A unique and rapid approach toward the efficient development of novel protein tyrosine phosphatase (PTP) inhibitors based on 'clicked' pseudo-glycopeptides

Article abstract of DOI:10.1016/j.bmcl.2010.12.126

There has been considerable interest in the development of protein tyrosine phosphatase (PTP) inhibitors since many of the PTP members are tightly associated with major human diseases including autoimmune disorders, diabetes and cancer. We report here a u

Full text of DOI:10.1016/j.bmcl.2010.12.126

Bioorganic & Medicinal Chemistry Letters 21 (2011) 1092–1096
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
A unique and rapid approach toward the efficient development of novel
protein tyrosine phosphatase (PTP) inhibitors based on ‘clicked’
pseudo-glycopeptides
Jin-Wei Yang a, Xiao-Peng He a,c,d, , Cui Li c, Li-Xin Gao b, Li Sheng b, Juan Xie d, Xiao-Xin Shi c,
⇑
a,
Yun Tang c, Jia Li b, , Guo-Rong Chen
⇑
⇑
a Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, Shanghai 200237, PR China
b National 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 201203, PR China
c Department of Pharmaceutical Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, PR China
d PPSM, ENS Cachan, CNRS, 61 av President Wilson, F-94230 Cachan, France
a r t i c l e i n f o
a b s t r a c t
Article history:
There has been considerable interest in the development of protein tyrosine phosphatase (PTP) inhibitors
since many of the PTP members are tightly associated with major human diseases including autoimmune
disorders, diabetes and cancer. We report here a unique and rapid approach toward the development of
novel PTP inhibitor entities based on triazolyl pseudo-glycopeptides. By employing microwave-acceler-
ated Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC or ‘click reaction’), a series of tria-
zole-linked serinyl, threoninyl, phenylalaninyl and tyrosinyl 1-O-gluco- or galactosides have been
efficiently synthesized in high yields within only ꢀ30 min. Successive biological assay identified these
glycopeptidotriazoles as favorable PTP1B and CDC25B inhibitors with selectivity over TCPTP, LAR, SHP-
1 and SHP-2. Both the structural diversity of the amino acid (Ser, Thr, Phe and Tyr) introduced and the
epimeric identity (Glc or Gal) on monosaccharide scaffold were determined to impact the corresponding
inhibitory activity and selectivity. In addition, the benzylated sugar scaffold was demonstrated to act as a
crucial role for enhancing the binding affinity of the inhibitors with the targeted PTP. Docking simulation
was eventually conducted to propose plausible binding modes of this compound series with PTP1B and
CDC25B. Our approach readily realized from naturally abundant raw materials (sugar and amino acid)
and via facile, regioselective and expeditious synthetic method (microwave-assisted click reaction) might
provide new insights toward the ‘click’ fabrication of structurally diverse PTP inhibitors.
Received 26 October 2010
Revised 16 December 2010
Accepted 28 December 2010
Available online 31 December 2010
Keywords:
Glycopeptides
Click reaction
Protein tyrosine phosphatase inhibitor
Microwave irradiation
Docking simulation
Ó 2010 Elsevier Ltd. All rights reserved.
The protein tyrosine phosphatase (PTP) superfamily comprises
over 100 PTP members and is responsible for, together with pro-
tein tyrosine kinases, the synergistic modulation of tyrosine phos-
phorylation events on cellular level.1 Inappropriately functioned
regulation of many PTP members has been reported causative to-
ward the pathogenesis of major human diseases involving autoim-
mune disorders, diabetes and cancer.1b,2
PTP1B represents one of the best therapeutically characterized
signaling enzyme that negatively regulates insulin and leptin
receptor pathways. Enhanced insulin sensitivity and ameliorated
glycemic control and resistance to diet-induced obesity were
observed on PTP1B-null mice, suggesting the inhibition of PTP1B
may efficiently combat type 2 diabetes and obesity.3 The cell
division cycle 25 homolog B (CDC25B) participates in cell division
and induces cell cycle arrest, leading to DNA repair or apoptosis.4a
Its overexpression in various cancers including breast, lung, gastric,
etc. has made CDC25B attractive as a novel therapeutic target to-
ward anticancer treatment.4b
Considering such compelling evidence, numerous programs
have been launched for the development of PTP inhibitors by both
pharmaceutical enterprises and the academia.5,6 However, only
limited drug candidates have entered clinical trials due to the inad-
equate pharmacological properties of most phosphate analogs for
achieving competitive PTP inhibition. In addition, non-specific
inhibitors such as quinone derivatives those constitute the major-
ity of CDC25 inhibitor class release reactive oxygen species (ROS),
simultaneously bringing unsatisfactory toxicity on normal tis-
sues.5c Consequently, the development of new chemical entities
that may effectively inhibit disease-related PTPs remains highly
desirable.
⇑
Corresponding authors. Tel.: +86 021 64253016; fax: +86 021 64252758.
E-mail addresses: frogmaster_eminem@yahoo.com.cn (X.-P. He), jli@mail.shcnc.
ac.cn (J. Li), mrs_guorongchen@ecust.edu.cn (G.-R. Chen).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.12.126

J.-W. Yang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1092–1096
1093
N
N
Sugar
Ref .10
Sugar
R'OOC
N3
R'OOC
NH2
HOOC
N
mw.
R
R
R
New potential p Tyr surrogate
MeOOC
N3
MeOOC
MeOOC
N3
R2
OBn
O
R1
Azido Amino acid=
OH
N3
Sugar =
OH
N3
a
c
b
d
O
BnO
OBn
MeOOC
1: R1 = OBn, R2 = H
2: R1 = H, R2 = OBn
OH
Figure 1. ‘Click’ strategy and azido amino acids and sugar alkynes used for click reaction in this study.
Glycopeptides universally exist in nature, governing a multi-
tude of pivotal biological and pathological events.7 Considerable
efforts have been devoted to the synthesis of glycopeptide mimet-
ics in the passing decade.8 Two independent research groups (i.e.,
Dondoni et al.9a and Rutjes and co-workers9b) first reported a range
of novel glycopeptide derivatives wherein the bioactive amino acid
and sugar moieties are rigidly coupled via the click reaction.10 The
expediently formed triazolyl linkage may furnish stable conjuga-
tion pattern between amino acid residue and the glycosyl scaffold,
which was also envisioned to display biological activity due to its
heterocyclic nature.9b
HO
N
N
R2
OBn
O
R3
OMe
N
R1
(1 or 2)+(a or b)
O
BnO
O
OBn
3: R1 = OBn, R2 = H, R3 = H (93%)
4: R1 = OBn, R2 = H, R3 = CH3 (91%)
5: R1 = H, R2 = OBn, R3 = H (92%)
6: R1 = H, R2 = OBn, R3 = CH3 (90%)
More recently, Goddard-Borger and Stick11a revealed a new dia-
zotransfer reagent based on sulfonyl imidazolate, enabling the con-
venient conversion of the primary amine of amino acids into an
azide. These amino acid derivatives bearing an azido precursor
could be further used as a starting material for the CuAAC, result-
ing in the formation of triazolyl acids that may potentially serve as
a new pTyr surrogate similar to the previously reported heterocy-
clic carboxylates by Abbott’s12a and Novo Nordisk’s12b groups.
We then sought to prepare, as shown in Figure 1, a series of
glycosyl triazolyl acids via click reaction as new PTP inhibitors.
HO
N
N
R2
OBn
O
R3
OH
N
R1
O
BnO
O
OBn
11: R1 = OBn, R2 = H, R3 = H (99%)
12: R1 = OBn, R2 = H, R3 = CH3 (97%)
13: R1 = H, R2 = OBn, R3 = H (90%)
14: R1 = H, R2 = OBn, R3 = CH3 (95%)
L-Ser-OMe, L-Thr-OMe, L-Phe-OMe and L-Tyr-OMe employed for
our preliminary investigation were first converted to the corre-
sponding azides a–d via the method established by Goddard-
Borger and Stick (Fig. 1).11a As noted, the pTyr itself is insufficient
for potently binding to its specific PTP and appropriately appended
residues such as benzene groups with pTyr may largely enhance
the entire binding affinity.5 We have identified in a very recent
study that the benzylated sugars could display micromole-ranged
PTP1B inhibitory activity for the first time.11b Therefore, the benzyl
1-O-propynyl glyco- and galactoside13 were used to couple with
the azido amino acids for concomitantly targeting the periphery
hydrophobic enzymatic surface of PTPs, enhancing the binding
affinity of the designed products (Fig. 1). Furthermore, in order to
evaluate the predominance of the benzyl sugar scaffold toward
PTP inhibition, triazolyl amino acid-benzamide conjugates were
prepared for structure–activity relationship (SAR) study.
The click reaction was initiated with the assistance of micro-
wave irradiation that has already proven practical toward the syn-
thesis of glycopeptide mimetics.14 As shown in Scheme 1, the
starting amino acid azide (a–d) and sugar alkyne (1 or 2) were first
dissolved in DMF/H2O (1:2, V/V), followed by the addition of
2 equiv Na ascorbate and 1 equiv CuSO4Á5H2O. The mixture was
then transferred to a Yalian (YL8023B1) microwave oven with vig-
orous stirring at a ramp time of 6 min and heating time of
10 min.17 To our delight, all click reactions promoted by the micro-
R4
N
N
R2
OBn
O
N
R1
(1 or 2)+( c or d)
O
BnO
OMe
O
OBn
7: R1 = OBn, R2 = H, R4 = Ph (97%)
8: R1 = OBn, R2 = H, R4 = p-OHC6H4 (92%)
9: R1 = H, R2 = OBn, R4 = Ph (91%)
10: R1 = H, R2 = OBn, R4 = p-OHC6H4 (92%)
R4
N
N
R2
OBn
O
N
R1
BnO
O
OH
O
OBn
15: R1 = OBn, R2 = H, R4 = Ph (93%)
16: R1 = OBn, R2 = H, R4 = p-OHC6H4 (95%)
17: R1 = H, R2 = OBn, R4 = Ph (98%)
18: R1 = H, R2 = OBn, R4 = p-OHC6H4 (97%)
Scheme 1. Reagents and conditions: (i) VcNa, CuSO4Á5H2O in DMF/H2O (1:2, V/V),
mw; (ii) LiOHÁH2O in MeOH, mw.

1094
J.-W. Yang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1092–1096
R4
R4
N
N
N
N
N
N
OMe
OH
NH
O
NH
O
NH
+( c or d)
O
O
O
19: R4 = Ph (73%)
20: R4 = (p-OH)C6H4 (62%)
e
21: R4 = Ph (95%)
22: R4 = p-OHC6H4 (90%)
Scheme 2. Reagents and conditions: (i) VcNa, CuSO4Á5H2O in DMF/H2O (1:2, V/V), mw; (ii) LiOHÁH2O in MeOH, mw.
wave irradiation proceeded smoothly, rapidly affording the glyco-
peptide triazoles 3–10 in excellent yields of >90% within this
16 min pattern. The following microwave-assisted saponification
with LiOHÁH2O gave the desired triazolyl acids 11–18 in excellent
to quantitative yields (90–99%).
In a similar way, as shown in Scheme 2, the triazolyl phenylal-
anine and tyrosine-benzamide conjugates 19 and 20 for SAR study
were afforded via the microwave-assisted click reaction between
the known N-(prop-2-yn-1-yl)benzamide e and azides c and d,
respectively in moderate yields. The saponification with LiOHÁH2O
under microwave irradiation of ester 19 and 20 successively gave
the desired acids 21 and 22 in good yields (for the full characteriza-
tion of all new compounds (3–22), see Supplementary data associ-
ated with this Letter).
Next, we assessed the inhibitory activity of the obtained prod-
ucts 11–18 and 20–22 on a panel of homologous PTPs including
PTP1B, CDC25B, T-Cell Protein Tyrosine Phosphatase (TCPTP), Leu-
kocyte Antigen-Related Tyrosine Phosphatase (LAR), SH2-Contain-
ing Protein Tyrosine Phosphatase1 (SHP1) and SHP2 by our
previously established methods.15 As listed in Table 1, the majority
of the glycosyl triazolyl acids constructed showed moderate-to-
good IC50 values on PTP1B and CDC25B in micromole range and
several-fold selectivity over TCPTP, SHP-1, SHP-2 and LAR whereas
no inhibitory potency was displayed while by the amino acid-
benzamide triazoles.
15 on PTP1B is twofold smaller than that on CDC25B (9.9
while a reverse inhibitory pattern was observed by comparing
the IC50 values of the tyrosine 16 on same PTPs (IC50 = 8.3 M on
PTP1B and 3.9 M on CDC25B). In addition, the PTP1B-privileged
inhibitor 15 showed relatively worse selectivity over CDC25B
(1.9-fold), TCPTP (1.5-fold), SHP-1 (3.5-fold), SHP-2 (3.1-fold) com-
pared with the CDC25B-privilegded inhibitor 16 (2.1-fold over
PTP1B, 4.5-fold over TCPTP, 6.6-fold over SHP-1 and 5.3-fold over
SHP-2) whereas both compounds showed weak inhibitory activity
lM)
l
l
on LAR (>50 lM).
On the other hand, the galactosyl amino acid series (13, 14, 17
and 18) adopted similar but slightly varied inhibition fashion com-
pared with their C4 epimers. Almost equal IC50 values were shown
by both compound 13 (39.7
whereas the serine 13 (IC50 = 16.8
inhibitor than the threonine 14 (IC50 = 42.3
l
M) and 14 (38.2
M) acted as a better PTP1B
M) considering its les-
lM) on CDC25B
l
l
ser IC50 value. Similar to their glucosyl epimer 11 and 12, they
exhibited weak inhibitory potency on TCPTP, SHP-1, SHP-2 and
LAR (IC50 >50 lM). However, phenylalaninyl triazole 17 and tyros-
inyl triazole 18 exhibited identical IC50 values on both PTP1B and
CDC25B, which is different from the inhibitory mode of their epi-
meric 15 and 16. Meanwhile, they showed low-to-moderate selec-
tivity (1.8 to 4.7-fold) over TCPTP, SHP-1 and SHP-2 and weak
inhibitory activity on LAR (IC50 >50 lM).
An obvious difference was observed by comparing the inhibi-
For the glucosyl amino acid series (11, 12, 15 and 16), both seri-
tory profile of glucosyl tyrosine 16 and the galactosyl tyrosine
nyl and threoninyl triazoles 11 (28.1
almost equal IC50 values on PTP1B while slightly better inhibitory
activity was shown by the threonine 12 on CDC25B (IC50
25.4 M) comparing to the serine 11 (IC50 = 43.3 M on CDC25B).
Moreover, they are not potent inhibitors of TCPTP, SHP-1, SHP-2
and LAR with IC50 values >50 M. In contrast, the phenylalaninyl
and tyrosinyl triazoles 15 and 16 that bear additional aryl residues
exhibited remarkably enhanced inhibitory activity comparing to
compound 11 and 12. The IC50 value (5.1 lM) of the phenylalanine
l
M) and 12 (31.2
l
M) possess
18. Glucoside 16 (IC50 = 3.9 lM) that bears an equatorial bond at
C4 position of monosaccharide scaffold possesses more then three-
fold enhanced inhibitory potency on CDC25B comparing to its epi-
mer 18 (IC50 = 11.9 lM) with a C4 axial bond. Moreover, compound
16 is also more specific than compound 18 when comparing their
IC50 values on other homologous PTPs, suggesting that the epi-
meric identity on the sugar scaffold may impact the inhibitory pro-
file of the corresponding triazolyl glycopeptide derivatives in
certain cases.
=
l
l
l
Interestingly, as shown in the last two entries in Table 1, while
the benzylated sugar scaffold was replaced by a benzaminde moi-
ety to couple with the relatively more bioactive phenylalaninyl and
tyrosinyl azide via the triazole, the corresponding inhibitory activ-
ity of compounds 20 and 22 totally faded on all PTPs tested. This
unambiguously demonstrated the benzyl sugar scaffold advanta-
geous for largely enhancing the binding affinity of the triazole-
linked glycopeptide mimetics with the targeted PTP.
In an attempt to investigate the possible binding modes of the
identified pseudo-glycopeptide-based inhibitors with the corre-
sponding PTP, we conducted docking simulation of compound 15
with PTP1B and compound 16 with CDC25B, respectively. As
shown in Figure 2A, compound 15 possibly adopted a hydrogen
bonding-dominated binding behavior, occupying the PTP1B cata-
lytic site (His214-Arg221). The carboxylic precursor of phenylalan-
inyl residue has made several hydrogen bonds with amino acid
residues including Gly218, Ile219, Gly220 and Arg221, respec-
tively. One hydrogen bond was also generated by the triazole ring
Table 1
Inhibitory activities on PTPs for triazolyl acids 11–18
Structureb
IC50
(l
M)
a
Code
PTP1B
CDC25B
TCPTP
SHP-1
SHP-2
LAR
11
12
13
14
15
16
17
18
20
22
Glc-Ser
Glc-Thr
Gal-Ser
Gal-Thr
Glc-Phe
Glc-Tyr
Gal-Phe
Gal-Tyr
—
28.1
31.2
16.8
42.3
5.1
8.3
7.0
11.2
>50
>50
43.3
25.4
39.7
38.2
9.9
3.9
7.0
11.9
>50
>50
>50
>50
7.7
17.6
12.6
29.9
>50
>50
>50
>50
>50
>50
17.7
25.7
18.5
53.1
>50
>50
>50
>50
>50
>50
15.7
20.6
17.4
33.3
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
—
a
Values are means of three experiments.
Abbreviations: Glc, glucose; Gal, galactose; Ser, serine; Thr, threonine; Phe,
b
phenylalanine; Tyr, tyrosine.

J.-W. Yang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1092–1096
1095
Figure 2. (A) PTP1B in complex with compound 15. (B) CDC25B in complex with compound 16. The surface of the protein was shown as colored in property of electrostatic
potential. The compounds were shown as green stick and residues in PTP were shown as light grey line. Nitrogen atoms are in blue and oxygen atoms in red. Hydrogen bonds
were shown as yellow dash lines and all nonpolar interactions were indicated by pink dash lines.
with Gln266 while three oxygen atoms on 2-, 3- and 6-position of
sugar moiety have made additional hydrogen bonds with Lys116
and Thr263, respectively.
lated sugar scaffold was demonstrated crucial for largely enhanc-
ing the binding affinity of the inhibitors with the targeted PTP.
Docking simulation eventually illustrated the plausible binding
modes of the most potent inhibitors in this series with PTP1B
and CDC25B. Our unique approach presented here by using inex-
pensive and abundant natural scaffolds (sugar and amino acid)
and via facile and expeditious synthetic method (microwave-as-
sisted click reaction) might furnish new insights toward the effi-
cient development of pseudo-glycopeptide-based PTP inhibitor
libraries.
Nonpolar interactions were simultaneously observed. A rela-
tively distant pi-pi stacking generated between the distal benzene
group on the phenylalaninyl residue of compound 15 with Tyr46
may generally account for the enhanced affinity of the phenylala-
nine and tyrosine-containing inhibitors (15–18) comparing to the
rest (11–14) that lack this essential benzene (or phenol) group.
More interestingly, the other edge-to-face pi-pi stacking made by
the distal benzene group on C3 position of the sugar scaffold with
Phe182 directly led to the prevention of WPD loop closure which is
similar to the reported binding mode of aryl diketoacid derivatives
with PTP1B by Zhang and co-workers16a Moreover, the sugar C6
benzyl group partially extended to the second phosphotyrosine
site of PTP1B, making hydrophobic interactions with Tyr20.
Next, the plausible binding mode of compound 14 with CDC25B
was proposed and illustrated in Figure 2B. The triazolyl acid pre-
cursor tended to fit in the large ‘swimming pool’16b cavity adjacent
to the catalytic pocket (Cys473, Glu474, Glu478 and Met531), gen-
erating densely functionalized hydrogen-bonding array with
Tyr428, Glu446, Arg479 and Arg482, respectively. Notably, the
two hydrogen bonds made between the hydroxy group on tyrosi-
Acknowledgements
Project supported by National Natural Science Foundation of
China (Grant Nos. 20876045, 30801405), National Basic Research
Program of China (No. 2007CB914201), National Science & Tech-
nology Major Project of China ‘Key New Drug Creation and Manu-
facturing Program’ (No. 2009ZX09302-001), Shanghai Science and
Technology Community (Nos. 10410702700, 09DZ2291200),
Chinese Academy of Sciences (No. KSCX2-YW-R-168) and the
Fundamental Research Funds for the Central Universities (No.
WK1013002). X.-P. H. also gratefully acknowledges the French
Embassy in Beijing, PR China for a co-tutored doctoral fellowship.
nyl residue of compound 16 (IC50 = 3.9
be causative toward its 2.5-fold enhanced activity comparing with
the phenylalanine 14 (IC50 = 9.9 M). The oxygen atoms on pyra-
lM) with Glu446 might
Supplementary data
l
noglucosyl scaffold and on C6 position also contributed to the
binding affinity by simultaneously making two hydrogen bonds
with the guanidyl residue of Arg544. In addition, apparent hydro-
phobic interactions were observed between benzyl moieties on
glucosyl C-2 and C-6 position with Phe475 and Leu 540,
respectively.
In summary, we have fulfilled in this study the rapid and effi-
cient synthesis of triazole-linked glucosyl or galactosyl serine,
threonine, phenylalanine and tyrosine derivatives via microwave-
accelerated click reaction. The prepared triazolyl acids were iden-
tified as novel PTP1B and CDC25B inhibitors with several fold
selectivity over other homologous PTPs. Amino acids with aryl res-
idues (Phe and Tyr) were preferential toward PTP inhibition while
the C-4 epimeric identity on sugar scaffold also proved unignorable
for both inhibitory activity and selectivity. In addition, the benzy-
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.12.126.
References and notes
1. (a) Tonks, N. K. Nat. Rev. Mol. Cell Biol. 2006, 7, 833; (b) Barr, A. J.; Ugochukwu,
E.; Lee, W. H.; King, O. N. F.; Filippakopoulos, P.; Alfano, I.; Savitsky, P.; Burgess-
Brown, N. A.; Müller, S.; Knapp, S. Cell 2009, 136, 352.
2. Zhang, Z.-Y. Curr. Opin. Chem. Biol. 2001, 5, 416.
3. (a) Elchelby, 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; (b)
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.
4. (a) Obaya, A. J.; Sedivy, J. M. Cell. Mol. Life Sci. 2002, 126; (b) Boutros, R.; Lobjois,
V.; Ducommun, B. Nat. Rev. Cancer 2007, 7, 495.

1096
J.-W. Yang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1092–1096
5. (a) Bialy, L.; Waldmann, H. Angew. Chem., Int. Ed. 2005, 44, 3814; (b) Zhang, S.;
Zhang, Z.-Y. Drug Discovery Today 2007, 12, 373; (c) Garuti, L.; Roberti, M.;
Pizzirani, D. Curr. Med. Chem. 2008, 15, 573; (d) Vintonyak, V. V.; Antonchick, A.
P.; Rauh, D.; Waldmann, H. Curr. Opin. Chem. Biol. 2009, 13, 272.
11. (a) Goddard-Borger, E. D.; Stick, R. V. Org. Lett. 2007, 9, 3797; (b) Zhang, Y.-J.;
He, X.-P.; Li, C.; Li, Z.; Shi, D.-T.; Gao, L.-X.; Qiu, B.-Y.; Shi, X.-X.; Tang, Y.; Li, J.;
Chen, G.-R. Chem. Lett. 2010, 39, 1261.
12. (a) Zhao, H.; Liu, G.; Xin, Z.; Serby, M. D.; Pei, Z.; Szczepankiewicz, B. G.; Hajduk,
P. J.; Abad-Zapatero, C.; Hutchins, C. W.; Lubben, T. H.; Ballaron, S. J.; Haasch, D.
L.; Kaszubska, W.; Rondinone, C. M.; Trevillyan, J. M.; Jirousek, M. R. Bioorg.
Med. Chem. Lett. 2004, 14, 5543; (b) Andersen, H. S.; Olsen, O. H.; Iversen, L. F.;
Soresen, A. L.; Mortensen, M. S.; Christensen, M. S.; Branner, S.; Hansen, T. K.;
Lau, J. F.; Jeppesen, L.; Moran, E. J.; Su, J.; Bakir, F.; Judge, L.; Shahbaz, M.;
Collins, T.; Vo, T.; Newman, M. J.; Ripka, W. C.; Moller, N. P. H. J. Med. Chem.
2002, 45, 4443.
6. (a) Combs, A. P. J. Med. Chem. 2010, 53, 2333; (b) Weide, T.; Arve, L.; Prinz,
H.; Waldmann, H.; Kessler, H. Bioorg. Med. Chem. Lett. 2006, 16, 59; (c)
Bäurle, S.; Blume, T.; Günther, J.; Henschel, D.; Hillig, R. C.; Husemann, M.;
Mengel, A.; Parchmann, C.; Schmid, E.; Skuballa, W. Bioorg. Med. Chem. Lett.
2004, 14, 1673; (d) Qiu, W.-W.; Shen, Q.; Yang, F.; Wang, B.; Zou, H.; Li, J.-Y.;
Tang, J. Bioorg. Med. Chem. Lett. 2009, 19, 6618; (e) Seo, C.; Sohn, J. H.; Oh,
H.; Kim, B. Y.; Ahn, J. S. Bioorg. Med. Chem. Lett. 2009, 19, 6095; (f) Lin, L.;
Shen, Q.; Chen, G.-R.; Xie, J. Bioorg. Med. Chem. 2008, 16, 9757; (g) Lin, L.;
Shen, Q.; Chen, G.-R.; Xie, J. Bioorg. Med. Chem. Lett. 2008, 18, 6348; (h)
Bhattarai, B. R.; Kafle, B.; Hwang, J.-S.; Khadka, D.; Lee, S.-M.; Kang, J.-S.;
Ham, S. W.; Han, I.-O.; Park, H.; Cho, H. Bioorg. Med. Chem. Lett. 2009, 19,
6161; (i) Chen, H.-J.; Liu, Y.; Wang, L.-N.; Shen, Q.; Li, J.; Nan, F.-J. Bioorg.
Med. Chem. Lett. 2010, 20, 2876; (j) Bhattarai, B. R.; Kafle, B.; Hwang, J.-S.;
Ham, S. W.; Lee, K.-H.; Park, H.; Han, I.-O.; Cho, H. Bioorg. Med. Chem. Lett.
2010, 20, 6758; (k) Cheng, Y.; Zhou, M.; Tung, C.-H.; Ji, M.; Zhang, F. Bioorg.
Med. Chem. Lett. 2010, 20, 3329.
7. (a) Varski, A. Glycobiology 1993, 3, 97; (b) Dwek, R.-A. Chem. Rev. 1996, 96, 683.
8. (a) Schweizer, F. Angew. Chem., Int. Ed. 2002, 41, 231; (b) Gruner, S. A. W.;
Locardi, E.; Lohof, E.; Kessler, H. Chem. Rev. 2002, 102, 491.
9. (a) Dondoni, A.; Giovannini, P. P.; Massi, A. Org. Lett. 2004, 6, 2929; (b) Kuijpers,
B. H. M.; Groothuys, S.; Keereweer, A. B. R.; Quaedflieg, P. J. L. M.; Blaauw, R. H.;
van Delft, F. K.; Rutjes, F. P. J. T. Org. Lett. 2004, 6, 3123.
10. (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004;
(b) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2002, 41, 2596.
13. Wardrop, D. J.; Fritz, J. Org. Lett. 2006, 8, 3659.
14. Miller, N.; Willianms, G. M.; Brimble, M. A. Org. Lett. 2009, 11, 2409.
15. (a) Zhang, W.; Hong, D.; Zhou, Y.-Y.; Zhang, Y.-N.; Shen, Q.; Li, J.-Y.; Hu, L.-H.; Li,
J. Biochim. Biophys. Acta 2006, 1760, 1505; (b) Shi, L.; Yu, H. P.; Zhou, Y. Y.; Du, J.
Q.; Shen, Q.; Li, J. Y.; Li, J. Acta Pharmacol. Sin. 2008, 29, 278.
16. (a) Liu, S.; Zeng, L.-F.; Wu, L.; Xue, T.; Gunawan, A. M.; Long, Y.-Q.; Zhang, Z.-Y.
J. Am. Chem. Soc. 2008, 130, 17075; (b) Rudolph, J. Mol. Pharmacol. 2004, 66,
780.
17. General procedure for the microwave-assisted click reaction: To a solution of
sugar alkyne 1 or 2 (1.0 mmol)13 and azide a–d (1.2 mmol) in DMF/H2O
(10 mL/5 mL), were added VcNa (2.0 mmol) and CuSO4Á5H2O (1.0 mmol) which
was then transferred to the microwave oven. The mixture was stirred for a
ramp time of 6 min and heating time of 10 min at 60 °C. With completion of
the reaction (monitored by TLC), the solvents were evaporated under reduced
pressure. The resulting residue was dissolved in dichloromethane, washed
with water and brine and extracted with CH2Cl2 (3 Â 10 mL). The combined
organic layers were dried over MgSO4, filtered and concentrated then the crude
product was purified by column chromatography.