Selective cadmium fluorescence probe based on bis-heterocyclic molecule and its imaging in cells

doi:10.21203/rs.3.rs-260927/v1

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Selective cadmium fluorescence probe based on bis-heterocyclic molecule and its imaging in cells

https://doi.org/10.21203/rs.3.rs-260927/v1

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published 13 May, 2021

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Fluorescence probes that selectively image cadmium are useful for detecting and tracking the amount of Cd²⁺ in cells and tissues. In this study, we designed and synthesized a novel Cd²⁺ fluorescence probe based on the pyridine-pyrimidine structure, 4-(methylsulfanyl)-6-(pyridin-2-yl)pyrimidin-2-amine (3), as a low-molecular-weight fluorescence probe for Cd²⁺. Compound 3 could successfully discriminate between Cd²⁺ and Zn²⁺ and exhibited a highly selective turn-on response toward Cd²⁺ over biologically related metal ions. The dissociation constant and detection limit of 5.4 x 10^− 6 mol L^− 1 and 4.4 × 10^− 7 mol L^− 1, respectively, were calculated using fluorescence titration experiments. Studies with closely related analogs showed that the bis-heterocyclic moiety of 3 acted as both a coordination site for Cd²⁺ and a fluorophore. Further, the methylsulfanyl group of compound 3 is essential for achieving selective and sensitive Cd²⁺ detection. Fluorescence microscopy studies using living cells revealed that the cell membrane permeability of compound 3 is sufficient to detect intracellular Cd²⁺. These results indicate that novel bis-heterocyclic molecule 3 has considerable potential as a fluorescence probe for Cd²⁺ in biological applications.

Cell & Tissue Engineering

Cd2+

Fluorescent probe

Bis-heterocyclic molecule

Low-molecular-weight

Cell membrane permeability

Cadmium, a toxic heavy metal that occurs naturally in soils and minerals, can accumulate in rice and vegetables through soil-to-plant transference [1,2]. The uptake of cadmium by food is unavoidable and causes serious health problems, especially in kidneys, lungs, liver, and the nervous system [1,3–5]. In addition, long-term exposure to cadmium is considered a causative factor in lung, prostate, breast, and kidney cancers because of its long biological half-life in humans (17–30 years) [3,6–8]. Therefore, reliable methods that can detect cadmium in living cells and tissues are urgently required.

To investigate heavy metal ions including Cd²⁺ in living systems, several analytical methods, such as atomic absorption spectrometry and inductively coupled plasma (ICP) mass spectrometry, have been commonly used [9,10]. These methods are suitable for measuring the total metal ion content in tissues, but unsuitable for real-time monitoring in specific cells or tissues. Alternatively, organic fluorescence probes are useful for real-time detection and tracking trace amounts of metal ions in living systems because of their selectivity and sensitivity. Further, their fluorescence properties can be tuned for targeting metal ions by chemical modification, which is an added advantage [11,12]. There have been efforts to develop Cd²⁺-selective fluorescence probes consisting of a metal coordination site and fluorophore [13–18]; however, only a few are available owing to their poor selectivity, solubility, or cell membrane permeability. More importantly, the inability to distinguish between Zn²⁺ and Cd²⁺ is a critical issue and hinders the development of Cd²⁺-selective fluorescence probes [13-16]. Zn²⁺ and Cd²⁺ exhibit comparable physical and chemical properties because they belong to the same group in the periodic table [12]; therefore, only a few probes that successfully discriminate Zn²⁺ and Cd²⁺ have been reported [17,18]. Although chemical modification is an effective method to overcome this issue, it yields a high molecular weight compound with a complex chemical structure. Consequently, the cell membrane permeability of fluorescence probes worsens.

Bis-heterocyclic compounds such as 2,2’-bipyridine are known as chelating ligands that form charge complexes with several types of metal ions and are used as core structures for drug-like molecules and fluorescence probes [19-22]. Previously, bis-heteroaryl core structures, which acted as the coordination site for Zn²⁺ and fluorophores, have been exploited as low-molecular-weight fluorescence probes for Zn²⁺ [23-25]. These probes based on the bis-heteroaryl core had molecular weights of less than 500 g mol⁻¹, which showed clear chelation enhanced fluorescence (CHEF) effect on target metal ions and enabled good cell membrane permeability. In addition, a simple tuning of the electron density of the core structure by introducing electron-donating or electron-withdrawing groups greatly affected the intermolecular charge transfer (ICT) state and metal selectivity including Cd²⁺.

Herein, we have designed and synthesized a novel low-molecular-weight Cd²⁺fluorescence probe (4-(methylsulfanyl)-6-(pyridin-2-yl)pyrimidin-2-amine, 3; MW 218 utilizing pyridine–pyrimidine as a bis-heteroaryl core structure, which functions as both a Cd²⁺coordination site and a fluorophore. Compound 3 showed sensitive sensing ability toward Cd²⁺ and could successfully discriminate Cd²⁺ from other ions. Furthermore, fluorescence imaging study indicated compound 3 had good cell membrane permeability to apply for a cellular system.

Materials and instruments

All chemicals were of the highest purity available. ¹H and ¹³C NMR spectra were recorded on Varian Gemini 300 and JEOL ECP-400 NMR systems, and the chemical shifts are reported in ppm. Mass spectra (MS) and HRMS were performed using a JMS-700 spectrometer (JEOL, Tokyo, Japan). UV-Vis absorption spectra were recorded using a UV-Vis spectrophotometer (Shimadzu, Kyoto, Japan). Fluorescence spectra were collected using on a fluorescence spectrophotometer (RF-5300PC, Shimadzu, Kyoto, Japan).

Synthesis of 4-(methylsulfanyl)-6-(pyridin-2-yl)pyrimidin-2-amine (3)

To a solution of 3,3-bis(methylsulfanyl)-1-(pyridin-2-yl)prop-2-en-1-one (1) (225 mg, 1 mmol) [26] in pyridine (5 mL), guanidine carbonate (2) (270 mg, 1.5 mmol) was added and the mixture was refluxed for 5 h. The reaction mixture was poured into 100 mL of ice water, and the precipitate was collected by filtration, washed with water, and dried overnight. The product was recrystallized from methanol to give 3 (64 g, 29% yield) as pale-yellow crystals. Mp 142–143 °C. ¹H-NMR (CDCl₃, 300 MHz) δ 2.54 (s, 3H), 5.14 (brs, 2H), 7.32 (dd, J = 1.2, 7.5 Hz, 1H), 7.55 (s, 1H), 7.77 (dd, J = 1.8, 7.5 Hz, 1H), 8.26 (d, J = 7.8 Hz, 1H), 8.65 (d, J = 4.8, Hz, 1H). ¹³C NMR (CDCl₃, 75 MHz) δ 12.9, 105.2, 121.9, 125.1, 137.1, 149.5, 154.5, 162.1, 162.5, 173.1. MS m/z: 219 [M + H⁺]. HRMS calcd for C₁₀H₁₁N₄S [M + H⁺]: 219.0704. Found: 219.0695.

Synthesis of 4-(methylsulfanyl)-6-phenylpyrimidin-2-amine (5)

Compound 5 was prepared from 3,3-bis(methylsulfanyl)-1-phenylprop-2-en-1-one (4, 224 mg, 1.0 mmol) and guanidine carbonate (2) (270 mg, 1.5 mmol) in a manner similar to that described for the synthesis of 3. Recrystallization from methanol gave 5 (68 mg, 31% yield) as pale-yellow crystals (mp 97–98 °C). ¹H-NMR (CDCl₃, 400 MHz) δ 2.52 (s, 3H), 6.65 (s, 2H), 7.03 (s, 1H), 7.46-7.50 (m, 3H), 8.06 (d, J = 7.6 Hz, 2H). MS m/z: 217 [M⁺]. HRMS calcd for C₁₁H₁₁N₃S [M⁺]: 217.0674. Found: 217.0666.

Synthesis of 4-(pyridin-2-yl)pyrimidin-2-amine (7) [27]

After dissolving sodium (500 mg, 21.8 mmol) in a solution of guanidine carbonate (2) (1350 mg, 7.5 mmol) in dry ethanol (10 mL), 3-(dimethylamino)-1-(2-pyridyl)-2-propen-1-one (6) (880 mg, 5 mmol) was added, and the mixture was refluxed for 24 h. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from methanol to give 7 (770 mg, 44% yield) as pale-yellow crystals (mp 136–137 °C). ¹H-NMR (CDCl₃, 300 MHz) δ 5.43 (brs, 2H), 7.33 (dd, J = 1.2, 7.5 Hz, 1H), 7.60 (d, J = 5.1 Hz, 1H), 7.76 (dd, J = 1.8, 6.0 Hz, 1H), 8.28 (d, J = 7.8 Hz, 1H), 8.41 (d, J = 5.1 Hz, 1H), 8.67 (d, J = 6.0 Hz, 1H). ¹³C NMR (CDCl₃, 75 MHz) δ 108.2, 121.7, 125.3, 137.1, 149.6, 154.6, 159.5, 163.4, 164.3. MS m/z: 173 [M + H⁺]. HRMS calcd for C₉H₉N₄ [M + H⁺]: 173.0827. Found: 173.0822.

Spectroscopic studies

A stock solution of each compound (1×10^-2mol L^-1) was prepared in DMSO. Solutions of metal ions were prepared by dissolving the perchlorate salts of metal ions (Na⁺, K⁺, Mg²⁺, Ca²⁺, Fe²⁺, Fe³⁺, Ni²⁺, Zn²⁺, Cd²⁺, Co²⁺, Cu²⁺, Mn²⁺, and Al³⁺) in deionized water. The fluorescence of each compound (10^-6 mol L^-1) was analyzed in the absence and presence of metal ions in EtOH/H₂O (1:1, v/v). A Job’ plot was used to investigate the binding stoichiometry of 3 to Cd²⁺. The dissociation constant (K_d) was determined from a Benesi–Hidebrand plot [28,29].

1/(F − F₀) = 1/{K_a(F_max − F₀)[Zn²⁺ ]ⁿ } + 1/(F_max − F₀)

where F, F₀, and F_max are the fluorescence intensity, the fluorescence intensity without Cd²⁺, and the fluorescence intensity in the presence of excess Cd²⁺, respectively. The association constant (K_a) (the inverse of K_d) was determined from the slope of the plot of 1/(F − F₀) against 1/[Cd²⁺]. The selectivity of 3 for Cd²⁺was investigated using 10⁻² mol L⁻¹ metal cation solutions. The effect of pH on the fluorescence properties of 3 was evaluated using various buffers: tris(hydroxymethyl)aminomethane hydrochloride buffer (pH 3.0), acetate buffer (pH 4.0–5.0), and tris-hydrochloric acid buffer (pH 6.0–8.0).

Cellular imaging using fluorescence microscope

Mouse macrophage-like cells (RAW264) were cultured in Dulbecco’s modified Eagle’s medium that included 10% fetal bovine serum and 1% penicillin at 37 °C in a humidified atmosphere with 5% CO₂. The cells were incubated with 3 (100 μmol L⁻¹) in culture media for 30 min at 37 °C. After washing with phosphate-buffered saline (PBS), the treated cells were incubated with Cd(ClO₄)₂·6H₂O (300 μmol L⁻¹) in culture media for 30 min at 37 °C. The incubated cells were imaged using a fluorescence microscope BZ-X710 (Keyence, Osaka, Japan).

Pyridine–pyrimidine compound 3 was synthesized with 29% yield via the one-pot reaction of 3,3-bis(methylsulfanyl)-1-(pyridin-2-yl)prop-2-en-1-one (1) and guanidine carbonate (2) in pyridine (Scheme 1).

The UV-Vis absorption spectra of 3 in EtOH/H₂O (1:1, v/v) were recorded during titration with Cd²⁺ (Fig. 1). The addition of Cd²⁺ altered the absorption spectrum of 3 in a Cd²⁺-concentration-dependent manner. Specifically, the absorption peaks at wavelengths 260 and 350 nm of 3 gradually increased with increasing amounts of Cd²⁺. Fig. 2 shows the course of the fluorescence titration of 3 with Cd²⁺ in EtOH/H₂O (1:1, v/v). Free compound 3 showed fluorescence centered at 412 nm upon excitation at 334 nm. With the addition of Cd²⁺, the fluorescence intensity gradually increased in a Cd²⁺-concentration-dependent manner and the emission maximum wavelength of 3 exhibited a bathochromic shift of 8 nm, indicating that a CHEF effect occurred with Cd²⁺. Job’ plot analysis revealed that the complex formed between compound 3 and Cd²⁺ had a 1:1 stoichiometry (Fig. S1). The dissociation constant (K_d) of this complex, as derived from the fluorescence titration data using Benesi–Hildebrand equation [28,29], was 5.4 x 10^-6 mol L^-1 (Fig. S2). In addition, the limit of detection (LOD) of 3, calculated using LOD = 3σ/slope, was 4.4 × 10⁻⁷ mol L⁻¹. Thus, the sensitivity of compound 3 is comparable to or better than those of other reported Cd²⁺ fluorescence probes.

The selectivity of 3 for Cd²⁺detection was evaluated by fluorescence spectrometry in the presence of various cations (Al³⁺, Ca²⁺, Co²⁺, Cu²⁺, Fe²⁺, Fe³⁺, K⁺, Mg²⁺, Mn²⁺, Na⁺, Ni²⁺, and Zn²⁺) in EtOH/H₂O (1:1, v/v). As shown in Fig. 3, the fluorescence turn-on response was only observed when Cd²⁺was added to the solution of 3. Upon the addition of Zn²⁺, no fluorescence enhancement was observed, indicating that compound 3 could completely discriminate Cd²⁺from Zn²⁺. Furthermore, biologically relevant ions such as alkali ions (Na⁺ and K⁺) and group 2 ions (Ca²⁺ and Mg²⁺) existing in the millimolar range in living systems had insignificant effects on the fluorescence spectrum of 3. In the presence of heavy metal ions (Co²⁺, Cu²⁺, Fe²⁺, Fe³⁺, Mn²⁺, and Ni²⁺) and Al³⁺, the emission maximum peak showed a bathochromic shift of approximately 10 nm and fluorescence quenching was observed. We also carried out competition experiments between Cd²⁺ and other cations (Fig. 4). After the addition of each metal ion (Al³⁺, Ca²⁺, Co²⁺, Cu²⁺, Fe²⁺, Fe³⁺, K⁺, Mg²⁺, Mn²⁺, Na⁺, Ni²⁺, and Zn²⁺) to the solution of 3, the same amount of Cd²⁺was added. Fluorescence quenching was observed in the presence of some heavy metal ions including Ni²⁺, Cu²⁺, and Fe³⁺, indicating that these metal ions interfere with the binding of Cd²⁺ to 3. In the presence of other metal ions including alkali ions (Na⁺ and K⁺), group 2 ions (Ca²⁺and Mg²⁺) and Zn²⁺, CHEF effects were observed with Cd²⁺. Although fluorescence quenching was observed with Fe²⁺, Co²⁺, Mn²⁺, and Al³⁺, the fluorescence intensity increased again upon adding Cd²⁺, indicating that these metals were displaced by Cd²⁺. These spectroscopic data indicated that compound 3 could be a selective probe for Cd²⁺.

The Cd²⁺selectivity of compound 3 was investigated using analogs 5 and 7, which are closely related to 3. As shown in Scheme 2, benzene–pyrimidine analog 5 without a terminal basic nitrogen and demethylsulfanyl analog 7 were prepared with 31% and 41% yields, respectively. Spectroscopic studies (Fig. 5) revealed that benzene–pyrimidine analog 5 did not show a turn-on response to Cd²⁺, likely due to the lack of a coordination site. Thus, the interaction of 3 with Cd²⁺ involves the pyridine–pyrimidine moiety. Furthermore, demethylsulfanyl analog 7 exhibited bathochromic shift of 10 nm upon adding both Cd²⁺and Zn²⁺, indicating that the methylsulfanyl group at the 4-position of the pyrimidine ring affects the ICT state and Cd²⁺selectivity. Based on this result, we will develop related compounds with different substituents at the 4-position of the pyrimidine ring in the future.

To evaluate the influence of pH on the Cd²⁺ detecting ability of 3, we measured the intensity at the fluorescent maximum wavelength (415 nm) in buffer solutions at different pH ranges in the absence and presence of Cd²⁺ (Fig. 6). The fluorescence of 3 at pH 3 decreased in the absence of Cd²⁺ owing to the disruption of 3-Cd²⁺complex formation by the protonation of the nitrogen atom of free 3. However, the fluorescence intensities of 3 in the absence and presence of Cd²⁺ were nearly constant in the range of pH 4–8. These results indicate that compound 3 can function as a Cd²⁺ probe under physiological conditions. Thus, we studied compound 3 via cellular imaging to evaluate its cell membrane permeability.

Fig. 7 shows the fluorescence microscopy images of living cells (mouse macrophage-like cells; RAW264). The cells cultured in the Dulbecco’s modified Eagle’s medium was incubated with 3 (100 µmol L^-1) for 30 min at 37 °C in a humidified atmosphere of 5% CO₂. After the cells were washed with PBS to remove excess of 3, they exhibited a very weak fluorescence signal [Fig. 7(a)]. In contrast, the cells treated with 3 (100 µmol L^-1) for 30 min and Cd²⁺(300 µmol L^-1) for another 30 min showed a bright intracellular fluorescence signal [Fig. 7(b)]. These data indicate that compound 3 has good cell membrane permeability and a fluorescence turn-on response to intracellular Cd²⁺. In addition, no significant cytotoxicity was observed during this study.

To develop a Cd²⁺ selective fluorescence probe with cell membrane permeability, we synthesized low-molecular-weight 3 (MW = 218) based on pyridine-pyrimidine as a bis-heterocyclic core structure from the one-pot synthesis of 3,3-bis(methylsulfanyl)-1-(pyridin-2-yl)prop-2-en-1-one with guanidine carbonate in pyridine and evaluated its fluorescence properties. Compound 3 could successfully discriminate between Cd²⁺ from Zn²⁺, and showed a Cd²⁺-selective fluorescence turn-on response in the presence of other biologically relevant metal ions. Moreover, fluorescence imaging of living cells showed that the cell membrane permeability of compound 3 is sufficient to respond to intracellular Cd²⁺. Thus, we expect that compound 3, as a novel low-molecular-weight fluorescence probe for Cd²⁺ will contribute to the selective detection and investigation of cadmium in biological and environmental systems.

Authors’ Contributions All the authors (M. Hagimori, Y. Karimine, N. Mizuyama, F. Hara, T. Fujino, H. Saji, T. Mukai) made substantial contribution while preparing the manuscript.

Funding This work was partly supported by the Konica Minolta Imaging Science Encouragement Award of Konica Minolta Science and Technology Foundation.

Data Availability The data used to support the findings of this study are included within the article.

Compliance with Ethical Standards

Conflict of Interest The authors declare that they have no conflict of interest.

Code Availability Not applicable.

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Scheme 1 and 2 are available in the Supplementary Files.

Scheme1.png
Scheme 1 Synthesis of compounds 3
Scheme2.png
Scheme 2 Synthesis of the close analogs (5 and 7)

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published 13 May, 2021

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Selective cadmium fluorescence probe based on bis-heterocyclic molecule and its imaging in cells

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