Cd2+ Complex of a Triazole-Based Calix[4]arene Conjugate as a

Jul 19, 2012 - and characterized, and its Cd2+ complex has been isolated and ... linked calix[4]arene conjugate, L, and its cadmium complex,. [CdL]...
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Cd2+ Complex of a Triazole-Based Calix[4]arene Conjugate as a Selective Fluorescent Chemosensor for Cys Rakesh K. Pathak,† Vijaya K. Hinge,‡ Kandula Mahesh,† Ankit Rai,‡ Dulal Panda,‡ and Chebrolu P. Rao*,†,‡ †

Bioinorganic Laboratory, Department of Chemistry, and ‡Department of Biosciences & Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai 400 076, India S Supporting Information *

ABSTRACT: An N,N-Dimethylamine ethylimino-appended triazole-linked calix[4]arene conjugate, L, has been synthesized and characterized, and its Cd2+ complex has been isolated and characterized. The structure of [CdL] was established by computational calculation using B3LYP/LANL2DZ. Timedependent density functional theory calculations were performed to demonstrate the electronic properties of [CdL]. This highly fluorescing [CdL] has been used to recognize Cys selectively among the 20 naturally occurring amino acids. [CdL] exhibits a minimum detection limit of 58 ppb for Cys, with reusability and reversibility being imparted to the system during sensing. Thus, the sensing of Cys was well demonstrated using various techniques, viz., fluorescence, absorption, visual color change, electrospray ionization MS, 1H NMR, and live cell imaging experiments.

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[CdL]. The structure of [CdL] was established by computational calculations using B3LYP/LANL2DZ. [CdL] has been demonstrated as a highly fluorescent molecular system to sense Cys selectively among the 20 naturally occurring amino acids through exhibiting reversibility in sensing Cd2+ and Cys. The conjugate L was demonstrated as a live cell imaging agent to visualize Cd2+ in cells through exhibiting switch on and off behavior in the presence of Cd2+ followed by Cys successively.

mino acids play crucial roles in maintaining several biological functions by exhibiting their specific metal ion binding property.1 Among these, cysteine (Cys) plays an essential role in biological systems by being present as a binding unit at the active site of several metalloproteins, particularly those based on zinc, copper, and nickel.2 Cys in its free as well as peptide and protein forms acts as a heavy metal detoxifier due to its strong binding affinity toward Cd2+ and Hg2+.3 While Cd2+ is a nutrient for the species present in the deep sea, the same is toxic to the living organisms present at the surface. In addition, a rare Cd2+-based carbonic anhydrase was also isolated from the marine diatom present in the deep sea, suggesting the importance of Cd2+ in the ocean.4 It has been widely used in biological systems for in vitro studies to decipher the protein structure and in metal ion homeostasis to assess the nature of metal ion binding sites owing to its NMR activity.5 In proteins, Cd2+ exhibits specific binding with Cys due to its soft character.6 In physiological systems the homeostasis of Cys is greatly affected by the presence of heavy metals such as Cd2+ and thereby indicates their reciprocal relation.7 To understand such homeostatic relations, it is necessary to detect and quantify the interrelated entities by using simple molecular systems. Currently, metal-based fluorescent sensors have been widely used as receptors for amino acids, and this has emerged as one of the most successful strategies since it provides specific metal ion−amino acid interactions.8 By keeping the Cd2+/Cys interactions in mind, a highly fluorescent molecular system based on calix[4]arene9,10 has been developed for the selective recognition of Cys. Therefore, in this paper we report the synthesis of an N,N-dimethylamine ethylimino-based triazolelinked calix[4]arene conjugate, L, and its cadmium complex, © 2012 American Chemical Society

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EXPERIMENTAL SECTION Experimental details corresponding to the synthesis, characterization, solution preparation for fluorescence and absorption titrations, materials and methods used, and computational and cellular studies are given in the Supporting Information (pp S2−S4). Synthesis and Characterization of [CdL]. A solution of L (0.25 g, 0.19 mmol) and Cd(CH3COO)2·2H2O (0.060 g, 0.22 mmol) in methanol was refluxed for 5 h. After that the solution was concentrated, a faint yellow off-white precipitate was observed, and the solid formed was then filtered, washed with methanol, and dried under vacuum to give the desired product [CdL]: yield 87%; 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 8.78 (s, 2H), 8.23 (s, 2H), 7.98 (s, 2H), 6.83−7.25 (br m, 12H), 5.64−5.45 (2 br d, 4H), 4.97 (br s, 4H), 4.32−4.03 (2 br d, 4H), 3.68 (br t, 4H), 3.19 (br d, 4H), 2.26 (br t, 4H), 2.20 (br s, 12H), 1.23 (br s, 18H), 1.16 (br s, 18H), 1.087 (br s, 18H); 13C NMR (CDCl3, 200 Hz) δ (ppm) 180.17, 170.43, Received: June 5, 2012 Accepted: July 5, 2012 Published: July 19, 2012 6907

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Scheme 1. Synthesis of the Calix[4]arene Conjugate, L, and Its Cd2+ Complex, [CdL]a

Reagents and conditions: (a) 5-tert-butyl-3-(azidomethyl)-2-hydroxybenzaldehyde, CuSO4·5H2O and sodium ascorbate in dichloromethane/water (1:1) rt, 12 h; (b) N1,N1-dimethylethane-1,2-diamine, rt, 12 h; (c) Cd(OAc)2·2H2O, methanol. R = tert-butyl.

a

Figure 1. (a) DFT-optimized structure of [CdL] where hydrogens were omitted for clarity. An expanded version of the primary coordination sphere of Cd2+ is shown. The bond lengths (Å) and bond angles (deg) in the coordination sphere are O1−Cd = 2.226, O2−Cd = 2.245, N1−Cd = 2.692, N2−Cd = 2.362, N3−Cd = 2.358, N4−Cd = 2.598, O1−Cd−O2 = 92.2, O1−Cd−N1 = 91.6, O1−Cd−N2 = 79.3, O1−Cd−N3 = 114.7, O1−Cd−N4 = 147.0, O2−Cd−N1 = 150.4, O2−Cd−N2 = 123.6, O2−Cd−N3 = 80.4, O2−Cd−N4 = 88.2, N1−Cd−N2 = 85.9, N1−Cd−N3 = 71.2, N1−Cd−N4 = 103.9, N2−Cd−N3 = 152.9, N2−Cd−N4 = 73.1, and N3−Cd−N4 = 97.8. (b) Isotopic peak pattern for the [CdL] complex in ESI mass spectra. The top one is observed, and the bottom one is calculated.

150.47, 149.75, 147.51, 144.27, 141.88, 133.19, 132.92, 132.49, 127.85, 125.90, 125.20, 123.52, 70.44, 60.27, 54.94, 50.62, 46.17, 34.15, 33.97, 33.64, 32.01, 31.85, 31.50, 31.17, 22.04. Anal. Calcd for C82H108N10O6Cd·2CH3CN·CHCl3: C, 63.57; H, 7.05; N, 10.23. Found: C, 64.06; H, 7.60; N, 10.33. HRMS m/z calcd for C82H109N10O6Cd (M + H+) 1443.7565, found 1443.7533.

various analytical and spectral techniques. In all these conjugates, calix[4]arene was found to be in cone conformation on the basis of NMR studies (Supporting Information, Figures S1−S3). The isolated 1H NMR spectra of [CdL] have broadened peaks, which are similar to those observed in the 1H NMR of L titrated with Cd2+ (Supporting Information, Figures S4 and S5), suggesting that the complex formed in solution is the same as the isolated product. Thus, the broadening is attributable to the Cd2+ interactions. The isolated [CdL] complex was further characterized by electrospray ionization (ESI) HRMS and elemental analysis. ESI MS obtained for the isolated complex, viz., [CdL], resulted in a molecular ion peak at m/z = 1443.76 (Supporting Information, Figure S3). The isotopic peak pattern observed for this peak is characteristic of the presence of cadmium and thus supports the complex formation of Cd2+

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RESULTS AND DISCUSSION The Cd2+ complex of the calix[4]arene conjugate [CdL] was synthesized by going through the steps given in Scheme 1.11 Initially, L was synthesized by the condensation of 2 with N1,N1-dimethylethane-1,2-diamine, followed by the reaction of L with cadmium acetate, and the product complex [CdL] was isolated. All the synthesized molecules were characterized by 6908

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Figure 2. (a) Fluorescence spectra obtained during the titration of [CdL] (2 μM) with Cys in methanol at λex = 380 nm. The inset shows the relative fluorescence intensity plot (I/I0) as a function of the [Cys]/[CdL] mole ratio. (b) Histogram showing the relative fluorescence response of [CdL] (2 μM) in the presence of amino acids (aa's) (20 μM). The inset histogram shows the fluorescence changes of [CdL] with different thiols. (c) Visual fluorescent color change of [CdL] with different amino acids.

molecular orbitals (MOs) are majorly localized on the salicylimine part of [CdL]. Even in transition “B”, the MOs are majorly localized on the salicylimine part of [CdL], but the transitions are from the π MO of one salicylimine to the π* MO of the other salicylimine of [CdL], and this corresponds to the pure HOMO − 1 → LUMO + 1 excitation. Transition “C” mainly corresponds to the transition from the π MO of salicylimine N,N-dimethylamine ethylimino to the π* MO of the other salicylimine of [CdL] and thus corresponds to the pure HOMO → LUMO excitation. The major transition of [CdL] and corresponding (A, B, and C transitions) MOs of the two one-electron excitations are shown in the Supporting Information, Figure S8 and Table S4. Selective Recognition of Cysteine by the [CdL] Complex. The Cd2+ complex [CdL] exhibits high fluorescence emission in methanol. The utility of [CdL] in recognizing a particular amino acid has been investigated on the basis of its preference of binding affinity toward various functional moieties present in natural amino acids. Fluorescence Spectra. The isolated complex of [CdL] shows strong fluorescence emission at ∼456 nm upon excitation at 380 nm. The fluorescence titrations were carried out with all 20 naturally occurring amino acids (Supporting Information, Figure S9). Upon titration of [CdL] with Cys, the fluorescence of this complex initially increases to a small extent, and thereafter, it decreases gradually until it attains saturation (Figure 2). This fluorescence change of [CdL] may be attributable to the initial involvement of Cys in the complex formation at the Cd2+ center, followed by the removal of Cd2+ from the complex. Similar fluorescence titrations were performed with other amino acids and found no significant change in the fluorescence intensity of [CdL] during the titration. The unaltered fluorescence behavior of [CdL] in the presence of other amino acids is suggestive of the noninteractive nature of these amino acids with [CdL]. To understand whether the selective recognition of [CdL] toward Cys is through the −SH moiety, fluorescence titrations were carried out with other biologically relevant −SHcontaining molecules, viz., mercaptopropionic acid (MPA), homocysteine (Hcy), and dithiothreitol (DTT(red)) (Supporting Information, Figure S10). The fluorescence of [CdL] has been quenched with these molecules (Figure 2b, inset),

with L (Figure 1b and Supporting Information, Figure S6). The structural features of [CdL] have been obtained by density functional theory (DFT) computational calculations. Structural Features of [CdL] by DFT Computations. Computational calculations were carried out using the Gaussian 03 package12 (Experimental Section) to establish the complexation features of [CdL], since single crystals with good diffraction quality could not be obtained owing to its low crystallinity (Supporting Information, Figure S7). To do that, initially the structure of L was optimized in DFT. The optimized L was subjected to the interaction with Cd2+ that was further optimized to obtain the complex [CdL] (Experimental Section and Supporting Information, Tables S1−S3). The frequency analysis calculations were performed with the FREQ key word, and the absence of imaginary frequencies indicated the low-energy minimum of the structure obtained. In the optimized structure of the complex, Cd2+ is in distorted octahedral geometry, by bonding through two each of salicyl oxygens, imine nitrogens, and N,N-dimethylethane nitrogens (Figure 1a). The Cd−N distances of the N,N-dimethylethane moiety are longer by ∼0.3 Å over the iminophenolic moiety, suggesting weaker Cd−N interactions in the case of the former. The formation of [CdL] has been demonstrated by the peak observed in ESI MS (Figure 1b). Calculations based on single-excitation time-dependent DFT (TDDFT) were performed to explain the electronic structural properties of the ground and excited states of [CdL]. The vertical transitions calculated by TDDFT (Supporting Information, Table S4) were comparable with the experimentally observed UV−vis spectra. The TDDFT calculations performed at the B3LYP/LANL2DZ level of theory revealed the absorption bands in the region of λmax = 270−420 nm (Supporting Information, Figure S7). The studies suggest that the vertical transitions observed at ∼375 nm are comparable to those of the experimentally observed spectra at ∼380 nm for [CdL]. In the case of the [CdL] complex, the highest observed oscillator strength (F) corresponds to the experimental λmax (∼375 nm), which is assigned to transition “A” that results from the π → π* transition of the salicylimine N,Ndimethylamine ethylimino fragment to the salicylimine (Supporting Information, Figure S8 and Table S4). These 6909

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Figure 3. Fluorescence spectra obtained for the competitive titration of [CdL] (2 μM) with Cys in the presence of different aa's (20 μM): (a) {[CdL] + Cys} + aa. (b) {[CdL] + aa} + Cys. (c) Absorption spectra obtained during the titration of [CdL] with Cys. The inset shows a plot of absorbance vs {[Cys]/[CdL]} for two different bands. (d) Histogram showing the absorption response of [CdL] at the 380 nm band when titrated with different aa's.

suggesting the involvement of −SH in the binding of Cd2+ followed by its removal from the complex. This is further strengthened by the titration of [CdL] with the oxidized form, DTT(ox). The fluorescence intensity of [CdL] remains the same even at higher equivalents of DTT(ox), further suggesting the involvement of the −SH group in the selective sensing of Cys by [CdL] (Figure 2 and Supporting Information, Figure S10). As [CdL] in methanol shows an intense fluorescent blue color under UV light, the color changes were monitored upon reacting this complex with naturally occurring amino acids (aa's) by keeping a 1:5 [CdL]:AA mole ratio. The visual blue color changes from fluorescent to nonfluorescent only in the presence of Cys, and the resultant behavior is similar to that of L, suggesting the removal of Cd2+ with the concomitant release of L from the complex by Cys. Thus, [CdL] clearly distinguishes the biologically important Cys from those naturally occurring amino acids. However, the color of [CdL] is unaltered in the presence of other amino acids, suggesting that [CdL] is intact in the complex even in the presence of these amino acids (Figure 2c). To check the selectivity of the recognition of [CdL] toward Cys, competitive amino acid titrations were carried out in the same medium with 19 other naturally occurring amino acids in two different ways. In one, {[CdL] + aa} was titrated with Cys (“aa” is any amino acid), and in the other, the {[CdL] + Cys} mixture was titrated with another amino acid. In the first, the unaltered fluorescence intensity of the {[CdL] + aa} mixture decreases upon the addition of Cys. In the second, the {[CdL] + Cys} mixture that is in the quenched state does not regain intensity upon titration with any of the other amino acids. These results suggest that [CdL] is selective for only Cys owing to their unique Cd2+···¯S−Cys interactions (Figure 3 and Supporting Information, Figure S11). The minimum detection limit of Cys has been calculated using a ∼50 arbitrary intensity unit difference between [CdL] and [CdL] upon addition of Cys. This is 6 times the standard deviation of the [CdL] intensity. Thus,

[CdL] is sensitive enough to detect a minimum concentration of 58 ppb Cys (Supporting Information, Figure S12). To the best of our knowledge, this is the first Cys sensor that functions on the basis of the Cd2+ complex of the calix[4]arene conjugate. Absorption Spectra. To further support the selective sensing of Cys by [CdL], absorption titrations were carried out. [CdL] shows mainly an absorption band at ∼380 nm and a shoulder at ∼275 nm. Upon titration of [CdL] with Cys, the absorbance of the ∼380 nm band decreases and two new bands appear at ∼325 and 440 nm (Figure 3c). The new band observed at ∼325 nm is assignable to the presence of keto species owing to the keto−enol tautomerization present only in the case of free L which otherwise is inhibited in [CdL] upon binding of Cd2+ to L13 (Figure 3c and Supporting Information, Figure S13). However, when [CdL] is treated with other amino acids, no change is observed in the absorption of the 380 nm band and no new band is observed (Supporting Information, Figure S13); thus, the spectra remain similar to that of [CdL]. The changes observed only in the case of Cys are attributable to its unique binding characteristic toward Cd2+ followed by its removal from [CdL] to liberate free L. This is further strengthened by carrying out the absorption titrations of [CdL] with DTT(ox). The absence of any change in the absorbance of the 380 nm band and also the absence of any new band in the titration suggests the noninteracting nature of DTT(ox) owing to the absence of the −SH group. However, DTT(red) possessing a free −SH moiety shows spectral changes similar to that of Cys (Supporting Information, Figure S14). Thus, [CdL] can differentiate the reduced form of DTT from its oxidized form through the recognition of the free −SH moiety. ESI MS Spectra. To provide further support for binding, followed by the removal of Cd2+ from [CdL] by Cys, ESI MS titrations were carried out. The complex species of Cys formed with Cd2+ has been demonstrated by ESI MS through observing the peaks at 1332.20 for (L + H) and 445.05 for 6910

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Figure 4. 1H NMR spectral titration of [CdL] with DTT(red) in DMOS-d6: (a) [CdL], (b−h) [CdL] followed by n equiv of DTT(red), where n = (b) 0.125, (c) 0.25, (d) 0.375, (e) 0.5, (f) 0.75, (g) 1.0, and (h) 2.0, and (i) L. Key: ●, imine H; ☆, triazole H; ⬢, calix OH; Δ, ▲, Sal H and Cal Ar H; ★, ○, ■, ⬡, bridged CH2 protons.

Figure 5. Fluorescence experiment to show the reversibility and reusability of the receptor for sensing Cys by alternate addition: (a) relative fluorescence intensity (I/I0) obtained during the titration of [CdL] with Cys followed by the addition of Cd2+ ([CdL] = 2 μM, and λex = 380 nm); (b) visual fluorescent color changes after each addition of Cys and Cd2+ sequentially.

Figure 6. Fluorescence images obtained from the MCF-7 cells (λex at ∼358 nm and λem at ∼461 nm) upon treatment with Cd2+ followed by Cys in PBS buffer at pH 7.4: (a) microscopy images of L (20 μM); (b) microscopy images of L (20 μM) in the presence of Cd2+ (25 μM); (c) microscopy images of L (20 μM) in the presence of Cd2+ followed by Cys (50 μM). The scale bar is 10 μm.

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(2Cys + Cd + CH3OH + H2O + 2Na+) (Supporting Information, Figure S15). Therefore, the changes observed in the titration of Cys are attributable to the release of Cd2+ and L from [CdL] followed by the complexation of Cd2+ by Cys, i.e., [CdL] + Cys → [L + {Cd·Cys}]. Both the absorption and fluorescence spectral studies clearly demonstrate the release of L from [CdL] upon titration with Cys. 1 H NMR Spectra. 1H NMR titrations were carried out to support the release of Cd2+ from the complex to generate free L. For this purpose DTT(red) was used instead of Cys because of the poor solubility of the latter when taken in DMSO-d6. During the titration, the signals corresponding to the complex start to disappear while those corresponding to the free L start to appear as the concentration of the added DTT(red) increases (Figure 4 and Supporting Information, Figure S16), thus clearly supporting the release of L from the complex. Reversibility of the Receptor. The reusability of [CdL] in sensing Cys has been demonstrated by carrying out four alternate cycles of titration of [CdL] with Cys followed by Cd2+. Titration of [CdL] with Cys shows significant switch of f fluorescence, and the fluorescence is regained when Cd2+ is added to result in the switch on mode. Four such consecutive cycles are shown in Figure 5, and the results clearly demonstrate the reversible property of L in sensing Cd2+ followed by Cys (Figure 5 and Supporting Information, Figure S17). Fluorescence Microscopy in Cells. To extend the utility of [CdL] for the detection of Cys in the in vitro biological medium, fluorescence microscopy studies were carried out using MCF-7 cells. MCF-7 cells were incubated for 20 min at 37 °C in PBS buffer (pH 7.4) containing a 20 μM concentration of the conjugate (L), and the cells were washed with the same buffer to remove the excess L. At this stage, the MCF-7 cells exhibit very weak fluorescence. Upon addition of Cd2+ to the cells via their incubation with Cd2+/pyrithione solution for 20 min at 37 °C, the cells show blue fluorescence (Figure 6). Differential interference contrast (DIC) microscopy images for each experiment confirm that the cells are viable throughout the imaging experiments, and the merged images support the fact that the fluorescence is being emerged through the cells (Figure 6). However, when L and Cd2+ preincubated cells were further treated with Cys for 20 min at 37 °C, fluorescence was quenched (Figure 6 and Supporting Information, Figure S18). Fluorescence emission measured from the area of MCF-7 cells was found to decrease in the case of {[L + Cd2+] + Cys} and found to have significant similarity with the fluorescence intensity of simple L (Supporting Information, Figure S19). Therefore, the cellular studies indicate that the conjugate L exhibits intracellular fluorescence in the presence of Cd2+, which in turn loses its fluorescence intensity upon treatment with Cys.

oxygens, two imine nitrogens, and two N,N-dimethylamine ethylimino nitrogens, emanating from both the arms of the conjugate L. TDDFT calculations were performed to demonstrate the electronic properties of [CdL], and significant similarities with the experimental results were found. In solution, [CdL] shows strong fluorescence emission at 456 nm when excited at 380 nm through exhibition of an intense blue color fluorescence under UV light. Owing to this unique characteristic of [CdL], its use has been extended to selectively recognize an amino acid as per the metal-to-amino acid preference. Thus, [CdL] has been found to recognize Cys selectively among the 20 naturally occurring amino acids through the removal of Cd2+ from [CdL] by Cys and releasing the free L. [CdL] exhibited a minimum detection limit of 58 ppb for Cys. The sensing of Cys was well demonstrated using various techniques, viz., fluorescence, absorption, visual color change, ESI MS, 1H NMR, and live cell imaging studies. The reusability and reversibility of [CdL] to sense Cys has been demonstrated by four alternative cycles. Thus, the present study demonstrates the utility of a highly fluorescent Cd2+ complex of L, [CdL], as a sensitive and selective chemosensor for Cys through exhibiting multiple reversible cycles.

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ASSOCIATED CONTENT

S Supporting Information *

Additional information as noted in text. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*Phone: 91 22 2576 7162. Fax: 91 22 2572 3480. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS C.P.R. acknowledges financial support from the Department of Science and Technology, Council for Scientific and Industrial Research (CSIR), and Board of Research in Nuclear Sciences, Department of Atomic Energy. R.K.P, V.K.H., and A.R. acknowledge the CSIR for research fellowships. D.P. thanks financial support from a DAE-SRC fellowship.

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CONCLUSIONS The N,N-dimethylamine ethylimino-based triazole-linked calix[4]arene conjugate, L, has been synthesized and characterized. The Cd2+ complex of L, i.e., [CdL], has been isolated and characterized by various spectroscopic and analytical techniques. Structural features of the Cd2+-bound L were established by computational calculations using the B3LYP/LANL2DZ methods, wherein the cadmium center shows a distorted octahedral coordination geometry by being bound through the N4O2 core formed from two phenolic 6912

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dx.doi.org/10.1021/ac301492h | Anal. Chem. 2012, 84, 6907−6913