Synthesis of Novel 3-aryl-1-oxa-2,8-diazaspiro[4.5]dec-2-ene Derivatives and Their Biological Evaluation Against Protein Tyrosine Phosphatase 1B

Article abstract of DOI:10.1111/cbdd.12587

A series of novel 3-aryl-1-oxa-2,8-diazaspiro[4.5]dec-2-ene derivatives were designed, synthesized, and evaluated as a new class of inhibitors against protein tyrosine phosphatase 1B. Among them, compound 6f displayed moderate inhibitory activity with IC₅₀ of 2.87 ± 0.24 μm and can be used as a novel lead compound for the design of inhibitors of protein tyrosine phosphatase 1B. A series of novel 3-aryl-1-oxa-2,8-diazaspiro[4.5]dec-2-ene derivatives were designed, synthesized, and evaluated as a new class of inhibitors against PTP1B. Among them, compound 6f displayed moderate inhibitory activity with IC₅₀ of 2.87 ± 0.24 μm and can be used as a novel lead compound for the design of inhibitors of PTP1B.

Full text of DOI:10.1111/cbdd.12587

Chem Biol Drug Des 2015; 86: 1161–1167
Research Article
Synthesis of Novel 3-aryl-1-oxa-2,8-diazaspiro[4.5]dec-
2-ene Derivatives and Their Biological Evaluation
Against Protein Tyrosine Phosphatase 1B
1
,2,†
1,†
, Xia Chen , Li-Xin Gao
2,†
Wen-Long Wang
,
challenges, such as high polarity and low enzyme selectiv-
ity (9), must still be overcome for the development of novel
PTP1B inhibitors (5). Therefore, there is a need to discover
novel potential drug scaffolds targeting PTP1B with high
selectivity, desirable physicochemical properties and
in vivo efficacies.
2
2
2,
Li Sheng , Jing-Ya Li , Jia Li * and
1
,
Bainian Feng *
1
School of Pharmaceutical Science, Jiangnan University,
Wuxi 214122, China
State key Laboratory of Drug Research, National Center
2
for Drug Screening, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences, Shanghai 201203, China
Many synthetic and naturally occurring spiroisoxazolines
have been found as pharmacophores with a wide array of
bioactivities (10–12). One such series is 3-aryl-1-oxa-2,8-
diazaspiro[4.5]dec-2-ene derivatives, which are selective
*
Corresponding authors: Bainian Feng,
fengbainian@jiangnan.edu.cn; Jia Li, jli@simm.ac.cn
†
These authors contributed equally to this work.
antagonists of the somatostatin subtype receptor
5
(
(
SSTR5) and useful for the treatment of type 2 diabetes
13). However, spiroisoxazoline-containing compounds, to
A series of novel 3-aryl-1-oxa-2,8-diazaspiro[4.5]dec-
2
-ene derivatives were designed, synthesized, and
our knowledge, have seldom been used as candidates for
PTP1B inhibitors.
evaluated as a new class of inhibitors against protein
tyrosine phosphatase 1B. Among them, compound 6f
displayed moderate inhibitory activity with IC50 of
2
.87 ꢀ 0.24 lM and can be used as a novel lead com-
Previously, we identified 1H-2,3-dihydroperimidine deriva-
tives as potent PTP1B inhibitors (14). To explore the struc-
tural diversity of PTP1B inhibitors, our initial approach was
to adjust the conformation between aryl ring and hydro-
primidine ring, using conformational restriction strategy to
replace aryl–dihydroprimidine unit with 1-oxa-2,8-diazaspi-
ro[4.5]dec-2-ene unit (Figure 1), and synthesize tert-butyl
pound for the design of inhibitors of protein tyrosine
phosphatase 1B.
Key words: 3-aryl-1-oxa-2,8-diazaspiro[4.5]dec-2-ene deriva-
tives, inhibitors, one-pot synthesis, protein tyrosine phospha-
tase 1B, structure–activity relationships
3
-aryl-1-oxa-2,8-diazaspiro[4.5]dec-2-ene-8-carboxylates
Received 3 February 2015, revised 8 April 2015 and accepted
for publication 27 April 2015
and their derivatives for biological evaluation against
PTP1B. General and classical syntheses of 1-oxa-2,8-di-
azaspiro[4.5]dec-2-ene derivatives are carried out via a
two-step reaction by 1,3-dipolar cycloadditions between
alkenes and a nitrile oxide (15,16). However, in the
reported examples, the oxime and the nitrile oxide precur-
sors are preformed separately before reaction with the alk-
enes. These methods are cumbersome and time-
consuming, and the yields are not satisfactory (15–17).
Therefore, we presented a simplified method to synthesize
3-aryl-1-oxa-2,8-diazaspiro[4.5]dec-2-ene derivatives. The
approach involved a one-pot, sequential synthesis of an
oxime and a nitrile oxide, followed by a 1,3-dipolar cyclo-
addition between the nitrile oxide and the tert-butyl 4-
methylene piperidine-1-carboxylate. Also, inspired by some
reported PTP1B dimer inhibitors (18–20), some dimer
derivatives were synthesized using oxalyl, succinyl, tereph-
Introduction
Protein tyrosine phosphatase 1B (PTP1B) is a prototypic
member of the PTP family that appears to be involved in
the regulation of several cellular functions (1). Biochemical
and genetic experiments have established that PTP1B is a
key negative regulator of insulin receptor and leptin recep-
tor-mediated signaling pathway and plays a critical role in
insulin and leptin signaling (2). Besides its central role in
the insulin cascade, PTP1B is involved in other important
pathways related to human breast and ovarian cancers
(
3,4). Consequently, the inhibition of PTP1B was consid-
ered to be a potential therapeutic for the treatment of type
diabetes mellitus, obesity, and cancer. A variety of
0
0
2
thaloyl, or [1,1 -biphenyl]-4,4 -dicarbonyl a as linker. All of
the synthesized compounds were evaluated for their inhibi-
tory activities against PTP1B.
PTP1B inhibitors have been disclosed among academic
and industrial laboratories (5–8). However, some
ª 2015 John Wiley & Sons A/S. doi: 10.1111/cbdd.12587
1161

Wang et al.
Aryl
N
O
N
Boc
Linker
X
HN
HN
Scaffold hopping
N
N
O
O
R1
N
N
R2
R3
Aryl
Aryl
X = CH, N
Figure 1: Structures of 1H-2,3-dihydroperimidine derivatives and 3-aryl-1-oxa-2,8-diazaspiro[4.5]dec-2-ene derivatives.
Methods and Materials
GST-PTP1B or GST-TCPTP, and 2% DMSO, and the catal-
ysis of pNPP was continuously monitored on a SpectraMax
340 microplate reader at 405 nm for 3 min at 30 °C. The
IC50 value was calculated from the nonlinear curve fitting of
the percent inhibition [inhibition (%)] versus the inhibitor
concentration using the following equation: %inhibi-
tion = 100/{1 + (IC50/[I]k}, where k is the Hill coefficient.
General procedure for the synthesis of compounds
4
a–4n (exemplified by 4a)
A mixture of aldehyde 1a (159 mg, 1.5 mmol), hydroxyl-
amine hydrochloride (125 mg, 1.8 mmol), and K CO
304 mg, 2.2 mmol) in ethyl acetate (2 mL) was refluxed.
2
3
(
After the consumption of aldehyde as indicated by TLC
analysis (3 h), the reaction mixture was cooled to 0 °C, fol-
lowed by the addition of 3 (purchased from Titanchem,
Shanghai, China) (197 mg, 1.0 mmol) in ethyl acetate
To study the inhibition on the other PTPase family mem-
bers, SHP1, SHP2, and LAR were prepared and assays
were performed according to the procedures described
previously (14,18). Briefly, the enzymatic activities of the
SHP1, SHP2, and LAR were determined at 30 °C by
monitoring the dephosphorylation of the substrate 3-o-
methylfluorescein phosphate (OMFP), and the product
was then detected at a 485 nm excitation wavelength
and 530 nm emission wavelength by the EnVision multila-
bel plate reader (Perkin-Elmer Life Sciences, Boston, MA,
USA). The assays were carried out in a final volume of
(1 mL), and NCS (334 mg, 2.5 mmol) was added portion-
wise under vigorous stirring. It was then stirred at room
temperature for an additional 40 min. The organic layer
was separated, and the residual aqueous layer was
extracted with ethyl acetate (3 9 50 mL). The combined
organic phases were then processed in the usual way and
chromatographed to yield the desired compound 4a
(268 mg, 85%).
5
0 lL containing 50 mmol/L MOPS, pH 6.8, 10 lmol/L
OMFP, 20 nmol/L recombinant enzyme, 2 mmol/L dith-
iothreitol, 1 mmol/L EDTA, and 2% DMSO. The initial rate
of dephosphorylation was presented by the early linear
region of the enzymatic reaction kinetic curve, and the
inhibitory activity of the compound was continuously
monitored.
General procedure for the synthesis of compounds
a–6k (exemplified by 6f)
A solution of 4a (316 mg, 1.0 mmol) in HCl/THF (3M,
mL) was stirred for 5 h at room temperature. The pre-
6
2
cipitate was filtered and dried to give 5a (155 mg, 61%) as
a white solid. The mixture of 5a (111 mg, 0.44 mol) and
triethylamine (92 lL, 0.66 mmol) in anhydrous dichlorome-
thane (2 mL) was stirred at 0 °C for 20 min, followed by
Characterization of the inhibitor on enzyme
kinetics
0
biphenyl-4,4 -dicarbonyl dichloride (60 mg, 0.22 mmol).
The mixture was warmed up to room temperature and stir-
red for 6 h. When the reaction was completed, the mixture
was purified by column chromatography (DCM:
MeOH = 80:1) to give 6f (83 mg, 59%) as a white solid.
In the fast-binding inhibition experiment, PTP1B was prein-
cubated with compounds (2% DMSO) on the ice for differ-
ent times, and then, a 10-lL mixture of enzyme and
compounds was added to the 90-lL assay system. To
characterize the inhibitor of PTP1B, the assay was carried
out in a 100-lL system containing 50 mmol/L MOPS, pH
6.5, 14 nmol/L PTP1B, pNPP in twofold dilution from
80 mmol/L, and different concentrations of the inhibitor. In
the presence of the competitive inhibitor, the Michaelis–
Protein tyrosine phosphatase 1B and related PTPs’
biological assay
A colorimetric assay to measure inhibition against PTP1B
and TCPTP was performed in 96-well plates. Briefly, the
tested compounds were solubilized in DMSO and serially
diluted into concentrations for the inhibitory test. The
assays were carried out in a final volume of 100 lL contain-
ing 50 mmol/L MOPS, pH 6.5, 2 mmol/L pNPP, 21 nmol/L
Menten equation is described as 1/v = (K
(1 + [I]/K)+1/Vmax, where K is the Michaelis constant, v is
the initial rate, Vmax is the maximum rate, and [S] is the
substrate concentration. The K value was obtained by the
linear replot of apparent K /Vmax (slope) from the primary
/[Vmax[S]])
m
i
m
i
m
1
162
Chem Biol Drug Des 2015; 86: 1161–1167

Novel PTP1B Inhibitors
reciprocal plot versus the inhibitor concentration [I] accord-
ing to the equation K /Vmax = 1 + [I]/K
higher using the optimized condition, with the yield of 85%
versus 57% as reported (15).
m
i
.
Based on the optimized reaction conditions, a series of tert-
butyl 3-aryl-1-oxa-2,8-diazaspiro[4.5]dec-2-ene-8-carboxy-
lates were synthesized. The results (Table 2) showed that
this methodology can be applied to benzaldehyde, 4-meth-
ylbenzaldehyde, 4-methoxybenzaldehyde, 4-bromobenzal-
dehyde, 3-bromobenzaldehyde, 3-fluorobenzaldehyde, or
picolinaldehyde in moderate yields. However, the desired
products (4d, 4g, 4h, 4j, 4l, 4m, 4n) were obtained in low
yields using 4-(methylthio)benzaldehyde, 2-bromobenzalde-
hyde, 4-fluorobenzaldehyde, 2-fluorobenzaldehyde, 6-
bromonicotinaldehyde, furan-2-carbaldehyde, or thiophene-
2-carbaldehyde. After the removal of the Boc group from
compounds 4a–4c and 4h–4j, the produced compounds
5a–5c and 5h–5j were coupled with oxalyl dichloride, succi-
Results and Discussion
Chemistry
We screened the experimental parameters extensively to
optimize the one-pot reaction protocol. Initially, benzalde-
hyde (1a) was chosen as a model substrate (Table 1). We
found that increasing the amount of benzaldehyde resulted
in high yields (entries 1–3). Various bases were investi-
gated. Compared to K CO , Cs CO was less effective,
2
3
2
3
3
whereas organic bases such as Et N and DIPEA were
completely ineffective (entries 5-6). The substitution of
NCS with bleach or TBHP was proved to be less effective
(entries 7-8). When using EtOAc as the solvent, the yield
0
was slightly improved compared to CH Cl (entry 9). After
an increase in temperature, the yield was improved
remarkably (entry 10). Some of the commonly used sol-
nyl dichloride, terephthaloyl dichloride, and [1,1 -biphenyl]-
2
2
0
4,4 -dicarbonyl dichloride, respectively, to yield compounds
6a–6k (Scheme 1).
3
vents, such as CH CN, DMF, THF, and EtOH, were used
at 90 °C as oil bath temperature, and the results demon-
strated that EtOAc was the most efficient solvent among
them. The reaction time was also investigated, and the
results showed that 3 h was the best choice for the model
reaction. To our delight, the yield of compound 4a was
Protein tyrosine phosphatase 1B inhibitory
activities and structure–activity relationships
The inhibitory activities of all synthesized compounds
against PTP1B were measured using p-nitrophenyl phos-
a
Table 1: Optimization studies of the one-pot reaction condition for compound 4a
O
CHO
N
O
N
O
O
NH OH.HCl
2
3
N
N
OH
Base, Solvent, Temp
Oxidant, 0 ºC to rt
O
1
a
2a
Base
4a
b
Entry
1a (mmol)
Solvent
Temp (°)
Time (h)
Oxidant
Yield (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
K
K
K
2
2
2
CO
CO
CO
3
CH
CH
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
2
2
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
2
2
2
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
40
Reflux
Reflux
90
Reflux
Reflux
Reflux
Reflux
Reflux
3
3
3
3
3
3
3
3
3
3
3
3
3
3
1
2
4
NCS
NCS
NCS
NCS
NCS
NCS
Bleach
TBHP
NCS
NCS
NCS
NCS
NCS
NCS
NCS
NCS
NCS
40
42
62
47
Trace
Trace
40
Trace
65
85
57
37
Trace
Trace
32
52
83
1.2
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
3
3
Cs
Et
DIPEA
2
CO
3
3
N
K
K
K
K
K
K
K
K
K
K
K
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
3
3
3
3
3
3
3
3
3
3
3
EtOAc
EtOAc
0
1
2
3
4
5
6
7
CH
3
CN
DMF
THF
EtOH
EtOAc
EtOAc
EtOAc
a
Reaction conditions: hydroxylamine hydrochloride (1.8 mmol, 1.8 eq), 3 (1 mmol, 1eq), solvent (3 mL), base (2.2 mmol, 2.2 eq), oxidant
2.5 mmol, 2.5 eq).
Isolated yield after chromatographic purification.
(
b
Chem Biol Drug Des 2015; 86: 1161–1167
1163

Wang et al.
Table 2: Synthesis of tert-butyl 3-aryl-1-oxa-2,8-diazaspiro[4.5]dec-2-ene-8-carboxylates under optimal conditions
O
N
O
N
O
NH OH.HCl
Ar
O
2
3
N
ArCHO
N
OH
a - 2p
Ar
K CO , EtOAc, 90 ºC
NCS, 0 ºC to rt
2
3
O
4a - 4p
1
a - 1p
2
a
a
Comp
Ar
Yield (%)
Comp
Ar
Yield (%)
b
4
4
4
a
85
4h
34
51
32
F
b
c
53
69
4i
4j
F
MeO
MeS
F
4
4
4
d
e
f
22
51
41
4k
4l
59
10
19
N
Br
Br
Br
N
4m
O
4
g
18
4n
S
31
Br
a
Isolated yield after chromatographic purification.
Compound 4a was reported in reference (15).
b
O
N
Boc
X
N
O
O
N
NHHCl
N
A
r
O
O
X
=
6
f Ar = phenyl
N
a
N
b
O
O
O
N
O
Ar
Ar
6g Ar = 2-fluorophenyl X =
6
a Ar = phenyl,
X=
4
a - 4c, 4h - 4j
5a Ar = phenyl
Ar
O
O
O
O
5
5
5
5
5
b Ar = p-toyl
c Ar = 4-methoxyphenyl
h Ar = 4-fluorophenyl
i Ar = 3-fluorophenyl
j Ar = 2-fluorophenyl
=
6h
X
=
6
b Ar = 2-fluorophenyl X
Ar = 3-fluorophenyl
O
O
O
O
6
c Ar = phenyl
X =
6i Ar = 4-fluorophenyl
6j Ar = p-toyl
X =
X =
O
O
O
O
O
6
d Ar = 2-fluorophenyl X =
O
O
O
6
e Ar = 4-fluorophenyl X =
k Ar = 4-methoxyphenyl X
=
6
O
3
Scheme 1: Reagents and conditions: (a) HCl/THF, 48–86%; (b) dicarboxylic acid dichloride, Et N, DCM, 43-96%.
phate (pNPP) as the substrate (14,18), and the results are
detailed in Table 3. As for compounds 4a–4e, compound
electron-withdrawing group (Br), showed slightly better
inhibitory activity than compound 4a.
4
a, which has unsubstituted phenyl group, exhibited
slightly better inhibitory activity than compounds 4b–4d,
which have electron-donating substitutes at the para posi-
tion of the phenyl ring, while compound 4e, which has
To further investigate the SAR of substitutes on the phenyl
ring, compounds 4f–4j were synthesized. Among com-
pounds 4e–4g, compound 4g with Br at the ortho position
1
164
Chem Biol Drug Des 2015; 86: 1161–1167

Novel PTP1B Inhibitors
Table 3: Protein tyrosine phosphatase 1B inhibitory activities of
compounds 4a–4n and 6a–6k
the phenyl ring on the spiroisoxazoline derivatives with het-
erocyclic ring may impact the enzyme inhibition. Also,
dimer derivatives 6a–6k were synthesized using oxalyl,
Inhibition(%) IC50
Comp at 20 lg/mL (lM)
Inhibition(%)
Comp at 20 lg/mL IC50 (lM)
0
0
a
a
succinyl, terephthaloyl, or [1,1 -biphenyl]-4,4 -dicarbonyl as
a linker. Compound 6a with oxalyl group, compound 6b
with succinyl group, or compounds 6c–6e with terephtha-
loyl group decreased the potency compared to their corre-
sponding compounds 4a, 4j, or 4h, respectively. When
b
4
4
4
4
4
4
4
4
4
4
4
4
4
a
b
c
d
e
f
31.83
18.58
24.62
9.52
34.29
38.54
44.04
25.21
44.84
47.69
11.07
40.67
19.77
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
4n
6a
6b
6c
6d
6e
6f
37.59
18.33
3.63
11.87
4.38
NT
NT
NT
NT
NT
NT
0
0
using [1,1 -biphenyl]-4,4 -dicarbonyl as a linker, however,
the activities of compounds 6f–6k were improved signifi-
cantly compared to their corresponding compounds.
Notably, compounds 6f–6g showed inhibitory activities
against PTP1B in the low micromolar range, especially
compound 6f with IC50 of 2.87 ꢀ 0.24 lM.
2.65
g
h
i
96.16
95.99
72.85
31.35
24.86
31.71
–
2.87 ꢀ 0.24
4.96 ꢀ 0.61
5.33 ꢀ 0.81
NT
NT
NT
6g
6h
6i
j
k
l
6j
6k
PC
c
m
1.95 ꢀ 0.29
Selectivity against other PTPs
a
In addition to the potency improvements, we investigated
the selectivity of the representative compound 6f against
other PTPs (TCPTP, SHP-1, SHP-2, LAR). Homogeneous
T-cell protein tyrosine phosphatase (TCPTP) inhibitory
activities were investigated simultaneously by the same
method (14,18). Compound 6f showed 42.2% inhibition at
the concentration of 20 lg/mL (31.35 lM), and the result
indicated that compound 6f had greater selectivity for
PTP1B than for TCPTP. Besides TCPTP, we tested the
inhibitory activity of 6f on other three homogenous
enzymes SHP-1, SHP-2, and LAR, all of the inhibitory
ratios were lower than 10% at the dose of 20 lg/mL, and
we concluded that compound 6f had no visible activities
against LAR, SHP-1, and SHP-2.
The pNPP assay. IC50 values were determined by regression
analyses and expressed as means ꢀ SD of three replications.
b
NT means not tested.
c
PC: using oleanolic acid as positive control for protein tyrosine
phosphatase 1B.
showed better inhibitory activity than compound 4e with
Br at the para position and compound 4f with Br at the
meta position. Similar results were observed among com-
pounds 4h–4j. These results indicated that the o-, m-,
and p-substitutions on the phenyl ring had some effect on
the inhibitory activity. Replacement of the phenyl group
(
(
4a) with pyridin-2-yl group (4k) and the furan-2-yl group
4m) led to decreased potency compared to compound
4a, while replacement of the phenyl group with thiophen-
2-yl group (compound 4n) exhibited similar activity com-
pared to compound 4a. On the other hand, compound 4l
with the 6-bromopyridin-3-yl group slightly improved the
inhibitory activity compared to compound 4e with 4-brom-
ophenyl group. These results indicated that replacement of
Characterization of the inhibitor 6f on enzyme
kinetics
A kinetic study was performed to identify the inhibitory
mechanism of compound 6f (Figure 2), using the reported
(
A)
(B)
(
C)
Figure 2: Characterization of 6f to protein
tyrosine phosphatase 1B.
Chem Biol Drug Des 2015; 86: 1161–1167
1165

Wang et al.
enzyme kinetics assays (14,18). As shown in Figure 2A,
compound 6f demonstrated a fast-binding inhibition of
PTP1B. The plots in Figure 2C indicated that compound
6. Sobhia M.E., Paul S., Shinde R., Potluri M., Gundam
V., Kaur A., Haokip T., Sobhia M.E. (2012) Protein tyro-
sine phosphatase inhibitors: a patent review (2002–
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6
f was a mixed-type inhibitor due to the increasing km
value and concomitantly decreasing Vmax value upon the
gradually increased compound concentration. Meanwhile,
the result of the Lineweaver–Burk plot further confirmed 6f
as a mixed-type inhibitor of PTP1B for intersecting at sec-
ond quadrant of a nest of lines with increased inhibitor
concentration (Figure 2B) (7).
7. Ramirez-Espinosa J.J., Rios M.Y., Paoli P., Flores-Mor-
ales V., Camici G., de la Rosa-Lugo V., Hidalgo-Figue-
roa S., Navarrete-Vazquez G., Estrada-Soto S. (2014)
Synthesis of oleanolic acid derivatives: In vitro, in vivo
and in silico studies for PTP-1B inhibition. Eur J Med
Chem;87:316–327.
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. Krishnan N., Koveal D., Miller D.H., Xue B., Akshin-
thala S.D., Kragelj J., Jensen M.R., Gauss C.M., Page
R., Blackledge M., Muthuswamy S.K., Peti W., Tonks
N.K. (2014) Targeting the disordered C terminus of
PTP1B with an allosteric inhibitor. Nat Chem
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Conclusion
In summary, we described a convenient method for the
synthesis of tert-butyl 3-aryl-1-oxa-2,8-diazaspiro[4.5]dec-
2
-ene-8-carboxylates by applying one-pot reaction through
9
. Iversen L.F., Moller K.B., Pedersen A.K., Peters G.H.,
Petersen A.S., Andersen H.S., Branner S., Mortensen
S.B., Moller N.P.H. (2002) Structure determination of T
two sequential steps and a series of novel dimer deriva-
tives were designed and synthesized. Biological evaluation
demonstrated that most of the synthesized compounds
showed inhibitory activity against PTP1B, and compound
cell protein-tyrosine phosphatase.
77:19982–19990.
J
Biol Chem;
2
6
f displayed the best inhibitory activity with IC50 of
1
1
0. Dallanoce C., Bazza P., Grazioso G., Marco D.A.,
2
.87 ꢀ 0.24 lM and good selectivity for PTP1B over
Cecilia G., Loredana R., Francesco C., Carlo D.M.
TCPTP. These preliminary results provided a possible
opportunity for the development of novel PTP1B inhibitors.
Further optimization and evaluation of this series of com-
pounds will be reported in due course.
2
(
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Acknowledgment
This work was supported by National Natural Science
Foundation of China (81125023, 21472069), the State Key
Laboratory of Drug Research (SIMM1302KF-05), and the
Fundamental Research Funds for the Central Universities
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Conflict of Interest
The authors have declared no conflict of interest.
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Supporting Information
1
2
Additional Supporting Information may be found in the
online version of this article:
0. Luo L., He X.P., Shen Q., Li J.Y., Shi X.X., Xie J., Li
J., Chen G.R. (2011) Synthesis of (glycopyranosyl-triaz-
olyl)-purines and their inhibitory activities against
Appendix S1. Synthetic details and spectral data of target
compounds in this manuscript are provided.
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