Click synthesis of triazolyl phenylalaninyl and tyrosinyl derivatives as new protein tyrosine phosphatase inhibitors

Article abstract of DOI:10.1002/jhet.1517

The efficient construction of triazolyl peptidomimetics via the powerful click chemistry for the discovery of small molecule-based chemotherapeutic agents represents a promising strategy in drug development today. Herein, the synthesis of novel mono-triaz

Full text of DOI:10.1002/jhet.1517

684
Click Synthesis of Triazolyl Phenylalaninyl and Tyrosinyl Derivatives as
New Protein Tyrosine Phosphatase Inhibitors
Vol 50
a
b
c
c
b
*
*
Lei Cui, Xiao-Peng He, Li-Xin Gao, Jia Li, and Guo-Rong Chen
aCollege of Science, University of Shanghai for Science and Technology, Shanghai, China
bKey Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and
Technology, Shanghai, China
cNational 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, China
*
E-mail: jli@mail.shcnc.ac.cn
Received July 19, 2011
DOI 10.1002/jhet.1517
Published online in Wiley Online Library (wileyonlinelibrary.com).
The efficient construction of triazolyl peptidomimetics via the powerful click chemistry for the discovery
of small molecule-based chemotherapeutic agents represents a promising strategy in drug development
today. Herein, the synthesis of novel mono-triazolyl or bis-triazolyl amino acid derivatives was rapidly
achieved via microwave-assisted Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC). Subse-
quent in vitro enzymatic assay on several homologous protein tyrosine phosphatases (PTPs) identified the
triazolyl dimers as new specific inhibitors of Cell Cycle Division 25B (CDC25B) phosphatase and Protein
Tyrosine Phosphatase 1B (PTP1B).
J. Heterocyclic Chem. 50, 684 (2013).
INTRODUCTION
amide bond that is liable toward enzymatic cleavage [9].
However, studies in which these interesting compounds
were developed as protein ligands have rarely been
reported [15].
Protein tyrosine phosphatases (PTPs) are a class of func-
tional enzymes regulating the dephosphorylation processes
involved in numerous crucial biological and pathological
events. The dysfunction and overexpression of many PTPs
have been demonstrated causative toward a number of
human major diseases. Therefore, the efficient discovery
of their inhibitors featuring good bioavailability became
fairly desirable [16,17].
Herein, we described the efficient preparation of some
new mono-amino or bis-amino acid derivatives via micro-
wave-assisted click chemistry. Subsequent in vitro enzy-
matic assay identified some of the triazolyl dimers as new
CDC25B and PTP1B inhibitors with micromole-ranged
activity and good specificity over other PTPs tested.
With an everlasting objective of effectively producing
molecules having therapeutic values, Sharpless and co-
workers addressed the notion of “click chemistry” more
than one decade ago, supporting the utilization of regiose-
lective carbon-heteroatom ligation reactions toward the
synthesis of useful compound libraries [1]. The Cu(I)-
catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC)
[2,3] represents unquestionably the best example for click
chemistry, which has indeed boosted the advancement of
modern drug discovery over the past decade. Numerous
starting materials containing alkynyl or azido functional
groups have been employed as participants for the versatile
CuAAC reaction [4–8]. However, without doubt, the pri-
mary metabolites of Mother Nature, namely, the peptides,
sugars, and nucleotides are among the most ideal ones for
developing functional compounds because of their struc-
tural diversity, relatively easy modifiability and particu-
larly, high biocompatibility [9–15].
RESULTS AND DISCUSSION
Considerable efforts have been devoted to the prepara-
tion of multifunctional triazolyl peptidomimetics wherein
the structurally rigid triazole ring was used to replace the
Synthesis. Microwave irradiation is a validated synthetic
accessory for potently reducing the time consumption of
© 2013 HeteroCorporation

May 2013
Triazolyl Peptidomimetics as PTP Inhibitors
685
chemical reactions, which has also proven efficacious in
enhancing the efficiency of Cu(I)-catalyzed Huisgen [3 + 2]
1,3-dipolar cycloadditions [18]. We therefore chose to
realize the “click” synthesis of the desired triazoles under
microwave irradiation shown in Scheme 1. Our previously
prepared azido phenylalanine 1 and tyrosine 2 [19,20] via a
method established by Goddard-Borger and Stick [21] and
the mono- and di-2-N-propynyl benzene 3 and 4 [22] were
used to construct new mono-triazoles or bis-triazoles. All
microwave-assisted reactions were performed in a Yalian
system (YL8023B1) (Shanghai Yalian Microwave S&T
Co., Ltd., Shanghai, PR China).
Mono-N-propynyl benzene 3 and the azido carboxylic
ester 1 or 2 were first equivalently added to a solvent mix-
ture of CH2Cl2/DMF/water, followed by 1 equiv. Na ascor-
bate and 0.4 equiv. CuSO4Á5H2O. This mixture was then
transferred to the microwave oven (with a ramp time of
8 min until 60ꢀC). To our delight, after stirring for only
5 min, the mono-triazolyl phenylalanine 5 and tyrosine 6
were given in moderate yields of 73% and 62%, respec-
tively. However, our successive attempt with respect to
the dual click reaction of bis-N-propynyl 4 with azides 1
and 2 under the same condition failed to give the title
bis-triazoles. It has been noted that the click reactions per-
formed on a dipropargyl molecular template require acces-
sorial catalyst loading to overcome the steric hindrance
[20]. Hence, we further conducted the dual click reactions with
increased Na ascorbate (3 equiv.) and CuSO4Á5H2O (2.5 equiv.)
under microwave heating, leading successfully to the for-
mation of bis-triazolyl phenylalanine 9 and tyrosine 10 in
modest yields of 62% and 48%, respectively, within 5 min.
The obtained triazolyl esters were subsequently sub-
jected to microwave-assisted saponification in the presence
of LiOH (1.5 equiv./ester) for 5 min (with a ramp time
of 3 min until 20ꢀC), giving the final mono-triazolyl or
bis-triazolyl carboxylic acids. The mono-acids 7 and 8 were
Scheme 1. Reagents and conditions: (a) Na ascorbate, CuSO4Á5H2O, CH2Cl2/DMF/water, microwave irradiation (60 ꢀC); LiOH, MeOH/H2O, microwave
irradiation (20 ꢀC).
Journal of Heterocyclic Chemistry
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L. Cui, X.-P. He, L.-X. Gao, J. Li, and G.-R. Chen.
Vol 50
afforded in excellent yields of 95% and 90%, respectively,
whereas the bis-acids 11 and 12 were obtained in much
lesser yields of 47% and 30%, respectively. The lower
yields of the latter could possibly be ascribed to the patial
cleavage of the amide bonds under strong basic condition.
Biological assay. Some triazolyl bis-amino acids were
recently prepared and identified as novel AMPA receptor
ligand, which implied the value of triazolyl amino acids
in medicinal chemistry [15]. The bioactivities of the
prepared triazolyl amino acid derivatives 5–12 were
subsequently assessed on a panel of homologous PTPs
including CDC25B, PTP1B, TCPTP, SHP-1, SHP-2, and
LAR via our previously developed methods at a
compound concentration of 100 mg/mL [23,24].
As listed in Table 1, the mono-esters 5 and 6 and the
mono-phenylalaninyl acid 7 were inactive on all PTPs tested.
However, the mono-tyrosinyl acid 8 displayed measurable
IC50 value on CDC25B and showed no inhibitory effect on
other homologous PTPs, indicating that its additional
hydroxyl group on tyrosine residue has contribution to the
activity. Similarly, whereas the bis-phenylalaninyl ester 9
was not an inhibitor of PTPs, its tyrosinyl counterpart 10
could weakly suppress the catalytic activity of CDC25B.
The bis-acids 11 and 12 showed considerably much
enhanced inhibitory potency on both CDC25B and PTP1B
with the bis-tyrosinyl derivative 12 being slightly more
potent. These data are in accordance with former reports
elaborating that the active sites of the PTPs are prone to
accommodate polar moieties such as aryl carboxylic acids
[16,17]. Moreover, the most active compounds in this series
(11, 12) simultaneously possessed remarkable selectivity
over other homologous PTPs including TCPTP, SHP, and
LAR. This may qualify as an essential merit for the further
development of specific PTP1B and CDC25B inhibitors.
novel series of monotriazolyl- and bis-triazolyl phenylala-
ninyl and tyrosinyl derivatives. Subsequently, performed
biological assay revealed some of these triazolyl peptido-
mimetics as new CDC25B and PTP1B inhibitors with
good selectivity over other homologous PTPs tested. This
paper would therefore furnish new insights into the devel-
opment of bioactive small-molecule PTPs inhibitors on the
basis of the structurally diverse and potentially biocompat-
ible triazolyl amino acids.
EXPERIMENTAL
General.
All purchased chemicals and reagents are of
commercially high available grade. Solvents were purified by
standard procedures. 1H and 13C NMR spectra were recorded
on a Bruker AM-400 spectrometer in CDCl3 or DMSO-d6
solutions. Microwave-assisted reactions were performed in a
Yalian (YL8023B1) system at 60ꢀC with a ramp time of 8 min.
All reactions were monitored by thin-layer chromatography
(TLC) with detection by UV or by spraying with 6 N H2SO4 in
EtOH and charring at 300ꢀC. Optical rotations were measured
using a Perkin–Elmer 241 polarimeter at room temperature and
a 10-mm/1-mL cell at rt. High resolution mass spectra (HRMS)
were recorded on a Waters LCT Premier XE spectrometer using
standard conditions (ESI, 70 eV).
General procedure for the microwave-assisted click
reaction. To a solution of the alkyne (1 equiv.) and the azide
(1.0 or 2.0 equiv.) dissolved in CH2Cl2/DMF/water (1:0.5:1, V/V/V),
Na ascrobate (1–3 equiv.) and CuSO4Á5H2O (0.4–2.5 equiv.) were
added. This mixture was then transferred into the microwave oven
with vigorous stirring for 5 min (ramp time: 8 min). The solvent
was then removed in vacuum, and the residue was washed with
brine and extracted with EtOAc. The combined organic layer was
dried over MgSO4, filtered, and then concentrated to give a crude
product, which was purified by column chromatography.
(S)-methyl 2-(4-(benzamidomethyl)-1H-1,2,3-triazol-1-yl)-3-
phenylpropanoate (5). From compound 1 (103mg, 0.5 mmol)
and 3 (93mg, 0.6 mmol), Na ascorbate (99 mg, 0.5 mmol),
CuSO4Á5H2O (61 mg, 0.25 mmol), column chromatography
(petroleum ether/EtOAc, 3:1) afforded 5 as a white solid (134mg,
73%); Rf = 0.58 (petroleum ether/EtOAc = 3:2); [a]D = À100
CONCLUSION
1
(c = 0.1, CH2Cl2); H NMR (400 MHz, CDCl3): d = 7.79 (d, 2H,
To summarize, we realized in this study the efficient and
prompt microwave-assisted click ligation synthesis of
J = 7.2 Hz), 7.70 (s, 1H), 7.50 (t, 1H, J = 7.2 Hz), 7.42 (t, 2H,
Table 1
Inhibitory activities of compounds 5–12 on PTPs.
IC50 (mM)a
Compound
CDC25B
PTP1B
TCPTP
SHP-1
SHP-2
LAR
5
6
7
8
> 140
> 140
> 140
> 140
> 140
> 140
> 140
> 140
> 140
> 140
> 140
> 140
> 140
> 140
> 140
> 140
> 140
> 140
> 140
> 140
> 140
> 140
> 140
> 140
> 140
> 140
> 140
> 140
> 140
> 140
> 140
> 140
> 140
> 140
> 140
> 140
> 140
> 140
> 140
> 140
79.5 Æ 21.7
9
> 140
10
11
12
113.9 Æ 26.7
31.9 Æ 5.4
24.7 Æ 1.3
> 140
54.9 Æ 1.7
42.4 Æ 2.3
a)
Values in the table are means of three experiments.
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Triazolyl Peptidomimetics as PTP Inhibitors
687
J = 7.6 Hz), 7.19–7.17 (m, 3H), 7.03–7.01 (m, 3H), 5.54 (dd, 1H,
J = 6.0, 8.8 Hz), 4.73–4.62 (m, 2H), 3.75 (s, 3H), 3.53 (dd, 1H,
J = 6.4, 14.4 Hz), 3.44 (dd, 1H, J = 9.2, 14.4 Hz); 13C NMR (100
MHz, CDCl3): d = 168.5, 167.5, 145.0, 134.7, 134.0, 131.6,
128.9, 128.7, 128.5, 127.5, 127.2, 123.0, 64.1, 53.1, 38.6, 35.3;
HRMS: calcd for C20H20N4O3 + Na: 387.1433. Found: 387.1426.
(S)-2-(4-(benzamidomethyl)-1H-1,2,3-triazol-1-yl)-3-(4-
hydroxyphenyl)propanoate methyl ester (6). From compound
2 (75 mg, 0.3 mmol) and 3 (66 mg, 0.4 mmol), Na ascorbate
(67 mg, 0.3 mmol), CuSO4Á5H2O (42 mg, 0.1 mmol), column
chromatography (petroleum ether/EtOAc, 2:3) afforded 6 as a
white solid (80 mg, 62%); TLC: Rf = 0.2 (petroleum ether/
EtOAc, 2:3); [a]D = À33 (c = 0.1, CH2Cl2); 1H NMR (400
MHz, CDCl3): d = 7.77 (d, 2H, J= 7.6 Hz), 7.68 (s, 1H), 7.51 (t,
1H, J= 7.2 Hz), 7.43 (t, 1H, J= 7.6 Hz), 6.97 (brs, 1H), 6.83 (d,
2H, J= 8.4 Hz), 6.64 (d, 2H, J= 8.4 Hz), 5.51 (dd, 1H, J= 5.6, 8.8
Hz), 4.73–4.62 (m, 2H), 3.78 (s, 3H), 3.45 (dd, 1H, J= 5.6, 14.0
Hz), 3.35 (dd, 1H, J= 9.2, 14.4 Hz); 13C NMR (100 MHz, CDCl3):
d = 168.7, 168.1, 156.1, 144.6, 133.6, 131.8, 130.0, 128.5, 127.2,
127.19, 125.6, 123.2, 115.8, 64.5, 53.1, 37.8, 35.1; HRESIMS:
calcd for C20H20N4O4 + Na: 403.1382. Found: 403.1375.
0.4 mmol), column chromatography (EtOAc/EtOH= 3:1) afforded
7
as a white solid (119 mg, 95%); Rf = 0.40 (CH2Cl2/
1
MeOH = 8:1); [a]D = À8 (c = 0.1, MeOH); H NMR (400 MHz,
DMSO-d6): d = 9.03 (t, 1H, J = 6.0 Hz), 7.93 (s, 1H), 7.89 (d, 2H,
J = 7.2 Hz), 7.53 (t, 1H, J = 7.2 Hz), 7.47 (t, 2H, J = 7.6
Hz), 7.14–7.04 (m, 5H), 5.25 (dd, 1H, J = 3.6, 10.0 Hz), 4.47–
4.41 (m, 2H), 3.51 (dd, 1H, J = 4.0, 14.4 Hz), 3.29 (dd, 1H,
J = 10.8, 14.0 Hz); 13C NMR (100 MHz, DMSO-d6):
d = 171.4, 166.1, 144.2, 137.8, 134.1, 131.2, 128.7, 128.2,
128.0, 127.2, 126.2, 122.5, 66.3, 38.2, 34.8; HRESIMS: calcd
for C19H18N4O3 + Na: 373.1277. Found: 373.1274.
(S)-2-(4-(benzamidomethyl)-1H-1,2,3-triazol-1-yl)-3-(4-
hydroxyphenyl)propanoic acid (8). From compound 6 (65 mg,
0.2 mmol), column chromatography (EtOAc/EtOH= 2:1) afforded
8 as a white solid (56 mg, 90%); Rf = 0.5 (CH2Cl2/MeOH = 5:1);
[a]D = À29 (c = 0.1, MeOH); 1H NMR (400 MHz, DMSO-d6):
d = 9.05 (t, 1H, J = 6.0 Hz), 7.97 (s, 1H), 7.90 (d, 2H, J = 7.2 Hz),
7.53 (t, 1H, J = 7.2 Hz), 7.47 (t, 2H, J = 7.6 Hz), 6.85
(d, 2H, J = 8.4 Hz), 6.55 (d, 2H, J = 8.4 Hz), 5.30 (dd, 1H,
J = 4.0, 10.8 Hz), 4.54–4.45 (m, 2H), 3.40 (dd, 1H, J = 4.0,
14.4 Hz), 3.22 (dd, 1H, J = 10.8, 14.0 Hz); 13C NMR (100
MHz, DMSO-d6): d = 171.2, 166.3, 155.9, 144.4, 134.2,
131.3, 129.7, 128.3, 127.3, 122.6, 115.0, 66.0, 37.1, 34.9;
HRESIMS: calcd for C19H18N4O4 + Na: 389.1226. Found:
389.1220.
(2S,2’S)-2,2’-(4,4’-((isophthaloylbis(azanediyl))bis(methylene))
bis(1H-1,2,3-triazole-4,1-diyl))bis(3-phenylpropanoic acid) (11).
From compound 9 (90 mg, 0.1 mmol), column chromatography
(EtOAc/EtOH = 2:1) afforded 11 as a white solid (40 mg, 47%);
Rf = 0.5 (CH2Cl2/MeOH = 1:1); [a]D = À35 (c = 0.3, MeOH);
1H NMR (400 MHz, DMSO-d6): d = 9.20 (brs, 2H), 8.45–8.41
(m, 1H), 8.02 (brs, 4H), 7.57 (t, 1H, J = 8.0 Hz), 7.17–7.10 (m,
10H), 5.60 (dd, 2H, J = 4.4, 9.6 Hz), 4.49 (d, 2H, J = 5.2 Hz),
3.52 (dd, 2H, J = 5.2, 14.4 Hz), 3.47–3.40 (m, 2H); 13C NMR
(100 MHz, DMSO-d6): d = 170.0, 165.7, 144.6, 136.6, 134.2,
130.0, 128.8, 128.4, 128.2, 126.6, 126.5, 123.1, 63.9, 37.0,
34.8; HRESIMS: calcd for C32H30N8O6 + Na: 645.2186.
Found: 645.2180.
(2S,2’S)-2,2’-(4,4’-((isophthaloylbis(azanediyl))bis(methylene))bis
(1H-1,2,3-triazole-4,1-diyl))bis(3-phenylpropanoate) methyl diester
(9).
From compound 1 (85 mg, 0.4 mmol) and 4 (50 mg,
0.2 mmol), Na ascorbate (82 mg, 0.4 mmol), CuSO4Á5H2O (103 mg,
0.4 mmol), column chromatography (EtOAc/EtOH, 20:1) afforded
9 as a white solid (83 mg, 62%); Rf1= 0.2 (petroleum ether/EtOAc,
1:6); [a]D =À90 (c=0.1, CH3OH); H NMR (400 MHz, CDCl3):
d = 8.15 (s, 1H), 7.91–7.89 (m, 4H), 7.76 (brs, 2H), 7.37–7.33 (m,
1H), 7.14–7.13 (m, 6H), 7.02–7.00 (m, 4H), 5.57 (t, 2H, J=7.6
Hz), 4.57 (brs, 4H), 3.69 (brs, 6H), 3.52 (dd, 2H, J= 6.4, 14.4 Hz),
3.43 (dd, 2H, J= 9.2, 13.6 Hz); 13C NMR (100 MHz, CDCl3):
d = 168.6, 166.7, 144.8, 134.7, 134.1, 130.6, 128.9, 128.8, 127.5,
125.2, 123.0, 64.2, 53.1, 38.6, 35.3; HRESIMS: calcd for
C34H34N8O6 + Na: 673.2499. Found: 673.2510.
(2S,2’S)-2,2’-(4,4’-((isophthaloylbis(azanediyl))bis(methylene))
bis(1H-1,2,3-triazole-4,1-diyl))bis(3-(4-hydroxyphenyl)propanoate)
methyl diester (10).
From compound 2 (124 mg, 0.6 mmol)
and 4 (70 mg, 0.3 mmol), Na ascorbate (195 mg, 1.0 mmol),
CuSO4Á5H2O (175 mg, 0.7 mmol), column chromatography
(EtOAc/EtOH, 15:1) afforded 10 as a white solid (91 mg,
48%); TLC: Rf = 0.5 (dichloromethane/MeOH, 9:1); [a]D = À80
(c = 0.1, CH3OH); 1H NMR (400 MHz, CDCl3): d = 7.91 (dd,
2H, J = 1.6, 8.0 Hz), 7.80 (s, 1H), 7.67 (s, 2H), 7.54 (t, 1H,
J = 7.6 Hz), 7.30–7.26 (m, 2H), 6.68 (d, 4H, J = 8.0 Hz), 6.50
(d, 4H, J = 8.4 Hz), 5.51 (dd, 2H, J = 4.8, 11.6 Hz), 4.76 (dd,
2H, J = 7.6, 15.2 Hz), 4.48 (dd, 2H, J = 4.8, 14.4 Hz), 3.88 (s,
6H), 3.51 (dd, 2H, J = 4.4, 14.0 Hz), 3.27 (dd, 2H, J = 11.6,
14.0 Hz); 13C NMR (100 MHz, CDCl3): d = 168.8, 165.7,
156.1, 144.8, 134.3, 129.9 (1), 129.9 (2), 128.4, 126.5, 125.7,
123.2, 115.1, 63.3, 52.7, 36.0, 34.8; HRESIMS: calcd for
C34H34N8O8 + Na: 705.2397. Found: 705.2396.
(2S,2’S)-2,2’-(4,4’-((isophthaloylbis(azanediyl))bis(methylene))
bis(1H-1,2,3-triazole-4,1-diyl))bis(3-(4-hydroxyphenyl)propanoic
acid) (12).
From compound 10 (90 mg, 0.1 mmol), column
chromatography (EtOAc/EtOH = 4:1) afforded 12 as a white solid
(27 mg, 30%); Rf =0.5 (CH2Cl2/MeOH = 1:1); [a]D =À27 (c=0.3,
1
MeOH); H NMR (400 MHz, DMSO-d6): d = 9.27 (brs, 2H), 8.49
(brs, 1H), 8.04–8.00 (m, 4H), 7.56 (t, 1H, J= 7.2 Hz), 6.85 (d, 4H,
J= 7.2 Hz), 6.57 (d, 4H, J= 7.6 Hz), 5.31 (brs, 2H), 4.48 (d, 4H,
J= 3.6 Hz), 3.38–3.35 (m, 2H), 3.24–3.15 (m, 2H); 13C NMR (100
MHz, DMSO-d6): d = 170.7, 165.8, 156.0, 144.3, 134.1, 130.1,
129.6, 128.5, 126.9, 126.4, 122.7, 115.0, 65.6, 36.8. 34.8;
HRESIMS: calcd for C32H30N8O8 + Na: 677.2084. Found:
677.2100.
PTP inhibitory assay.
Recombinant human PTP1B
General procedure for the microwave-assisted saponification.
To a solution of the ester dissolved in MeOH/H2O (1:1, V/V/V),
LiOH (1.5 equiv./ester), which was then transferred into the
microwave oven with vigorous stirring for 5 min (ramp time:
3 min) was added. H+ resin was then added to the resulting
mixture for removing lithium salts. After filtration, the filtrate
was concentrated in vacuum, and the residue was successively
purified by column chromatography.
catalytic domain was expressed and purified according to
procedures described previously [23]. Enzymatic activity of
PTP1B was determined at 30ꢀC 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
monitored on a SpectraMax 340 microplate reader at 405 nm for
2 min at 30ꢀC and the initial rate of the hydrolysis was
determined using the early linear region of the enzymatic
(S)-2-(4-(benzamidomethyl)-1H-1,2,3-triazol-1-yl)-3-
phenylpropanoic acid (7).
From compound 5 (130 mg,
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reaction kinetic curve. For calculating IC50, 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 inhibition (inhibition (%))
versus inhibitor concentration [I] by using the following
equation: inhibition (%) = 100/{1 + (IC50/[I])k}, where k is the
Hill coefficient. To study the inhibition selectivity on other PTP
family members, human CDC25B, TCPTP, SHP-1, SHP-2, and
LARD1 were prepared and assays were performed according to
procedures described previously [24].
Acknowledgments. We thank the National Natural Science
Foundation of China (Grant No. 21176076, No. 30801405), National
Basic Research Program of China (No. 2007CB914201), Shanghai
Science and Technology Community (No. 10410702700),
Chinese Academy of Sciences (No. KSCX2-EW-R-15), the
Fundamental Research Funds for the Central Universities
(No. WK1013002) for generously providing the funding, and
China Postdoctoral Science Foundation (No. 2011M500069).
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X.-X.; Tang, Y.; Li, J.; Chen, G.-R. Bioorg Med Chem Lett 2011, 21, 1092.
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C.-J.; Shen, Q.; Zhang, W.; Sheng, L.; Shi, X.-X.; Tang, Y.; Li, J.; Chen,
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet