'Click' to bidentate bis-triazolyl sugar derivatives with promising biological and optical features

Article abstract of DOI:10.1016/j.tetlet.2010.12.055

Bidentate 1-O-methyl-α-d-pyranoglucosides bearing two triazolyl α-ketoester groups on the 2,6- or 3,4-positions of sugar scaffold were efficiently synthesized via Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (click reaction) in good yields. Thes

Full text of DOI:10.1016/j.tetlet.2010.12.055

Tetrahedron Letters 52 (2011) 894–898
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
‘Click’ to bidentate bis-triazolyl sugar derivatives with promising biological
and optical features
Zhuo Song a, Xiao-Peng He a,c, Xiao-Ping Jin a, Li-Xin Gao b, Li Sheng b, Yu-Bo Zhou b, Jia Li b,
,
⇑
Guo-Rong Chen a,
⇑
a Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, Shanghai 200237, PR China
b National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes of Biological Sciences,
Chinese Academy of Sciences, Shanghai 201203, PR China
c School of Pharmacy, East China University of Science and Technology, Shanghai 200237, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Bidentate 1-O-methyl-a-D-pyranoglucosides bearing two triazolyl a-ketoester groups on the 2,6- or 3,4-
Received 7 November 2010
Revised 3 December 2010
Accepted 14 December 2010
Available online 21 December 2010
positions of sugar scaffold were efficiently synthesized via Cu(I)-catalyzed azide-alkyne 1,3-dipolar cyclo-
addition (click reaction) in good yields. These newly featured sugar derivatives displayed favorable inhib-
itory activity on protein tyrosine phosphatase 1B (PTP1B) and unexpected selective fluorescence
quenching in the presence of Ni2+
.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Click reaction
PTP1B inhibitor
Ni2+ sensor
Glycosyl bis-triazole
Bidentate O-glucoside
1. Introduction
toward the proliferation of novel functional heterocyclic glyco-ser-
ies.7,8 One of the latest fascinating successes of click-assisted sugar
chemical biology shall be the revelation of Cu-free click reaction9
in conjunction with fluorescent chemistry toward the in-vivo
labeling of living organisms, enabling spatiotemporal tracking of
their development processes by Bertozzi and co-workers.7c,10 In
addition, the modular, quick, and regioselective click chemistry
has also proven efficacious toward the combinatorial synthesis of
sugar-based bioactive compounds.7a,8a
Sugars are one of the most abundant natural ingredients, which
govern myriad biological and pathological processes.1 Considering
their functional diversity, natural abundance and high biocompat-
ibility, the versatile sugar moieties have been employed as the
essential structure for the design of various functionalized glyco-
conjugates, facilitating a multitude of practical physical, chemical
and biological studies.
For example, modified sugars could be immobilized on properly
derivatized surfaces to fabricate glycan microarrays for the elabo-
ration of carbohydrate-receptor interactions.2 Intact sugars may
participate in the glycoprotein synthesis,3a serving as a leading
precursor for lectin-directed enzyme activated prodrug therapy
(LEAPT).3b Recent studies also indicated the sugar-containing
amphiphilic glycolipids favorable as non-ionic and green surfac-
tants with low toxicity and high biodegradation.4 In addition to
these compelling functionalities, the structurally and configura-
tionally diverse sugars have fueled considerable interest as a cen-
tral scaffold for drug design.5
We have recently synthesized triazole-linked dimeric aryl C-
glycosides11a via Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycload-
dition (i.e., click reaction) as inhibitors of protein tyrosine phos-
phatase 1B,11b a negative signaling enzyme associated with type
2 diabetes, obesity, and breast cancer.12 With a continuous attempt
to prepare ‘bidentate’ sugar-based PTP1B inhibitors via click
reaction as a strategy for enhancing the binding affinity with the
enzyme target,13 we sought to synthesize chelator-like14 disubsti-
tuted glycosides based on a monosaccharide scaffold. The previ-
ously validated
a
-ketoester derivative 6 (Scheme 1)15 was used
as the primary pharmacophore, which was envisioned to be simul-
Since the definition of click chemistry by Sharpless and co-
taneously coupled on two adjacent positions (C2,6 or C3,4) of an
aryl 1-O-methyl-a-D-pyranoglucosyl ring.
workers,6 the sugar family has turned up its robust chemical ally
Furthermore, enlightened by a large number of recent investi-
gations on click-based fluorescent chemistry,16 we have tentatively
assessed the ion-sensing property of the synthesized compounds
via fluorescence spectroscopy. To our surprise, these bis-triazolyl
⇑
Corresponding authors. Tel.: +86 021 64253016; fax: +86 021 64252758.
E-mail addresses: jli@mail.shcnc.ac.cn (J. Li), mrs_guorongchen@ecust.edu.cn
(G.-R. Chen).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.055

Z. Song et al. / Tetrahedron Letters 52 (2011) 894–898
895
Table 1
Inhibitory activity of compounds 7 and 8 tested on PTP1B
a
Entry
Compound
Inhibition ratea (%)
IC50 (lM)
1
2
7
8
96.3
94.0
1.5
4.8
a
Values are means of three experiments.
sugar derivatives exhibited marked and selective fluorescence
quenching in the presence of Ni2+ over a panel of tested metal cat-
ions. We thus report here the ‘click’ synthesis, preliminary biolog-
ical activity, and unexpected optical properties of two newly
featured difunctional triazolyl O-glycosides.
2. Results and discussion
2.1. Synthesis
To achieve the triazole-linked bidentate glycosides, 2,6- or 3,4-
di-2-O-propynyl 1-O-methyl-a-D-pyranoglucosides were first pre-
pared while the -ketoester azide 6 (Scheme 1) was synthesized
a
according to a known literature report.15 Since the aryl substitu-
ents have proven crucial for PTP1B inhibition via our former
study,11b benzylated sugar alkynes were prepared. As shown in
Scheme 1, The 2,6-di-2-O-propynyl glucoside 2 were synthesized
by introducing propargyl bromide onto the 2,6-positions of 3,4-
di-O-benzyl glucoside 117a in the presence of NaH. For the prepara-
tion of benzylated 3,4-di-2-O-propynyl glucoside 5, selectively
silylated 317b was first propargylated and then followed by AcCl
promoted desilylation and O-benzylation.
The click reaction of the azide with sugar alkynes was sequen-
tially performed. However, our initial attempt toward such reac-
tion under the promotion of catalytic amount of sodium
ascorbate (VcNa, 0.4 equiv) and CuSO4Á5H2O (0.2 equiv) failed to
completely give bis-triazoles after over night stirring. This might
be ascribed to the spatial hindrance of the previously formed
monomeric triazolyl intermediates, which largely impede the fur-
ther formation of the difunctional final cycloadducts.14a We then
tended to optimize the reaction condition by increasing the cata-
lyst loading. To our delight, in the presence of 6 equiv VcNa and
Scheme 1. Reagents and conditions: (a) propargyl bromide, NaH, DMF, 0 °C to rt;
(b) (i) AcCl, MeOH, rt; (ii) BnBr, NaH, DMF, 0 °C to rt; (c) VcNa, CuSO4Á5H2O, CH2Cl2/
water, rt.
Figure 1. UV–vis and fluorescence spectra of (a) compound 7 and (b) compound 8 in MeCN.

896
Z. Song et al. / Tetrahedron Letters 52 (2011) 894–898
À
Figure 2. Fluorescence spectra of (a) compound 7 (10
various NO3 salt (40 equiv).
l
M) in CH3CN upon addition of various NO3 salt (10 equiv) and (b) compound 8 (10
lM) in CH3CN upon addition of
À
3 equiv CuSO4Á5H2O with 6 h stirring, both desired bis-triazoles 7
and 8 were achieved efficiently in good yields of 80% and 87%,
respectively (Scheme 1).19
at 265 nm and a major fluorescence emission at 409 nm (Fig. 1b) in
CH3CN.
We then tended to monitor the fluorescence changes upon
addition of the nitrate of a wide range of metal cations in MeCN,
including Na+, K+, Mn2+, Ca2+, Co2+, Ag+, Mg2+, Cd2+, Cu2+, and
Ni2+. To our surprise, upon addition of Ni2+, the fluorescence inten-
sity of both compounds 7 and 8 decreased remarkably as reflected
in their fluorescence emission spectra (Fig. 2). In contrast, other
metal cations added gave unapparent changes in fluorescence
intensity, suggesting they could act as selective fluorescence sen-
sor for Ni2+. The emission of compound 7 was almost totally
quenched by 10 equiv of Ni2+ (Fig. 2a) whereas 40 equiv of Ni2+
2.2. Biological activity
The inhibitory activity of the prepared glucosides 7 and 8 was
assayed on PTP1B via our previously developed methods.18 As
shown in both entries 1 and 2 in Table 1, the two compounds first
exhibited excellent inhibitory effect against PTP1B as reflected by
their high inhibitory rates (96% for 7 and 94% for 8). Their IC50 val-
ues were then calculated from the nonlinear curve fitting of per-
cent inhibition (inhibition (%)) vs inhibitor concentration [I] by
using the following equation: inhibition (%) = 100/{1 + (IC50/[I])k},
was required for quenching the emission of compound
(Fig. 2b), suggesting its relatively worse sensitivity.
8
where k is the Hill coefficient and were assigned to 1.5
pound 7 and 4.8
M for compound 8.18 In addition, the 2,6-disub-
stitued glucoside (entry 1) possesses more than 3.5-fold
enhanced inhibitory activity comparing to 3,4-disubstituted gluco-
side 8 reflected by IC50 values. Such biological results suggest
disubstitution on monosaccharide scaffold viable as a strategy to-
ward the development of novel enzymatic inhibitors and for the
probing of structural preference of the targeted enzyme by varying
substitution position(s).
l
M for com-
The fluorescence spectra of compounds 7 and 8 observed during
l
the titration of various concentrations of Ni2+ were then shown in
7
Figure 3. When solutions containing 10 lM of compound 7 were
gradually added with Ni2+ (0-6 equiv) in CH3CN, the fluorescence
emission (excited at 268 nm) peaked at 408 nm precipitously
dropped (Fig. 3a). Meanwhile, when solutions containing 10 lM
of compound 8 were gradually added with Ni2+ (0-40 equiv) in
CH3CN, the fluorescence intensity (excited at 265 nm) decreased
remarkably at 409 nm (Fig. 3b). In addition, the complexation
times were determined and were shown in Supplementary Fig. 1
(Supplementary data, 2.0 min for 7 (Supplementary Fig. 1a) and
1.4 min for 8 (Supplementary Fig. 1b)).
2.3. Photochemistry
Click chemistry has recently been fruitfully introduced into the
design of fluorescent ion-chemosensors due to its high regioselec-
tivity and synthetic expediency. Meanwhile, the formed triazole
group(s) may simultaneously enhance the fluorescence inten-
sity16a and/or act as an ion binding site owning to its N-rich nature.
A large number of sugar-based ion-sensors have been disclosed in
the past few years via click chemistry.16 Enlightened by these
interesting results, we envisioned our newly constructed chela-
tor-like glycosyl bis-triazoles applicable as potential metal sensors
that are optically detectable.
The optical properties of compounds 7 and 8 were first studied
by monitoring their UV–vis absorption and fluorescence spectra. As
given in Figure 1, compound 7 showed an absorption band cen-
tered at 268 nm and a major fluorescence emission at 408 nm
(Fig. 1a) while compound 8 displayed an absorption band centered
Next, for further ascertaining their selectivity toward Ni2+, the
competition experiment by adding 10 equiv Ni2+ to the competing
metal ion (10 equiv)-ligand 7 and 40 equiv Ni2+ to metal ion
(40 equiv)-ligand 8 mixtures was conducted, respectively, and
was illustrated in Figure 4. The I0/In ratio directly reflects their fluo-
rescence quenching efficiency. Clearly, in the presence of a repre-
sentative selection of alkali metal ions (Na+, K+), alkaline earth
metal ions (Mg2+, Ca2+), and transition-metal ions (Ag+, Co2+
,
Cd2+, Mn2+, Cu2+), the fluorescence intensity of both compounds 7
(Fig. 4a) and 8 (Fig. 4b) was not significantly affected (gray col-
umns). In contrast, upon successive addition of Ni2+, the emission
of compound 7 (10 equiv Ni2+) and compound 8 (40 equiv Ni2+
)
was similarly quenched (black columns) as in the case of Ni2+ alone
with compound 8 (Fig. 4b) being comparatively less interfered by
other competing metal cations.

Z. Song et al. / Tetrahedron Letters 52 (2011) 894–898
897
Figure 3. Fluorescence spectra obtained during the titration of (a) compound 7 (10
excited at 268 nm and (b) compound 8 (10
M) in CH3CN with Ni2+ ion (from top to bottom: 0, 4.0, 8.0, 12, 16, 20, 24, 28, 32, 36, 40 equiv) excited at 265 nm.
l
M) with Ni2+ ion (from top to bottom: 0, 0.2, 0.4, 0.6, 0.8, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0 equiv)
l
Figure 4. Fluorescence intensity change profiles of (a) compound 7 (10
kex = 268 nm and (b) compound 8 (10
M) at 409 nm in CH3CN with selected cations (40 equiv) in the absence or presence of Ni2+ (40 equiv), kex = 265 nm.
l lM),
M) at 408 nm in CH3CN with selected cations (10 equiv) in the absence or presence of Ni2+ (100
l
The preliminary optical spectra depicted above have thus re-
vealed an unexpected selective Ni2+-quenching property of the
bidentate bis-triazolyl glucosides prepared in this study, thus
prompting more advanced relevant studies in the future.
on the versatile sugar scaffold and such study is currently under-
way in our laboratories.
Acknowledgments
Project supported by National Natural Science Foundation of
China (Grant No. 20876045, No. 30801405), National Basic Re-
search Program of China (No. 2007CB914201), National Science &
Technology Major Project of China ‘Key New Drug Creation and
Manufacturing Program’ (No. 2009ZX09302-001), Shanghai
Science and Technology Community (No. 10410702700,
09DZ2291200) and Chinese Academy of Sciences (No. KSCX2-YW-
R-168). X.-P.H. also gratefully acknowledges the French Embassy
in Beijing, PR China for a co-tutored doctoral fellowship and his
French co-advisor Professor Juan Xie (ENS Cachan, Paris, France).
Professor Jian-Li Hua (East China University of Science and Technol-
ogy) is warmly thanked for her critical reading on the paper.
3. Conclusion
In summary, we have achieved in this study the efficient syn-
thesis of two multifunctional bidentate sugar derivatives via click
reaction. They were determined to serve as favorable PTP1B inhib-
itors, which simultaneously displayed unexpected selective fluo-
rescence quenching in the presence of Ni2+. Such newly featured
chelator-like glyco-structures may furnish new insight toward
the development of both sugar-based PTP1B inhibitors and fluores-
cent Ni2+ chemosensors. Furthermore, the ‘click-to-bidentate-su-
gar-triazole’ strategy employed here is deemed desirable for
constructing more multi-functionalized glyco-derivatives based

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Z. Song et al. / Tetrahedron Letters 52 (2011) 894–898
15. Xie, J.; Seto, C. T. Bioorg. Med. Chem. 2007, 15, 458–473.
Supplementary data
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Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.12.055.
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a
]
D = +58.0 (c 0.4, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d = 8.19–8.15 (m, 4H), 7.93 (s, 1H), 7.74 (d, 2H, J = 8.8 Hz),
7.69 (d, 2H, J = 8.8 Hz), 7.39 (d, 2H, J = 7.2 Hz), 7.35–7.22 (m, 8H), 5.02 (d, 1H,
J = 11.6 Hz), 4.99 (d, 1H, J = 8.4 Hz), 4.97 (d, 1H, J = 8.4 Hz), 4.97 (d, 1H,
J = 7.6 Hz), 4.93–4.88 (m, 2H), 4.80 (d, 1H, J = 12.0 Hz), 4.66 (d, 1H, J = 12.0 Hz),
4.53 (d, 1H, J = 12.0 Hz), 4.02 (s, 6H), 4.00–3.95 (m, 1H), 3.82 (d, 1H,
J = 10.4 Hz), 3.75 (d, 1H, J = 5.2 Hz), 3.71–3.68 (m, 2H), 3.44 (s, 3H); 13C NMR
(100 MHz, CDCl3): d = 184.1, 163.3, 146.4, 141.1, 138.8, 137.9, 132.0, 128.6,
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73.6, 70.1, 68.4, 65.9, 64.2, 55.3, 53.1; HRMS: calcd for
C45H44N6O12+H:
861.3095, found: 861.3096. Characterization of compound 8. Methyl 2-(4-(4-
((((2S,3R,4S,5R,6R)-4,5-bis(benzyloxy)-2-methoxy-6-(((1-(4-(2-methoxy-2-
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2H, J = 8.4 Hz), 8.01 (s, 1H), 7.86 (s, 1H), 7.83 (d, 2H, J = 8.8 Hz), 7.63 (d, 2H,
J = 8.8 Hz), 7.40–7.17 (m, 10H), 5.17 (d, 1H, J = 12.8 Hz), 5.09 (d, 1H,
J = 12.8 Hz), 4.87 (d, 1H, J = 11.2 Hz), 4.83 (d, 1H, J = 12.8 Hz), 4.80 (d, 1H,
J = 12.0 Hz), 4.74–4.68 (m, 3H), 4.60 (d, 1H, J = 11.2 Hz), 4.02 (s, 6H), 4.00 (t, 1H,
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J = 9.2 Hz), 3.58 (dd, 1H, J = 3.6, 9.6 Hz), 3.39 (s, 3H); 13C NMR (100 MHz,
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131.9, 131.8, 128.5, 128.4, 128.0, 127.9, 127.7, 127.4, 120.3, 120.0, 119.8, 97.7,
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45H44N6O12+H: 861.3095, found: 861.3096.
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