Facile synthesis of 1,2,3-triazole analogs of SGLT2 inhibitors by 'click chemistry'

Article abstract of DOI:10.1016/j.bmcl.2011.10.062

Novel analogs of SGLT2 inhibitors containing the 1,2,3-triazole motif were designed and synthesized for urinary glucose excretion evaluation. The C-glucosides with triazole aglycone can be easily constructed by click chemistry. Most of the synthesized compounds increased urinary glucose excretion and demonstrated inhibition of glucose transport.

Full text of DOI:10.1016/j.bmcl.2011.10.062

Bioorganic & Medicinal Chemistry Letters 22 (2012) 642–644
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Bioorganic & Medicinal Chemistry Letters
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Facile synthesis of 1,2,3-triazole analogs of SGLT2 inhibitors by ‘click chemistry’
⇑
⇑
Lan-Tao Li, Li-Fei Zhou, Yan-Jun Li, Juan Huang, Rui-Hua Liu, Bin Wang , Peng Wang
State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, 94 Weijin Road, Tianjin 300071, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel analogs of SGLT2 inhibitors containing the 1,2,3-triazole motif were designed and synthesized for
urinary glucose excretion evaluation. The C-glucosides with triazole aglycone can be easily constructed
by click chemistry. Most of the synthesized compounds increased urinary glucose excretion and demon-
strated inhibition of glucose transport.
Received 2 September 2011
Revised 14 October 2011
Accepted 19 October 2011
Available online 24 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Metabolic diseases
SGLT2
Click chemistry
Triazole
Diabetes
Diabetes prevalence throughout the world has rapidly increased
over the past decades and has become a major health issue. It is
predicted that in 2030, 439 million people worldwide will live with
diabetes.1 Type 2 diabetes is a very costly disease because of its
chronic, progressive nature, the severity of related complications,
and the medical treatment required to treat advanced stages. De-
spite lifestyle intervention and the availability of several classes
of oral antidiabetic agents and insulin, most diabetic patients are
still failing to achieve adequate glycaemic control.2 Recently,
sodium–glucose cotransporter 2 (SGLT2) inhibitors with novel
mechanism have received considerable attentions for the treat-
ment of type 2 diabetes. Inhibitors of SGLT2 can prevent reabsorp-
tion of glucose in the proximal tubule and will result in urinary
glucose loss.3 To date, dapagliflozin (Bristol-Myers Squibb),
canagliflozin (Johnson & Johnson/Mitsubishi Tanabe), ASP1941
(Astellas/Kotobuki), and BI-10773 (Boehringer Ingelheim) with
C-aryl glucosides are undergoing phase III clinical trials (Fig. 1).
It has been reported that many heterocyclic C-aryl glucosides
are potent inhibitors with indole,2a benzisothiazole, and indoli-
zine4 aglycones. Substituted 1,2,3-triazole is a very important
building block for more complex bioactive compounds, such as
Tazobactam,5 antiviral,6 anti-HIV,7 antibacterial,8 and antiallergic
agents.9 Recently, N-glucosides with tetrazole10 or triazole11 agly-
cones have been investigated for inhibition of SGLT2. In our
program to discover novel SGLT2 inhibitors, we focused on the
C-glucosides with triazole aglycon, which can be constructed easily
by copper catalyzed azide–alkyne cycloadditions (CuAACs).12
Herein, we report the synthesis and glucosuria assessment of tria-
zolylmethylaryl glucoside congeners.
The synthesis of the key alkyne intermediate is outlined in
Scheme 1. Alkyne 6 can be obtained from commercially available
2,3,4,6-tetra-O-benzyl-
Tetra-O-benzyl- -(+)-glucono-1,5-lactone
Swern oxidation of benzyl protected -glucopyranose 1 in good
D
-glucopyranose 1 in five steps.13 2,3,4,6-
D
2 was prepared by
D
yield (93%). Trimethylsilylacetylene was deprotonated with n-BuLi
and treated with lactone 2 to provide ketose 3. The anomeric iso-
mers 3 can be confirmed by the 1H NMR spectrum of crude prod-
uct. The free hydroxyl group was reduced and the trimethylsilyl
group can be removed easily by stirring in a mixture of NaOH,
methanol, and dichloromethane, yielding the benzyl protected
alkyne 5. In our initial work, alkyne 5 and azides were used directly
to construct triazole aglycon by click chemistry. However,
Cl
OEt
F
O
O
S
HO
HO
HO
HO
OH
OH
OH
OH
Dapagliflozin
Canagliflozin
F
Cl
O
O
O
O
S
HO
HO
HO
HO
OH
OH
OH
OH
⇑
Corresponding authors. Tel.: +86 22 23506290; fax: +86 22 23507760.
E-mail addresses: wangbin@nankai.edu.cn (B. Wang), pwang@nankai.edu.cn
ASP1941
BI-10773
(P. Wang).
Figure 1. Representative SGLT2 inhibitors.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.10.062

L.-T. Li et al. / Bioorg. Med. Chem. Lett. 22 (2012) 642–644
643
OBn
OBn
OBn
Si
O
O
O
a
b
BnO
BnO
BnO
BnO
BnO
BnO
OH
OBn
OBn
OH
OBn
O
1
2
3
c
OAc
OBn
OBn
Si
O
O
d
O
e
AcO
AcO
BnO
BnO
BnO
BnO
OAc
OBn
OBn
6
5
4
Scheme 1. Synthesis of key alkyne 6 (a) DMSO, Ac2O, rt; (b) trimethylsilylacetylene,
n-BuLi, THF, ꢀ78 °C; (c) Et3SiH, BF3ꢁEt2O, CH3CN/CH2Cl2, ꢀ15 °C; (d) NaOH, CH3OH/
CH2Cl2, rt; (e) Ac2O, BF3ꢁEt2O, rt.
complete removal of benzyl protecting groups was very difficult in
the Pd/C H2 system. As a result, compound 5 was transformed into
the acetyl protected form 6 by the reported procedure.14 The azide
intermediates can be obtained from corresponding benzyl bromide
according to Miller0 procedure15 or prepared by the substitution
reactions of DPPA and alcohols catalyzed by DBU, a method used
by Melander.16
With the key alkyne 6 in hand, triazoles 7a–m were then
synthesized through CuAAC with the corresponding azides
(Table 1).12 Finally, the acetyl protecting groups were removed to
give the triazole-linked C-glycosides compounds 7a–m. A repre-
sentative procedure is shown in Table 1. Substituted phenyl, naph-
thyl groups and heterocycles were easily introduced by click
chemistry in good yields (55–88%).
Figure 2. Rat 24 h UGE following treatment with compounds 7a–m.
compounds (30 mg/kg) increased urinary glucose excretion
(7a–c, 7i, and 7k–m). However, we observed that all the com-
pounds were less potent than dapagliflozin. Exploring the triazole
analogs of known inhibitors ASP1941 and canagliflozin, we found
that the benzothiophene analog 7k and 4-fluorophenyl thiophene
analog 7m displayed less inhibition potential than dapagliflozin.
In summary, we have taken advantage of ‘click chemistry’ to
synthesize a series of triazole C-glucosides, and evaluated their
urinary glucose excretion. Most of the compounds demonstrated
increased urinary glucose excretion in SD rats, but they increased
urine volume to a lesser degree than that of dapagliflozin.
Compound 7a–m was tested in normal SD rats to assess inhibi-
tion of glucose transport via urinary glucose excretion.1a,17 As
shown in Figure 2, compared to the vehicle control, most of the
Table 1
Representative procedure of target compounds 7a–m
OAc
OH
OAc
a
b
N
N
N3
N
N
O
N
O
OH
O
+
AcO
AcO
HO
HO
AcO
AcO
N
R
R
R
OAc
OAc
6
7a-m
R
Yield (%)
81
R
Yield (%)
55
N
7a
7b
7c
7h
7i
75
77
79
88
NO2
CN
CH3
Cl
7j
S
N
CF3
7d
75
7k
74
Cl
S
S
7e
7f
82
77
87
7l
78
80
7m
F
F
7g
OCH3
Reagents and conditions: (a) sodium ascorbate, CuSO4, H2O/CH2Cl2, rt; (b) CH3ONa, CH3OH, rt.

644
L.-T. Li et al. / Bioorg. Med. Chem. Lett. 22 (2012) 642–644
5. Bennet, I.; Brooks, G.; Broom, N.; Calvert, S.; Coleman, K.; François, I. J. Antibiot.
Acknowledgments
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We gratefully acknowledge financial support by the National
Science Foundation of China (No. 21172120 and 20902050) and
Tianjin Municipal Science and Technology Commission (No.
09JCYBJC09200).
Supplementary data
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