Selective glucose recognition by boronic acid azoprobe/γ-cyclodextrin complexes in water

Article abstract of DOI:10.1039/b819938h

The phenylboronic acid azoprobe (BA-Azo)/γ-cyclodextrin (γ-CD) complex exhibits a selective response for d-glucose by forming a supramolecular 2: 1 inclusion complex of the azoprobes with d-glucose inside the γ-CD cavity. The Royal Society of Chemistry.

Full text of DOI:10.1039/b819938h

Chemical Communications
www.rsc.org/chemcomm
Number 13 | 7 April 2009 | Pages 1585–1780
ISSN 1359-7345
COMMUNICATION
Takashi Hayashita et al.
FEATURE ARTICLE
Peter M. Maitlis and Valerio Zanotti
Selective glucose recognition by
boronic acid azoprobe/γ-cyclodextrin The role of electrophilic species in the
complexes in water
Fischer–Tropsch reaction

COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Selective glucose recognition by boronic acid azoprobe/c-cyclodextrin
complexes in waterwz
Chie Shimpuku,a Rimiko Ozawa,a Akira Sasaki,a Fuyuki Sato,a Takeshi Hashimoto,a
Akiyo Yamauchi,b Iwao Suzukic and Takashi Hayashita*a
Received (in Cambridge, UK) 7th November 2008, Accepted 5th January 2009
First published as an Advance Article on the web 27th January 2009
DOI: 10.1039/b819938h
The phenylboronic acid azoprobe (BA-Azo)/g-cyclodextrin
(g-CD) complex exhibits a selective response for D-glucose by
forming a supramolecular 2 : 1 inclusion complex of the
azoprobes with D-glucose inside the g-CD cavity.
Herein, we report the first success in the design of a
supramolecular phenylboronic acid azoprobe/g-CD complex
for D-glucose recognition in water. The sensor represents the
2 : 1 inclusion complex formation of the azoprobes with g-CD
in the presence of D-glucose depending on the azoprobe
structure. B-Azo and BA-Azo were synthesized as simple
structures of the phenylboronic acid azoprobe. Interestingly,
only BA-Azo exhibited D-glucose selectivity in water. The
structure of BA-Azo has a benzamide spacer in addition to
B-Azo. This difference in only a part of the spacer was found
to greatly affect the D-glucose selectivity.
Sugars are essential biological molecules as regards nutrition,
metabolism, and cell structure, and they play elemental
roles in controlling an individual’s birth, differentiation and
immunity.1 In this context, the development of a selective and
sensitive method for in vivo sugar recognition has been an
important subject. Although enzyme-based sensors are highly
selective and efficient, there are some problems from the aspect
of durability, continuous monitoring, and in vivo analysis.2
In contrast, chemical sensors based on boronic acid have
attracted much attention because of their greater stability.3
Phenylboronic acids form stable cyclic esters with diol moieties
of sugars in aqueous solution.4 However most monophenyl-
boronic acids exhibited D-fructose selectivity.5 Due to the
importance of D-glucose in diabetes management and fermen-
tation processes, much attention has been paid to the design of
glucose selective probes.6
In the pioneering studies of Shinkai7 and Norrild,8 some
diboronic acids have been shown to exhibit D-glucose
selectivity.9 Two boronic acids possessing the proper spatial
positioning can selectively form a 2 : 1 complex with D-glucose.
Wang and co-workers have reported a dianthracene-boronic
acid probe that exhibited high D-glucose selectivity with the
greatest fluorescence intensity change.10 However the precise
design of bisboronic acid probes often causes a decrease in
water solubility. As a versatile design approach to form
supramolecular 2 : 1 complexes of boronic acids with
D-glucose,11 we have been investigating various types of
phenylboronic acid/g-cyclodextrin (g-CD) complexes, because
g-CD can accommodate two phenylboronic acid probes and
they may catch D-glucose with a high D-glucose selectivity.12
The azobenzene chromophores are known to exhibit a
strong induced circular dichroism (ICD) by forming an
inclusion complex with cyclodextrins (CDs) based on the
chiral nature of the CD cavities.13 This ICD response would
be affected by the dimer formation of the azoprobes inside
g-CD. In addition, an exciton interaction of the azodimer
would induce efficient spectral changes in the UV-Vis
a Department of Materials and Life Sciences, Faculty of Science and
Technology, Sophia University, Chiyoda-ku, Tokyo 102-8554, Japan.
E-mail: ta-hayas@sophia.ac.jp; Fax: +81-3-3238-3361;
Tel: +81-3-3238-3372
b Department of Biochemistry, Nara Medical University,
Nara 634-8521, Japan
c Graduate School of Pharmaceutical Science, Tohoku University,
Sendai 980-8578, Japan
w This work is dedicated to Professor Seiji Shinkai for his retirement
and 65th birthday.
z Electronic supplementary information (ESI) available: Synthesis
of B-Azo, BA-Azo, and their response behavior [Schemes S1–S2,
Fig. S1–S4]. See DOI: 10.1039/b819938h
Fig. 1 (a) ICD and (b) UV-Vis spectra of B-Azo/g-CD complex,
(c) ICD and (d) UV-Vis spectra of BA-Azo/g-CD complex in 1%
DMSO–99% water (v/v) containing 3.0 mM g-CD. [Azoprobe] =
5.0 ꢀ 10ꢁ5 M (a, c), 2.5 ꢀ 10ꢁ5 M (b, d), [saccharide] = 30 mM, I =
0.1 M with NaCl, pH 10.0 adjusted by Na2CO3–HCl buffer, 25 1C.
ꢂc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 1709–1711 | 1709

absorption.13 Fig. 1 shows the ICD spectra (a and c) and the
UV-Vis spectra (b and d) of the B-Azo/g-CD complex and the
BA-Azo/g-CD complex. Both the ICD spectra (a) and UV-Vis
spectra (b) of the B-Azo/g-CD complex changed slightly in the
presence of saccharides, while those of the BA-Azo/g-CD
complex exhibited rather obvious spectral changes for
D-glucose: the split type Cotton effect from ICD spectrum (c),
and the blue shift in the maximum absorbance of UV-Vis
spectrum (d). No changes in the corresponding spectra of
BA-Azo without g-CD were observed (Fig. S1z), indicating the
importance of the nano-sized hydrophobic microenvironment
for complex formation of BA-Azo with D-glucose. In addition,
no spectral response was noted for the BA-Azo/g-CD complex
(Fig. S2z). The split type Cotton effect from the ICD spectrum
indicates the clockwise positioning of the two azo-units inside
g-CD,14 and this positioning was selectively induced by
forming the 2 : 1 complex of the azoprobes with D-glucose (c).
These results indicate that BA-Azo forms the 2 : 1 complex
with D-glucose inside g-CD (Scheme 1).8 On the other hand,
the B-Azo/g-CD is considered not to form the 2 : 1 complex.
This may be due to the relatively rigid structure of B-Azo
possessing no amide spacer unit, which inhibits a stable 2 : 1
complex formation inside g-CD.
Fig. 2 Absorbance ratio (A436/A446) of BA-Azo as a function of g-CD
concentration without saccharide (1), with 30 mM D-fructose (2), and
30 mM D-glucose (3). [BA-Azo] = 2.5 ꢀ 10ꢁ5 M in 1% DMSO–99%
water (v/v), I = 0.1 M with NaCl, pH 10.0 adjusted by Na2CO3–HCl
buffer, 25 1C.
To clarify the 2 : 1 inclusion complex formation of BA-Azo
with g-CD in the presence of D-glucose, the effect of g-CD
concentration on the absorbance from the UV-Vis spectra for
BA-Azo was examined. With an increase in g-CD concentra-
tion, the absorbance ratio (A436/A446) for BA-Azo increased in
the presence of D-glucose (Fig. 2). Based on the assumption
that the absorbance change was only induced by the formation
of a 2 : 1 complex between BA-Azo and g-CD, a curve fitting
analysis was carried out.z The results were well fitted with the
experimental results (solid line in Fig. 2), and the binding
constant for the 2 : 1 inclusion complex of BA-Azo with g-CD
Fig. 3 Changes in the UV-Vis spectra of the BA-Azo/g-CD complex
upon addition of D-glucose. Inset: absorbance ratio (A436/A446) of
BA-Azo as a function of saccharide concentration of D-glucose and
D-fructose. [BA-Azo] = 2.5 ꢀ 10ꢁ5 M in 1% DMSO–99% water (v/v),
I = 0.1 M with NaCl, pH 10.0 adjusted by Na2CO3–HCl buffer, 25 1C.
was calculated as (2.7 ꢃ 0.4) ꢀ 107
M
ꢁ2. The binding
constants without saccharide and with D-fructose were not
calculated due to their low spectral responses. Similarly the
UV-Vis spectral changes for the BA-Azo/g-CD complex upon
the addition of saccharides were examined (Fig. 3). With an
increase in D-glucose concentration, the absorbance ratio
(A436/A446) for the BA-Azo/g-CD complex increased, but with
an increase in D-fructose, only small changes were noted (inset
figure in Fig. 3). The apparent binding constant of the
BA-Azo/g-CD complex for D-glucose was determined as
(3.0 ꢃ 0.5) ꢀ 107 Mꢁ2 based on the 2 : 1 boronate ester
formation (azoprobes : D-glucose, see Scheme 1). The 1H
NMR analysis of the BA-Azo/g-CD complex in the presence
of D-glucose in 80% D2O–20% DMSO-d6 (v/v) showed the
upfield shift of the phenyl protons based on the ring current
effect by forming dimers inside g-CD (Fig. S4z). These results
strongly demonstrate that azoprobe dimers are selectively
formed inside g-CD in the presence of D-glucose. It should
be noted that the present system was only conducted at pH
10.0 due to the low solubility of BA-Azo as its acid form even
in the presence of g-CD in water. The D-glucose recognition at
physiological pH conditions is the next step to be overcome in
this study.
In conclusion, the phenylboronic acid azoprobe (BA-Azo)/
g-CD complex sensor was found to show high D-glucose
selectivity by forming a 2 : 1 inclusion complex of BA-Azo
with g-CD. It is interesting that the inclusion complex of
B-Azo, which does not have benzamide in the spacer, unlike
BA-Azo, with g-CD exhibited no D-glucose recognition.
Scheme 1 The 2 : 1 inclusion complex formation of BA-Azo with
g-CD in the presence of D-glucose.
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1710 | Chem. Commun., 2009, 1709–1711

The result demonstrates that the difference in the spacer
significantly affected the sensing function of supramolecular
g-CD complexes for D-glucose. To clarify the spacer effect of
the azoprobes and to gain further efficient sensing ability for
D-glucose as well as to realize supramolecular sensing at
neutral pH, the structural tuning of boronic acid probes are
underway in our laboratory.
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We are grateful for the support by a Grant-in-Aid
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Sports, Science and Technology, Japan and from the Toray
Scientific Foundation. We also thank Dr R. Kato (Toyohashi
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