Synthesis of selenium containing quinoline probe for superoxide sensing and its anticancer activity study

Abstract

Herein, we have reported the highly effective use of the Knoevenagel condensation reaction to synthesize organoselenium containing quinoline-based probe. The probe was characterized by Nuclear Magnetic Resonance and Infra-Red spectroscopy and mass spectrometry. The probe selectively detects KO₂ with high sensitivity over other reactive oxygen species and biothiols. Photo-induced electron transfer process is responsible for fluorescence “turn-on” event through transformation of selenide to selenoxide. The probe reacted with KO₂ in less than a second with lower detection limit (0.14 μM). The probe have better anticancer potency as compared to standard drug Cisplatin.

Keywords

Quinoline BODIPY sensor selenium

1. Introduction

A primary amine and a ketone or aldehyde reacts to form Schiff bases, which are then converted into secondary ketimines or aldimines [1]. Imines are frequently referred as “azomethines.” Azo compounds have ability to operate as biologically active agents allowed their use in treating diseases like antitumor, antibacterial, antiseptic, and antineoplastic disorders [2, 3]. Azomethine dyes are used more frequently in the leather, plastic, and textile sectors [4]. In recent decades, the synthesis of Schiff bases has been considered for excellent significance to organic chemists owing to its wide range of biological and pharmaceutical properties [5–12]. They are also used as fluorescent laser dyes [13].

Reactive Oxygen Species (ROS) is a group that contains both oxygen radicals like superoxide (O₂^·–), hydroxyl (OH^·), peroxyl (RO₂^·), hydroperoxyl (HO₂^·) radicals, and molecules like singlet oxygen (¹O₂), ozone (O₃), hypochlorous acid (HOCl), hydrogen peroxide (H₂O₂), which can be converted easily into radicals [14–17]. The ROS shows a different role in various pathological, and physiological processes such as it elaborates on enzymatic reaction, neurotransmission, signal transduction, blood pressure control, and gene expression, among other aspects of life function. The ROS are used in biology and neurobiology, yet they are responsible for the so-called oxidative stress if present in unwanted excess, which injures the biomolecules such as DNA, protein, and lipids of the cellular membrane [18]. The long span harms the cardiovascular and leads to inflammatory disease, cancer, neurodegenerative injury, etc [19]. Many researchers from all over the world have been drawn to the development of small fluorescent probes for detection of analytes like ROS, biothiols and metal ions under physiological settings because of their non-invasiveness, quick reaction times, high sensitivity, and straightforward detection media.

Selenium is crucial for mammals, including humans [20, 21]. It shows vital physiological and wide pharmacological actions [22]. The diet contains a variety of organic forms of selenium, including selenomethionine. Selenocysteine has also been found to be a very useful form for selenium supplementation [23]. Additionally, selenium plays a significant role in the selenium-dependent enzymes peroxidase, thioredoxin reductase, iodothyronine deiodinase, and others. Numerous selenoproteins are critical to many physiological processes, including anticancer, antibacterial, antioxidant, glutathione peroxidase (GPx) activity, antiviral, and other vital physiological functions. As a result, Organoselenium chemistry developed into a reputable area of study, and subsequent developments have been driven by the potential future uses of organoselenium compounds [24–27].

The use of organoselenium compounds as fluorophores is becoming more popular due to the biological significance of Se and its hard/soft donor feature. The property of Se to exist in multiple oxidation states, biological properties, and the unique ability of organoselenium compounds to react with ROS and biothiols make them perfect candidates for designing probes. Another challenge is to make selano-fluorophores selective towards specific ROS or biothiols, world-wide efforts have been made in this direction [28, 29].

In the fields of chemical and medicinal chemistry, quinoline and its derivatives have a significant role and thus have been widely used as prototype substances for numerous medications [30–33]. The synthesis of quinoline-fused heterocyclic molecules with a range of biological features, such as anticancer, antibacterial, antimicrobacterial, anticonvulsant, anti-inflammatory, and cardiovascular effects, has been used in the recent research [34]. The various benefits of fluorescence bioimaging technology, including its exceptional sensitivity, excellent selectivity, rapid reaction, and non-invasive detection, make it easy to identify as compare to other biological detection methods. The characteristics of physiologically active species in biological systems are low concentration, high responsiveness, and short lives. Consequently, it is currently extremely difficult to estimate the precise intracellular concentration of these species. In recent years, reaction-based fluorescent probes have been developed to satisfy these demanding requirements [34–39].

In this study, we developed a phenylselenide functionalized quinoline-based probe for the sensitive and specific detection of KO₂. The probe has been evaluated as sensor and for its cytotoxicity in MDCK and HeLa cells.

2. Experimental section

2.1. Material and methods

The chemicals and solvents (analytical grade) used were purchased from commercial sources (Aldrich, TCI, and Junsei chemical companies), and used without further purifications. 5-Aminoquinoline was purchased from Sigma Aldrich and 4-(phenylselenyl)benzaldehyde (1) was prepared as reported in the literature [41]. Silica gel used in column chromatography was of diameter 60–120 MESH size (Merck). The solvents like anhydrous ethanol were dried by standard methods. Madin-Darby canine kidney cells (MDCK) and breast cancer cells (HeLa) were used to carry out cytotoxicity study. The cells were acquired from National Centre for Cell Sciences (NCCS), Pune, India. Antibiotics, 3-(4,5-Dimethylthiazol-2-yl)-2,5- diphenyltetrazoliumbromide (MTT), and Minimum Essential Medium Eagle (MEM) were purchased from Hi-Media Laboratories Ltd. Phosphate buffered saline (PBS), Fetal bovine serum (FBS), and Trypsin-EDTA were purchased from Thermo scientific (Gibco). The ¹H and ¹³C NMR spectra of all the synthesized compounds were recorded in deuterated solvents CDCl₃ and DMSO-d₆. Tetramethylsilane (TMS) as the internal standard; whereas for ⁷⁷Se NMR, Ph₂Se₂ was used as the external standard. The NMR spectra were recorded using Bruker Avance II (300 MHz and 500 MHz respectively) NMR spectrometer. Mass spectra of compounds were recorded using Alliance LCMS spectrometer. UV-vis spectra were recorded on a Shimadzu UV2450 PC recording spectrophotometer. The Fluorescence spectra were obtained from Shimadzu RF 5301PC fluorescence spectrometer. The reaction was monitored by thin-layer chromatography using aluminum-coated silica plates.

2.2. Synthesis of compounds

2.2.1. Synthesis of 1-(4-(phenylselanyl)phenyl)-N-(quinoline-5-yl)methanimine (3)

1-(4-(Phenylselanyl)phenyl)-N-(quinolin-5-yl)methanimine (probe 3) was synthesized by reported literature procedure [42–44]. The equimolar quantity of 4-(phenylselanyl)benzaldehyde (0.18 g, 0.694 mmol, 1eq^v) and 5-aminoquinoline (0.100 g, 0.694 mmol, 1 eq^v) was refluxed with catalytic amount of glacial acetic acid in anhydrous ethanol (10 mL) under nitrogen atmosphere for 6 h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to obtain crude product. The crude was recrystallized with petroleum ether and DCM. The yellow colour probe 3 was obtained in the yield of 90% . The compound was characterized by the ¹H, ¹³C and ⁷⁷Se NMR, IR spectroscopy, and mass spectrometry (Figure S3–S8). ¹H NMR (300 MHz, CDCl₃) δ ppm 9.17 (s, 1H), 8.92 (d, J = 7.6 Hz, 1H), 8.74 (s, 1H), 8.22 (d, J = 7.8 Hz, 1H), 8.09 (d, J = 6.3 Hz, 2H), 7.87 (m, 3H), 7.72 (d, J = 6.4 Hz, 2H), 7.60 (m, 4H), 7.36 (d, J = 6.3 Hz, 1H). ¹³C NMR (151 MHz, CDCl₃) δ ppm 160.3, 150.9, 149.0, 148.6, 137.9, 134.7, 134.6, 132.7, 131.5, 129.7, 129.7, 129.6, 129.4, 128.4, 127.2, 124.4, 120.9, 113.1. ⁷⁷Se NMR (114 MHz, CDCl₃) δ ppm 427. IR: (cm^–1) (C = N) stretch at 1613. MS-ESI m/z: calculated for [C₂₂H₁₆N₂Se]⁺ was 388.05 and found 388.92 [M]⁺.

2.2.2. Synthesis of oxidized probe (4)

Probe 3 (0.1 g, 0.2582 mmol) and KO₂ (0.18 g, 2.582 mmol, 10 eq^v) were mixed and dissolved in DMSO (2 mL). The reaction mixture was stirred at room temperature for 40 min. The oxidized probe (4) was confirmed by mass spectrometry without isolation (Figure S9). Spectrometric Data: ESI-MS calculated for [C₂₂H₁₆N₂SeO]⁺: 404.04, found m/z 404.95 [M]⁺.

2.3. Spectrophotometric studies

All spectrophotometric studies were performed in DMSO, taking constant concentration of the probe (5 μM) throughout the study. ROS (H₂O₂, ^·OCl, ^tBuOOH, ^·OCl, ^·OH, and ^tBuO^·; 0.1 M) and biothiols (L-cysteine, DL-homocysteine, glutathione, N-acetyl-L-cysteine, and D-methionine; 0.1 M) were prepared in double distilled water, whereas DMSO was used to prepared superoxide. Entire, fluorescence measurements of the probe were performed at maxima of 352 nm. Probe 3 was incubated for 2 min with ROS and biothiols in the complete spectrophotometric study. The probe was screened with all freshly prepared ROS (667 μM) and biothiols (667 μM) to check the selectivity of the probe with the help of UV-visible and fluorescence spectrophotometer [43, 44].

2.3.1. Generation of ROS

Distilled water was used to produce ROS (H₂O₂, ^tBuOOH, ^— OCl, ^· OH, and ^tBuO ^· ) with 0.1 M concentration.

2.3.1.1. Generation of O₂

Commercially available potassium superoxide was used as source of the superoxide radical anion and was used by dissolving in DMSO.

2.3.1.2. Generation of H₂O₂

Deionized water was used to dilute the commercially available hydrogen peroxide solution.

2.3.1.3. Generation of ^tBuOOH

Deionized water was used to dilute the tert-butyl hydrogen peroxide solution that is available commercially.

2.3.1.4. Generation of ^—OCl

The source of sodium hypochlorite was commercial bleach and was diluted with deionized water.

2.3.1.5. Generation of ^·OH

The Fenton reaction was used to generate the hydroxide radical (^·OH), to which ferrous sulphate (4 mg) was added to produce the radical in the presence of 10 equivalents of H₂O₂. The concentration of ^·OH was equal to the concentration of Fe²⁺.

2.3.1.6. Generation of ^tBuO^·

By the use of Fenton reaction, tert-butoxide radical (^tBuO^·) was also generated. It was formed by tert-butyl hydrogen peroxide when ferrous sulphate was added (4 mg).

2.4. Selectivity

Probe 3 was screened using ROS (KO₂, H₂O₂, ^tBuOOH, NaOCl, ^·OH, and ^tBuO^·; 667 μM) and biothiols (L–cysteine, DL–homocysteine, glutathione, N–acetyl–L–cysteine, and D-methionine; 667 μM). In this study, probe 3 (5 μM, 3 mL) was incubated with analytes for 2 min.

2.5. Time dependent study

Probe 3 (3 mL, 5 μM) was exposed to a time-dependent emission experiment with KO₂ (20 μL, 0.1 M) for 60 min (λ_ex = 347 nm, λ_em = 497 nm), excitation and emission slit width was kept at 5/3 nm, respectively.

2.6. Interference study

Further, to study the interference of other ROS (H₂O₂, ^–OCl, ^tBuOOH, ^·OH, and ^tBuO^·), solutions of the probe (5 μM) were incubated with KO₂ (667 μM) for 2 min, and then other ROS (667 μM) and biothiols (667 μM) were added and the emission spectra were recorded.

2.7. Detection limit

The detection limit was calculated using fluorescence titration data. Three fluorescence measurements of probe 3 were taken, to measure the standard deviation of a blank. The fluorescence intensity at 352 nm was plotted versus concentration of KO₂ to obtain the slope. Consequently, Equation 1 was used to determine the detection limit:

(i) For Limit of Detection

Detection limit = \frac{3 σ}{k}

(1)

Where, σ is the standard deviation of blank measurement,

K is the slop between the fluorescence versus KO₂ concentration.

(ii) For Determination of Quantum Yield

Q_{s} = Q_{r} \frac{A_{r}}{A_{s}} \times \frac{E s}{E r} \times (\frac{η_{s}}{η_{r}})

(2)

Where, · Q = Fluorescence quantum yield

· m = Gradient of the plot of integrated fluorescence intensity against absorbance

· n = Refractive index of the solvent

· A = Absorbance of the solution

· E = Integrated fluorescence intensity of the emitted light

· Subscripts ‘r’ and ‘s’ refer to the reference and unknown fluorophore respectively. Quinine sulphate was used as standard, which has a quantum yield of 0.577 [31].

2.8. Cell culture

The MTT Formazan Assay was used to calculate the cytotoxicity on Madin-Darby canine kidney cells (MDCK) and HeLa breast cancer cells. In a nutshell, 96-well plates containing Minimum Essential Medium Eagle, with 10% FBS, and penicillin-streptomycin (50 U/mL, 50 g/mL) were grown at 37 °C with 5% CO₂ in about 10,000 cells per well.

2.9. In vitro cytotoxic activity assay

The cells were preserved with probe 3 (1–1000 μM in triplicate) after a 24-hour incubation period, and they were then incubated for 48 hours at 37°C with 5% CO₂. Each well received a post-incubation dose of 20 μL of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide), which was applied to the plate and incubated for 4 hours at 37°C with 5% CO₂. After incubation, the contents of the wells were gently emptied without disturbing the cells. The formazan crystals were dissolved in DMSO (100 μL), and the plate was then left to incubate for 30 min. The plate was scanned at 570 nm after incubation using a BioTek Synergy HT Multi-Mode Microplate Reader. Equation 3 was used to enhance the absorbance of each well to determine the percentage of cell growth inhibition [40].

(iii) For Cell Cytotoxicity

% Cell cytotoxicity = [1 - \frac{{Abs}_{(Control)}}{{Abs}_{(Drug)}}] \times 100

(3)

The IC50 value, states that the drug concentration causes a 50% reduction in cellular proliferation viability, which was also calculated similarly.

3. Results and discussion

3.1. Synthesis

4-(Phenylselanyl)benzaldehyde (1) was synthesized by the literature procedure [41]. Synthesis of 1-(4-(phenylselanyl)phenyl)-N-(quinolin-5-yl)methanimine (probe 3) was carried out from the reaction of 4-(phenylselanyl)benzaldehyde (1) and 5-amino quinoline (2) with a glacial acetic acid (catalytic amount) in anhydrous ethanol (Scheme 1) [42–44]. TLC was used to keep an eye on the reaction’s development. The crude product was recrystallized in hot ethanol to get a yellow-coloured pure solid product with 70% yield. The compounds were characterized by spectroscopic techniques (Figure S1–S8).

Scheme 1.

Synthesis of compound 3.

In the ¹H NMR of probe 3 a singlet at 8.51 ppm exhibits for imine proton (–HC = N–) (Figure S3). In the ⁷⁷Se NMR spectrum of 3, signal of selenium was observed at 427 ppm (Figure S6), whereas, the IR spectrum of probe 3 showed peak at 1613 cm^–1 indicating C = N stretching vibrations (Figure S7). In the HR-LCMS of the probe (3) showed an ion peak of (C₂₂H₁₆N₂Se)⁺ at 388.92 with a selenium isotopic pattern (Figure S8). Thus, the spectroscopic and spectrometric data confirmed the successful synthesis of probe 3. After the successful characterization of probe 3, further, it was studied for various photophysical study.

3.2. Photophysical study of probe 3

To check the selectivity, the probe 3 was screened with several ROS (O₂·¯, H₂O₂, ¯OCl, ^tBuOOH, ·OH, and ^tBuO·) and biothiols (L–cysteine, glutathione, DL–homocysteine and N–acetyl–L–cysteine) by subjecting to UV-visible and fluorescence (Fig. 1, S10–S13) spectroscopic techniques. Probe 3 showed absorption maxima at 352 nm before and after reacting with ROS (Figure S10, S11). In the emission spectrum, the probe with superoxide exhibited strong bluish-green “turn-on” fluorescence (λ_em = 493 nm), while with other ROS and biothiols there was no change in the fluorescence of the probe (Fig. 1, S12, S13). The stoke shift was calculated and found to be 141 nm for the probe with KO₂, which is large as compared to the many reported organoselenium-based probes [45–48]. The fluorescence intensity of the fluorophore in probe 3 was quenched after insertion of organoselenium moiety, due to the PET process and heavy atom effect of chalcogen [49]. Fluorescence quantum yield of probe 3 (ϕ_F) was calculated by using Equation 2 and found to be increased from 0.0021 to 0.333 upon addition of superoxide (158 fold).

Figure 1.

Selectivity study error bar graph for fluorescence emission of probe 3 (5 μM) in DMSO with A) ROS (667 μM) (A = probe, B = probe + KO₂, C = probe + H₂O₂, D = probe + NaOCl, E = probe + ^tBuO₂H, F = probe + ^·OH, G = probe + ^tBuO^·); B) biothiols (667 μM), (A = probe, B = probe + KO₂, C = probe + GSH, D = probe + CYS, E = probe + HCY, F = probe + NAC, G = probe + D-Meth), incubated for 2 min at rt (λ_ex = 352 nm, and λ_em = 493 nm) with slit width 5/3.

The interference experiment was performed for the probe with superoxide in the presence of ROS and biothiols. The fluorescence spectra evidenced that there was no effect of other ROS and biothiols on the fluorescence intensity of probe 3 with superoxide (Fig. 2). The result suggested the selectivity towards the sensing of superoxide by the probe in the presence of other ROS and biothiols.

Figure 2.

Fluorescence spectra of probe 3 (5 μM) and superoxide (667 μM) in presence of A) ROS (667 μM) (A = probe, B = probe + KO₂, C = probe + KO₂₊ H₂O₂, D = probe + KO₂₊ NaOCl, E = probe + KO₂₊ ^tBuOOH, F = probe + KO₂+^·OH, G = probe + KO₂₊ ^tBuO^·); B) Biothiols (667 μM) (A = probe, B = probe + KO₂, C = probe + KO₂₊ GSH, D = probe + KO₂₊ CYS, E = probe + KO₂₊ HCY, F = probe + KO₂ + NAC, G = probe + KO₂₊ D-Meth); incubated for 2 min at rt, (λ_ex = 352 nm, λ_em = 493 nm), slit width 5/3 nm.

To reveal the detection limit, an increasing superoxide concentration study was executed with probe 3 (5 μM) (Fig. 3). It was found that, as concentration of superoxide (0–667 μM) increases, the fluorescence intensity of the probe (3) increases steadily. The detection limit for superoxide was derived using equation 3σ/k and found to be 0.14 μM, which was found to be low as compared to the previously reported few probes (Figure S14) [45, 47].

Figure 3.

Emission spectra of probe 3 in DMSO with increasing concentration of KO₂ (0–667 μM), incubated for 2 min at rt (λ_ex = 352 nm, λ_em = 493 nm), slit width 5/3.

To check the time-dependent emission spectrum, KO₂ (20 μL, 667 μM) was added to probe 3 and the spectrum was recorded for 1 h at rt (Fig. 4). Fluorescence of the probe with superoxide was increased rapidly and was stable for a longer time. The result confirmed photostability of the probe with fast response time for superoxide.

Figure 4.

Time-dependent emission spectrum of probe 3 (5 μM) with KO₂ (667 μM) in DMSO at rt (λ_ex = 352 nm, λ_em = 493 nm), slit width 5/3 nm.

Scheme 2.

Sensing mechanism of compound 3.

3.3. Proposed reaction mechanism for turn-on event of probe 3

To study the sensing mechanism, reaction of probe 3 with KO₂ was carried out in acetonitrile. The reaction mixture was submitted to mass spectrometry without isolating the product. The estimated mass for C₂₂H₁₆N₂SeO of the oxidized product was m/z 404.04, and the observed m/z was 404.95 with a selenium isotope pattern (Figure S9). This implied that the selenium was oxidized to selenoxide. Because of the inability of the selenium (after oxidation) to transfer electrons to the quinoline-based moiety, the blockage of the PET process occurred and the fluorescence was “turned on” [28, 48, 50]

3.4. Cytotoxicity studies

To determine the probe’s cell cytotoxicity, an in-vitro cell culture investigation was conducted. MTT assay method was used to find out the cytotoxicity of probe 3 against the MDCK and HeLa cell lines using the cisplatin as a positive control (Figure S15–S17). The probe’s IC₅₀ value was evaluated for the MDCK and HeLa cell lines between concentration ranges from 0.2 μM and 20 μM, and the IC₅₀ values were calculated to be 18.21 μM and 3.64 μM, respectively. In contrast, the IC₅₀ value for cisplatin for HeLa cells was found to be 2.66 μM.

The microscopic images of the probe and cisplatin in MDCK and HeLa cells demonstrated that the number of cells dropped in a concentration-dependent way as the probe concentration increased (Fig. 5). The result showed comparable anticancer activity of probe 3 for HeLa cells when compared with standard drug Cisplatin and it may be utilised to treat cervical cancer cell lines at lower doses (Table 1).

Figure 5.

Microscopic photographs of MDCK and HeLa cells treated with probe 3 at concentrations of (A) cell control, (B) 0.2 μM, (C) 10 μM and (D) 20 μM, (E) cell control, (F) 0.2 μM, (G) 10 μM and (H) 20 μM. Microscopic photographs of HeLa cells treated with Cisplatin at concentrations of (I) cell control (J) 0.2 μM, (L) 10 μM and (I) 20 μM.

Table 1.

IC₅₀ (μM) values of probe 3 against MDCK and HeLa cell lines.

Compound	HeLa	MDCK
Probe 3	3.64 μM	18.21 μM
Cisplatin	2.66 μM	18 μM [51]

4. Conclusion

Selenium based quinoline probe was synthesized in one pot and characterized successfully. The probe is selective and sensitive towards superoxide with a 158-fold increment in fluorescence intensity. The Probe showed a very quick response for KO₂ with detection limits of 0.14 μM. There was no interference of other ROS and biothiols for selective detection of superoxide. The microscopic images of the probe and cisplatin in MDCK and HeLa cells were captured, and they revealed a concentration-dependent decrease in the number of cells as the probe concentration increased. In comparison to cisplatin, probe 3 showed comparable anticancer activity for HeLa cell line.

Footnotes

Acknowledgments

S. T. S. acknowledges principal (Dr.) Avinash S. Jagtap for their constant help and support. S. T. M. acknowledge the Science and Engineering Research Board (SERB), Govt. of India, New Delhi, for financial support (YSS/2014/000726). D.S.S. thanks to University Grant Commission in the terms of UGC-NET Fellowship for SRF. We acknowledge SAIF, IIT Bombay for core instrumentation facility.

The supplementary material is available in the electronic version of this article: .

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Synthesis of selenium containing quinoline probe for superoxide sensing and its anticancer activity study

Abstract

Keywords

1. Introduction

2. Experimental section

2.1. Material and methods

2.2. Synthesis of compounds

2.2.1. Synthesis of 1-(4-(phenylselanyl)phenyl)-N-(quinoline-5-yl)methanimine (3)

2.2.2. Synthesis of oxidized probe (4)

2.3. Spectrophotometric studies

2.3.1. Generation of ROS

2.3.1.1. Generation of O2

2.3.1.2. Generation of H2O2

2.3.1.3. Generation of tBuOOH

2.3.1.4. Generation of —OCl

2.3.1.5. Generation of ·OH

2.3.1.6. Generation of tBuO·

2.4. Selectivity

2.5. Time dependent study

2.6. Interference study

2.7. Detection limit

2.9. In vitro cytotoxic activity assay

3.1. Synthesis

3.4. Cytotoxicity studies

Footnotes

Acknowledgments

References

2.3.1.1. Generation of O₂

2.3.1.2. Generation of H₂O₂

2.3.1.3. Generation of ^tBuOOH

2.3.1.4. Generation of ^—OCl

2.3.1.5. Generation of ^·OH

2.3.1.6. Generation of ^tBuO^·