Boronic Acid Functionalized Boron Dipyrromethene Fluorescent

Article pubs.acs.org/ac

Boronic Acid Functionalized Boron Dipyrromethene Fluorescent Probes: Preparation, Characterization, and Saccharides Sensing Applications Jingying Zhai,† Ting Pan,† Jingwei Zhu, Yanmei Xu, Juan Chen,‡ Yuanjie Xie, and Yu Qin* State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China, 210093 S Supporting Information *

ABSTRACT: Fluorescent probes based on boron dipyrromethene functionalized with a phenylboronic acid group (BODIPY−PBAs) were synthesized in high yield for the first time by Suzuki coupling of bis(pinacolato)diboron and 8-(4bromophenyl)-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4adiaza-s-indacene (BODIPY). Wavelength tuning of the fluorophores was achieved by attaching an auxochromic substituent to the 5-position of the BODIPY core structure through Knoevenagel condensation. The emission intensity of fluorophores increases when binding to the analytes with diol groups and forming boronic esters at fixed pH. These compounds can detect monosaccharides in the concentration range of 0.1−100 mM. Whereas glycogen was found to quench the fluorescence of BODIPY−PBAs in an aqueous solution due to the self-quenching of the fluorophores after attaching in the extensively branched and compact glucose polymer, further addition of D-fructose to the solution can release the fluorophores from the polymer and the fluorescence regains. The BODIPY−PBA fluorophore has been applied in polymeric optodes containing anion exchangers to perform repetitive measurement. Such sensors respond to different monosaccharides in the range of 0.1−100 mM and demonstrate an improved selectivity toward D-fructose over other saccharides, compared to the results obtained from homogeneous assay.

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group while the anionic form acts as an electron-donating group. In order to design an optical sensor for saccharide sensing with boronic acid, the photochemical properties of the dye should be switched on or off upon interaction with the analyte. Sandanayake and Shinkai reported the internal charge-transfer (ICT) types of colorimetric sensors for saccharides based on the intramolecular interaction between the tertiary amine and the boronic acid group using a UV−vis absorption method in 1994.7 At the same time, fluorescence measurement became one of the most sensitive and available detection methods for saccharides based on molecular rigidification,8,9 photoinduced electron transfer (PET),10,11 or excited-state charge transfer (CT) mechanisms.12 Yoon and Czarnik first reported an anthracene compound modified with a boronic acid as receptor for saccharide sensing.10 Wulff recognized that a benzylic amine at the ortho position of phenylboronic acid (PBA) allowed for B−N bond formation.13 Cooper and James investigated factors that influenced the B−N strength after saccharides bound to boronic acids.14 More recently, Yang et al. used the influence of

accharides, including monosaccharide, disaccharide, oligosaccharide, or polysaccharide, are part and parcel of living cells and a source of energy for animals so that the detection of saccharides has attracted considerable interest in diagnostic analysis, food technology, and biological science.1 One of the most successful and historically significant electrochemical approaches for monitoring saccharides is based on the enzymatic electrodes which have been under development since the 1960s,2 whereas chemosensors for sugar signaling involving fluorescent dyes and chelator groups have gained more and more attention in the last few decades.3,4 Especially, the stable boronic acid based saccharide receptors have been used to create saccharide sensors because boronic acids are electron deficient Lewis acids having an sp2-hybridized boron atom with a planar trigonal conformation under its neutral form that can rapidly and reversibly react with 1,2 or 1,3 diols of carbohydrates to form five- or six-membered cyclic esters in nonaqueous or basic aqueous media.5,6 The complexation leads to a decrease of the pKa value and induces the formation of the anionic form of the boronic group at a specific pH. The anionic form of the boron group is electron-rich and possesses an sp3hybridized boron atom with a tetrahedral conformation. When the boronic acids are conjugated with fluorophores, the neutral form of the boron group may act as an electron-withdrawing © 2012 American Chemical Society

Received: May 27, 2012 Accepted: November 9, 2012 Published: November 16, 2012 10214

dx.doi.org/10.1021/ac301456s | Anal. Chem. 2012, 84, 10214−10220

Analytical Chemistry

Article

Figure 1. Schemes for the syntheses of 2b and 4b.

dehyde, and other synthetic reagents and solvents were purchased from Sigma-Aldrich (Switzerland). High molecular weight poly(vinyl chloride) (PVC), anion-exchanger tridodecylmethylammonium chloride (TDMACl), bis (2-ethylhexyl) sebacate (DOS), 2-nitrophenyl octyl ether (NPOE), and tetrahydrofuran (THF) were purchased from Fluka (Switzerland). Sodium phosphate dibasic anhydrate, sodium phosphate monobasic monohydrate, sodium hydroxide, D-glucose, Dfructose, D-(+)-galactose, D-sorbitol, and glycogen were obtained from Sangon (Shanghai, China). All aqueous solutions were prepared by dissolving the appropriate salts or diluting standard solutions as specified in nanopure-purified (18.2 MΩ·cm) deionized water. Phosphate buffer solutions were prepared from 10−3 M sodium phosphate dibasic, adjusted with 10−2 M NaOH to the desired pH. All saccharides were dissolved in phosphate buffer solution. The preparation of BODIPY−PBA derivatives 2b and 4b is depicted in Figure 1; the syntheses and characterizations have been described in detail in the Supporting Information. A Shimadzu RF-5301PC fluorescence spectrometer and Thermo Scientific Varioskan Flash spectral scanning multimode reader were used for fluorescence measurements in homogeneous assay and membrane phase. The pH was monitored with a calibrated glass pH electrode (Sartorius PB-10). Homogeneous Measurements. Fluorescent boronic acids 2a, 2b, 4b were dissolved in ethanol with all 1 μM concentration for homogeneous fluorescence detection using a Shimadzu RF-5301PC fluorescence spectrometer; the maximum excitation and maximum emission wavelengths of 2a, 2b, and 4b are as follows: 2a λex = 490 nm, λem = 502 nm; 2b λex = 493 nm, λem = 510 nm; 4b λex = 564 nm, λem = 580 nm (excitation slit width, 3 nm; emission slit width, 1.5 nm; scanning speed, 3000 nm/min).

the B−N strength to develop a series of diboronic acid compounds to label cells based on cell surface carbohydrate structures.15 Shinkai’s and Wang’s groups have reported ICT fluorescent sensors for saccharides.16,17 Another study based on the disruption of an ion-pair interaction between poly(phenylene ethylene) and a boronic acid functionalized benzyl viologen derivative has been reported by DiCesare et al. for saccharide detection.18 One of the key requirements for establishing robust fluorescence sensing systems is a strong, reversible, and sufficiently rapid response over the concentration range of interest. This requires the optimization of fluorophore properties including large absorption coefficients, high quantum yield (typically, QY > 0.1) upon binding of analytes, suitable excitation and emission wavelengths to minimize the background signal, and good chemical and photostability. Various chromophores and fluorophores have been conjugated with boronic acid;3 however, dipyrromethene boron difluoride (BODIPY)-based boronic acid probes are rarely seen.19 BODIPY dyes are well-known to be highly fluorescent, very stable, having narrow emission bandwidths and amenable to structure modification.20 At the same time, very few lipophilic polymer membrane sensors have been reported21 for boronic acid based saccharides detection, although such membranes have been widely utilized for operative extraction of saccharides from aqueous solutions.22 In this work, we developed the new synthetic route to obtain BODIPY−PBA derivatives with different emission wavelengths in high yield. Such probes have been fully characterized and applied in homogeneous assay and polymeric optical sensors for detection of monosaccharides and glycogen.

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EXPERIMENTAL SECTION Reagents and Instrumentation. 4-Bromobenzaldehyde, 2,4-dimethylpyrrole, bis(pinacolato)diboron, 4-methoxybenzal10215



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for acid catalysis, which led to a much reduced reaction time (within 1 h) compared to the reaction catalyzed with acetic acid. Similar to other BODIPY fluorophores, compounds 2b and 4b exhibited high quantum yields and were relatively insensitive to solvent polarity. The quantum yield of 2b in ethanol is 0.37 (using fluorescein as a standard), and the quantum yield of 4b was calculated to be 0.25 (using rhodamine B in ethanol as a standard). The emission wavelength of these compounds is slightly red-shifted in less polar dichloromethane than in the polar solvent acetonitrile. As shown in Figure 2, due to

For glycogen detection, 2b in ethanol (1.6 mM) was diluted with pH 9.0 phosphate buffer solution to obtain 5 μM 2b solutions. The different concentrations of glycogen buffer solution (pH 9.0) were mixed with the above solution, respectively. After 20 min, the mixture was transferred into a quartz cuvette for fluorescence measurement using a Shimadzu RF-5301PC fluorescence spectrometer (λex = 450 nm, λem = 510 nm; excitation slit width, 5 nm; emission slit width, 5 nm; scanning speed, 3000 nm/min). For the pH response, 10−4 M 2b in ethanol was diluted by different pH values of phosphate buffer solutions to obtain 1 μM BODIPY−PBA solution. For the saccharides detection, 10−3 M 2b was dissolved in ethanol and then diluted with different amounts of monosaccharides which were prepared by pH 9.0 phosphate buffer solution to obtain 2.3 × 10−6 M BODIPY−PBAs. Preparation and Measurements of Polymeric Optodes. A total amount 100 mg of mixture containing 5 mmol/kg BODIPY−PBA, 2.5 mmol/kg TDMACl, PVC, and the plasticizer DOS or NPOE (1:2 by weight) was prepared and dissolved in 1 mL of THF. After complete dissolution, these cocktails were then uniformly dispensed (5 μL/well) into each U-bottomed microwell of polypropylene plate. The plates were air-dried in a dust-free vessel for at least 4 h prior to use. In all measurements, the excitation wavelength was chosen at 450 nm and the emission wavelength was at 536 nm. All membranes inside the wells were conditioned with pH 9.0 buffer solution until the polymer film-coated wells had stable fluorescence intensities.

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RESULTS AND DISCUSSION Boron dipyrromethane dyes are usually produced from commercially available pyrrole-based starting materials. The target probe 2b can be synthesized from condensation of 2,4dimethyl-1H-pyrrole and 4-formylbenzeneboronic acid that is obtained from 4-bromobenzaldehyde.23 However, the boronic acid substituted benzaldehyde has low reactivity and boronic acid groups tend to bind to silica gel, which makes the separation extremely difficult. Alternatively, protected 4formylphenylboronic acid with less polarity was used to simplify the separation step, but the reaction yield is comparatively low due to the electron-donating property of boronic ester.19 In this work, we first prepared 8-(4bromophenyl)-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4adiaza-s-indacene 1 according to the literature,24 followed by conversion of bromide to phenyl boronic ester through Suzuki coupling in high yield (93%) as shown in Figure 1. It was found that the hydrolysis of BODIPY−boronic acid ester using conventional methods with only HCl was unsuccessful due to the presence of the relatively large BODIPY structure. By adding sodium periodate in HCl solution or using diethanolamine, the yield of hydrolysis reaction improved up to 90%. BODIPY dyes with absorption and emission in the visible or near-infrared range are more favorable.20 The methods to tune the fluorescence emission of the dye to longer wavelength include the attachment of strong electron-donating groups to the core structure,25 rigidifying the core structure of the dye molecules26, and extending conjugation of the system.27 Here compound 3 was synthesized by adding an auxochromic substituent to the 5-position of the BODIPY core structure through Knoevenagel condensation as shown in Figure 1. We used a microwave reactor instead of the traditional Soxhlet extractor to provide a more efficient dehydration condition. At the same time, 4-methylbenzenesulfonic acid (TsOH) was used

Figure 2. Fluorescence spectra of 1 μM 2a, 2b, and 4b in ethanol; the maximum excitation and maximum emission wavelengths of 2a, 2b, and 4b are 2a λex = 490 nm, λem = 502 nm; 2b λex = 493 nm, λem = 510 nm; 4b λex = 564 nm, λem = 580 nm.

conjugation extending of the BODIPY core the fluorescence excitation and emission wavelengths of 4b are red-shifted compared with 2b in ethanol. The maximum excitation and emission wavelengths of 4b are 564 and 580 nm, respectively, while compound 2b has been excited and emits at 493 and 510 nm in the same solvent. Figure 3 shows the pH response of 2b; the fluorescence intensity increases when the sample becomes more basic. The pKa values of 2b and 4b determined from the pH calibration curves are 10.1 ± 0.15 (Figure 3) and 10.4 ± 0.03 (Supporting Information Figure S1). The values are higher than the ones of unsubstituted phenyl boronic acid, which is mainly due to the attachment of the BODIPY structure.28 In the BODIPY−PBA structure, appending the phenyl boronic acid at the meso position of the BODIPY fluorophores decouples the two subunits because of the almost perpendicular arrangement between the fluorophores and phenyl ring. Trisubstituted boron atom has an sp2 trigonal planar geometry with an empty p orbital that makes the boronic acid an electron acceptor. Obviously, the electron-withdrawing capability of the phenyl boronic acid is moderate, since both 2b and 4b demonstrate relatively high quantum yields. The fluorescence lifetime of 2b was measured to be 3.27 ns in ethanol (Supporting Information Figure S17), and the lifetime of the BODIPY core is 5.45 ns in 10216



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Figure 3. pH response of 2b (1 μM in ethanol−H2O): λex = 450 nm, λem = 510 nm; error bars indicate standard deviation (n = 5).

Figure 4. Fluorescence emission spectra of 2b (2.3 μM) with different concentrations of D-fructose at pH 9.0; λex = 450 nm, λem = 510 nm.

ethanol.29 It has been reported that the PET process leads to the decrease of fluorescence lifetime.30 Furthermore, the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) energy of the phenylboronic acid and BODIPY core (Supporting Information Figure S16) calculated from the cycle voltammogram were EHOMO (phenylboronic acid) = −8.31 eV, ELUMO (phenylboronic acid) = −3.88 eV, EHOMO (BODIPY) = −5.82 eV, ELUMO (BODIPY) = −2.97 eV. The results showed that the LUMO energy level of phenyl boronic acid is slightly lower than the LUMO energy level of the BODIPY, which leads to an indistinct PET process. When OH− attaches to boron, the boronic acid begins a transition to its corresponding anionic tetrahedral species, which makes the subunit electron-rich. The change increases the LUMO energy level of the phenyl boronic acid and further suppresses the PET process from BODIPY to the chelator so that the fluorescence enhancement has been observed. Boronic acids can form compounds with 1,2 or 1,3 diols to produce five- or six-membered cyclic esters in nonaqueous or basic aqueous media, and the cyclic esters dissociate when the medium is changed to acidic pH. The complexation of boronic acids with diol groups is usually more preferred in basic solution. In this work, pH 9.0 buffer solutions were used due to the better sensitivity of 2b toward diols at pH 9.0 than at pH 7.4 (Supporting Information Figure S5). When the concentration of D-fructose changed from 0.1 to 100 mM in pH 9.0 buffer solution containing 2b, the fluorescence intensity increased accordingly as shown in Figure 4. Similar results were observed for other monosaccharides including D-sorbitol, D-(+)-galactose, and D-glucose, as demonstrated in Figure 5. It has been reported that, upon formation of boronic ester, the fluorescence intensity decay remains monoexponential for the complex, but with a longer fluorescence lifetime.19 At the same time, the process of boronic acid changing to cyclic boronic ester decreases the pKa value and induces the equilibrium to the direction of formation of anionic cyclic boronic ester that is electron-rich. When the phenylboronic acid is conjugated with a BODIPY, the neutral form of the

Figure 5. Fluorescence intensity changes of 2b (2.3 μM) as a function of different saccharide concentrations in 0.001 M phosphate buffer solution at pH 9.0; λex = 450 nm, λem = 510 nm: (◆) D-fructose; (●) D-sorbitol; (▲) D-(+)-galactose; (■) D-glucose; error bars indicate standard deviation (n = 5).

boron group acts as an electron-withdrawing group, while the anionic form acts as an electron-donating group.31 Similar to the pH response, by increasing the concentration of the monosaccharides, more anionic cyclic boronic ester will be produced, and therefore the fluorescence intensity is enhanced. The association constants orders for phenylboronic acid with different monosaccharides are D-sorbitol > D-fructose > D(+)-galactose > D-glucose.32 The larger the association constant, the more stable the anionic boronic ester. Sorbitol and fructose are both capable of binding with boronic acid to form a tridentate compound, which gives higher affinity than other saccharides.33 The sequence of the association constants of 2b with different monosaccharides are D-fructose (297 M−1) 10217



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> D-sorbitol (262 M−1) > D-(+)-galactose (31 M−1) > D-glucose (29 M−1) in solution at pH 9.0. BODIPY−PBA derivatives exhibited fructose selectivity over other monosaccharides. Similarly, the probe 4b responded to D-fructose and D-sorbitol in the range of 1−100 mM and showed almost no response to D-(+)-galactose and D-glucose in homogeneous solutions (Supporting Information Figure S3). Both 2b and 4b showed selective response to fructose in the presence of interfering monosaccharides (glucose, galactose, and sorbitol) as shown in Supporting Information Figures S9 and S11. The relatively narrower response range of 4b might be due to its weaker complexation with monosaccharides as shown in Supporting Information Table S1. Considering its higher affinity to diols, 2b was chosen for the following experiments. Glycogen is an extensively branched and compact glucose polymer that serves as the secondary long-term energy storage in animal and fungal cells, with the primary energy stores being held in adipose tissue. The routine approach for glycogen detection is to use the periodic-acid-Schiff (PAS) reaction which is originally described by MacManus in 1948.34,35 Other methods such as incorporation of radioisotopes,36,37 immunocytochemistry, 38 or quantification of glucose after the hydrolysis of glycogen39 are widely used for analyses of glycogen. Nevertheless, few fluorescent approaches were reported to directly measure the glycogen. In this work, when adding glycogen into 2b solution, we observed fluorescence quenching in the glycogen concentration range from 0.39 to 6.60 mg/mL, which is completely opposite to the response toward monosaccharides, as shown in Figure 6. Due to the

Utilization of polymer-based optical sensors offers several advantages over homogeneous assay, especially for noninvasive continuous monitoring. In this work, BODIPY−PBAs were constructed into a bulk film to form an optical sensor for detecting various monosaccharides. The sensing film contains fluorescent probe 2b, TDMACl as anion exchanger, PVC and plasticizer as the membrane solvent. Polar plasticizer NPOE rather than nonpolar DOS results in a better response to saccharides, because the polar plasticizer can facilitate transporting saccharides from the aqueous phase to membrane phase.22 Due to the higher concentration of the probes and the hydrophobic nature of the membrane, the fluorescence of the membrane is stronger than in the homogeneous assay. It is expected that the saccharides extracted into the membrane phase form the anionic BODIPY−PBA−diol complexes that are ion-paired with TDMA+ in the membrane (Scheme 1). A Scheme 1. Complexation of Diols with BODIPY−PBA Formed Ion Pair with TDMA+

severe leaching of the dye was observed when the lipophilic membranes containing only BODIPY−PBA, but without cationic sites, were immersed in basic or high-concentration saccharide solution. Similar to homogeneous assay, the response of the polymeric sensor toward different monosaccharides was studied in pH 9.0 buffer solution due to the better sensitivity at pH 9.0 than at pH 7.4 (Supporting Information Figure S6). The fluorescence enhancement was observed in monosaccharide solutions from 0.1 to 100 mM as shown in Figure 7. The proposed sensor exhibited selective response to fructose in pH 9.0 buffer solution. The detection limit of 2 × 10−4 M for fructose was obtained from the cross section of the two extrapolated linear calibration curves in Supporting Information Figure S6.41 It was found that the response of the membrane sensor exhibited an unusual fluorescence decrease at 10 −4 to 10 −3 M for some monosaccharides. When the concentration was higher than 10−3 M, the fluorescence intensity gradually increased, and similar results were also observed for 4b-based film (Supporting Information Figure S4). It is possible that, after soaking the membrane containing neutral dye (1) and anion exchanger TDMACl in pH 9 buffer solutions, the OH− was exchanged by Cl− into the membrane and attached to boron (1 → 3 in Scheme 1); some portion of boronic acid dyes became anionic tetrahedral species 3 which are ion-paired with TDMA+. The boronic acid subunit is electron-rich in anionic tetrahedral structure, which increases the LUMO energy level of the phenyl boronic acid and suppresses the PET process from BODIPY to the chelator so that the fluorescence enhancement of 3 compared to 1 has been observed as shown in Figure 3. The fluorescence of the membrane increased after conditioning in

Figure 6. Fluorescence emission spectra of 2b (5 μM) in different concentrations of glycogen buffer solution at pH 9.0, and the effect of D-fructose addition on the fluorescence spectrum of 2b−glycogen solution; λex = 450 nm, λem = 510 nm.

large amount of binding sites in glycogen and its extensively branched and compact structure, BODIPY−PBAs bound to glycogen in close proximity could be self-quenched.40 When Dfructose was added into 5 μM 2b solution containing 0.98 mg/ mL glycogen, the fluorescence regained, because fructose competes with glycogen and releases BODIPY−PBA into the solution. 10218



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The sensors also showed excellent reversibility, reproducibility, and relatively fast response within 20 min by switching fructose concentration between 10−2 and 10−1 M and monitoring the fluorescence intensity at 536 nm as shown in Figure 8. These results confirmed that no BODIPY−PBA was

Figure 7. Selectivity of the PVC−NPOE film containing 5 mmol/kg 2b and 2.5 mmol/kg TDMACl toward different saccharides in 10−3 M phosphate buffer solution at pH 9.0; λex = 450 nm, λem = 536 nm: (◆) D-fructose; (●) D-sorbitol; (▲) D-(+)-galactose; (■) D-glucose; error bars indicate standard deviation (n = 5). Figure 8. Response time curve of the PVC−NPOE film in the alteration of the 10−2 M D-fructose and 10−1 M D-fructose in pH 9.0 phosphate buffer solution; λex = 450 nm, λem = 536 nm.

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buffer. In the 10 M saccharides solution, the small amount of diols extracted into the membrane react preferably with anionic boronic acid 3 rather than with neutral dye 1 because of the larger reaction constant (K2 > K1),32 and then form ester 4. The electron density in the boronic acid subunit of the ester 4 is less than 3 due to the distribution of electron over the carbon atoms, which results in slight decrease of fluorescence emission. At relatively high concentration the diols react with neutral dyes and form esters, increasing the fluorescence. Due to the larger apparent association constant, we did not observe the fluorescence decrease for fructose at 10−4 M. Compared to the homogeneous assay, the selectivity of the optical membrane toward fructose was improved. In solution the association constants of 2b with D-sorbitol (K = 262 M−1) and D-fructose (K = 297 M−1) were quite close, and response difference between the two analytes was limited. In the optode, the apparent association constant of 2b with D-fructose (K = 88 M−1) is over 4 times the values for D-sorbitol (K = 20 M−1), D(+)-galactose (K = 23 M−1), and D-glucose (K = 8 M−1), although the complexation in membrane phase is generally weaker than in the solution (Supporting Information Table S1). It was found that the 4b-based optode exhibited responses to different monosaccharides in the range of 1−100 mM as shown in Supporting Information Figure S4, which corresponded well to the apparent association constants determined in Supporting Information Table S1. Our results suggest that the discrimination of different monosaccharides not only depends on the binding constant of the receptor with saccharides but also relates to the distribution constant of various analytes between the organic phase and aqueous phase. Consequently, the selectivity pattern of the polymeric optodes is different from the one of homogeneous assay. Such optodes can perform reliable measurements of fructose in the presence of interfering monosaccharides (Supporting Information Figures S10 and S12).

leaching from the membrane to the aqueous phase since the quaternary ammonium was the lipophilic countercation that can stabilize anionic BODIPY−PBA in the membrane phase and suppress the leaching process.

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CONCLUSIONS In summary, we have developed a new synthetic route to prepare boronic acid functionalized boron dipyrromethene fluorescent probes with tunable wavelength in high yield. The optical responses of BODIPY−PBAs to pH and monosaccharides have been studied in detail. Such probes have been used to directly monitor 0.39−6.60 mg/mL concentration of glycogen in the homogeneous phase for the first time. Furthermore, reusable polymeric optodes based on BODIPY−PBA probes have been fabricated to perform monosaccharide measurements in the linear range of 0.1−100 mM with 2 × 10−4 M detection limit for fructose. The proposed sensors exhibited good reproducibility and photostability with less than 1% signal change after three measurement cycles in solutions of different fructose concentrations and a relatively fast response time of within 20 min.

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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

*E-mail: [email protected]. Phone: +86(25) 83592562. Fax: +86(25) 83592562. 10219



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Present Address

(33) Yan, J.; Fang, H.; Wang, B. Med. Res. Rev. 2005, 25, 490−520. (34) McManus, J. F. A. Biotech. Histochem. 1948, 23, 99−108. (35) Schaart, G.; Hesselink, R. P.; Keizer, H. A.; Kranenburg, G. V.; Drost, M. R.; Hesselink, M. K. C. Histochem. Cell Biol. 2004, 122, 161−169. (36) Agbanyo, M.; Taylor, N. F. Biosci. Rep. 1986, 6, 309−316. (37) Fernández-Novell, J. M.; López-Iglesias, C.; Ferrer, J. C.; Guinovart, J. J. FEBS Lett. 2002, 531, 222−228. (38) Graf, R.; Klessen, C. Histochem. Cell Biol. 1981, 73, 225−232. (39) Carr, R. S.; Neff, J. M. Comp. Biochem. Physiol., Part B: Biochem. Mol. Biol. 1984, 77, 447−449. (40) Wu, J. H.; Diamond, S. L. Anal. Biochem. 1995, 224, 83−91. (41) Bakker, E.; Bülmann, P.; Pretsch, E. Chem. Rev. 1997, 97, 3083− 3132.

‡

PharmaBlock (Nanjing) R&D Co., Ltd., 10 Xuefu Road, Nanjing Hi-Tech Zone, Nanjing, China, 210061. Author Contributions †

These authors contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (Nos. 21135002, 21075062, and 21121091).

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Boronic Acid Functionalized Boron Dipyrromethene Fluorescent

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