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Selective and sensitive time-gated luminescence detection of hydrogen sulfide
Tetrahedron Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Selective and sensitive time-gated luminescence detection of hydrogen sulfide Kaiming Zhang, Wei Dou, Xiaoliang Tang, Lizi Yang, Zhenghua Ju, Yumei Cui, Weisheng Liu ⇑ Key Laboratory of Nonferrous Metals Chemistry and Resources Utilization of Gansu Province and State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, PR China
a r t i c l e
i n f o
Article history: Received 6 January 2015 Revised 23 March 2015 Accepted 3 April 2015 Available online xxxx Keywords: Lanthanide-complex Luminescent probe Hydrogen sulfide detection Time-gated measurement
a b s t r a c t Hydrogen sulfide (H2S) is emerging as an important biological messenger, and a number of H2S fluorescent probes have been developed. However, lanthanide-based luminescent H2S probes are rarely reported. Here, a terbium complex-based luminescent H2S probe based on the reduction reaction of azide with H2S to amine is present. In the presence of H2S, the probe shows fluorescence ‘turn-on’ response with 12-fold enhancement of Tb3+ emission intensity by modulating excited state energy of the antenna based on intramolecular charge transfer (ICT), and it exhibits high selectivity for H2S over competitive anions and small-molecule biothiols. Moreover, the long luminescence lifetime of the probe facilitates the implementation of time-delayed experiment, whereby the fluorescence with short lifetime can be readily gated out. The time-gated studies demonstrate that time-gated luminescence detection of the probe toward H2S is more precise, not influenced by the background noises caused by fluorescent with short lifetime. Ó 2015 Published by Elsevier Ltd.
Introduction Recently, the chemistry and biology of hydrogen sulfide (H2S) have attracted much attention due to its importance in human health. The endogenous H2S is generated from cysteine or its derivatives catalyzed by several enzymes: cystathionine b-synthase (CBS), cystathionine c-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST).1 Like nitric oxide (NO) and carbon monoxide (CO), H2S is a biological signaling molecule that regulates many physiological and pathological processes of biological systems, such as blood pressure, inflammation, neurotransmission, myocardial contractility, and insulin secretion.2 However, abnormal level of H2S is in association with diseases including pulmonary hypertension, neurodegeneration, cardiovascular dysfunction, diabetes, and Alzheimer’s disease.3 So it is essential to develop sensitive and selective method for the detection of H2S. Small-molecule fluorescent probe is always applied to investigate biological signaling pathways because of its high sensitivity, low destruction of tissues, and real time detection. A commonly used strategy for the design of H2S fluorescent probe is to link the azido group to an organic fluorophore based on the selective reduction of azide by H2S into amide. The change from electronwithdrawing to electron-donating can modulate the probe ⇑ Corresponding author. Tel.: +86 0931 8915151; fax: +86 931 8912582. E-mail address: [email protected] (W. Liu).
emission properties. Recently, there has been a sharp rise in the number of fluorescent probes for H2S.4 However, the life-time of small-molecular probe is short, and the detection is hampered by the background fluorescence derived from the endogenous components of biological samples. Compared with usual organic small molecules, lanthanide complexes have long luminescence lifetime, which can effectively eliminate auto-fluorescence and scattered light from the samples and nearby optics through time-gating measurements.5 Besides, large visible stocks shifts and sharp emission bands for lanthanide complexes can also decrease the background noises. Thanks to these advantages of lanthanide complex-based luminescent probes, they have been used to detect kinds of bioactive species, such as 1O2,6 CO2,7 NO,8 H2O2,9 HO,10 and GSH.11 However, at least to our knowledge, very limited H2S probe based on lanthanide complexes12 has been reported. Therefore, the development of luminescent chemosensors for selective and sensitive detection of H2S in combination with time-gating measurements is an important goal. As we know, 4-aminobenzyl is an efficient antenna group for terbium (Tb3+), and it has been successfully applied to design the probes for protease13 and H2O2.9b On the other hand, –N3 can be reduced to obtain –NH2. Inspired by these, we designed and synthesized a H2S probe 1Tb, 4-azidobenzyl DO3A conjugate, possessing the 4-azidobenzyl group as the receptor unit of H2S. Owing to the strong electron-withdrawing ability of –N3, intramolecular charge transfer (ICT) can occur, resulting in the
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Please cite this article in press as: Zhang, K.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.04.012
2
K. Zhang et al. / Tetrahedron Letters xxx (2015) xxx–xxx NH 2
N3 ICT E.T.
N
N O O
N
ICT O
Tb
E.T.
H2S
O
O N
O
Tb
O
N
N
N
N
O
O O 1-NH2 Tb strong luminescence
O
O 1-N 3 Tb weak luminescence
Scheme 1. Proposed mechanism of H2S sensing by probe 1-N3Tb.
NH 2
N3
O NH HN NH HN Cyclen
t
BuO O
N
N
N
N
t
O
OtBu t
BuO
N
N
N
N
O
BuO
t
O
2
BuO 3
OtBu
O
N3
N3
O
O
HO O
N
N
N
N
OH
N O O
HO 1-N3
O
N
N Tb
O
N
O 1-N3 Tb
Figure 2. Time-gated emission spectrum (kex = 295 nm) of 1-N3Tb in the presence of different NaHS concentrations (0, 2, 4, 6, 8, 10, 12, 14, 16, 18 and 20 equiv) after 30 min. The inset figure shows that the Tb3+ luminescent intensity (545 nm) as a function of the NaHS concentrations (0–10 equiv).
O
Scheme 2. Design and synthesis of the luminescent turn-on probe 1-N3Tb for H2S.
excited state energy of the 4-azidobenzyl group which is distinguishing from that of 4-aminobenzyl, and it cannot efficiently transfer energy to Tb3+. As expected, 4-azidobenzyl is indeed a poor Tb3+ sensitizer. Here, a new lanthanide complex-based luminescent H2S probe 1-N3Tb, which possesses the 4-azidobenzyl group as the receptor unit of H2S, was designed and synthesized. It was water-soluble, and almost nonluminescent. However, upon treatment with H2S, 1-N3Tb was reduced to 1-NH2Tb, and the luminescence enhanced 12-fold accordingly (Scheme 1). Results and discussion The synthesis of ligand 1-N3 was achieved in 5 steps starting from cyclen (Scheme 2). Compound 2 was synthesized according to the reported method,13 and then was converted to compound 3 through the Sandmeyer reaction. At last, the desired ligand 1-N3 was obtained by deprotection with CF3COOH. The 1-N3Tb was prepared by mixing equivalent molar of ligand 1-N3 and Tb(NO3)3 in HEPES buffer.
With probe 1-N3Tb in hand, the optical properties were studied (Fig. 1). As shown in Figure 1, probe 1-N3Tb was weakly luminescent with low quantum yields (Absmax = 252 nm, Exmax = 250 nm, s = 0.88 ms, U = 0.24%), and the intensity of Tb3+ emission was weaker than antenna emission at 360 nm, which indicated that 4-azidobenzyl was certainly not an efficient antenna group for Tb3+. However, 1-N3Tb could convert to 1-NH2Tb (s = 1.42 ms, U = 5.26%)13 upon addition of 100 equiv of Na2S (a common source for hydrogen sulfide), in which the antenna emission gradually increased with slight blue-shift due to the block of ICT process, and the Tb3+ emission with bands at 490, 545, 586 and 622 nm apparently enhanced upon excitation at 295 nm. Moreover, Probe 1-N3Tb showed a rapid luminescent increase, finally a 12-fold turn-on response at 545 nm was observed within 60 min (Fig. 1d). Then the effect of Na2S concentration on the luminescent intensity of the probe was investigated. The intensity at 545 nm was linearly proportional to the Na2S concentration with R2 = 0.9968 (Fig. S1, Supplementary data), which indicated the probe had potential in quantitative analysis for H2S. However, 1-N3Tb seemed to be not sensitive for H2S since showed large luminescence enhancement toward 100 equiv Na2S within 60 min (Fig. 1d), Actually, when NaHS was used to work as H2S source instead of Na2S, the reaction of probe 1-N3Tb with 20 equiv NaHS was almost completed within 30 min (Fig. S2, Supplementary data). Thus probe 1-N3Tb was sensitive and useful for luminescent detection of H2S. Further a typical time-gated titration of 1-N3Tb toward H2S was evaluated. As shown in Figure 2, the probe could efficiently work the concentration of NaHS from 10 lM up to 100 lM. Moreover, the auto-fluorescence from antenna of the sample with short lifetime could be efficiently gated out. In order to embody the advantage of long lifetime of the probe, a comparison experiment was performed (Fig. S3, Supplementary data). To HEPES solution
Figure 1. Optical spectra of 1-N3Tb: (a) absorption spectrum; (b) excitation spectrum (kem = 545 nm); (c) emission spectrum (kex = 295 nm); (d) emission spectra as a function of time in the presence of 100 equiv of Na2S (data were collected every 5 min).
Please cite this article in press as: Zhang, K.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.04.012
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3
photo-resistance. These results revealed that the probe would have the potential to detect H2S in complex biological systems both qualitatively and quantitatively. In summary, we have designed and developed a Tb3+ complexbased luminescent turn-on probe for H2S based on the reduction reaction of azide with H2S to amine. The probe can respond H2S with high selectivity and sensitivity with large luminescence enhancement. Moreover, the probe, presenting long lifetime, large stokes shift, good water-solubility, and photo-resistance, facilitates the accurate detection of H2S in biological samples with time-gated detection mode. Acknowledgements
Figure 3. Selectivity of 1-N3Tb for H2S versus other species. Data were acquired as the Tb3+ intensity at 545 nm after 60 min. 1, probe alone; 2, F ; 3, Cl ; 4, Br ; 5, I ; 6, N3 ; 7, OH ; 8, HCO3 ; 9, AcO ; 10, H2PO4 ; 11, HPO24 ; 12, SO24 ; 13, HSO4 ; 14, HSO3 ; 15, GSH; 16, Cys; 17, Hcy; 18, 20 equiv NaHS within 30 min; 19, 100 equiv Na2S within 60 min.
This work is financially supported by the National Natural Science Foundation of China (Grant Nos. 21431002 and 91122007) and the Specialized Research Fund for the Doctoral Program of Higher Education of China (Grant No. 20110211130002). Supplementary data
of 1-N3Tb was added fluorescent compound 8-benzothiazole-7hydroxy-4-methylcoumarin (BHMC),15 the emission of 1-N3Tb was barley observed in the steady spectrum; by contrast, timegated luminescence emission was barely affected by the fluorescent compound. All these results suggested that the time-gated luminescence detection of the probe toward H2S could be more precise, not influenced by the background noises caused by fluorescent compound with short lifetime. In order to study the specificity toward H2S, the probe 1-N3Tb was treated with various biological species (100 equiv), including small-molecule biothiols (Cys, Hcy, GSH) and common inorganic anions. As is shown in Figure 3, only H2S could trigger obvious luminescent intensity enhancement, while others exhibited negligible responses. Besides, the luminescent intensity of the probe 1-N3Tb scarcely declined even upon addition of 100 equiv various anions. If DO3A is displaced by other excess anions, we could expect the Tb3+ luminescent intensity apparently decreases since the antenna cannot efficiently transfer energy to lanthanide center, so DO3A could act as a strong lanthanide chelator for design reaction-based anion probe. The photostability of probe 1-N3Tb was also evaluated since it is particularly crucial in the biological application.14 After the probe was exposed to light irradiation with a UV lamp (254 or 365 nm) for 60 min, the luminescent intensity of Tb3+ had almost no changes (Fig. 4), showing that the probe had good
Figure 4. Photostability of 1-N3Tb under light irradiation with a UV lamp. Data were acquired as the Tb3+ intensity at 545 nm, and the exposure time was 0, 10, 20, 30, 40, 50 and 60 min, respectively.
Supplementary data (experimental details, NMR and MS spectra) associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.04.012. References and notes 1. (a) Li, L.; Rose, P.; Moore, P. K. Annu. Rev. Pharmacol. Toxicol. 2011, 51, 169–187; (b) Szabo, C. Nat. Rev. Drug Disc. 2007, 6, 917–935. 2. (a) Yang, G.; Wu, L.; Jiang, B.; Yang, W.; Qi, J.; Cao, K.; Meng, Q.; Mustafa, A. K.; Mu, W.; Zhang, S.; Snyder, S. H.; Wang, R. Science 2008, 322, 587–590; (b) Li, L.; Bhatia, M.; Moore, P. K. Curr. Opin. Pharmacol. 2006, 6, 125–129; (c) Abe, K.; Kimura, H. J. Neurosci. 1996, 16, 1066–1071; (d) Kaneko, Y. Diabetes 2006, 55, 1391–1397; (e) Kimura, H. Amino Acids 2011, 41, 113–121; (f) Yang, W.; Yang, G.; Jia, X.; Wu, L.; Wang, R. J. Physiol. 2005, 569, 519–531. 3. (a) Eto, K.; Asada, T.; Arima, K.; Makifuchi, T.; Kimura, H. Biochem. Biophys. Res. Commun. 2002, 293, 1485–1488; (b) Fiorucci, S.; Antonelli, E.; Mencarelli, A.; Orlandi, S.; Renga, B.; Rizzo, G.; Distrutti, E.; Shah, V.; Morelli, A. Hepatology 2005, 42, 539–548; (c) Hu, L. F.; Lu, M.; Wu, Z. Y.; Wong, P. T.; Bian, J. S. Mol. Pharmacol. 2009, 75, 27–34; (d) Kamoun, P.; Belardinelli, M. C.; Chabli, A.; Lallouchi, K.; Chadefaux-Vekemans, B. Am. J. Med. Genet. A 2003, 116A, 310– 311; (e) Kulkarni, K. H.; Monjok, E. M.; Zeyssig, R.; Kouamou, G.; Bongmba, O. N.; Opere, C. A.; Njie, Y. F.; Ohia, S. E. Neurochem. Res. 2009, 34, 400–406. 4. (a) Chen, S.; Chen, Z. J.; Ren, W.; Ai, H. W. J. Am. Chem. Soc. 2012, 134, 9589– 9592; (b) Peng, H.; Cheng, Y.; Dai, C.; King, A. L.; Predmore, B. L.; Lefer, D. J.; Wang, B. Angew. Chem., Int. Ed. 2011, 50, 9672–9675; (c) Lippert, A. R.; New, E. J.; Chang, C. J. J. Am. Chem. Soc. 2011, 133, 10078–10080; (d) Jiang, Y.; Wu, Q.; Chang, X. J. Talanta 2014, 121, 122–126; (e) Zheng, Y.; Zhao, M.; Qiao, Q. L.; Liu, H. Y.; Lang, H. J.; Xu, Z. C. Dyes Pigm. 2013, 98, 367–371; (f) Zhang, H. T.; Wang, P.; Chen, G. C.; Cheung, H. Y.; Sun, H. Y. Tetrahedron Lett. 2013, 54, 4826–4829; (g) Chen, T.; Zheng, Y.; Xu, Z. C.; Zhao, M.; Xu, Y. N.; Cui, J. N. Tetrahedron Lett. 2013, 54, 2980–2982; (h) Sun, W.; Fan, J.; Hu, C.; Cao, J.; Zhang, H.; Xiong, X.; Wang, J.; Cui, S.; Sun, S.; Peng, X. Chem. Commun. 2013, 3890–3892. 5. (a) Eliseeva, S. V.; Bünzli, C. G. Chem. Soc. Rev. 2010, 39, 189–227; (b) Bünzli, J.C. G. Chem. Rev. 2010, 110, 2729–2755; (c) Thibon, A.; Pierre, V. C. Anal. Bioanal. Chem. 2009, 394, 107–120; (d) Wang, X.; Chang, H.; Xie, J.; Zhao, B.; Liu, B.; Xu, S.; Pei, W.; Ren, N.; Huang, L.; Huang, W. Coord. Chem. Rev. 2014, 273–274, 201– 212; (e) Heffern, M.; Matosziuk, L.; Meade, T. Chem. Rev. 2014, 114, 4496–4539; (f) Pershagen, E.; Borbas, K. E. Coord. Chem. Rev. 2014, 273–274, 30–46. 6. Song, B.; Wang, G.; Tan, M.; Yuan, J. J. Am. Chem. Soc. 2006, 128, 13442–13450. 7. Tang, X. L.; Wang, W. H.; Dou, W.; Jiang, J.; Qin, W. W.; Zhang, G. L.; Zhang, H. R.; Yu, K. B.; Zheng, L. M.; Liu, W. S. Angew. Chem., Int. Ed. 2009, 48, 3499–3502. 8. Chen, Y.; Guo, W.; Ye, Z.; Wang, V.; Yuan, J. Chem. Commun. 2011, 6266–6268. 9. (a) Pershagen, E.; Nordholm, J.; Borbas, K. E. J. Am. Chem. Soc. 2012, 134, 9832– 9835; (b) Lippert, A. R.; Gschneidtner, T.; Chang, C. J. Chem. Commun. 2010, 7510–7512. 10. (a) Page, S. E.; Wilke, K. T.; Pierre, V. C. Chem. Commun. 2010, 2423–2425; (b) Peterson, K. L.; Margherio, M. J.; Doan, P.; Wilke, K. T.; Pierre, V. C. Inorg. Chem. 2013, 52, 9390–9398. 11. McMahon, B. K.; Gunnlaugsson, T. J. Am. Chem. Soc. 2012, 134, 10725–10728. 12. Tropiano, M.; Faulkner, S. Chem. Commun. 2014, 4696–4698. 13. Mizukami, S.; Tonai, K.; Kaneko, M.; Kikuchi, K. J. Am. Chem. Soc. 2008, 130, 14376–14377. 14. Wu, X.; Zhu, W. Chem. Soc. Rev. 2015. http://dx.doi.org/10.1039/c4cs00152d. 15. Xie, L.; Chen, Y.; Wu, W.; Guo, H.; Zhao, J.; Yu, X. Dyes Pigm. 2012, 92, 1361– 1369.
Please cite this article in press as: Zhang, K.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.04.012
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Selective and sensitive time-gated luminescence detection of hydrogen sulfide Kaiming Zhang, Wei Dou, Xiaoliang Tang, Lizi Yang, Zhenghua Ju, Yumei Cui, Weisheng Liu ⇑ Key Laboratory of Nonferrous Metals Chemistry and Resources Utilization of Gansu Province and State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, PR China
a r t i c l e
i n f o
Article history: Received 6 January 2015 Revised 23 March 2015 Accepted 3 April 2015 Available online xxxx Keywords: Lanthanide-complex Luminescent probe Hydrogen sulfide detection Time-gated measurement
a b s t r a c t Hydrogen sulfide (H2S) is emerging as an important biological messenger, and a number of H2S fluorescent probes have been developed. However, lanthanide-based luminescent H2S probes are rarely reported. Here, a terbium complex-based luminescent H2S probe based on the reduction reaction of azide with H2S to amine is present. In the presence of H2S, the probe shows fluorescence ‘turn-on’ response with 12-fold enhancement of Tb3+ emission intensity by modulating excited state energy of the antenna based on intramolecular charge transfer (ICT), and it exhibits high selectivity for H2S over competitive anions and small-molecule biothiols. Moreover, the long luminescence lifetime of the probe facilitates the implementation of time-delayed experiment, whereby the fluorescence with short lifetime can be readily gated out. The time-gated studies demonstrate that time-gated luminescence detection of the probe toward H2S is more precise, not influenced by the background noises caused by fluorescent with short lifetime. Ó 2015 Published by Elsevier Ltd.
Introduction Recently, the chemistry and biology of hydrogen sulfide (H2S) have attracted much attention due to its importance in human health. The endogenous H2S is generated from cysteine or its derivatives catalyzed by several enzymes: cystathionine b-synthase (CBS), cystathionine c-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST).1 Like nitric oxide (NO) and carbon monoxide (CO), H2S is a biological signaling molecule that regulates many physiological and pathological processes of biological systems, such as blood pressure, inflammation, neurotransmission, myocardial contractility, and insulin secretion.2 However, abnormal level of H2S is in association with diseases including pulmonary hypertension, neurodegeneration, cardiovascular dysfunction, diabetes, and Alzheimer’s disease.3 So it is essential to develop sensitive and selective method for the detection of H2S. Small-molecule fluorescent probe is always applied to investigate biological signaling pathways because of its high sensitivity, low destruction of tissues, and real time detection. A commonly used strategy for the design of H2S fluorescent probe is to link the azido group to an organic fluorophore based on the selective reduction of azide by H2S into amide. The change from electronwithdrawing to electron-donating can modulate the probe ⇑ Corresponding author. Tel.: +86 0931 8915151; fax: +86 931 8912582. E-mail address: [email protected] (W. Liu).
emission properties. Recently, there has been a sharp rise in the number of fluorescent probes for H2S.4 However, the life-time of small-molecular probe is short, and the detection is hampered by the background fluorescence derived from the endogenous components of biological samples. Compared with usual organic small molecules, lanthanide complexes have long luminescence lifetime, which can effectively eliminate auto-fluorescence and scattered light from the samples and nearby optics through time-gating measurements.5 Besides, large visible stocks shifts and sharp emission bands for lanthanide complexes can also decrease the background noises. Thanks to these advantages of lanthanide complex-based luminescent probes, they have been used to detect kinds of bioactive species, such as 1O2,6 CO2,7 NO,8 H2O2,9 HO,10 and GSH.11 However, at least to our knowledge, very limited H2S probe based on lanthanide complexes12 has been reported. Therefore, the development of luminescent chemosensors for selective and sensitive detection of H2S in combination with time-gating measurements is an important goal. As we know, 4-aminobenzyl is an efficient antenna group for terbium (Tb3+), and it has been successfully applied to design the probes for protease13 and H2O2.9b On the other hand, –N3 can be reduced to obtain –NH2. Inspired by these, we designed and synthesized a H2S probe 1Tb, 4-azidobenzyl DO3A conjugate, possessing the 4-azidobenzyl group as the receptor unit of H2S. Owing to the strong electron-withdrawing ability of –N3, intramolecular charge transfer (ICT) can occur, resulting in the
http://dx.doi.org/10.1016/j.tetlet.2015.04.012 0040-4039/Ó 2015 Published by Elsevier Ltd.
Please cite this article in press as: Zhang, K.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.04.012
2
K. Zhang et al. / Tetrahedron Letters xxx (2015) xxx–xxx NH 2
N3 ICT E.T.
N
N O O
N
ICT O
Tb
E.T.
H2S
O
O N
O
Tb
O
N
N
N
N
O
O O 1-NH2 Tb strong luminescence
O
O 1-N 3 Tb weak luminescence
Scheme 1. Proposed mechanism of H2S sensing by probe 1-N3Tb.
NH 2
N3
O NH HN NH HN Cyclen
t
BuO O
N
N
N
N
t
O
OtBu t
BuO
N
N
N
N
O
BuO
t
O
2
BuO 3
OtBu
O
N3
N3
O
O
HO O
N
N
N
N
OH
N O O
HO 1-N3
O
N
N Tb
O
N
O 1-N3 Tb
Figure 2. Time-gated emission spectrum (kex = 295 nm) of 1-N3Tb in the presence of different NaHS concentrations (0, 2, 4, 6, 8, 10, 12, 14, 16, 18 and 20 equiv) after 30 min. The inset figure shows that the Tb3+ luminescent intensity (545 nm) as a function of the NaHS concentrations (0–10 equiv).
O
Scheme 2. Design and synthesis of the luminescent turn-on probe 1-N3Tb for H2S.
excited state energy of the 4-azidobenzyl group which is distinguishing from that of 4-aminobenzyl, and it cannot efficiently transfer energy to Tb3+. As expected, 4-azidobenzyl is indeed a poor Tb3+ sensitizer. Here, a new lanthanide complex-based luminescent H2S probe 1-N3Tb, which possesses the 4-azidobenzyl group as the receptor unit of H2S, was designed and synthesized. It was water-soluble, and almost nonluminescent. However, upon treatment with H2S, 1-N3Tb was reduced to 1-NH2Tb, and the luminescence enhanced 12-fold accordingly (Scheme 1). Results and discussion The synthesis of ligand 1-N3 was achieved in 5 steps starting from cyclen (Scheme 2). Compound 2 was synthesized according to the reported method,13 and then was converted to compound 3 through the Sandmeyer reaction. At last, the desired ligand 1-N3 was obtained by deprotection with CF3COOH. The 1-N3Tb was prepared by mixing equivalent molar of ligand 1-N3 and Tb(NO3)3 in HEPES buffer.
With probe 1-N3Tb in hand, the optical properties were studied (Fig. 1). As shown in Figure 1, probe 1-N3Tb was weakly luminescent with low quantum yields (Absmax = 252 nm, Exmax = 250 nm, s = 0.88 ms, U = 0.24%), and the intensity of Tb3+ emission was weaker than antenna emission at 360 nm, which indicated that 4-azidobenzyl was certainly not an efficient antenna group for Tb3+. However, 1-N3Tb could convert to 1-NH2Tb (s = 1.42 ms, U = 5.26%)13 upon addition of 100 equiv of Na2S (a common source for hydrogen sulfide), in which the antenna emission gradually increased with slight blue-shift due to the block of ICT process, and the Tb3+ emission with bands at 490, 545, 586 and 622 nm apparently enhanced upon excitation at 295 nm. Moreover, Probe 1-N3Tb showed a rapid luminescent increase, finally a 12-fold turn-on response at 545 nm was observed within 60 min (Fig. 1d). Then the effect of Na2S concentration on the luminescent intensity of the probe was investigated. The intensity at 545 nm was linearly proportional to the Na2S concentration with R2 = 0.9968 (Fig. S1, Supplementary data), which indicated the probe had potential in quantitative analysis for H2S. However, 1-N3Tb seemed to be not sensitive for H2S since showed large luminescence enhancement toward 100 equiv Na2S within 60 min (Fig. 1d), Actually, when NaHS was used to work as H2S source instead of Na2S, the reaction of probe 1-N3Tb with 20 equiv NaHS was almost completed within 30 min (Fig. S2, Supplementary data). Thus probe 1-N3Tb was sensitive and useful for luminescent detection of H2S. Further a typical time-gated titration of 1-N3Tb toward H2S was evaluated. As shown in Figure 2, the probe could efficiently work the concentration of NaHS from 10 lM up to 100 lM. Moreover, the auto-fluorescence from antenna of the sample with short lifetime could be efficiently gated out. In order to embody the advantage of long lifetime of the probe, a comparison experiment was performed (Fig. S3, Supplementary data). To HEPES solution
Figure 1. Optical spectra of 1-N3Tb: (a) absorption spectrum; (b) excitation spectrum (kem = 545 nm); (c) emission spectrum (kex = 295 nm); (d) emission spectra as a function of time in the presence of 100 equiv of Na2S (data were collected every 5 min).
Please cite this article in press as: Zhang, K.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.04.012
K. Zhang et al. / Tetrahedron Letters xxx (2015) xxx–xxx
3
photo-resistance. These results revealed that the probe would have the potential to detect H2S in complex biological systems both qualitatively and quantitatively. In summary, we have designed and developed a Tb3+ complexbased luminescent turn-on probe for H2S based on the reduction reaction of azide with H2S to amine. The probe can respond H2S with high selectivity and sensitivity with large luminescence enhancement. Moreover, the probe, presenting long lifetime, large stokes shift, good water-solubility, and photo-resistance, facilitates the accurate detection of H2S in biological samples with time-gated detection mode. Acknowledgements
Figure 3. Selectivity of 1-N3Tb for H2S versus other species. Data were acquired as the Tb3+ intensity at 545 nm after 60 min. 1, probe alone; 2, F ; 3, Cl ; 4, Br ; 5, I ; 6, N3 ; 7, OH ; 8, HCO3 ; 9, AcO ; 10, H2PO4 ; 11, HPO24 ; 12, SO24 ; 13, HSO4 ; 14, HSO3 ; 15, GSH; 16, Cys; 17, Hcy; 18, 20 equiv NaHS within 30 min; 19, 100 equiv Na2S within 60 min.
This work is financially supported by the National Natural Science Foundation of China (Grant Nos. 21431002 and 91122007) and the Specialized Research Fund for the Doctoral Program of Higher Education of China (Grant No. 20110211130002). Supplementary data
of 1-N3Tb was added fluorescent compound 8-benzothiazole-7hydroxy-4-methylcoumarin (BHMC),15 the emission of 1-N3Tb was barley observed in the steady spectrum; by contrast, timegated luminescence emission was barely affected by the fluorescent compound. All these results suggested that the time-gated luminescence detection of the probe toward H2S could be more precise, not influenced by the background noises caused by fluorescent compound with short lifetime. In order to study the specificity toward H2S, the probe 1-N3Tb was treated with various biological species (100 equiv), including small-molecule biothiols (Cys, Hcy, GSH) and common inorganic anions. As is shown in Figure 3, only H2S could trigger obvious luminescent intensity enhancement, while others exhibited negligible responses. Besides, the luminescent intensity of the probe 1-N3Tb scarcely declined even upon addition of 100 equiv various anions. If DO3A is displaced by other excess anions, we could expect the Tb3+ luminescent intensity apparently decreases since the antenna cannot efficiently transfer energy to lanthanide center, so DO3A could act as a strong lanthanide chelator for design reaction-based anion probe. The photostability of probe 1-N3Tb was also evaluated since it is particularly crucial in the biological application.14 After the probe was exposed to light irradiation with a UV lamp (254 or 365 nm) for 60 min, the luminescent intensity of Tb3+ had almost no changes (Fig. 4), showing that the probe had good
Figure 4. Photostability of 1-N3Tb under light irradiation with a UV lamp. Data were acquired as the Tb3+ intensity at 545 nm, and the exposure time was 0, 10, 20, 30, 40, 50 and 60 min, respectively.
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Please cite this article in press as: Zhang, K.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.04.012