Monoterpenoid derivative based ratiometric ...

Journal of Photochemistry & Photobiology A: Chemistry 364 (2018) 758–763

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Journal of Photochemistry & Photobiology A: Chemistry journal homepage: www.elsevier.com/locate/jphotochem

Monoterpenoid derivative based ratiometric fluorescent chemosensor for bioimaging and intracellular detection of Zn2+ and Mg2+ ions

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Manohar Patila, Karunesh Keshavb, Mukesh Kumar Kumawatc, Shilpa Bothrad, Suban K. Sahood, , ⁎ ⁎ Rohit Srivastavac, Jamatsing Rajputa, Ratnamala Bendrea, , Anil Kuwara, a

School of Chemical Science, North Maharashtra University, Jalgaon-425001, India Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai-400076, India c Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai-400076, India d Department of Applied Chemistry, SV National Institute of Technology, Surat-395007, India b

A R T I C LE I N FO

A B S T R A C T

Keywords: Fluorescent sensor Zn2+ Mg2+ Monoterpenoid Nanomolar detection Cellular imaging

A new monoterpenoid based fluorescent receptor (E)-2-(5-allyl-2-hydroxy-3-methoxybenzylidene)-N-phenylhydrazinecarbothioamide (1) was synthesized and applied as a fluorescent chemosensor for the selective detection of bioactive Zn2+ and Mg2+ ions over other tested cations and anions. The selective complexation with the receptor 1 provides a fluorescence enhancement that is highly specific for the determination of Zn2+ and Mg2+ ions. Under optimal conditions, the limit of detection was estimated down to 59.4 nM and 89.1 nM for Zn2+ and Mg2+ ions, respectively. Furthermore, the receptor 1 showed good cell permeability and was successfully applied for the monitoring of Zn2+ and Mg2+ ions in live cells.

1. Introduction

important and play vital roles in biological and environmental processes. Magnesium is a most copious intracellular metal ion essential for many processes such as ion channel regulation, DNA and protein synthesis, membrane stabilization and cytoskeletal activity. Also, the allocation of Mg2+ in the cytosol and subcellular areas emerges to be important in the control and regulation of the cell cycle and cell differentiation [23–26]. Therefore, there is expedite growth in the development of novel fluorescent sensors for the qualitative and quantitative monitoring of Zn2+ and Mg2+ ions. However, the magnetically silent properties and the similar coordination properties with other metal ions create challenges for the designing of selective fluorescent sensors for Zn2+ and Mg2+ ions [27–32]. In this communication, we develop a new monoterpenoid based fluorogenic receptor (E)-2-(5-allyl-2-hydroxy-3-methoxybenzylidene)N-phenylhydrazinecarbothioamide (1) for the fluorescence turn-on detection of Zn2+ and Mg2+ ions with a nanomolar detection limit even in the presence of several other metal ions (Scheme 1). In this receptor 1, the aldehyde used i.e. 5-allyl-2-hydroxy-3-methoxybenzaldehyde is structurally similar to eugenol found in essential oils of many plants that classified under naturally occurring phenolic monoterpenoids [33] whereas the analyte binding part N-phenylhydrazine-carbothioamide is well know to form complex with various metal ions.

In recent years, the artificial organic receptors have significantly used for the development of chemosensors [1–5]. The chemosensor imparts through a change in magnetic, electronic or optical properties when it binds to an analyte. Out of the different chemosensing approaches, the development of fluorescence-based chemosensors gained a burgeoning interest because of simplicity, high sensitivity [6–8] and its real application in biological systems without any need of pretreatment procedure [9–12]. The chemosensor possesses a unique binding site and a light-emitting group which upon binding of the target analyte shows a selective change in the fluorescence profile [13–16]. Due to the importance of cations in the industrial, biological and environmental processes, the researchers got attracted towards the determination of metal ions [17,18]. Among the various metal ions, Zn2+ is the second most abundant and essential trace element after iron in the body [19,20] and known to involve in various biological processes like gene transcription, cell apoptosis, and DNA binding or recognition. It also serves as an essential ingredient for the enzyme. On the other hand, excess accumulation of Zn2+ ions in the body marks the symptoms of some diseases like Parkinson disease, Alzheimer’s disease, Wilson’s disease, prostate cancer and diabetes [21,22]. Likewise, the Mg2+ ions are also equally

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Corresponding authors. E-mail addresses: suban_sahoo@rediffmail.com (S.K. Sahoo), bendrers@rediffmail.com (R. Bendre), [email protected] (A. Kuwar).

https://doi.org/10.1016/j.jphotochem.2018.07.015 Received 17 March 2018; Received in revised form 21 June 2018; Accepted 5 July 2018 1010-6030/ © 2018 Elsevier B.V. All rights reserved.


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Scheme 1. Synthesis of the receptor 1.

2. Experimental

metal ion. The excitation and emission slits were both set to 5.0 nm. The collected titration data were processed by using the BindFit v0.5 program available freely at supramolecular.org website to calculate the association constant (log Ka) of the appropriate cation complexes [35]. This program allowed to fit the experimental titration data with various possible complexation modes.

2.1. Materials and methods All reactions were carried out by using oven-dried glassware under a slight positive pressure of nitrogen unless otherwise specified. All necessary solvents were purified before use by following the standard procedure. All chemicals were purchased from Sigma Aldrich, India. All reactions were magnetically stirred and monitored by thin-layer chromatography (TLC). The 1HNMR (400 MHz) and 13CNMR (100 MHz) spectra were recorded on a Bruker AVANCE II 400 spectrometer. Chemical shifts for NMR are reported in parts per million (ppm), calibrated to the solvent peak set. Fluorescence measurements were made with a HORIBA JOBIN YVON, Fluoromax-4 Spectrofluorometer equipped with a xenon lamp. UV–Vis absorption spectra were recorded on a Shimadzu UV-2450 spectrophotometer. The receptor 1 was synthesized by following the reported method and characterized by various spectral data [34].

2.3. Cellular imaging study To investigate the sensing of Mg2+ and Zn2+ ions in a biological sample, ∼20,000 L929 mouse fibroblasts cells were seeded over acidetched sterilized glass coverslips immersed in each well of the 12-well plates containing complete media. The cells were allowed to grow for 24 h under humidified incubation condition with 5% CO2 and 37 °C temperature. After incubation, the cells of one well were kept untreated considering them as control cells, and the cells from other wells were treated with the receptor 1 retaining the final concentration 50 μg/mL in the complete media. After 30 min, the treated cells were washed gently with PBS thrice to ensure the removal of traces of receptor 1 from the extracellular environment. A well with the receptor 1-treated cells is set as a reaction control and remaining probe-treated cells from different wells are treated with the salt solutions of Mg2+ and Zn2+ ions for 10 min. The final salt concentrations in each well are set as 500 μg/ mL. After treatment, the cells were gently washed thrice to remove the traces of ions and culture media. The cells were fixed using 3.7% formaldehyde solution (pH = 7.0). The cells were imaged under the confocal microscope in different filters.

2.2. Spectral analysis All stocks and working solutions were prepared in ultrapure water and spectroscopic grade acetonitrile. The stock solutions of receptor 1 (c = 1 × 10−5M) were prepared in acetonitrile whereas the cations and anions (c =1 × 10-4M) solutions were prepared in water. The UV–vis absorption and fluorescence experiments were carried out at room temperature (298 K) with the aim of determining the selectivity of the receptor 1 towards different cations such as Cr3+, Fe3+, Co2+, Ni2+, Cu2+, Zn2+, Cd2+, Hg2+, Pb2+, Na+, K+, Mg2+, Ca2+, Al3+, Cs2+ and Ag+. The spectral titrations with the selective metal ions (i.e. Zn2+ and Mg2+) showed the satisfactory linear relationship between the added concentrations and the fluorescence intensity. These titrations were accomplished through a stepwise addition of metal salt solutions (0.01 ml, 1 × 10-4 M) in water to a solution of receptor 1 (2 ml, 1 × 10−5 M) in acetonitrile. The fluorescence spectra were recorded at an excitation wavelength of 323 nm after each aliquot addition of the

3. Results and discussion Receptor 1 was synthesized by Schiff base condensation of one mole of N-phenylhydrazine-carbothioamide with one mole of 5-allyl-2-hydroxy-3-methoxy benzaldehyde in ethanol (Scheme 1) [34]. The molecular structure of the receptor 1 was characterised by various spectral data and then applied for the sensing of cations. The interactions of receptor 1 (1 × 10−5 M) with cations were

Fig. 1. The UV–vis absorption spectral changes of 1 (1 × 10−5 M) in the presence of equivalent amount of different metal ions (a), and the titration experiment with incremental addition of Zn2+ ions (0.01 ml, 1 × 10-4 M) (b). 759


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investigated both by UV–vis absorption and fluorescence methods. As shown in Fig. 1a, the receptor 1 itself exhibits an absorption at 323 nm, a typical absorption due to the presence of the phenolic ring. With the addition of equivalent amount of Zn2+ ions, the absorption at 323 nm was decreased, and concomitantly a new peak appeared at 402 nm due to the possible complexation occurred in the ground state. However, addition of equivalent amount of other metal ions including Mg2+ ion into the receptor 1 solution, no distinguishable change in the absorption profile of receptor 1 was observed except Cd2+. This is the fact that the UV–vis spectra of receptor 1 remained unchanged even upon addition of Mg2+ ion which illustrated that receptor 1 did not bind with a Mg2+ ion in the ground state and it needs to be excited for binding with the Mg2+ ion. Because of the similar coordination behavior, the addition of Cd2+ ions also showed the appearance of the new peak at 402 nm, but the intensity was lowered in compared to Zn2+ ions. Upon continuous addition of Zn2+ ion (0.01 ml, 1 × 10-4 M) to the solution of receptor 1 (1 × 10−5 M), the absorption peak of 1 at 323 nm decreases gradually and concomitantly new absorption peaks appeared at 402 nm with the formation of an isosbestic point at 370 nm (Fig. 1b). The changes in the absorption spectra indicates the formation of a stable complex between receptor 1 and Zn2+ ions at a certain stoichiometric ratio. The receptor 1 exhibited a fluorescence emission at 407 nm due to the presence of the phenolic monoterpenoids moiety, when excited at 323 nm. However, upon addition of Mg2+ and Zn2+ ions (1 × 10−4 M, H2O), the fluorescence of 1 was red-shifted and enhanced selectively at 458 nm and 478 nm, respectively (Fig. 2). However, such selective fluorescence changes of receptor 1 were not observed in the presence of other tested metal ions (Fig. S1), which reveals the high selectivity of receptor 1 towards Mg2+ and Zn2+ ions. Under similar conditions, the receptor 1 did not shows any selectivity towards the tested anions (Fig. S1). The chelation-enhanced fluorescence (CHEF) effect observed upon complexation of receptor with Mg2+ and Zn2+ions was most probably due to the inhibition of the photoinduced electron transfer (PET) process occurred from the electron-donating group to the fluorophore and/ or the C]N isomerisation at the excited state [36]. Also, the red-shift indicates the possible intramolecular charge transfer (ICT) occurred in receptor 1 on interaction with Mg2+and Zn2+ ions [37]. The specificity of 1 for the detection of Mg2+ and Zn2+ were also examined in the presence of other metal ions. The interference experiment was performed by taking the fluorescence of receptor 1 with one equiv. of Mg2+ and Zn2+ ions in the presence of one equiv. of other

interfering metal ions. As shown in Figs. S2 and S3, the response of receptor 1 for Mg2+ and Zn2+ ions in the presence of competing for metal ions showed no remarkable changes. The fluorescence titrations of receptor 1 with Mg2+ and Zn2+ ions were carried out to examine the quantitative binding affinity and the limit of detection. The titration data shown in Fig. 3a and b were first fitted with the Benesi-Hildebrand equation by considering 1:1 binding ratio, but the obtained plot ditn’t fit well (Fig. S4). Therefore, the nonlinear curve fitting method proposed by Thordarson [35] was adopted to calculate the association constants (log Ka) of the complexes formed in solution. The titration data fitted well (Figs. S5 and S6), when the complexing model 2:1 was considered between the receptor 1 and the metal ions (Mg2+/Zn2+). The estimated log Ka of 1 with Zn2+: log K11 = 4.74, log K21 = 4.21 (i.e. log β21 = 8.95); whereas with Mg2+: log K11 = 4.88, log K21 = 4.33 (i.e. log β21 = 9.21). The association constants inferred that the receptor exhibits similar binding strength at the excited state towards the metal ions, Mg2+ and Zn2+. From the titration results (Figs. S7 and S8), the limit of detection for the detection of Mg2+ and Zn2+ ions were respectively estimated to be 89.1 nM and 59.4 nM, which is superior/comparable than the reported sensors so far [38]. Further, the Job's plot of receptor 1 with Mg2+ and Zn2+ ions were drawn to explore the binding stoichiometry (Figs. S9 and S10). A maximum emission was observed when the molar fraction was reached ∼0.33, which indicates a 2:1 binding stoichiometry between the receptor 1 and the metal ions (Mg2+ and Zn2+). Also, the formation of 2:1 complex between 1 and Zn2+ was further confirmed by the appearance of a peak at 745.25, assignable to (1.Zn2+) in the LC–MS (Fig. S11). The structure of such a Zn2+ complex can induce a π-π stacking contact between phenyl rings most important to a slightly rigid structure quite strong fluorescence properties, as compared to without charge receptor. Based on the experimental findings, the possible coordination modes for the 2:1 binding stoichiometry between the receptor 1 and the metal (Mg2+ and Zn2+) ions were explored theoretically first by applying the semi-empirical PM6 method. The receptor 1 was considered to act as a bidentate or tridentate through the phenolic-O, imine-N and the S atoms. The calculations for the tridentate coordination modes by 1 with Zn2+/Mg2+ resulted in a highly distorted and unstable geometry. However, the coordination modes described in the (Fig. 4a) gave a stable geometry to accommodate the metal ions. Among the two coordination modes, the receptor 1 energetically preferred to bind the metal ions through the imine-N and the phenolic-O atoms of the

Fig. 2. Fluorescence emission spectra of receptor 1 in the presence of different Mg2+ and Zn2+ions (λexc = 323 nm). 760


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Fig. 3. Fluorescence spectra of receptor 1 (c = 1 × 10−5 M, CH3CN) after the successive addition of Mg2+ (c = 1 × 10-4 M, H2O) at 323 nm. (a) Fluorescence spectra of receptor 1 (c = 1 × 10−5 M, CH3CN) after the successive addition of Zn2+ (c = 1 × 10-4 M, H2O) at 323 nm. (b).

receptor 1. Therefore, the stable geometry obtained with the PM6 method was further optimised by applying the DFT method using the B3LYP exchange-correlation functional, and the basis sets 6-31G** for the N, O, C, H, S atoms whereas LANL2DZ for the Mg and Zn atoms. The DFT computed structure of 1 and its complexes with Mg2+ as well as Zn2+ in 2:1 binding stoichiometry are shown in Fig. 4b–d. Based on the obtained optimised structure of the receptor 1, there is a need for apparent conformation change to coordinate the metal ions. Both the metal ions preferred a slightly distorted square-planar geometry upon complexation with receptor 1. The thiourea-NH groups of one receptor make the hydrogen bonding with the phenolic-O atoms of another coordinated receptor, which may provide additional stability to the proposed 2:1 complexation model. The frontier molecular orbitals (FMOs) plots of 1 and its complex with Zn2+ was also analyzed which indicates the uniform distribution of charge density over the surface of monoterpenoid, C]N and thiol of receptor 1 before complexation Fig. S12. After complexation, the charge density was mainly observed above the monoterpenoid unit, and the density around the thiol and C]N groups

were decreased. Therefore, the possible PET process can also be suggested for the significant fluorescence enhancement of receptor 1 upon complexation. Also, the red-shift in the absorption band was supported by the lowering in the band gap between the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) of receptor 1 on complexation with Zn2+. The reversibility of a chemosensor is a prerequisite in developing it for practical application. Therefore, to inspect the chemical reversibility of the receptor 1, we conducted reversibility experiments by carrying out four alternate cycles of titration of 1 with Zn2+ ion followed by addition of the strong chelating agent, i.e., EDTA (Fig. S13). Interestingly, it was found that by the addition of Zn2+ (1.0 equiv.) the relative fluorescence intensity (F/F0) of 1.Zn2+ complex at 478 nm noticeably increased and the solution color change from non-fluorescent to yellow fluorescent under UV light irradiation. However, on the addition of a chelating reagent such as EDTA (1.0 equiv.), an immediate reversible fluorescence change was seen and the solution became non-fluorescent. This switching on the addition of EDTA was

Fig. 4. (a) The possible bi-dentate coordination modes of 1 with Zn2+/Mg2+ ions, the DFT computed optimisedstructure of (b) receptor 1 and the complexes with (c) Zn2+ and (d) Mg2+. 761


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Fig. 5. Sensing of Mg2+ and Zn2+ ions in L929 cells in the presence of receptor 1 under confocal microscopy. The figure is divided into four rows and four columns. The images lie in each column belongs to a particular filter written on the top of the column. The images included in the first row (a–d) correspond to the control cells. Second-row images (e–h) belong to the cells treated with the receptor 1. Third row images (i–l) are of the cells treated with Mg2+ salt solutions, and fourth-row images (m–p) are of the cells treated with a Zn2+ salt solution. (Excitation: 488 nm, Emission: 500–550 nm). (For interpretation of the references to colour in the figure text, the reader is referred to the web version of this article).

probably caused by the reduction of the ratio of Zn2+/[EDTA + Zn2+] to regenerate receptor 1, which is accompanied by significant decrease in the fluorescence intensity (Fig. S13a). Importantly, this reversible fluorescence behavior of 1 towards Zn2+ can be repeated several times with only slight fluorescence efficiency loss in relative fluorescence intensity. This experiment suggests that receptor 1 can act as a promising recyclable probe for Zn2+ detection (Fig. S13b). A similar type of experiment has been carried out to check the reversibility of the probe towards Mg2+. The solution of receptor 1 was alternatively treated with Mg2+ and EDTA solutions. The excited complexation between 1 and Mg2+ was proved from the fluorescent Off-On-Off behavior upon alternate addition of Mg2+ and EDTA solutions (Fig. S14). The excellent sensing response for both Zn2+ and Mg2+ prompted us to explore its utility in intracellular detections of these ions using confocal laser scanning microscopy. The L929 cells treated with receptor 1 on excitation at 488 nm exhibits no intracellular fluorescence in both red and green filters (Fig. 5). Interestingly, upon addition of Zn2+ to these cells cause strong fluorescence enhancement in the green filter and mild in the red filter. (Fig. 5n–o) When the incubated cells were treated with Mg2+ similar fluorescent enhancement was observed. (Fig. 5j–k). An overlay of fluorescence and brightfield channels indicates that the receptor 1 can cross the cell membrane and detect these ions at cytoplasm level of L929 cells. These results demonstrate that the receptor 1 can be used as a potential receptor for the intracellular detection of Zn2+ and Mg2+ exhibit a strong dual fluorescent light. This dual emission is very important in the easy cellular detection of both Zn2+ and Mg2+ ions.

bioactive metal ions, Zn2+ and Mg2+ ions. Intracellular sensing of Mg2+ and Zn2+ ions has been demonstrated due to fluorescent chelation products of receptor 1 with Mg2+ and Zn2+ ions. The recognition events of the receptor 1 towards Zn2+ and Mg2+ are demonstrated satisfactorily by absorbance, fluorescence and DFT calculations. Receptor 1 showed fluorescence ‘turn-on’ responses towards Zn2+ and Mg2+ with nanomolar detection limit and without any interference from other tested metal ions, and thus is promising for the detection of Zn2+ and Mg2+ in living L929 cells. Acknowledgements Author thankful to UGC SAP (DSA-I) and department of science and technology (DST) India for financial support. Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.jphotochem.2018.07. 015. References [1] Z. Xu, J. Yoon, D.R. Spring, Fluorescent chemosensors for Zn2+, Chem. Soc. Rev. 39 (2010) 1996–2006. [2] S.K. Kim, D.H. Lee, J.-I. Hong, J. Yoon, Chemosensors for pyrophosphate, Acc. Chem. Res. 42 (2008) 23–31. [3] Y. Qian, J. Lin, T. Liu, H. Zhu, Living cells imaging for copper and hydrogen sulfide by a selective “on–off–on” fluorescent probe, Talanta 132 (2015) 727–732. [4] M. Shamsipur, M. Sadeghi, A. Garau, V. Lippolis, An efficient and selective flourescent chemical sensor based on 5-(8-hydroxy-2-quinolinylmethyl)-2, 8-dithia-5aza-2, 6-pyridinophane as a new fluoroionophore for determination of Iron (III) ions. A novel probe for iron speciation, Anal. Chim. Acta 761 (2013) 169–177. [5] S.O. Tümay, S.Y. Sarıkaya, S. Yeşilot, Novel iron (III) selective fluorescent probe based on synergistic effect of pyrene-triazole units on a cyclotriphosphazene scaffold and its utility in real samples, J. Lumin. 196 (2018) 126–135.

4. Conclusions In summery, we have successfully introduced a new fluorescence receptor based on monoterpenoid for the selective detection of two 762


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