Click to a focused library of benzyl 6-triazolo(hydroxy)benzoic glucosides: Novel construction of PTP1B inhibitors on a sugar scaffold

Article abstract of DOI:10.1016/j.ejmech.2011.06.025

With an aim of developing novel protein tyrosine phosphatase (PTP) 1B inhibitors based on sugar scaffolds, a focused library of benzyl 6-triazolo(hydroxy)benzoic glucosides was efficiently constructed via the modular and selective Cu(I)-catalyzed azide-al

Full text of DOI:10.1016/j.ejmech.2011.06.025

European Journal of Medicinal Chemistry 46 (2011) 4212e4218
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Click to a focused library of benzyl 6-triazolo(hydroxy)benzoic glucosides: Novel
construction of PTP1B inhibitors on a sugar scaffold
,
,
Cui Li a, Xiao-Peng He a c, Yin-Jie Zhang a, Zhen Li a, Li-Xin Gao b, Xiao-Xin Shi a, Juan Xie c, Jia Li b
**
,
Guo-Rong Chen a , Yun Tang
,
a,
*
*
a School of Pharmacy, and Key Laboratory for Advanced Material and Fine Chemicals, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, PR China
b National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China
c PPSM, Institut d’Alembert, ENS de Cachan, CNRS UMR 8531, 61 Avenue du Pt Wilson, F-94235 Cachan, France
a r t i c l e i n f o
a b s t r a c t
Article history:
With an aim of developing novel protein tyrosine phosphatase (PTP) 1B inhibitors based on sugar
scaffolds, a focused library of benzyl 6-triazolo(hydroxy)benzoic glucosides was efficiently constructed
via the modular and selective Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddtion (click chemistry).
These glycoconjugates bearing alkyl chain length-varied bridges between the sugar and (hydroxy)-
benzoic moieties were identified as new PTP1B inhibitors with selectivity over T-Cell PTP (TCPTP), SH2-
Containing PTP-1 (SHP-1), SHP-2 and Leukocyte Antigen-Related Tyrosine Phosphatase (LAR). Molecular
docking study sequentially elaborated the plausible binding modes of the structurally diverse sugar-
based inhibitors with PTP1B.
Received 24 March 2011
Received in revised form
23 May 2011
Accepted 18 June 2011
Available online 25 June 2011
Keywords:
Click chemistry
PTP1B inhibitor
Sugar scaffold
Ó 2011 Elsevier Masson SAS. All rights reserved.
(Hydroxy)benzoate
Molecular docking
1. Introduction
Recently, sugar itself has been recognized as a desirable central
scaffold for drug design owing to its ability to rigidly expand
Sugars are ubiquitous natural building blocks, governing
numerous crucial pathological processes through specific sugar-
protein recognitions on cellular level. Based on such unique
intercellular interactions, they were used as efficient tools for
the diagnosis or protection of sugar-mediated human diseases
[1]. Meanwhile, the preparation of glycomimetics based on the
structural modification of natural sugar units that target disease-
related glycoproteins has considerably boosted the modern drug
discovery [2]. For example, the only two validated drugs, namely
zanamivir and oseltamivir to combat both influenza A and B were
derived from sialic acid that is specifically recognized by neur-
aminidase [3]. On the other hand, the glycosylation of some
known bioactive small-molecules has proven to be efficacious for
enhancing their pharmacodynamics and/or pharmacokinetics
[4,5].
covalently attached pharmacophores toward drug target in
a controlled “three-dimensional” way [6,7]. Glucose represents one
of the simplest monosaccharide structures, which furnishes
multiple readily modifiable hydroxyl functional groups with
diverse naturally defined spatial orientations. As shown in Fig. 1,
while pharmacophores are presented on a folded glucose scaffold
rather than on planer molecular templates such as benzene, they
would be advantageous to gain more spatial flexibility to probe
their proper docking sites on the enzymatic target [6].
Protein tyrosine phosphatase 1B (PTP1B) has been identified as
a negative regulator of insulin and leptin pathways. Recent reports
also suggest that this functional enzyme may become an oncogene
in the context of breast cancer [8]. Consequently, considerable
efforts have been devoted to the development of small-molecule
PTP1B inhibitors for the treatment of type-2 diabetes, obesity and
cancer. To circumvent drawbacks such as the lack of cellular activity
of the highly charged phosphonates, aryl carboxylic acids including
isoxazole acid [9], 2-oxalylamino benzoic acid (OBA) [10], hydrox-
ylpropionic acid [11] and thiophene diacid [12] have been identified
as alternative phosphotyrosine (pTyr) surrogates. Furthermore,
* Corresponding authors. Tel.: þ86 21 64251052; fax: þ86 21 64253651.
** Corresponding author.
E-mail addresses: jli@mail.shcnc.ac.cn (J. Li), mrs_guorongchen@ecust.edu.cn
(G.-R. Chen), ytang234@ecust.edu.cn (Y. Tang).
Zhang has revealed in a recent study that benzyl aryl
a-ketoacid
derivatives exhibited unexpected noncompetitive PTP1B inhibition
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.06.025

C. Li et al. / European Journal of Medicinal Chemistry 46 (2011) 4212e4218
4213
2.2. Inhibitory activity on PTP
The focused sugar library prepared was sequentially assayed
toward PTP1B via our previously developed method in employing
benzoates bed as references at a compound concentration of
100
mg/mL [23]. As shown in Table 1, compounds bed without
structural modifications were first determined not to inhibit
PTP1B-catalyzed dephosphorylation. However, while the benzyl
glucosyl moiety was connected with these (hydroxy)benzoic
precursors via chain length-varied alkyl triazoles, the resulting
glycoconjugates 22e30 exhibited moderate-to-good inhibitory
activities on PTP1B.
Obviously, while a benzoic acid group was linked with the sugar
moiety (22, 25, 28), only moderate inhibitory potency was obtained.
Glycoconjugate 28 with a 5C linkage between the benzoate
precursor and the benzyl glucoside appeared to be more potent
(IC50 ¼ 39
m
M) than its 3C-linked counterpart 22 (IC50 ¼ 65
mM) and
M), indicating the prolonged
4C-linked counterpart 25 (IC50 ¼ 60
m
chain length could favor the corresponding inhibitory activity.
Interestingly, compounds 23, 26 and 29 bearing a 2-hydroxybenzoic
acid moiety displayed considerably much improved inhibitory
Fig. 1. Construction of PTP1B inhibitors based on a “three-dimensional” sugar scaffold.
potency. Compounds 26 (IC50 ¼ 9
respectively, 4C and 5C linkers are around 3e4-fold moreactive than
M), demonstrating their
prolonged molecular length has contributed evidently to PTP1B
inhibition. In contrast, while the substitution site of the hydroxyl
group was varied to the meta-position, the inhibitory activity of the
corresponding triazole-linked glucosyl 3-hydroxybenzoates 24
m
M) and 29 (IC50 ¼ 7
mM) with,
pattern, targeting the open conformation of WPD loop [13]. It was
also accentuated that the benzyl groups involved in these bioactive
molecules are crucial for enhancing their binding affinity with
PTP1B as well as their cell membrane permeability probably due to
the increased hydrophobicity.
their 3C-linked counterpart 23 (IC50 ¼ 29
m
Prompted by such compelling evidence, we sought to construct
novel PTP1B inhibitors based on a benzylated glucopyranosyl
template whereon diverse (hydroxy)benzoic precursors that are
readily available pTyr surrogates [14,15] would be introduced via
the modular and selective click chemistry (Fig. 1) [16,17]. The
synthesis of this focused library and their subsequent inhibitory
assay and molecular docking study were described in detail.
(IC50 ¼ 20
m
M), 27 (IC50 ¼ 19
m
M) and 30 (IC50 ¼ 17
mM) tended to
decrease modestly. Their approximately identical IC50 values
suggest that they may bind with PTP1B in a similar fashion howbeit
with different alkyl chain linkages.
Compounds 26 and 29 owning best PTP1B inhibitory activities
among this series were then subjected to the inhibitory assays on
several other PTPs for evaluating their specificity (Table 2） [24].
Apparently, these glycoconjugates possess at least 3-fold, 8-fold, 5-
fold, and 12-fold selectivity over the homologous TCPTP, SHP-1,
SHP-2 and LAR, respectively.
2. Result and discussion
2.1. Chemistry
2.3. Molecular docking study
The discovery of a modular synthetic approach for efficiently
building glycomimetic libraries had been remaining as an intractable
issue. Fortunately, ever since the definition of “click chemistry” by
Sharpless and co-workers [16,17], the carbohydrate chemistry has
searched out its very powerful ally for efficaciously assembling a wide
range of glycon and aglycon moieties, yielding structurally diverse
glycomimetics in a productive way. The Cu(I)-catalyzed azide-alkyne
1,3-dipolar cycloaddition (CuAAC) stands for the most widely utilized
click reaction, which has already fulfilled the preparation of various
1,4-triazolyl glycoconjugates that are biologically active [18e21].
Herein, we used a known benzyl 6-propargyl glucoside a as the
sugar template [22] whereon azido (hydroxy)benzoic derivatives
could be readily introduced via click reaction, shown in Scheme 1.
From commercially available methyl 3-hydroxylbenzoate (1), methyl
2,5-dihydroxybenzoate (2) and methyl 3,5-dihydroxybenzoate (3),
theazides4e12 bearingalkyl chainlengths rangingfrom3to5Cwere
synthesized via a straightforward two-step sequence involving O-
alkylationinthepresenceofK2CO3 andafollowingnucleophilicazide
substitution. Then, the Huisgen [3 þ 2] cycloaddition between sugar
alkyne a and the various prepared azides was easily realized under
the promotion of sodium ascorbate and CuSO4$5H2O, affording the
triazolyl intermediates 13e21 in good-to-excellent yields of 70e95%.
Subsequent saponification of the methyl esters with 1 N NaOH aq.
eventually led to the desired glucosyl (hydroxy)benzoic acids 22e30
in moderate yields.
Having preliminarily approved that the introduction of known
pharmacophores onto a benzyl glucopyranoside could obtain
sugar-based PTP1B inhibitors, we sequentially attempted to
propose the plausible binding modes of these triazolyl glyco-
conjugates with the enzymatic target via molecular docking study.
Considering both the flexibility of the protein and the inhibitors,
compounds were docked to the binding pocket of the active site
area using the Induced Fit protocol. The principal ligandereceptor
interactions were analyzed and the optimal orientation of these
compounds was selected for further comparison, illustrated in
Fig. 2.
As shown in Fig. 2AeC, the (hydroxy)benzoic precursors of all
inhibitors 22e30 tended to fit in the first phosphotyrosine site of
PTP1B, which accords with the crystal structures of PTP1B-ligand
complexes wherein polar moieties were preferable toward this
catalytically active site [25]. In addition, the simultaneously
generated nonpolar contacts of the benzyl groups on sugar moiety
with peripheral hydrophobic surface of PTP1B could probably
enhance the binding affinity of these glycoconjugates with the
targeted enzyme [13]. However, the above-mentioned intermo-
lecular interactions are distinct in terms of the structural variation
of the small-molecule inhibitors.
The sole carboxylic acid group on the benzoic moiety of glyco-
conjugates 22, 25 and 28 generated dense hydrogen bonds with

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C. Li et al. / European Journal of Medicinal Chemistry 46 (2011) 4212e4218
Scheme 1. Reagents and conditions: (i) K2CO3, dibromoalkane, MeCN/H2O (3:1, V/V); (ii) NaN3, MeCN/H2O (3:1, V/V); (iii) sodium ascorbate, CuSO4$5H2O, CH2Cl2/H2O (5:2, V/V);
(iv) 1N aq. NaOH, THF.
amino acid residues including Ser216, Ala217, Gly218, Ile219,
Gly220 and Arg221 in the catalytic loop of PTP1B while one addi-
tional hydrogen bond was made between the triazole ring (22,
Figs. 2A-1) or the benzoic moiety (25-Fig. 2A-2; 28-Fig. 2A-3) with,
respectively, Lys116 or Tyr46. Interestingly, one benzyl group of
their glucosyl moiety could make additional hydrophobic contacts
with Phe182, which spatially enlarges the hydrophobic surface of
PTP1B by preventing the close conformation of WPD loop. This is
similar the crystallized binding motif of the reported aryl ketoacid
derivatives with PTP1B [13]. Furthermore, due to the longer and
more flexible alkyl chain linkage (5C), a second benzyl group on
sugar moiety of compound 28 could partially extend to the second
site of PTP1B and make hydrophobic contacts with Tyr20 (Figs. 2A-3),
which may possibly account for its slightly enhanced inhibitory
Table 1
Inhibitory activity of compounds bed and 22e30 on PTP1B.
Compound
Structure
Benzoate
IC50 (m
M)b
Linkagea
b
c
d
OH-free
2-OH
3-OH
e
>100
>100
>100
22
25
28
23
26
29
24
27
30
OH-free
3C
4C
5C
3C
4C
5C
3C
4C
5C
64.6 ꢀ 16.8
60.1 ꢀ 21.5
38.7 ꢀ 10.9
28.9 ꢀ 6.3
8.7 ꢀ 1.4
Table 2
2-OH
3-OH
Inhibitory activity of compounds 26 and 29 on PTPs.
Compound
IC50
(m
M)a
6.7 ꢀ 0.5
19.7 ꢀ 2.6
19.3 ꢀ 4.3
16.6 ꢀ 4.9
PTP1B
TCPTP
SHP-1
SHP-2
LAR
26
29
8.7 ꢀ 1.4
6.7 ꢀ 0.5
25.0 ꢀ 5.6
24.0 ꢀ 4.9
68.9 ꢀ 4.4
52.6 ꢀ 9.7
54.3 ꢀ 4.7
34.5 ꢀ 4.1
>100
>100
a
This is the carbon (C) number between glucosyl triazole and benzoic precursors.
Values are means of three experiments.
b
a
Values are means of three experiments.

C. Li et al. / European Journal of Medicinal Chemistry 46 (2011) 4212e4218
4215
Fig. 2. Proposed binding modes of (A-1) compound 22; (B-1) compound 23; (C-1) compound 24; (A-2) compound 25; (B-2) compound 26; (C-2) compound 27; (A-3) compound 28;
(B-3) compound 29; (C-3) compound 30 in complex with PTP1B: Carbon atoms of the inhibitors are shown in light blue, pink or green sticks, and those for the enzyme are shown in
gray sticks. Nitrogen atoms are shown in blue and oxygen atoms in red. Hydrogen bonds are shown in yellow dashed lines (For interpretation of the references to colour in this
figure legend, the reader is referred to the web version of this article.)
activity (IC50 ¼ 39
(IC50 z 60 M).
m
M) compared to compound 22 and 25
Fig. B-2: aglycon-OH with Arg221-N (3ꢁ: 4.23 Å, 4.28 Å, 4.66 Å) and
sugar-O (C1) with Lys120-N (4.88 Å); Fig. B-3: aglycon-OH with
Lys120-N (3.73 Å) and Arg221-N (3ꢁ: 3.87 Å, 4.22 Å, 4.52 Å), and
sugar-O (C1) with Arg47-N (3ꢁ: 3.55 Å, 4.02 Å, 4.39 Å).
m
Unlike their benzoic counterparts, the hydroxybenzoic deriva-
tives 23, 24, 26, 27, 29 and 30 are in trends to occupy both the
catalytic site and the YRD motif, which may probably illuminate
their generally enhanced inhibitory potency (Fig. 2B and C).
Densely functionalized hydrogen bonding network was observed
between the 2-hydroxybenzoic groups of compounds 23, 26 and 29
and residues including Ser216, Ala217, Gly218, Ile219, Gly220 and
Arg221 of PTP1B active site. Additionally, hydrogen bonds were also
made between the hydroxybenzoic moiety of 23 (Figs. 2B-1), the
sugar moiety of 26 (Fig. 2B-2) and the triazole ring of 29 (Figs. 2B-3)
with Gln262, Lys116 and Arg 24, respectively. However, due to
a short linkage (3C) between the 2-hydroxybenzoic precursor and
the triazolyl sugar template, only very weak nonpolar contacts
were found between the benzyl groups of compound 23 with the
groove of YRD. In contrast, having adequate molecular length, the
4C- and 5C-linked glycoconjugates 26 and 29 may extend their
benzyl glucosyl scaffold to YRD motif, making strong hydrophobic
interactions with the phenol residue of Tyr46 while the latter also
make nonpolar contacts with Val49. This could plausibly clarify the
As shown in Fig. C, very similar binding modes were sequen-
tially acquired for compounds 24, 27 and 30 with PTP1B. By making
hydrogen bonding array, their 3-hydroxybenzoic precursors were
settled in the active site. Moreover, the benzyl sugar moieties of
these glycoconjugates with gradually prolonged alkyl chain length
analogously made hydrophobic contacts with residue Tyr46 in YRD
motif for enhancing the binding affinity, which might account for
their parallel inhibitory effects on PTP1B. Electrostatic interactions
were concomitantly observed: Fig. C-1: triazole-N with Gln266-O
(3.84 Å); Fig. C-2: sugar-O (C3) with Arg47-N (4.78 Å) and sugar-
O (C4) with Arg48-N (4.66 Å); Fig. C-3: aglycon-OH with Lys120-
N (4.43 Å).
3. Conclusion
In summary, we have shown in this study that by ‘clicking’
validated pTyr surrogates onto a benzyl glucoside template, potent
PTP1B inhibitors could be obtained efficiently. Molecular docking
study sequentially proposed the plausible complexes of the struc-
turally diverse triazolyl (hydroxy)bezoic glucosides with the
enzymatic target on the basis of their assessed inhibitory activities.
improved IC50 values of compounds 26 (IC50 ¼ 9
mM) and 29
(IC50 ¼ 7
m
M) compared to their counterpart 23 (IC50 ¼ 29
mM).
Finally, electrostatic interactions were observed between these
inhibitors with PTP1B: Fig. B-1: triazole-N with Asp48-O (4.35 Å);

4216
C. Li et al. / European Journal of Medicinal Chemistry 46 (2011) 4212e4218
We therefore envision that the introduction of pTyr mimetics onto
aryl sugar templates that possess extensive configurational diver-
sities via the modular click chemistry would represent an effica-
cious strategy for fabricating new competent PTP inhibitor entities
in a productive way. Programs related to this subject are currently
underway in our laboratories.
J ¼ 12.2 Hz,1H), 4.63e4.55 (m, 2H), 4.54e4.42 (m, 3H), 4.01e3.94 (m,
1H), 3.93(s, 3H), 3.86(t, J¼ 5.7Hz,2H), 3.75(ddd, J¼ 14.3,10.0, 3.4 Hz,
2H), 3.68 (d, J ¼ 10.2 Hz,1H), 3.58 (t, J ¼ 9.3 Hz,1H), 3.52 (dd, J ¼ 9.6,
3.5 Hz, 1H), 3.35 (s, 3H), 2.30 (p, J ¼ 6.4 Hz, 2H); 13C NMR (101 MHz,
CDCl3):
d
¼ 170.2, 156.4, 150.8, 145.0, 138.8, 138.4, 138.2, 128.5, 128.5,
128.4, 128.2, 128.0, 128.0, 127.8, 127.8, 127.7, 124.5, 122.9, 118.8, 112.9,
112.0, 98.3, 82.1, 79.9, 77.6, 75.8, 75.0, 73.4, 70.0, 68.9, 65.0, 64.8, 55.3,
52.4, 47.0, 29.9; HRESIMS: calcd for C42H47N3O10 þ Na: 776.3159;
found: m/z 776.3159.
4. Experimental section
All purchased chemicals and reagents are of high commercially
available grade. Solvents were purified by standard procedures. 1H
and 13C NMR spectra were recorded on a Bruker AM-400 spec-
trometer in CDCl3 or DMSO-d6 solutions using tetramethylsilane as
the internal standard (chemical shifts in ppm). All reactions were
monitored by TLC (thin-layer chromatography) with detection by
UV or by spraying with 6 N H2SO4 and charring at 300 ꢂC. Optical
rotations were measured using a PerkineElmer 241 polarimeter at
room temperature and a 10-cm/1-mL cell. High resolution mass
spectra (HRMS) were recorded on an MA1212 instrument using
standard conditions (ESI, 70 eV). For detailed experimental sections
of the preparation of azides 4e12 and the saponification, see
Supplementary Data associated with this article.
4.1.3. Methyl 3-hydroxy-5-(3-(4-((((2R,3R,4S,5R,6S)-3,4,5-
tris(benzyloxy)-6-methoxytetra hydro-2H-pyran-2-yl)methoxy)
methyl)-1H-1,2,3-triazol-1-yl)propoxy)benzoate (15)
From compound 6 (150.0 mg, 0.60 mmol), compound a (298.5mg,
0.60 mmol), column chromatography (petroleum ether/EtOAc ¼ 1:2)
afforded compound 15 as a pale yellow syrup (414.7 mg, 92.2%);
Rf ¼ 0.42 (petroleum ether/EtOAc ¼ 1:2); [
a
]
¼ þ37.5 (c ¼ 0.12,
D
CH2Cl2); 1H NMR (400 MHz, CDCl3):
d
¼ 7.46 (s, 1H), 7.38e7.25 (m,
13H), 7.23e7.17 (m, 2H), 7.13 (s, 1H), 7.05 (s, 1H), 6.57 (s, 1H), 4.98 (d,
J ¼ 10.8 Hz,1H), 4.82 (dd, J ¼ 10.9, 2.5 Hz, 2H), 4.78 (d, J ¼ 12.1 Hz,1H),
4.69 (d, J ¼ 12.5 Hz, 1H), 4.65 (d, J ¼ 12.1 Hz, 1H), 4.63e4.56 (m, 2H),
4.53e4.42 (m, 3H), 3.99 (t, J ¼ 9.3 Hz,1H), 3.86 (t, J ¼ 5.3 Hz, 2H), 3.85
(s, 3H), 3.80e3.65 (m, 3H), 3.62e3.50 (m, 2H), 3.35 (s, 3H), 2.35e2.19
4.1. General procedure for the click reaction (13e21)
(m, 2H); 13C NMR (101 MHz, CDCl3):
d
¼ 167.0, 159.5, 158.2, 138.8,
138.4, 138.2,132.1, 128.6, 128.6, 128.5, 128.3,128.2, 128.1, 127.9, 127.9,
127.8, 110.2, 107.2, 106.9, 98.3, 82.1, 80.0, 77.6, 75.9, 75.0, 73.5, 70.0,
69.0, 64.7, 64.4, 55.4, 52.3, 47.4, 29.8; HRESIMS: calcd for
C42H47N3O10 þ Na: 776.3159; found: m/z 776.3164.
To a solution of azides 4e12 (1 equiv) and alkyne a (1 equiv) in
CH2Cl2 (5 mL) and H2O (2 mL), sodium ascorbate (3 equiv) and
CuSO4$5H2O (2 equiv) were added. After stirring for 6 h at rt, the
mixture was diluted with CH2Cl2 and washed with water. The
combined organic layer was dried over MgSO4, filtered and then
concentrated to give the crude product which was purified by
column chromatography.
4.1.4. Methyl 3-(4-(4-((((2R,3R,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-
methoxytetrahydro-2H- pyran-2-yl)methoxy)methyl)-1H-1,2,3-
triazol-1-yl)butoxy)benzoate (16)
From compound 7 (119.6 mg, 0.48 mmol), compound a (240 mg,
0.48 mmol), column chromatography (petroleum ether/
EtOAc ¼ 2:3) afforded compound 16 as a pale yellow syrup
(284.2 mg, 78.8%); Rf ¼ 0.22 (petroleum ether/EtOAc ¼ 1:1);
4.1.1. Methyl 3-(3-(4-((((2R,3R,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-
methoxytetrahydro-2H- pyran-2-yl)methoxy)methyl)-1H-1,2,3-
triazol-1-yl)propoxy)benzoate (13)
From compound 4 (113.0 mg, 0.48 mmol), compound a (240 mg,
0.48 mmol), column chromatography (petroleum ether/EtOAc ¼ 1:2)
afforded compound 13 as a pale yellow syrup (247.8 mg, 70.0%);
[a
]
¼ þ51.7 (c ¼ 0.14, CH2Cl2); 1H NMR (400 MHz, CDCl3):
¼ 7.64
d
D
(d, J ¼ 7.7 Hz, 1H), 7.55e7.50 (m, 1H), 7.48 (s, 1H), 7.39e7.24 (m,
14H), 7.23e7.18 (m, 2H), 7.05 (dd, J ¼ 8.2, 2.1 Hz, 1H), 4.97 (d,
J ¼ 10.9 Hz, 1H), 4.88e4.75 (m, 3H), 4.72 (d, J ¼ 12.6 Hz, 1H),
4.69e4.57 (m, 3H), 4.51 (d, J ¼ 10.9 Hz, 1H), 4.41e4.27 (m, 2H),
4.03e3.94 (m, 3H), 3.91 (s, 3H), 3.80 (dd, J ¼ 10.3, 3.5 Hz, 1H),
3.77e3.66 (m, 2H), 3.60 (t, J ¼ 9.4 Hz, 1H), 3.54 (dd, J ¼ 9.6, 3.5 Hz,
1H), 3.37 (s, 3H), 2.12e1.96 (m, 2H), 1.78 (dq, J ¼ 12.5, 6.1 Hz, 2H);
Rf ¼ 0.27 (petroleum ether/EtOAc ¼ 1:1); [
a
]
¼ þ11.5 (c ¼ 1.0,
D
CH2Cl2); [
a
]
¼ þ39.9 (c ¼ 0.27, CH2Cl2); 1H NMR (400 MHz, CDCl3):
D
d
¼ 7.64(d, J ¼ 7.7Hz,1H), 7.52(d, J ¼ 1.9Hz,1H), 7.47 (s,1H), 7.38e7.25
(m, 14H), 7.23e7.18 (m, 2H), 7.05 (dd, J ¼ 8.2, 2.5 Hz, 1H), 4.97 (d,
J ¼ 10.9 Hz, 1H), 4.86e4.74 (m, 3H), 4.71 (d, J ¼ 12.6 Hz, 1H), 4.65 (d,
J ¼ 12.2 Hz, 1H), 4.63e4.55 (m, 2H), 4.51 (d, J ¼ 4.8 Hz, 1H), 4.47 (d,
J ¼ 7.2 Hz, 2H), 4.01e3.92 (m, 3H), 3.90 (s, 3H), 3.75 (ddd, J ¼ 14.9, 10.1,
3.4 Hz, 2H), 3.68 (d, J ¼ 10.1 Hz, 1H), 3.58 (t, J ¼ 9.3 Hz, 1H), 3.53 (dd,
J ¼ 9.6, 3.5 Hz,1H), 3.35 (s, 3H), 2.38e2.28(m, 2H);13C NMR (101MHz,
13C NMR (101 MHz, CDCl3):
d
¼ 166.9, 158.7, 145.0, 138.8, 138.3,
138.2, 131.5, 129.5, 128.5, 128.4, 128.4, 128.2, 128.0, 127.9, 127.8,
127.7, 127.6, 122.4, 122.2, 119.8, 114.6, 98.2, 82.1, 79.8, 77.6, 75.8,
75.0, 73.4, 70.0, 68.9, 67.1, 65.0, 55.2, 52.2, 49.9, 27.2, 26.1; HRE-
SIMS: calcd for C43H49N3O9þNa: 774.3367; found: m/z 774.3361.
CDCl3):
d
¼ 166.7, 158.3, 144.8, 138.7, 138.3, 138.1, 131.5, 129.5, 128.4,
128.4, 128.3, 128.1, 127.9, 127.8, 127.7, 127.6, 127.5, 122.9, 122.4, 119.6,
114.7, 98.2, 82.0, 79.8, 77.5, 75.7, 74.9, 73.3, 69.9, 68.7, 64.8, 64.2, 55.1,
52.1, 46.9, 29.7; HRESIMS: calcd for C42H47N3O9þNa: 760.3210;
found: m/z 760.3215.
4.1.5. Methyl 2-hydroxy-5-(4-(4-((((2R,3R,4S,5R,6S)-3,4,5-
tris(benzyloxy)-6-methoxytetra hydro-2H-pyran-2-yl)methoxy)
methyl)-1H-1,2,3-triazol-1-yl)butoxy)benzoate (17)
From compound 8 (127.3 mg, 0.48 mmol), compound a (240 mg,
0.48 mmol), column chromatography (petroleum ether/EtOAc ¼ 1:4)
afforded compound 17 as a yellow syrup (303.8 mg, 82.5%); Rf ¼ 0.57
4.1.2. Methyl 2-hydroxy-5-(3-(4-((((2R,3R,4S,5R,6S)-3,4,5-
tris(benzyloxy)-6-methoxytetra hydro-2H-pyran-2-yl)methoxy)
methyl)-1H-1,2,3-triazol-1-yl)propoxy)benzoate (14)
(petroleum ether/EtOAc ¼ 1:4); [
a
]
¼ þ44.2 (c ¼ 0.05, CH2Cl2); 1H
D
From compound 5 (120.6 mg, 0.48 mmol), compound a (240 mg,
0.48 mmol), column chromatography (petroleum ether/EtOAc ¼ 1:4)
afforded compound 14 as a yellow syrup (287.6 mg, 79.5%); Rf ¼ 0.56
NMR (400 MHz, CDCl3):
d
¼ 10.36 (s, 1H), 7.48 (s, 1H), 7.41e7.26 (m,
13H), 7.25e7.17(m, 3H), 7.04(dd, J¼ 9.0, 2.9Hz,1H), 6.91(d, J¼ 9.0Hz,
1H), 4.97 (d, J ¼ 10.8 Hz,1H), 4.82(t, J ¼ 9.7Hz, 2H), 4.78 (d, J ¼ 10.1 Hz,
1H), 4.72 (d, J ¼ 12.6 Hz, 1H), 4.68e4.56 (m, 3H), 4.51 (d, J ¼ 11.0 Hz,
1H), 4.34 (t, J ¼ 6.9 Hz, 2H), 4.02e3.95 (m, 1H), 3.94 (s, 3H), 3.89 (t,
J ¼ 5.8 Hz, 2H), 3.76 (ddd, J ¼ 27.9,13.8, 6.9 Hz, 3H), 3.60 (t, J ¼ 9.4 Hz,
1H), 3.53 (dd, J ¼ 9.6, 3.3 Hz, 1H), 3.37 (s, 3H), 2.10e1.99 (m, 2H),
(petroleum ether/EtOAc ¼ 1:4); [
a
]
¼ þ32.6 (c ¼ 0.1, CH2Cl2); 1H
D
NMR (400 MHz, CDCl3):
d
¼ 10.38 (s, 1H), 7.46 (s, 1H), 7.39e7.26 (m,
13H), 7.24 (d, J ¼ 3.1 Hz,1H), 7.23e7.17 (m, 2H), 7.04 (dd, J ¼ 9.0, 3.1 Hz,
1H), 6.91 (d, J ¼ 9.0 Hz,1H), 4.97 (d, J ¼ 10.9 Hz,1H), 4.82 (t, J ¼ 8.9 Hz,
2H), 4.78 (d, J ¼ 9.7 Hz, 1H), 4.70 (d, J ¼ 12.6 Hz, 1H), 4.65 (d,
1.81e1.68 (m, 2H); 13C NMR (101 MHz, CDCl3):
d
¼ 170.2,156.2,151.1,

C. Li et al. / European Journal of Medicinal Chemistry 46 (2011) 4212e4218
4217
145.0,138.8,138.3,138.2,128.5,128.4,128.4,128.2,128.0,127.9,127.8,
127.7, 127.6,124.4,122.4,118.6,112.8,111.9, 98.2, 82.1, 79.8, 77.6, 75.8,
75.0, 73.4, 70.0, 68.9, 67.6, 65.0, 55.2, 52.4, 49.9, 27.2, 26.2; HRESIMS:
calcd for C43H49N3O10 þ Na: 790.3316; found: m/z 790.3316.
52.3, 50.1, 29.9, 28.6, 23.1; HRESIMS: calcd for C44H51N3O10 þ Na:
804.3472; found: m/z 804.3472.
4.1.9. Methyl 3-hydroxy-5-(5-(4-((((2R,3R,4S,5R,6S)-3,4,5-
tris(benzyloxy)-6-methoxytetra hydro-2H-pyran-2-yl)methoxy)
methyl)-1H-1,2,3-triazol-1-yl)pentyloxy)benzoate (21)
From compound 12 (166.7 mg, 0.60 mmol), compound a (300 mg,
0.60 mmol), column chromatography (petroleum ether/EtOAc ¼ 1:4)
afforded compound 21 as a pale yellow syrup (408.5 mg, 87.6%);
4.1.6. Methyl 3-hydroxy-5-(4-(4-((((2R,3R,4S,5R,6S)-3,4,5-
tris(benzyloxy)-6-methoxytetra hydro-2H-pyran-2-yl)methoxy)
methyl)-1H-1,2,3-triazol-1-yl)butoxy)benzoate (18)
From compound 9 (158.4 mg, 0.60 mmol), compound a (300 mg,
0.60 mmol), column chromatography (petroleum ether/EtOAc ¼ 1:4)
afforded compound 18 as a pale yellow syrup (413.8 mg, 90.3%);
Rf ¼ 0.54 (petroleum ether/EtOAc ¼ 1:4); [
a
]
¼ þ45.1 (c ¼ 0.28,
D
CH2Cl2); 1H NMR (400 MHz, CDCl3):
d
¼ 7.45 (s, 1H), 7.37e7.25 (m,
Rf ¼ 0.45 (petroleum ether/EtOAc ¼ 1:4); [
a
]
¼ þ36.5 (c ¼ 0.25,
13H), 7.23e7.19 (m, 2H), 7.13 (s, 1H), 7.07 (s, 1H), 6.58 (s, 1H), 4.97 (d,
J ¼ 10.9 Hz,1H), 4.87e4.74 (m, 3H), 4.71 (d, J ¼ 12.6 Hz,1H), 4.67e4.56
(m, 3H), 4.51 (d, J ¼ 10.9 Hz,1H), 4.34e4.21 (m, 2H), 3.98 (t, J ¼ 9.3 Hz,
1H), 3.91 (t, J ¼ 6.1 Hz, 2H), 3.86 (s, 3H), 3.83e3.69 (m, 3H), 3.60 (t,
J ¼ 9.3 Hz,1H), 3.53 (dd, J ¼ 9.6, 3.5 Hz,1H), 3.35 (s, 3H),1.95e1.83 (m,
2H), 1.80e1.69 (m, 2H), 1.48e1.38 (m, 2H); 13C NMR (101 MHz,
D
CH2Cl2); 1H NMR (400 MHz, CDCl3):
d
¼ 7.48 (s, 1H), 7.37e7.24 (m,
13H), 7.23e7.18 (m, 2H), 7.14 (s, 1H), 7.06 (s, 1H), 6.58 (s, 1H), 4.97 (d,
J ¼ 10.9 Hz,1H), 4.89e4.74 (m, 3H), 4.70 (d, J ¼ 12.6 Hz,1H), 4.67e4.56
(m, 3H), 4.51 (d, J ¼ 11.0 Hz, 1H), 4.32 (t, J ¼ 6.9 Hz, 2H), 3.98 (t,
J ¼ 9.3 Hz,1H), 3.91 (t, J ¼ 5.8 Hz, 2H), 3.86 (s, 3H), 3.82e3.68 (m, 3H),
3.59 (t, J ¼ 9.3 Hz, 1H), 3.53 (dd, J ¼ 9.6, 3.5 Hz, 1H), 3.35 (s, 3H),
2.09e1.95 (m, 2H), 1.77e1.67 (m, 2H); 13C NMR (101 MHz, CDCl3):
CDCl3):
d
¼ 167.2, 160.1, 158.1, 144.9, 138.8, 138.4, 138.2, 132.0, 128.6,
128.6,128.6,128.3,128.2, 128.1,128.0,127.9, 127.8, 122.8,109.8,107.5,
107.0, 98.3, 82.2, 80.0, 77.7, 75.9, 75.1, 73.5, 70.1, 69.1, 67.7, 64.9, 55.4,
52.4, 50.4, 29.9, 28.5, 23.2; HRESIMS: calcd for C44H51N3O10 þ Na:
804.3472; found: m/z 804.3471.
d
¼ 167.2, 160.0, 158.1, 138.8, 138.4, 138.2, 132.1, 128.6, 128.6, 128.6,
128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 109.9, 107.3, 107.0, 98.3, 82.2,
80.0, 77.7, 75.9, 75.1, 73.5, 70.1, 69.1, 67.2, 64.9, 55.4, 52.4, 50.2, 27.2,
26.2; HRESIMS: calcd for C43H49N3O10 þ Na: 790.3316; found: m/z
790.3318.
4.2. Inhibitory assay
4.1.7. Methyl 3-(5-(4-((((2R,3R,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-
methoxytetrahydro-2H- pyran-2-yl)methoxy)methyl)-1H-1,2,3-
triazol-1-yl)pentyloxy)benzoate (19)
From compound 10 (112.7 mg, 0.43 mmol), compound a (215 mg,
0.43 mmol), column chromatography (petroleum ether/EtOAc ¼ 1:1)
afforded compound 19 as a pale yellow syrup (312.1 mg, 95.2%);
Recombinant human PTP1B catalytic domain was expressed and
purified according to procedures described previously [23]. Enzy-
matic activity of PTP1B was determined at 30 ꢂC by monitoring the
hydrolysis of pNPP. Dephosphorylation of pNPP generates product
pNP, which can be monitored at 405 nm. In a typical 100 mL assay,
mixture containing 50 mM MOPS, pH 6.5, 2 mM pNPP and
recombinant enzymes, PTP1B activities were continuously moni-
tored on a SpectraMax 340 microplate reader at 405 nm for 2 min at
30 ꢂC and the initial rate of the hydrolysis was determined using the
early linear region of the enzymatic reaction kinetic curve. For
calculating IC50 values, inhibition assays were performed with
30 nM recombinant enzyme, 2 mM pNPP in 50 mM MOPS at pH 6.5,
and the inhibitors diluted around the estimated IC50 values. IC50
was calculated from the nonlinear curve fitting of percent inhibi-
tion (inhibition (%)) vs. inhibitor concentration [I] by using the
following equation: inhibition (%) ¼ 100/{1 þ(IC50/[I])k}, where k is
the Hill coefficient. To study the inhibition selectivity on other PTP
family members, human TCPTP, SHP-1, SHP-2 and LARD1 were
prepared and assays were performed according to procedures
described previously [24].
Rf ¼ 0.17 (petroleum ether/EtOAc ¼ 3:5); [
a
]
¼ þ36.6 (c ¼ 0.15,
D
CH2Cl2); 1H NMR (400 MHz, CDCl3):
d
¼ 7.62 (d, J ¼ 7.7 Hz, 1H), 7.52
(dd, J ¼ 2.4, 1.5 Hz, 1H), 7.46 (s, 1H), 7.38e7.25 (m, 14H), 7.23e7.18 (m,
2H), 7.06 (ddd, J ¼ 8.2, 2.6, 0.8 Hz, 1H), 4.97 (d, J ¼ 10.9 Hz, 1H),
4.88e4.75 (m, 3H), 4.72 (d, J ¼ 12.6 Hz, 1H), 4.69e4.58 (m, 3H), 4.51
(d, J ¼ 10.9 Hz,1H), 4.34e4.20 (m, 2H), 4.02e3.93 (m, 3H), 3.90 (s, 3H),
3.80 (dd, J ¼ 10.2, 3.4 Hz, 1H), 3.77e3.68 (m, 2H), 3.60 (t, J ¼ 9.3 Hz,
1H), 3.54 (dd, J ¼ 9.6, 3.6 Hz, 1H), 3.37 (s, 3H), 1.97e1.86 (m, 2H),
1.85e1.74 (m, 2H), 1.54e1.43 (m, 2H); 13C NMR (101 MHz, CDCl3):
d
¼ 167.2, 159.1, 139.0, 138.5, 138.4, 131.7, 129.6, 128.7, 128.6, 128.6,
128.4, 128.2, 128.1, 128.0, 127.9, 127.8, 122.2, 120.1, 114.8, 98.4, 82.3,
80.0, 77.8, 76.0, 75.2, 73.6, 70.2, 69.0, 67.8, 65.2, 55.4, 52.4, 50.3, 30.2,
28.7, 23.4; HRESIMS: calcd for C44H51N3O9þNa: 788.3523; found: m/z
788.3524.
4.1.8. Methyl 2-hydroxy-5-(5-(4-((((2R,3R,4S,5R,6S)-3,4,5-
tris(benzyloxy)-6-methoxytetra hydro-2H-pyran-2-yl)methoxy)
methyl)-1H-1,2,3-triazol-1-yl)pentyloxy)benzoate (20)
From compound 11 (134.1 mg, 0.48 mmol), compound a (240 mg,
0.48 mmol), column chromatography (petroleum ether/EtOAc ¼ 1:5)
afforded compound 20 as a pale yellow syrup (298.5 mg, 79.6%);
4.3. Molecular docking study
Plausible binding modes of compounds 22e30 with PTP1B were
proposed via docking simulation by starting with a crystal structure
in complex with a reference ligand (PDB code: 3EB1, resolution:
2.40 Å) [13]. Water was removed from the original structure, and
the rest protein was prepared using the “Protein preparation
wizard” protocol [26]. Hydrogens were added, bond orders were
assigned and overlaps were treated. The impref utility was run to
perform restrained optimizations of the protein. The compound
was prepared using Ligprep [26]. OPLS2005 Force field were
employed, and Epik were used to perform the ionization. Chiralities
were corrected. Then the compounds were docked to the active site
of the protein using the Induced Fit Docking protocol [26]. The
center atom was set to be a virtual center of referenced key resi-
dues: Phe182, Cys215 and Gly259 [27]. Each ligand was initially
docked by Glide, then the proteineligand complex was minimized
by Prime, and the complex structure was redocked by Glide within
a specified energy of the lowest-energy structure.
Rf ¼ 0.59 (petroleum ether/EtOAc ¼ 1:4); [
a
]
¼ þ39.3 (c ¼ 0.12,
D
CH2Cl2); 1H NMR (400 MHz, CDCl3):
d
¼ 10.39 (s, 1H), 7.46 (s, 1H),
7.38e7.26 (m, 13H), 7.25 (d, J ¼ 3.1 Hz, 1H), 7.23e7.18 (m, 2H), 7.04
(dd, J ¼ 9.0, 3.1 Hz, 1H), 6.90 (d, J ¼ 9.0 Hz, 1H), 4.97 (d, J ¼ 10.8 Hz,
1H), 4.87e4.80 (m, 2H), 4.79 (d, J ¼ 7.7 Hz, 1H), 4.72 (d, J ¼ 12.6 Hz,
1H), 4.66 (d, J ¼ 12.2 Hz, 1H), 4.64e4.57 (m, 2H), 4.50 (d, J ¼ 10.9 Hz,
1H), 4.34e4.20 (m, 2H), 3.98 (t, J ¼ 9.3 Hz, 1H), 3.94 (s, 3H), 3.87 (t,
J ¼ 6.2 Hz, 2H), 3.80 (dd, J ¼ 10.2, 3.2 Hz, 1H), 3.77e3.66 (m, 2H), 3.61
(t, J ¼ 9.4 Hz, 1H), 3.53 (dd, J ¼ 9.6, 3.5 Hz,1H), 3.36 (s, 3H), 1.96e1.84
(m, 2H), 1.81e1.71 (m, 2H), 1.52e1.40 (m, 2H); 13C NMR (101 MHz,
CDCl3):
d
¼ 170.2, 156.1, 151.2, 144.9, 138.8, 138.3, 138.1, 128.4, 128.4,
128.4, 128.1, 128.0, 127.9, 127.8, 127.7, 127.6, 124.5, 122.3, 118.5, 112.8,
111.8, 98.2, 82.0, 79.8, 77.5, 75.7, 75.0, 73.3, 69.9, 68.8, 68.1, 65.0, 55.2,

4218
C. Li et al. / European Journal of Medicinal Chemistry 46 (2011) 4212e4218
F. Bakir, L. Judge, M. Shahbaz, T. Collins, T. Vo, M.J. Newman, W.C. Ripka,
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Project supported by National Natural Science Foundation of
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