Design and synthesis of 2-substituted benzoxazoles as novel PTP1B inhibitors

Article abstract of DOI:10.1016/j.bmcl.2013.02.109

A series of benzoxazole compounds containing oxamic acid were synthesized and screened for the PTP1B inhibition. Compound 31d showed best biochemical potency (K_i) of 6.7 μM. Structure-activity relationship were explained with the help of molecular modeling approach.

Full text of DOI:10.1016/j.bmcl.2013.02.109

Bioorganic & Medicinal Chemistry Letters 23 (2013) 2579–2584
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design and synthesis of 2-substituted benzoxazoles as novel
PTP1B inhibitors
a
b
a
Arun P. Chandrasekharappa a, , Sangamesh E. Badiger , Pramod K. Dubey , Sunil K. Panigrahi ,
⇑
Sekhar Reddy V. V. V. Manukonda a
a Aurigene Discovery Technologies Limited, 39-40, KIADB Industrial Area, Phase II, Electronic City, Hosur Road, Bangalore 560 100, India
b Department of Chemistry, JNTUH College of Engineering, Hyderabad 500 085, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of benzoxazole compounds containing oxamic acid were synthesized and screened for the PTP1B
Received 14 August 2012
Revised 22 February 2013
Accepted 26 February 2013
Available online 7 March 2013
inhibition. Compound 31d showed best biochemical potency (Ki) of 6.7 lM. Structure–activity relation-
ship were explained with the help of molecular modeling approach.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Benzimidazole
Benzoxazole
Oxamic acids
PTP1B
Diabetes
pTyr mimetics
Protein tyrosine phosphatases constitute a large family of sig-
naling enzymes that control several fundamental cellular functions
via phosphorylation and dephosphorylation reactions.1–5 Among
PTP’s the aberrant expression of Protein tyrosine phosphatase 1B
(PTP1B) can contribute to diabetes and obesity.6–8 Independent
studies from two laboratories showed that PTP1B knockout mice
exhibit phenotypes of increased insulin sensitivity, improved glu-
cose tolerance and resistance to high fat induced weight gain all
without any adverse effects.9,10 After establishing the PTP1B as
an effective target for treatment of both type 2 diabetes and obes-
ity, a lot of efforts were made in the development of potent and
selective inhibitors. Designing selective PTP1B inhibitors is a big
challenge since PTP1B has highly conserved active site which is
found in most of the other PTP’s, especially T-cell protein tyrosine
phosphatase (TCPTP), a major hurdle in the development of safe
and effective PTP1B inhibitors.11,12 There exists a second non cata-
lytic binding site adjacent to the active site in PTP1B which has
been explored for selectivity. PTP1B active site contains phospho-
tyrosine (pTyr) containing two negative charges at physiological
pH. Therefore most of the competitive PTP1B inhibitors have high
charge density mimicking pTyr which limits their drug-like prop-
erties with limited cell permeability or bioavailability.
Many competitive inhibitors reported contains highly charged
anions that mimic the pTyr substrate 1, such as dif-
luoromethylphosphonates (DFMP) 2, carboxymethylsalicyclic
acids (CMS) 3, and oxalylaminobenzoic acids (OBA) 4 (Fig. 1). Com-
pound 513 reported earlier has shown good inhibitory potency
against PTP1B (Ki = 18 nM) as it had a benzoic acid and a diaryl
oxamic acid, a catalytic site binding pharmacophore, but it has
exhibited very low cell permeability. Compound 614 reported by
the same group had only monoaryl oxamic acid at para position
exhibited moderate inhibitory (with R = Boc, Ki = 8.8 lM and with
R = Ac, Ki = 6.1 l
M) activity towards PTP1B. Compounds 7a15 and
7b,16 are nonpeptidic sulfonamide containing novel (S)-isothiazo-
lidinone ((S)-IZD) which are pTyr mimetics having IC50 of 32 nM
and 100 nM respectively.
Based on the above literature data, we designed a series of
benzimidazole and benzoxazole molecules. These designs were
prioritized based on molecular docking studies in both PTP1B
and TCPTP X-ray structures. Molecular docking study was carried
out in PDB ID: 2VEU16 and 1L8K corresponding to PTP1B and TCPTP
respectively. These proteins were prepared using protein prepara-
tion wizard in the Schrodinger software (Version 2011). 3-D struc-
ture of all synthesized compounds was prepared using ligprep17
module of Schrodinger software (Version 2.5) prior to docking.
Docking was carried out in GOLD18 version 5.1 using very flexible
docking methods, which represent high precision docking protocol
using GoldScore.
⇑
Corresponding author. Tel.: +91 8028521314.
E-mail address: arun_pc@aurigene.com (A.P. Chandrasekharappa).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.02.109

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A. P. Chandrasekharappa et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2579–2584
O
P
F
F
OH
O
OH
OH
O
O
O
OH
HO
HN
O
O
OH
OH
H
N
H
N
O
O
O
P
O
OH
OH
HO
O
N
H
O
P
NH2
F
O
O
OH
O
F
1
2
3
4
pTyr
DFMP
OBA
CMS
O
HO
NH
HO
O
O
O
O
S
O
O
O
NH
N
NH
N
O
O
NH
OH
O
OH
O
O
N
NH
S
S
O
O
HO
O
F
F
O
O
O
N
N
H
O
S
O
H
N
H
N
H
N
HN
F
O
R
O
O
5
7b
6
7a
Figure 1. Structures of some known pTyr mimetics and literature known compounds.
Table 1
benzoxazole compounds with oxamic acid containing compounds
showed better activity compared to the other compounds. Substitu-
tion on the sulfonamide with methyl group reduced potency
significantly.
Inhibitory activities of the synthesized compounds against PTP1B
R3
Molecular docking study on compound (19b) suggests oxamic
acid found to be hydrogen bonded to with key residues like Ser-
216, Ala-217, Gly-218, Ile-219, Arg-221 at site A (Fig. 2). These
are the same residues that interact with p-Tyr. Thus oxamic acid
was found to be a good replacement of highly charged p-Tyr motif.
It is evident from modeling study that 4-fluorobenzene ring of the
R2
N
S
X
F
O
N
O
R1
Entry
X
R1
R2
R3
PTP1B Ki (lM)
R–isomer26 found to be stabilized by a
p-stacking interaction with
16
NH
NH
NH
NH
O
H
H
H
H
H
H
Me
CO2H
H
OH
H
OH
OH
H
>500
162
67.5
211.5
66.5
35
residue Phe-182. Compound 19b benzoxazole moiety is positioned
at Site-B. Comparing binding model of 19a and 19b with respect to
benzimidazole and benzoxazole, we could not observe any differ-
ence in terms of additional interaction at Site-B. However due to
favorable electronegativity of oxygen in benzoxazole compared
to benzimidazole nitrogen 19b shows better potency. Compound
19c contains benzimidazole and methyl substitution at sulfon-
amide position showed less PTP1B biochemical potency compared
to 19a. Loss of potency in the case of compound 19c can be ex-
plained based on the fact that methyl incorporation at sulfonamide
20a
19a
18c
20b
19b
19c
OCH2CO2H
NHCOCO2H
OH
OCH2CO2H
NHCOCO2H
NHCOCO2H
O
NH
H
125
Molecules prioritized based on modeling study were synthe-
sized. Biochemical potency of these compounds was determined
in both PTP1B and TCPTP enzymes, results is summarized show in
Table 1. Synthesis of benzimidazole and benzoxazole derivatives
16–20 is outlined in Scheme 1. Initially benzimidazole and benzox-
azole molecules were synthesized using the 4-fluorobenzene
sulfonamide as scaffold and by changing the pharmacophore group.
Ethyl bromoacetate, 8 was reacted with sodium sulfite and the
resulting sodium salt 9 was reacted with phosphorous pentachlo-
ride to get the sulfonyl chloride 10. This sulfonyl chloride was
further reacted with 4-fluoroaniline to obtain the sulfonamide,
11a–b.19 The ethyl ester hydrolyzed to corresponding acids 12a–b
using aqueous potassium hydroxide. These carboxylic acids is fur-
ther reacted with the O-phenylene diamine or 2-amino phenol in
presence of Lawesson’s reagent, neat, in sealed tube at 150 °C to
get the corresponding benzimidazoles and benzoxazoles, 13a–c.20
The active methylene group of these compounds was condensed
with substituted benzaldehydes via Knoevenagel condensation
using trimethyl silyl chloride and DMF to obtain the olefins, 14a–f.21
Olefins were reduced with 10% Pd/C in methanol in presence of
hydrogen gas at pressure of 15–60 pounds per square inch (psi)
to furnish compounds 15a–f. Compounds 15a–f were reacted with
different reagents to provide compounds 16, 18c, 19a–c and 20a–b.
Biochemical potency of all these compounds was determined for
PTP1B. Among the benzimidazole and benzoxazoles synthesized,
might destabilize p-stacking interaction with residue Phe-182.
Benzoxazole are preferred at Site-B compared to benzimidazole
as observed in compound 19a. Thus oxamic acids with benzoxaz-
ole found to enhance PTP1B biochemical potency so to further ana-
lyze the SAR, we thought of modifying the sulfonamide group with
different substitutions.
For effecting such a change, we followed similar scheme which
is shown in the Scheme 1. As it is explained in the Scheme 2 the
sulfonyl chloride, 10 was reacted with t-butyl amine in presence
of triethyl amine to get the sulfonamide 21. The ester was hydro-
lyzed to get the acid, 22 and was reacted with 2-aminophenol in
presence of Lawesson’s reagent as reported earlier to yield benzox-
azole 23. This was condensed with 4-nitrobenzaldehyde via Knoe-
venagel condensation, using trimethyl silyl chloride and DMF to
furnish the olefin 24. Both the olefin and nitro groups were reduced
using 10% Pd/C under 60 psi hydrogen pressure. The amine 25 was
reacted with ethyl oxalyl chloride to form the oxamic acid ethyl es-
ter 26. Removal of the tertiary group of compound 26 by trifluoro-
acetic acid furnished the desired primary sulfonamide 28.
Sulfonamide was reacted with alkyl halides to get mono as well
as disubstituted products, 30,22 which upon hydrolysis furnished
oxamic acids, 31. Similarly sulfonamide 28 was reacted with acid

A. P. Chandrasekharappa et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2579–2584
2581
R1
O
S
O
N
O
O
S
O
O
O
O
O
Na
ii
iii
i
O
S
Br
Cl
O
O
O
O
10
F
O
11
1
9
8
11a
, R = H
11b,
R
1 = Me
R1
R2
R3
N
F
N
X
R1
N
O
OH
O
F
S
X
N
vi
iv
O
v
O
F
S
S
N
O
1
O
O
R1
1
, R1 = H, X = NH, R2=NO2, R3 = H
12a
12b
, R = H
13a
13b
14a
, R = H, X = NH
, R1 = Me
, R1 =H, X = O
14b, R1 = H, X =O, R2 =NO2, R3 = H
13c, R1 = Me, X = NH
14c, R1 = H, X = NH, R2 =CO2Me, R3 = H
14d, R1 = H, X = NH, R2 =OCH2CO2Et, R3 = OMe
, R1 = H, X = O, R2 =OCH2CO2Et, R3 = OMe
, R1 = H, X = NH, R2 =OH, R3 = OMe
14e
14f
14f, R1 = H, X = NH, R2 =NO2, R3 = H
R3
R3
R3
R2
N
X
R2
F
viii
R2
N
X
N
S
X
vii
ix
F
F
O
S
O
O
S
N
N
N
O
O
O
R1
R1
R1
, R1 = H, X = NH, R2 =NH2, R3 = H
, R1 = H, X = NH, R2 =NHCOCO2Et, R3 = H
15a
15b
, R1 = H, X = NH, R2=NHCOCO2H, R3 = H
17a
17b
19a
19b
, R1 = H, X =O, R2 =NH2, R3 = H
, R1 = H, X = O, R2 =NHCOCO2Et, R3 = H
, R = H, X = O, R2 =NHCOCO2H, R3 = H
1
15c, R1 = H, X = NH, R2 =CO2Me, R3 = H
17c, R1 = Me, X = NH, R2 =NHCOCO2Et, R3 = H
19c, R1 = Me, X = NH, R2 =NHCOCO2H, R3 = H
15d, R1 = H, X = NH, R3 =OCH2CO2Et, R3 = OMe
15e, R1 = H, X = O, R2 =OCH2CO2Et, R3 = OMe
, R1 = H, X = NH, R2 =OH, R3 = OMe
, R1 = H, X = NH, R2 =NH2, R3 = H
15f
15f
x
viii
R3
R3
R2
X
N
S
X
R2
N
S
viii
F
F
R3
O
O
R2
N
S
X
N
R
N
R
F
O
O
O
, R1 = H, X = NH, R2 =OCH2CO2Et, R3 = OH
, R = H, X = NH, R2 =OCH2CO2H, R3 = OH
1
18a
18b
20a
20b
N
R
, R = H, X = O, R2 =OCH2CO2Et, R3 = OH
, R1 = H, X = O, R2 =OCH2CO2H, R3 = OH
O
1
18c, R1 = H, X = NH, R2=OH, R3 = OH
16, R1 = H, X = NH, R2 =CO2H, R3 = H
Scheme 1. Reagents and conditions: (i) Sodium bisulfite, ethanol/H2O, rt, 16 h; (ii) PCl5, neat, 100 °C, 4 h; (iii) 4-Fluoroaniline or N-methyl 4-fluoro aniline, Et3N, DCM, 0 °C to
rt, 16 h; (iv) KOH, THF, H2O,rt, 4 h; (v) (a) O-Phenylene diamine, or 2-amino phenol, Lawesson’s reagent, 150 °C, sealed tube, 2 h; (vi) substituted benzaldehydes, TMSCl, DMF,
135 °C, sealed tube, 4 h; (vii) 10% Pd/C, MeOH, 1–4 Kg H2, 4–16 h; (viii) KOH, THF/H2O, rt, 4 h; (ix) Ethyl oxalyl chloride, DMAP, DCM, 0 °C to rt,16 h; (x) BBr3, DCM, À40 to 0 °C,
1 h.
chlorides to give sulfomoyl amides, 3223 and upon hydrolysis
yielded 33. Monophenyl sulfonamides, 34 were prepared by
Chan–Lam coupling,24 using copper(ii)acetate and after hydrolysis
furnished oxamic acids 35. For all the synthesized compounds
in vitro assay was carried out and the results obtained are shown
in Tables 2–4.
All assays were carried out using a standard protocol. The 50 lL
reaction was carried out at room temperature in a buffer consisting
of 25 mM Tris pH 7.5, 75 mM NaCl, 1 mM DTT and 0.1% BSA. The
reaction was started by adding PTP1B protein at 5 nM concentra-
tions. The diluted compounds ranging from 10 mM to 0.1 lM con-
centration were added to the reaction mixtures in a 96 well plate.
The reaction was terminated after 60 min by 1NaOH. The absor-
bance values of the p-nitrophenol were measured at 405 nm using
spectrophotometer (spectra MAX190). Enzymatic activity was
determined by measuring the absorbance values of 4-nitrophenol
with the appropriate correction for the substrate pNPP and the
absorbance of the compounds. Assays were carried out keeping
Figure 2. Docking model of compound 19b (yellow, R-isomer) in PTP1B phospho-
tyrosine binding site. X-ray structure of one of the potent compound16 from
literature (compound 7b (S-isomer), PTP1B IC50 = 100 nM, TCPTP IC50 = 61 nM)
shown in cyan color.
the sodium orthovanadate (Ki = 0.67 l
M)25 as reference com-
pound. The inhibition (Ki) values were obtained by fitting the data
using non linear regression hyperbolic fit to Michaelis–Menten

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A. P. Chandrasekharappa et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2579–2584
O
S
O
O
O
S
O
21
O
O
S
O
O
O
S
O
N
H
N
iii
H
N
i
ii
H
N
Cl
O
O
OH
O
10
23
22
O
S
O
N
O
S
O
N
O
S
O
N
O
S
O
N
HN
H
N
H
N
O
HN
O
O
O
iv
vi
xi
v
O
O
O
N
H
O
N
H
O2N
H2N
O
26
25
27
24
OH
R4
N
R4
N
O
O
O
S
H, R4
O
S
H,R4
xi
N
O
N
O
O
viii
O
HO
N
H
O
N
H
O
O
O
31
30
O
S
O
N
H
O
H2N
O
R5
H
N
O
O
S
O
N
R5
xi
vii
S
N
N
O
O
O
ix
O
O
O
O
N
H
HO
O
N
H
O
28
N
H
33
O
32
O
xi
O
S
O
N
H
N
H
N
O
O
O
O
S
H2N
R6
S
R6
O
N
N
O
O
x
O
xi
O
O
O
HO
O
N
N
N
H
29
H
OH
H
O
O
35
34
Scheme 2. Reagents and conditions: (i) t-Butyl amine, Et3N, DCM, 0 °C to rt; (ii) KOH, THF, H2O; (iii) 2-Amino phenol, Lawesson’s reagent, 150 °C, 2 h, sealed tube; (iv) 4-Nitro
benzaldehyde, TMSCl, DMF, 135 °C, 4 h, sealed tube; (v) Pd/C, MeOH, 4 Kg H2, rt, 16 h; (vi) Ethyl oxalyl chloride, DMAP, DCM, 0 °C to rt, 16 h; (vii) TFA, 50 °C, 6 h; (viii) R4Br,
K2CO3, DMF, rt, 16h; (ix) R5COCl, K2CO3, acetone, reflux, 4 h; (x) R6B(OH)2, Cu(OAc)2, pyridine, DCM, rt, 48 h; (xi) KOH, THF/H2O, rt, 4h.
Table 2
Table 3
Inhibitory activities of the alkylated compounds against PTP1B and TCPTP
Inhibitory activities of the aryl compounds against PTP1B and TCPTP
R4
N
H
N
O
O
O
S
O
S
R4
R5
N
N
O
O
O
O
HO
HO
N
H
N
H
O
O
Entry
R4
R4
PTP1B Ki (
l
M)
TCPTP Ki (
lM)
Entry
R5
PTP1B Ki (
l
M)
TCPTP Ki (lM)
29
27
H
t-Bu
n-Bu
CH2CH2(4-Cl Ph)
4-FBn
4-ClBn
2-CF3Bn
3-CF3Bn
4-CF3Bn
4-OMeBn
4-OCF3Bn
4-t-BuBn
CH2CO2H
H
H
H
H
331
228
82.4
41
136.5
135
33.4
—
—
3.7
—
35a
35b
35c
35d
4-MePh
4-CF3Ph
4-OMePh
4-Oi-PrPh
62
9.2
8
134
101
23.6
68.8
92
31a
31b
31c
31d
31e
31f
31g
31h
31i
31j
31k
4-Fbn
4-ClBn
10
6.7
6.8
35
7.7
14
16.8
14.9
235
2-CF3Bn
3-CF3Bn
4-CF3Bn
4-OMeBn
4-OCF3Bn
4-t-BuBn
CH2CO2H
21
potency. Introducing the n-butyl (31a) and 4-chlorophenethyl
groups (31b) on the sulfonamide slightly improved the activity.
Direct substitution of the phenyl ring to the sulfonamide pro-
vided no major increase in activity. Among the 4-fluoro (19b),
4-methyl (35a), 4-trifluoromethyl (35b), 4-methoxy (35c) and
4-isopropoxy (35d) substituted phenyl rings, 4-trifluoromethyl
substituted (35b) product showed marginally better inhibition.
Di-substitution of the benzyl groups on sulfonamide NH2 has
shown better potency in both PTP1B and TCPTP compared to the
mono substituted compounds. Molecular docking study in PTP1B
suggests compound 31d oxamic acid found to hydrogen bonded
to with key residues like Ser-216, Ala-217, Gly-218, Ile-219,
12.5
18.9
17.2
6.4
22
enzyme kinetic model. These molecules showed the moderate
activity against the PTP1B.
Compound 28, without any substitution on the sulfonamide has
shown very less inhibition towards PTP1B. Mono substitution of
the sulfonamide with tertiary butyl group (27) failed to improve

A. P. Chandrasekharappa et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2579–2584
2583
Table 4
Inhibitory activities of the acyl compounds against PTP1B and TCPTP
H
N
O
O
S
R6
N
O
O
O
HO
N
H
O
Entry
R6
PTP1B Ki (
lM)
TCPTP Ki (lM)
33a
33b
33c
Ac
Ph
4-ClPh
63
125
82.4
86.5
256
13.1
Arg-221 at site A (Fig. 3). 4-chlorobenzene ring of the R-isomer26
found to be stabilized by a -stacking interaction with residue
Figure 4. Docking model of compound 31d (yellow, R-isomer) and 29 (magenta, S-
isomer) is shown in TCPTP phosphotyrosine binding site.
p
Phe-182. Similar bioactive conformation was seen in compound
7b16 where phenyl ring attached to imidazole ring has found to
occupancy of benzylic groups at Site-A in the case of compound
31d provides better TCPTP potency compared to other compounds.
In summary, two series of compounds containing benzimid-
azole and benzoxazole were prioritized and synthesized, based
on molecular modeling studies. Novel benzoxazole series with
di-substitution on the sulfonamide showed the better inhibition
have
p-staking interaction with same residue. It is possible that
residue Tyr-46 may facilitate similar stacking interaction in Site-
A. Optimum positioning of the benzylic groups in Site-A optimizes
the
resulting in better potency. Loss of biochemical potency for 29
might be attributed to lack of any -stacking interaction with
p-stacking interaction with both residues Phe-182 and Tyr-46
p
toward PTP1B due to the
p-stacking interaction with the residue
Phe-182. With various halo substituted benzyl ring at this position
has resulted in better potency due to their highly electronegative
effect. Similarly 2-trifluoromethyl (31e) and 4-trifluoromethyl
(31g) substituted benzyl compounds shown reasonably good po-
tency but with the 3-trifluoromethyl substituted compound (31f)
there was fourfold decrease in PTP1B biochemical potency. Com-
pound 31k with disubstituted polar group acetic acid lost potency
Phe-182. Compound 31d found to be the best among these di-
substituted sulfonamide compounds reported with Ki value of
6.7 lM, due to the electronegative effect of para chloro substitu-
tion. Further investigation of these derivatives with change of
pharmacophore and in vitro assays of the benzothiazole series
are in progress and will be reported in due course.
due to the loss of the
p-stacking interaction. In similar direction,
Acknowledgments
compounds 33a, 33b and 33c with acylsulfomoyl groups on the
sulfonamide NH2 showed less potency compared to the dibenzyl
sulfonamides because of the absence of any stacking interactions
with residues Phe-182 and Tyr-46.
Docking model of compounds 31d and 29 in TCPTP suggests
these compounds are confided to Site-A (Fig. 4). Oxamic acid of
these compounds found to be hydrogen bonded with key residues
like Ser-217, Ala-218, Gly-219, Ile-220, Arg-222 at Site-A in TCPTP.
Positioning of oxamic acid along with benzoxazole at Site-A for
compound 31d and 29 found to be similar. However additional
The authors thank Aurigene Discovery Technologies, Bangalore
for funding and facilitating this research. Arun P Chandrasekharap-
pa would like to specially thank Department of Chemistry, JNTUH
College of Engineering, Hyderabad for facilitating this research
work.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.bmcl.2013.
02.109. These data include MOL files and InChiKeys of the most
important compounds described in this article.
References and notes
1. Neel, B. G.; Tonks, N. K. Curr. Opin. Cell Biol. 1997, 9, 193.
2. Hunter, T. Cell 2000, 100, 113.
3. Neel, B. G.; Tonks, N. K. Curr. Opin. Cell Biol. 2001, 13, 182.
4. Alonso, J.; Sasin, N.; Bottini, I.; Friedberg, A.; Osterman, A.; Godzik, T.; Hunter,
J.; Dixon, T.; Mustelin Cell 2004, 117, 699.
5. Schiller, K. R.; Mauro, L. J. J. Cell. Biochem. 2005, 96, 262.
6. Blume-Jensen, P.; Hunter, T. Nature 2001, 411, 355.
7. Cook, W. S.; Unger, R. H. Dev. Cell 2002, 2, 385.
8. Montalibet, J.; Kennedy, B. P. Drug Discovery Today Ther. Strateg. 2005, 2, 129.
9. Elchebly, M.; Payette, P.; Michaliszyn, E.; Cromlish, W.; Collins, S.; Loy, A. L.;
Normandin, D.; Cheng, A.; Himms-Hagen, J.; Chan, C. C.; Ramachandran, C.;
Gresser, M. J.; Tremblay, M. L.; Kennedy, B. P. Science 1999, 283, 1544.
10. Klaman, L. D.; Boss, O.; Peroni, O. D.; Kim, J. K.; Martino, J. L.; Zabolotny, J. M.;
Moghal, N.; Lubkin, M.; Kim, Y. B.; Sharpe, A. H.; Stricker-Krongrad, A.;
Shulman, G. I.; Neel, B. G.; Kahn, B. B. Mol. Cell. Biol. 2000, 20, 5479.
11. Anderson, H. S.; Iversen, L. F.; Jeppesen, C. B.; Branner, S.; Norris, K.;
Rasmussen, H. B.; Moller, K. B.; Moller, N. P. H. J. Biol. Chem. 2000, 275, 7101.
12. Burke, T. R., Jr.; Ye, B.; Akamatsu, M.; Ford, H.; Yan, X.; Kole, H. K.; Wolf, G.;
Shoelson, S. E.; Roller, P. P. J. Med. Chem. 1996, 39, 1021.
Figure 3. Docking model of compound 31d (yellow, R-isomer) and 29 (magenta, R-
isomer) shown in PTP1B phosphotyrosine binding site. X-ray structure of one of the
potent compound16 from literature (compound 7b, PTP1B IC50 = 100 nM, TCPTP
IC50 = 61 nM) shown in cyan color.

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13. Liu, G.; Xin, Z.; Liang, H.; Abad-Zapatero, C.; Hadjuk, P. J.; Janowick, D. A.;
Szczepankiewicz, B. G.; Pei, Z.; Hutchins, C. W.; Ballaron, S. J.; Stashko, M. A.;
Lubben, T.; Berg, C. E.; Rondinone, C. M.; Trevillyan, J. M.; Jirousek, M. R. J. Med.
Chem. 2003, 46, 3437.
14. Xin, Z.; Liu, G.; Abad-Zapatero, C.; Pei, Z.; Szczepankiewick, B. G.; Li, X.; Zhang,
T.; Hutchins, C. W.; Hajduk, P. J.; Ballaron, S. J.; Stashko, M. A.; Lubben, T. H.;
Trevillyan, J. M.; Jirousek, M. R. Bioorg. Med. Chem. Lett. 2003, 13, 3947.
15. Combs, A. P.; Zhu, W.; Crawley, M. L.; Glass, B.; Polam, P.; Sparks, R. B.; Modi,
D.; Takvorian, A.; McLaughlin, E.; Yue, E. W.; Wasserman, Z.; Bower, M.; Wei,
M.; Rupar, M.; Ala, P. J.; Reid, B. M.; Ellis, D.; Gonneville, L.; Emm, T.; Taylor, N.;
Yeleswaram, S.; Li, Y.; Wynn, R.; Burn, T. C.; Hollis, G.; Liu, P. C.; Metcalf, B. J.
Med. Chem. 2006, 49, 3774.
18. Jones, G.; Willett, P.; Glen, R. C.; Leach, A. R.; Taylor, R. J. Mol. Biol. 1997, 267,
727.
19. Oliver, J. E.; DeMilo, A. B. Synthesis 1975, 321.
20. Seijas, J. A.; Vázquez-Tato, M. P.; Carballido-Reboredo, M. R.; Crecente-Campo,
J.; Romar-López, L. Synlett 2007, 313.
21. Ryabukhin, S. V.; Plaskon, A. S.; Volochnyuk, D. M.; Pipko, S. E.; Shivanyuk, A.
N.; Tolmachev, A. A. J. Comb. Chem. 2007, 9, 1073.
22. Fujita, T.; Lehn, J.-M. Tetrahedron Lett. 1988, 29, 1709.
23. Uno, H.; Kurokawa, M.; Masuda, Y.; Nishimura, H. J. Med. Chem. 1979, 22, 180.
24. Chan, D. M. T.; Monaco, K. L.; Wang, R. P.; Winters, M. P. Tetrahedron Lett. 1998,
39, 2933.
25. Guo, X. L.; Shen, K.; Wang, F.; Lawrence, D. S.; Zhang, Z. Y. J. Biol. Chem. 2002,
277, 41014.
26. Supplementary data includes following documents: NMR data, experimental
procedures, docking results of each enantiomers mentioned in the main text,
compounds mol files.
16. Douty, B.; Wayland, B.; Ala, P. J.; Bower, M. J.; Pruitt, J.; Bostrom, L.; Wei, M.;
Klabe, R.; Gonneville, L.; Wynn, R.; Burn, T. C.; Liu, P. C. C.; Combs, A. P.; Yue, E.
W. Bioorg. Med. Chem. Lett. 2008, 18, 66.
17. LigPrep, version 2.5, Schrödinger, LLC., New York, NY, 2011.