Click-reaction generated [12]aneN3-based fluorescent sensor for Zn(II) ions

Inorganic Chemistry Communications 23 (2012) 67–69

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Click-reaction generated [12]aneN3-based fluorescent sensor for Zn(II) ions Li-Jun Zhang a, Hua-Long Chen a, Zhi-Fen Li a, Zhong-Lin Lu a,⁎, Ruibing Wang b a b

The College of Chemistry, Beijing Normal University, Xinjiekouwai Street 19, Beijing 100875, China Global R&D, Nordion Inc., 447 March Road, Ottawa, Ontario, Canada K2K 1X8

a r t i c l e

i n f o

Article history: Received 4 April 2012 Accepted 8 June 2012 Available online 18 June 2012

a b s t r a c t A new [12]aneN3-based fluorescent sensor 3 has been efficiently synthesized through click chemistry. This sensor demonstrates high selectivity for Zn(II) ions in aqueous solution at pH 7.2, even in the presence of other competitive cations. © 2012 Elsevier B.V. All rights reserved.

Keywords: Macrocyclic polyamine [12]aneN3 Fluorescent senor Zn(II)

The importance and chemistry of macrocyclic polyamines is well known and continues to be of topical interest due to their widespread applications in coordination chemistry, medicine chemistry, as bio-mimic catalysts, and as functional materials [1–5]. As binding units, macrocyclic polyamines have also been applied in the development of a number of PET (photo-induced electron transfer) based chemical sensors to monitor in vitro and/or in vivo biologically- and environmentally-relevant metal ions [6,7]. Among the transition metal elements, Zn(II) ion has received much attention. As the second most abundant d-block metal ion in the human body, Zn(II) plays a critical role in enzyme regulation, structure and function, neural signal transmission, gene expression, and apoptosis [8–10]. The development of fluorescent sensors has greatly helped researchers to quantify and explore the role of Zn(II) in biology, medicine and in the environment [11–16]. Despite of the availability of many zinc ion sensors, chemists continue to design new sensors and are endeavoring to improve their sensitivity, selectivity, and reliability in order to satisfy various needs. Recently, Tamanini and El Majzoub et al. reported on the preparation of cyclam ([12]aneN4) derived fluorescent sensors for Zn(II) ion and found their high selectivity and sensitivity [17–19]. Our group has recently focused on the design and synthesis of various macrocyclic polyamine [12]aneN3 compounds and their applications in artificial nucleases and DNA condensation agents [20–23]. Encouraged by the above work, we decided to evaluate the capability of the [12]aneN3 unit as a receptor in the chemical sensors for Zn(II) ion. To the best of our knowledge, there are no examples of 12]aneN3 units being used as a receptor in chemical sensor in literature. In this report we describe the efficient synthesis of a [12]aneN3-derived fluorescent sensor 3 and its performance in the selective sensing of Zn(II) ion. ⁎ Corresponding author. Tel./fax: + 86 1058801804. E-mail address: [email protected] (Z.-L. Lu). 1387-7003/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.inoche.2012.06.009

Naphthalimide is an excellent fluorophore that is used for chemical and biological sensors in many fields [14]. To combine the macrocyclic polyamine [12]aneN3 unit with the fluorophore naphthalimide, click reaction, which is a modular synthetic procedure [24,25], was utilized (Scheme 1). An azide-bearing fluorophore 1 was synthesized following a literature method by using commercially available 4-bromo-1,8napththalic anhydride as the starting material [26]. The alkyne 2 derived from [12]aneN3 was obtained through a propargylation reaction following a procedure we had previously developed [20]. The click reaction between azide 1 and alkyne 2 proceeded smoothly and efficiently in a H2O-THF mixture (with a volume ratio of 1:1) in the presence of hydrated copper(II) sulfate and sodium ascorbate at room temperature under N2. The reaction was monitored by TLC and stopped when the starting materials had disappeared. After the treatment with a saturated aqueous solution of NH4Cl, the resultant triazole compound Boc2-3 was isolated through flash chromatography on silica gel with a yield of 81% (see Supporting Information). The Boc protecting groups were removed at room temperature by mixing this compound in methanol solution containing acetyl chloride. The resultant hydrochloride salt 3 4HCl was completely dried and fully characterized due to its stability and easy storage for extended period [27]. The free sensor 3 was obtained through neutralization with sodium hydroxide (10 M) and extraction with chloroform, which was fully characterized [28]. In the 1H-NMR spectrum of the free sensor 3, it can be seen that the protons from the naphthalimide ring appear at 8.71, 8.26, and 7.85 ppm as a doublet, another doublet, and a multiplet, respectively, in a 2:1:2 integration ratio. The proton on the triazole moiety appears at 8.08 ppm as a singlet, and the protons of the CH2 group between the triazole and the [12]aneN3 units appear at 3.94 ppm as a singlet. The protons of the N-butyl group appear at 4.22, 1.75, 1.48, and 1.00 ppm as a triplet, a multiplet, another multiplet, and a triplet, respectively, in a 2:2:2:3 integration ratio. The protons corresponding to the methylene groups in

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L.-J. Zhang et al. / Inorganic Chemistry Communications 23 (2012) 67–69

Scheme 1. Synthesis of the [12]aneN3 based fluorophores 3. i) VcNa, CuSO4, THF/H2O; ii) CH3COCl/CH3OH; iii) 10 M NaOH.

the [12]aneN3 unit appear near 2.77, 2.71, and1.78 ppm as multiplets, which are consistent with those reported in the literature [20,21]. At first, the coordination mode of 3 with Zn(II) ion was investigated by monitoring the fluorescence emissions at 410 nm (using an excitation wavelength of 344 nm) upon the titration of a 1.0 mM solution of Zn(II) into a 10 μM solution of the fluorophore 3 in a HEPES buffer at pH 7.2. Upon addition of increasing quantities of Zn(II), the fluorescence response of 3 was linear up until the addition of 1 equivalent of Zn(II) ions, as would be expected for the formation of 1:1 complexes (Fig. 1). The enhanced fluorescence of sensor 3 is

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typical of a chelation-enhanced fluorescence (CHEF) effect, in which the Zn(II) coordination causes the coordinated [12]aneN3 unit to become a less efficient donor toward the naphthalimide moiety than the uncoordinated macrocyclic polyamine. Consequently, the PETtype fluorescence quenching is less probable, and the native fluorescence of the naphthalimide is thus restored. The stability constant for the Zn(II) complex of 3 was estimated to be 1.44 × 10 4 M− 1, which is less than that (2.30 × 107 M − 1) of between Zn(II) complex and the [12]aneN4 derived sensor [17]. The detection limit is estimated to be 0.48 μM, which is significantly lower than the physical concentration of 10–300 μM estimated in zinc pools. The fluorescence spectra of 3 in the presence of various metal ions at pH 7.2 in H2O (HEPES)/CH3CN were measured and the relative emission intensities were shown in Fig. 2. Obviously, compound 3 showed excellent selectivity for Zn(II) over other cations including Cd(II) and Hg(II) ions, which is comparable to the selectivity of the cyclam-derived sensors [17]. It should be noted that the fluorescence of the free sensor 3 was quenched by most other cations, especially by Co(II), Ni(II) and Cu(II) ions. The ability of 3 to competitively bind with Zn(II) in the presence of other metal ions was also investigated. 5-fold molar excess of 13 other metal ions was added to the respective solution of 3, and the mixture was equilibrated for 25 min before 1 equivalent of Zn(II) was added. The emission spectra before and after addition of Zn(II) were recorded and compared (Fig. 3). It can be seen that the addition of Zn(II) resulted in the apparent increase of the fluorescence response of the solutions containing 3 and the respective Li(I), Na(I), K(I), Mg(II), Ca(II), Co(II), Ni(II), Hg(II), Ag(I) and Pb(II). In the case of Cd(II), Cu(II), and Fe(III), only slight increases in the emission intensity of sensor 3 were observed after the addition of Zn(II), which can be attributed to the high stabilities of these complexes. In contrast to the cyclam-based sensor [17], the quenched fluorescent emission of sensor 3 by Hg(II) was greatly restored, while that quenched by Fe(III) was not restored. In summary, a novel fluorescent sensor 3 has been prepared through the click reactions between naphthalimide azide and N-propargylated [12]aneN3. This sensor provided high selectivity for Zn(II) ions over a range of other metal ions. Results from this work have demonstrated that [12]aneN3 units can provide good receptors for fluorescent sensing applications. The modular nature of the synthetic procedure will promote the linkage of a number of fluorophores to [12]aneN3 units. Further work to improve the selectivity and sensitivity of these sensors is being performed in our lab.

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Wavelength(nm) Fig. 1. Fluorescence emission response upon titration of 1.0 mM Zn(II) into a 10 μM solution of 3 at 25 °C and pH 7.2 (100 mM HEPES buffer), λex = 344 nm. Inset: the increase in fluorescence emission intensity relative to the number of equivalents of Zn(II) added.

The authors gratefully acknowledge the financial assistances from Program for New Century Excellent Talents at Universities, the Ministry of Education of China (NCET-08-0054); Nature Science Foundation of

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Fig. 2. The fluorescence profile of sensor 3 (1 × 10− 5 M) in mixture of H2O (HEPES, 0.1 M, pH 7.2)/CH3CN buffer (8:2) in the presence of different metal ions (1 × 10− 5 M).

L.-J. Zhang et al. / Inorganic Chemistry Communications 23 (2012) 67–69

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Fig. 3. Competitive binding experiments of sensor 3 in which the competing metals (50 μM) (yellow bars) were added to the solution of 3 (10 μM) followed by Zn(II) (10 μM) (green bars) in HEPES buffer/acetonitrile (8:2) at pH 7.2.

China (20972019); and the Fundamental Research Funds for the Central Universities, Beijing Municipal Commission of Education (2009SC-1). We also thank Prof. S. Gilbertson for his English help. Appendix A. Supplementary material Supplementary data to this article can be found online at http:// dx.doi.org/10.1016/j.inoche.2012.06.009. References [1] P. Mateus, N. Bernier, R. Delgado, Recognition of anions by polyammonium macrocyclic and cryptand receptors: influence of the dimensionality on the binding behavior, Coord. Chem. Rev. 254 (2010) 1726–1747. [2] T.-B. Lu, The recognition and activation of molecules and anions by polyaza macrocyclic ligands and their complexes, Macrocyclic Chem. (2010) 417–433. [3] A. Chaudhary, R.V. Singh, Metal complexes of polyaza and polyoxaaza macrocyclic ligands: a look into the past and present work, Rev. Inorg. Chem. 28 (2008) 35–75. [4] F. Liang, S. Wan, Z. Li, X. Xiong, L. Yang, X. Zhou, C. Wu, Medical applications of macrocyclic polyamines, Curr. Med. Chem. 13 (2006) 711–727. [5] Q.-X. Xiang, C.-Q. Xia, X.-Q. Yu, L.-Q. Zhang, R.-G. Xie, Recent advances in macrocyclic polyamines and their metal complexes, Youji Huaxue 24 (2004) 981–986. [6] A. Bencini, A. Bianchi, C. Giorgi, B. Valtancoli, Fluorescent chemosensors based upon macrocyclic polyamines containing aromatic sectors, J. Inclusion Phenom. Macrocyclic Chem. 41 (2001) 87–93. [7] Y. Kohno, Y. Shiraishi, T. Hirai, Effects of proton and metal cations on the fluorescence properties of anthracene-bearing macrocyclic polyether and polyamine receptors, J. Photochem. Photobiol., A 195 (2008) 267–276. [8] H. Vahrenkamp, Why does nature use zinc-a personal view, Dalton Trans. (2007) 4751–4759. [9] J.J. Wright, K.C. Gunter, H. Mitsuya, S.G. Irving, K. Kelly, U. Siebenlist, Expression of a zinc finger gene in HTLV-I- and HTLV-II-transformed cells, Science 248 (1990) 588–591. [10] S. Yamaguchi, C. Miura, K. Kikuchi, F.T. Celino, T. Agusa, S. Tanabe, T. Miura, Zinc is an essential trace element for spermatogenesis, Proc. Natl. Acad. Sci. U. S. A. 106 (2009) 10859–10864. [11] J.-F. Zhu, W.-H. Chan, A.W.M. Lee, Both visual and ratiometric fluorescent sensor for Zn2 + based on spirobenzopyran platform, Tetrahedron Lett. 53 (2012) 2001–2004. [12] N. Zhang, Y. Su, M. Yu, A novel cell-impermeable fluorescent zinc sensor containing poly(ethylene glycol) chain, Chin. Chem. Lett. 22 (2011) 863–866. [13] J.A. Drewry, P.T. Gunning, Recent advances in biosensory and medicinal therapeutic applications of zinc(II) and copper(II) coordination complexes, Coord. Chem. Rev. 255 (2011) 459–472. [14] X. Qian, Y. Xiao, Y. Xu, X. Guo, J. Qian, W. Zhu, “Alive” dyes as fluorescent sensors: fluorophore, mechanism, receptor and images in living cells, Chem. Commun. 46 (2010) 6418–6436.

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