Reversibility and the influence of solvents. The reversibility of sensor L was measured by the titration of EDTA with (L + Al³⁺). The fluorescence intensity was quenched thoroughly after the addition of EDTA (1.0 equiv.) (Fig. 9). The fluorescence emission intensity due to the L–Al³⁺ probe returned to a lower level for sensor L indicating the regeneration of free chemosensors L, quenching in fluorescence intensity.

Fig. 9 Fluorescence emission spectra of compound L (10 μM) in the presence of Al³⁺ ions (1.0 equiv.) or EDTA (1.0 equiv.) in methanol.

The effect of different solvents THF, DMSO, DMF, DCM, acetonitrile, ethanol and methanol on the detection of Al³⁺ by L was explored. It can be seen (Fig. 10) that the fluorescence was changed due to different binding modes with different solvents and the best result was observed with methanol.

Fig. 10 Effects on fluorescence intensity of L in different solvents methanol, DMSO, DMF, DCM, ethanol, THF and acetonitrile.

3.4. Sensing mechanism

As the recognition unit, Schiff bases have been widely used for the development of fluorescent sensors based on various sensing mechanisms. In this case, the Off–On properties of sensor L may operate by a photoinduced electron transfer (PET) mechanism. In the Off state, when the UV-light was created, the lone pair of electrons from the CH=N unit to the quinoline fluorophore quenches the fluorescence. In the presence of Al³⁺, the lone pair of electrons on the nitrogen atom is perturbed by the coordination of Al³⁺, which consequently suppresses the quenching process, resulting in fluorescence enhancement (On-state). This suggests that PET is a suitable mechanism for explaining the Off–On fluorescence for L after binding to Al³⁺ (Scheme 2).

Scheme 2 Proposed scheme of the fluorescence enhancement mechanism of compound L and Al³⁺.

3.5. Fluorescence imaging of intracellular L and Al³⁺

The effect of pH, in the range of pH 3.0–12.0, on the emission intensity of L was examined both in the absence and presence of Al³⁺ ions. It can be clearly seen from Fig. 11, that the emission intensity of L was significantly high in the pH region of 6.0–10.0 compared to that of L in the absence of Al³⁺ ions. Thus, L may be a suitable sensor for imaging Al³⁺ in living cells under physiological conditions. To further demonstrate the potential of L in monitoring Al³⁺ in living matrices, the Al³⁺ imaging behavior of the sensor L was studied using fluorescence microscopy using HeLa cells. HeLa cells were first incubated with various concentrations of Al³⁺ (0, 5, 10, 20 and 40 μM) and then exposed to L (10 μM) for 30 min at 37 °C, and images were taken (Fig. 12). The fluorescence emission might be due to the complex formation between Al³⁺ and the sensor L. These results confirm that L can be a suitable and biocompatible sensor to detect Al³⁺ in living cells.

Fig. 11 Fluorescence intensity of L, and L in the presence of Al³⁺ at various pH values.

Fig. 12 Representative fluorescence images of HeLa cells incubated with 10 μM L and 0 μM (A and F), 5 μM (B and G), 10 μM (C and H), 20 μM (D and I), and 30 μM (E and J) Al³⁺. The top images (A, B, C, D, and E) were observed using a light microscope and the bottom images were taken using a fluorescence microscope. The scale bar is 20 μm.

3.6. Determination of the fluorescence quantum yield

The quantum yield ϕ of sensor L and L + Al³⁺ complex^45,46 were calculated by

ϕ_x = ϕ_s (F_x/F_s)(A_s/A_x)(η_x/η_s) (2)

Here, x and s indicate the unknown and standard samples, ϕ = quantum yield, F = integrated fluorescence intensity, A = absorbance, and η = refractive index of the solvent (rhodamine B is used as a standard in ethanol [ϕ = 0.69]). The quantum yield of L is 0.016, and on complexation with Al³⁺, the value significantly increases to 0.62.

4. Conclusion

In conclusion, we have synthesized a highly selective and sensitive Al³⁺ fluorescent sensor (E)-4-methoxy-N-((8-methylquionline-2yl)methylene)aniline (L). The fluorescence emission intensity of sensor L is remarkably enhanced by more than 38-fold after the addition of aluminum ions, and the association constant (K_a) and the detection limit (DL) were calculated to be 2.4 × 10⁴ M⁻¹ and 1.2 × 10⁻⁷ M, respectively. Moreover, the sensor L is attributed to the formation of a 1 : 1 complex, according to Job’s plot and electrospray ionization mass spectrometry (ESI-MS). The outstanding property of L is that the selectivity to Al³⁺ ions is not subject to interference by other mixed metal ions and the fluorescent nature of the L–Al³⁺ complex goes to “turn-On” in the presence of Al³⁺. It has been applied in a biological system to study living cell imaging. Therefore, Al³⁺ ions can be easily detected by fluorescent sensor L using fluorescence spectroscopy in biological systems.

Acknowledgements

We are grateful to the Nature Science Foundation of China for financial support (No. 21265010).

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra17557g

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