Synthesis of stable and selective inhibitors of human galectins-1 and -3

Article abstract of DOI:10.1016/j.bmc.2008.06.044

The syntheses of glycolytically stable galactosides and lactosides have been made toward the selective inhibition of human galectins-1 and -3. Transition metal-catalyzed cross-coupling reactions were used to create carbon-carbon bond formation (Sonogashira, Suzuki, Heck, Glaser). Additionally, Hantzsch condensation was used to create novel 2-aminothiazoles which reacted with a panel of acylating and sulfonylating reagents. Moreover, dimeric galactosides and lactosides bearing triazoles, regiospecifically prepared using copper-catalyzed Huisgen azide-alkyne [1,3]-dipolar cycloaddition, provided efficient galectins-1 and -3 inhibitors. Best monovalent inhibitor among the tested series was (E)-methyl 2-phenyl-4-(β-d-galactopyranosyl)-but-2-enoate 15 with inhibitory potency of 313 μM against galectin-1 and best dimers were bis-lactoside 68 and 75 having both inhibitory properties of 160 μM against Galectin-3.

Full text of DOI:10.1016/j.bmc.2008.06.044

Bioorganic & Medicinal Chemistry 16 (2008) 7811–7823
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis of stable and selective inhibitors of human galectins-1 and -3
Denis Giguère a, Marc-André Bonin a, Philipe Cloutier a, Ramesh Patnam a, Christian St-Pierre b,
Sachiko Sato b, René Roy a,
*
a Department of Chemistry, Université du Québec à Montréal, PO Box 8888, Succ. Centre-Ville, Montreal, Que., Canada H3C 3P8
b Research Center for Infectious Diseases, Faculty of Medicine, Université Laval, 2705 boul. Laurier, RC-9700 Sainte-Foy, Que., Canada G1V 4G2
a r t i c l e i n f o
a b s t r a c t
Article history:
The syntheses of glycolytically stable galactosides and lactosides have been made toward the selective
inhibition of human galectins-1 and -3. Transition metal-catalyzed cross-coupling reactions were used
to create carbon–carbon bond formation (Sonogashira, Suzuki, Heck, Glaser). Additionally, Hantzsch con-
densation was used to create novel 2-aminothiazoles which reacted with a panel of acylating and sulf-
onylating reagents. Moreover, dimeric galactosides and lactosides bearing triazoles, regiospecifically
prepared using copper-catalyzed Huisgen azide-alkyne [1,3]-dipolar cycloaddition, provided efficient
galectins-1 and -3 inhibitors. Best monovalent inhibitor among the tested series was (E)-methyl 2-phe-
Received 26 May 2008
Revised 23 June 2008
Accepted 24 June 2008
Available online 26 June 2008
Keywords:
Glycomimetic
Galectins
Galactoside
Cancer
nyl-4-(b-
best dimers were bis-lactoside 68 and 75 having both inhibitory properties of 160
Ó 2008 Elsevier Ltd. All rights reserved.
D-galactopyranosyl)-but-2-enoate 15 with inhibitory potency of 313
l
M against galectin-1 and
l
M against Galectin-3.
HIV
1. Introduction
ple analogs, methyl b-
D-N-acetyllactosaminide, methyl b-D-lacto-
side, and methyl b- -galactoside (Fig. 1) have low affinities, are
D
Galectins1 are a family of cytosolic b-
D
-galactoside binding pro-
too polar to be used as oral drugs, and possess low physiological
stabilities due to their acid sensitive glycosidic bonds.13 Although
the CRDs of galectins show structural homologies and a binding
teins for which fourteen members have been identified in mam-
mals.2 Galectin-1 (Gal-1) is a homo-dimer composed of subunits
of approximately 130 amino acids and each subunit folds as one
compact globular domain.1 Galectin-3 (Gal-3) is quite unique and
has one carbohydrate recognition domain (CRD) ending with a col-
lagen-like repeat of peptides rich in proline and glycine capable of
self association and receptor clustering after binding to galactoside
clusters.3 The roles of the galectin family are numerous, but a strik-
ing common feature of all galectins is the strong modulation of
their expression during development, differentiation stages, and
under different physiological or pathological conditions.4 Studies
have demonstrated that Gal-3 is involved in colon cancer metasta-
sis,5 brain tumor progression,6 inhibition of metastasis-associated
cancer cell adhesion,7 is playing a key role in innate immunity,8
and can regulate apoptotic processes9 together with Gal-110 which
can additionally act as a soluble host factor that promotes HIV-1
infectivity through stabilization of virus attachment to host cells.11
Moreover, a recent study suggests that Gal-1, but not Gal-3, can
facilitate HIV-1 infection in monocyte-derived macrophages
(MDMs) by promoting early events of the virus replicative cycle.12
Naturally occurring carbohydrate ligands for galectins bind to
galectins and can inhibit their biological activity. Among their sim-
preference toward the b-D-galactoside residues in subsite C (partic-
ularly OH-40 and 60), flexibility exists for the design of specific
inhibitors bearing variable pharmacophores in subsites B (OH-30)
and D (Glc residue).14 Moreover, when administered intraperitone-
ally (2 mg/g body weight in mice),
D-galactose can completely
abolish L-1 sarcoma cells metastasis to liver.15 Hence, relatively
high IC50s do not necessarily reflect low in vivo potency. A rational
design approach for the development of a new class of glycomi-
metic inhibitors with high affinity, stability, and specificity to tar-
get Gal-1 versus Gal-3 is thus needed.16 Chemical modification at
the anomeric position led us to the discovery of stable C-galacto-
side
methyl}acetate 117 (Fig. 1) with binding affinities of 5 mM against
Gal-1. Moreover, b-
-lactosyl naphthyl sulfone 218 and dimeric lac-
toside 319 had binding affinities and IC50 of 40
M against Gal-1
and 163 M against Gal-3, respectively. As exemplified by the suc-
cess encountered with analogs 4 (0.3 M), 5 (33 nM), and 6
(110
M) against Gal-3,20 it is anticipated that further develop-
methyl
2-{4-(b-D-galactopyranosyl)-[1,2,3]triazole-2-yl-
D
l
l
l
l
ment in galactoside and lactoside modifications should provide
efficient and selective galectin inhibitors.
Transition metal-catalyzed cross-couplings have proven to be
powerful tools for mild, highly efficient carbon–carbon bond for-
mations. Among these processes, those involving palladium
* Corresponding author. Tel.: +1 514 987 3000x2546; fax: +1 514 987 4054.
E-mail address: roy.rene@uqam.ca (R. Roy).
0968-0896/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.06.044

7812
D. Giguère et al. / Bioorg. Med. Chem. 16 (2008) 7811–7823
HO
HO
HO
OMe HO
HO
HO
OH
O
OH
O
OH
O
HO
AcHN
HO
O
HO
O
OMe
OMe
O
OH
O
OH
HO
HO
HO
4400 μM (Gal-3)
220 μM (Gal-3)
HO
70 μM (Gal-1); 67 μM (Gal-3)
HO
HO
OH
O
OH
O
O
S
HO
HO
HO
O
O
OH
O
N
HO
HO
N
N
COOMe
1
2
5 mM (Gal-1)
40 μM (Gal-1)
HO
HO
OH
O
OH
HO
HO
HO
-O2NPhCOHN
OH
O
HO
O
OH
O
O
O
6
OH
O
O
HO
O
OH
S
p
HO
HO
OH
HO
2
3
5
163 μM (Gal-3)
Kd = 33 nM (Gal-3)
HO
N
HO
OH
O
OH
O
HO2C
O
AcHN
HO
N
OMe
N
SMe
N
H
O
O
OH
BnHN
HO
HO
O
6
4
Kd = 110 μM (Gal-3)
Kd = 0.3 μM (Gal-3)
Figure 1. Simple and synthetic ligands for galectins: methyl b-D-galactoside, methyl b-D
-lactoside, methyl N-acetyllactosaminide, triazolyl galactoside 1,17 sulfonaphthyl
lactoside 2,18 dimeric lactoside 3,19 and best candidates from varied libraries 4–6.20
(Heck21 or Sonogashira22) catalysis are particularly powerful for
the synthesis of complex molecules, owing to their excellent level
of selectivity and high functional group compatibility. Conse-
quently and on the basis of previous expertises,23 the palla-
dium(0)-catalyzed Heck or Sonogashira reactions were used to
synthesize C-galactoside modified aglycons and a small family of
dimeric glycoclusters. Moreover, dimeric galactosides and lacto-
sides bearing triazoles, regiospecifically prepared using copper-
catalyzed Huisgen azide-alkyne [1,3]-dipolar cycloaddition,24 pro-
vided efficient Gal-1 and -3 inhibitors. Finally, first application of
the Hantzsch 2-aminothiazole synthesis toward preparation of gly-
coside inhibitors is described.25 We thus report herein the straight-
forward synthesis and evaluation of galectin inhibitors made by
palladium coupling, Hantzsch 2-aminothiazole synthesis, and click
chemistry.
Thus, condensation of the carbanion of b-diketone with D-galactose
followed by b-elimination of water and then cyclization to the
intermediate C-galactoside which undergoes a retro-Claisen aldoli-
sation under basic conditions with concomitant sodium acetate
elimination provided ketone 18 after acetyl protection (90% over
two steps, Scheme 2). Two transformations were initiated on ke-
tone 18: (1) vinyl triflate formation under basic condition provided
compound 20 in 54% yield and (2) preparation of a-bromoketone
21 using Br2 in 95% yield. Treatment of vinyl triflate 20 under Su-
zuki-coupling using two different arylboronic acids gave adducts
22 and 24 in moderate yields. Ketone 18 along with alkenes 22
and 24 was deprotected (NaOMe/MeOH) to afford free alcohols
19, 23, and 25, respectively.
a-Bromoketone 21 was treated with
thiourea in propionitrile32 to give galacto-aminothiazole 26 in
65% yield (32% of ketone 18 was also recovered).33 2-Aminothia-
zole-bearing C-galactoside 26 is expected to possess improved sta-
bility against hydrolysis under physiological pH and may provide
improved cell membrane permeability. Moreover, 26 is a good can-
didate as a mimic of methyl N-acetyllactosaminide, having the
amine in the same region in Gal-1 and -3 CRDs. Following the
above rationale, derivatization of amine 26 could provide good
candidate as galectin inhibitors. Table 1 shows the synthesis of a
small library of modified 2-aminothiazoles along with deprotec-
tion of the newly formed compounds. 2-Aminothiazole 26 reacted
with various sulfonyl chlorides (entries 1–6) to give a range of sul-
fonamides 27–32 in good to excellent yields 67–91%. Subse-
quently, imine formation with two aromatic aldehydes (entries 7
and 8) followed by reduction using sodium borohydride yielded
secondary amines 33 and 34 in 42% and 47% yields over two steps.
Then, amide formation with a variety of acyl chlorides (entries 9–
14) provided final products in 44–92% yields (35–40). Finally, reac-
tion of amine 26 with methyl chloroformate (entry 15) allowed the
formation of carbamate 47 in 67% yield. Ultimately, 2-aminothia-
zole derivatives 27–41 were subjected to deprotection with meth-
anolic sodium methoxide, followed by treatment with Amberlite
2. Results and discussions
The syntheses were initiated with the known b-C-allyl galacto-
side 7,26 which was subjected to a stereoselective isomerization in
presence of the cationic iridium(I) catalyst to give the (E)-C-vinyl
glycoside 8 in 92% yield (Scheme 1).27 Under Heck conditions, allyl
7 was converted to (E)-styrene derivative 10 (89%) in presence of
phenyl iodide. Cross metathesis23a,28 was also used on allyl 7 to
provide unsaturated ester 12 in 94% yield, which was transformed
into compound 14 under palladium cross-coupling.29 Finally, di-
mer 16 was easily prepared using the same Heck conditions be-
tween allyl 7 and m-diiodobenzene in 79% yield.30 All acylated
glycosides 8, 10, 12, 14, and 16 were deprotected using a catalytic
amount of sodium methoxide in methanol to provide free alcohols
9, 11, 13, 15, and 17 in all almost quantitative yield.
In our ongoing effort to synthesize stable glycosides,18,28 the
Knoevenagel condensation under aqueous conditions could pres-
ent a very convenient method for the preparation of pure b-C-gly-
cosidic ketones directly from unprotected sugars in one step.31

D. Giguère et al. / Bioorg. Med. Chem. 16 (2008) 7811–7823
7813
RO
RO
RO
RO
OR
O
OR
O
Pd(OAc)2, NaHCO3,
(Ph2MeP)2Ir(cod)PF6,
Bu4NBr, PhI,
RO
DMF, 85oC
THF
RO
92%
8 R = Ac
9 R= H
NaOMe,
MeOH
quant.
NaOMe,
MeOH
quant.
10 R = Ac
11 R= H
89%
AcO
OAc
O
AcO
Grubb's 2nd generation,
DCM, reflux
AcO
Pd(OAc)2, NaHCO3,
7
Bu4NBr, PhI,
COOMe
94%
DMF, 85oC
RO
RO
OR
O
I
I
79%
COOMe
RO
RO
RO
OR
OR
O
RO
NaOMe,
MeOH
quant.
12 R = Ac
13 R= H
RO
O
OR
RO
Pd(OAc)2, NaHCO3,
16 R = Ac
17 R= H
Bu4NBr, PhI,
DMF, 85oC
74%
NaOMe,
MeOH
95%
RO
RO
OR
O
COOMe
NaOMe,
14 R = Ac
15 R= H
MeOH
quant.
RO
Ph
Scheme 1. Synthesis of various b-C-galactosides 9, 11, 13, and 15 and b-C-galactoside dimer 17.
1) 2,4-pentanedione,
HO
OH
O
RO
RO
OR
O
NaHCO3, H2O
18 R = Ac
19 R= H
NaOMe,
MeOH
quant.
HO
2) Ac2O, pyridine
90% over two steps
HO
OH
RO
O
D-Galactose
Tf2O, DIPEA
54%
Br2, DCM
95%
AcO
AcO
AcO
OMe
OAc
O
OAc
O
Br
AcO
AcO
AcO
B(OH)2
O
OTf
21
20
DIPEA, propionitrile,
Reflux, 4h
Pd(PPh3)4, DIPEA,
CsF, DME, Reflux
S
(HO)2B
38%
NO2
57%
65%
H2N
NH2
OMe
RO
RO
NH2
AcO
OAc
OR
O
RO
RO
OR
O
S
NO2
O
AcO
AcO
N
RO
RO
24 R = Ac
25 R= H
NaOMe,
MeOH
quant.
26
22 R = Ac
23 R= H
NaOMe,
MeOH
quant.
Scheme 2. Synthesis of various C-galactosides starting from D-galactose.
IR-120 (H+) resin to give free alcohols 42–56 in yields ranging from
46% to 93%.34
have gained great interest. We recently described the use of tran-
sition metal-catalyzed syntheses of ‘rod-like’ thioglycoside di-
mers.37 Sonogashira coupling between thiopropynyl lactoside
5737 and galactoside 5837 with 1,4-diiodobenzene and Pd2(dba)3,
PPh3 and Et3N in DMF (1:1, v/v) under nitrogen at 60 °C for 2 h
provided lactoside dimer 63 (89% yield) and galactoside dimer
66 (93% yield) (Scheme 4). Moreover, using the same strategy,
we used the Glaser coupling, which is the Cu(I)-catalyzed homo-
coupling of 2-propynyl glycoside. The reaction proceeded using
Prop-2-ynyl galactoside and lactoside alkynes 57, 58 along
with galactosyl and lactosyl azides 59, 60 were used for carbon–
carbon coupling and/or click chemistry (Scheme 3). Unprotected
lactoside 61 and galactoside 62 were used as control. Homo-cou-
pling between sp and sp carbon atoms and cross-coupling be-
tween sp2 and sp carbon atoms (such as Glaser35 and
Sonogashira reactions36) as methods to build such compounds

7814
D. Giguère et al. / Bioorg. Med. Chem. 16 (2008) 7811–7823
Table 1
Synthesis of sulfonamides 42–47, amines 48–49, amides 50–55 and carbamate 56, followed by deprotection of alcohols, starting from 2-aminothiazole galactoside 26
HN R
N
HO
HO
NH2
HN R
N
OH
O
AcO
AcO
AcO
AcO
NaOMe,
MeOH
OAc
O
OAc
O
S
S
E+
S
N
Conditions
HO
AcO
AcO
42-56
26
27-41
Entry
1b
Reagent
Product (R)
Yield (%)a
86
Deprotected compounda,e (yield (%))
O
S
p-Toluenesulfonyl chloride
42 (61)
O
27
O
S
Br
2b
3b
4b
4-Bromobenzene-sulfonyl chloride
2-Naphthalene-sulfonyl chloride
2-Chlorobenzene-sulfonyl chloride
91
76
83
43 (64)
44 (92)
45 (85)
O
28
O
S
O
29
O
S
O
Cl
30
O
S
5b
6b
7c
4-tert-Butylbenzene-sulfonyl chloride
2,5-Dibromobenzene-sulfonyl chloride
Benzaldehyde
80
67
42
46 (74)
47 (83)
48 (69)
O
31
Br
O
S
O
Br
32
33
8c
4-Nitrobenzaldehyde
47
58
49 (75)
50 (93)
NO2
34
O
9d
Benzoyl chloride
35
O
10d
4-Nitrobenzoyl chloride
80
51 (74)
NO2
36
O
11d
4-Methoxybenzoyl chloride
44
52 (62)
OMe
37

D. Giguère et al. / Bioorg. Med. Chem. 16 (2008) 7811–7823
7815
Table 1 (continued)
Entry
Reagent
Product (R)
Yield (%)a
Deprotected compounda,e (yield (%))
O
12d
4-Bromobenzoyl chloride
77
53 (80)
Br
38
O
13d
14d
Phenylacetyl chloride
Acetyl chloride
59
92
73
54 (46)
55 (60)
56 (60)
39
O
40
O
O
15d
Methyl chloroformate
41
a
Yields refer to isolated pure products.
Sulfonyl chloride was stirred under reflux to a solution of aminothiazole and DMAP in DCM.
Aldehyde was heated at 140 °C neat with 2-aminothiazole, then dissolved in MeOH, and NaBH4 was added.
Acyl chloride was added to a solution of aminothiazole and Et3N in THF.
b
c
d
e
Acylated carbohydrate was dissolved in MeOH and a catalytic amount of sodium methoxide was added, and the mixture was stirred for less than overnight at room
temperature. Treatment with Amberlite IR-120 (H+) resin, followed by filtration and concentration afforded unprotected carbohydrates.
3. Bioassays
AcO
AcO
OAc
O
OAc
O
AcO
AcO
OAc
O
O
All compounds and controls (lactose and galactose) were tested
by inhibition of hemagglutination assay at a concentration of 1 lM
S
S
AcO
AcO
AcO
AcO
of both galectins. Hemagglutination assays were performed using
red blood cells, type O, fixed with 3% glutaraldehyde–0.0025%
NaN3 in PBS11a,41 to confer both lectins equal relative affinities. Ta-
ble 3 shows inhibitory properties and relative activities of our
derivatives toward Gal-1 and -3. The monosaccharides inhibitory
potencies varied from inactive to moderately active with a IC50 of
57 R = Ac
58 R = Ac
62 R= H
NaOMe
MeOH
quant.
NaOMe
MeOH
quant.
61 R= H
AcO
AcO
OAc
O
AcO
AcO
OAc
OAc
O
O
O
N
N
3
3
AcO
313 lM for compound 15 (160 times better then galactose), indi-
AcO
AcO
60
AcO
59
cating that a sp2 carbon at the b-position to the anomeric carbon
increases the affinity toward Gal-1 and, -3; this is consistent with
other compounds having such scaffolds (compounds 13, 23 and
25). Best 2-aminothiazole derivatives toward Gal-1 and -3 were
sulfonamide 46, amines 48 and 49, along with amides 52 and 53.
Most of the lactoside dimers were effective against Gal-1 and -3
and dimers 68 and 75 gave inhibitory properties as low as
Scheme 3. Lactosides and galactosides alkynes 57, 58, and azides 59, 60.
CuCl as source of Cu(I) and tetramethylethylenediamine (TMEDA)
as base at 40 °C in oxygenated DMF. Thiopropyl lactoside 57 and
galactoside 58 were successfully coupled to afford lactoside dimer
67 and galactoside dimer 69 in 82% and 85% yields, respectively
(Scheme 4). All acylated glycosides 63, 65, 67, and 69 were sub-
jected to deprotection with methanolic sodium methoxide to give,
respectively, unprotected dimers 64, 66, 68, and 70 in almost
quantitative yields.
160 lM against Gal-3 for a relative affinity of 5 (2.5 times better
for each lactose unit). Surprisingly, in this assay, no multivalent ef-
fect was observed for hetero-dimers 76 and 77 (for a relative po-
tency similar to methyl b-D-lactoside). It is important to note
that compound 15 is not only the most promising candidate
against galectin-1, but is also the most selective, being ineffective
Recent developments have been reported in the synthesis of
carbohydrate-based 1,2,3-triazoles.38 Application of the Cu(I)-cata-
lyzed Huisgen azide-alkyne [1,3]-dipolar cycloaddition24 is power-
ful for the synthesis of non-natural heterocycles which are
attractive due to their stability.39 In our ongoing effort to make gly-
coclusters using click chemistry,17,40 we used lactosyl azide 59 and
galactosyl azide 60 as starting materials (Scheme 3). Table 2 shows
reactions of these azides with both thiopropynyl lactoside 57 and
galactoside 58 to give homo-dimers 71 and 74, along with het-
ero-dimers 72 and 73 in yields ranging from 77% to 89%. Final
de-O-acetylation occurred as above with methanolic sodium meth-
oxide to give unprotected dimers 75–78 in high yields.
against Gal-3. This result compared well with b-
D
-lactosyl naph-
M)
thyl sulfone 218 which also have better affinity to Gal-1 (40
l
compared to Gal-3 (313 lM).
4. Conclusions
In conclusion, we described the synthesis of stable galactosides
and lactosides which have potential Gal-1 and -3 inhibitory prop-
erties against galectins which compared well with known inhibi-
tors.17–20,42 The best monovalent inhibitor among the tested
series was C-galactoside 15 with inhibitory properties of 313 lM

7816
D. Giguère et al. / Bioorg. Med. Chem. 16 (2008) 7811–7823
OR
OR
RO
RO
OR
O
OR
O
S
OR
O
OR
OR
O
RO
O
RO
O
S
AcO
RO
RO
63 R = Ac
64 R= H
NaOMe
MeOH
95%
OR
RO
S
OR
OR
O
O
RO
RO
S
OR
RO
65 R = Ac
66 R= H
NaOMe
MeOH
quant.
RO
RO
OR
O
OR
OR
O
OR
OR
S
S
O
OR
OR
O
O
RO
S
O
RO
RO
RO
RO
NaOMe
MeOH
95%
67 R = Ac
68 R= H
OR
RO
RO
OR
O
OR
O
RO
S
OR
RO
NaOMe
MeOH
90%
69 R = Ac
70 R= H
Scheme 4. Deprotection of acetylated dimeric glycosides 63, 65 (made from palladium(0)-catalyzed Sonogashira coupling) and dimeric glycosides 67, 69 (made from the
Glaser Cu(I)-catalyzed homo-coupling reactions) afforded unprotected dimeric lactosides 64, 68, and dimeric galactosides 66, 70.
against Gal-1 and inhibitory >5 mM against Gal-3. Best dimers
were bis-lactosides 68 and 75 having both inhibitory properties
of160 lM. Although the above compounds are notably less effi-
cient than those described by Nilsson et al. in solution assays,20,42a
the present work described inhibition of hemagglutination assays
usually known to require higher concentrations.
Table 2
Synthesis of triazole dimers 75–78 using the copper-catalyzed Huisgen azide-alkyne [1,3]-dipolar cycloaddition, followed by deprotection of alcohol
N
AcO
CuI, DIPEA,
THF
AcO
RO
N
O
O
O
N
S
N3
S
O
OR
57, 58
59, 60
71-74 R = Ac
75-78 R= H
NaOMe
MeOH
Entry
Alkynes
Azides
Products
R = Ac yielda,b (%)
R = H yielda,c (%)
RO
RO
OR
O
OR
OR
O
N
OR
N
OR
N
1
57
59
60
71 (81)
75 (92)
O
O
OR
OR
O
RO
S
RO
O
RO
RO
RO
RO
RO
OR
O
OR
OR
O
N
N
OR
OR
2
3
57
N
72 (89)
76 (quant.)
O
S
O
RO
RO
RO
RO
RO
RO
OR
O
OR
N
N
OR
N
OR
O
OR
OR
58
58
59
60
73 (77)
74 (88)
77 (75)
S
S
O
RO
O
RO
RO
RO
RO
OR
O
N
OR
N
N
OR
4
78 (quant.)
O
RO
RO
OR
a
Yields refer to isolated pure products.
b
c
Alkyne, azide, DIPEA and CuI were dissolved in THF and stirred at room temperature for less than 3 h.
Acetylated carbohydrates were dissolved in MeOH and a catalytic amount of sodium methoxide was added and the mixture was stirred for less than overnight at room
temperature.

D. Giguère et al. / Bioorg. Med. Chem. 16 (2008) 7811–7823
7817
du Québec à Montréal). Either protonated molecular ions [M+H]+
or sodium adducts [M+Na]+ were used for empirical formula
confirmation.
Table 3
Inhibitory properties and relative activity of compounds 9, 11, 13, 15, 17, 19, 23, 25,
42-56, 61, 62, 64, 66, 68, 70, 75, 76, 77, and 78 against Gal-1 and -3
Compound
Inhibitory properties (mM)
Relative activitya
Galectin-1 Galectin-3
5.1.2. Typical de-O-acetylation procedure
Galectin-1
Galectin-3
The acetyls protected glycoside (0.1 mmol) was dissolved into
methanol (2 mL), to which was added a catalytic amount of sodium
methoxide. The solution was stirred at room temperature from 3 to
15 h. After neutralization of sodium methoxide with Amberlite IR-
120 (H+) resin, the solution was filtered and removal of the meth-
anol under reduced pressure afforded the fully deprotected
glycoside.
Lactoseb
Galactose
9
11
13
0.8
50
>5
>5
5
0.313
5
>5
>5
5
>5
>5
>5
>5
5
>5
5
2.5
>5
>5
5
2.5
>5
>5
>5
0.6
>5
0.3
2.5
0.3
5
0.8
50
>5
>5
5
>5
>5
5
5
>5
5
5
2.5
5
1
1
<10
<10
10
160
10 (5)
<10
<10
10
<10
<10
<10
<10
10
<10
10
20
<10
<10
10
20
<10
<10
<10
1
1
<10
<10
10
<10
<10
10
10
<10
10
10
20
10
10
20
20
20
20
<10
20
20
<10
10
<10
2.6
15
17c
19
23
25
42
43
44
45
46
47
48
49
50
51
52
53
54
55
5.1.3. (E)-Methyl 4-(2,3,4,6-tetracetyl-b-D-galactopyranosyl)-
but-2-enoate (12)
To a 0.04 M solution of b-C-allyl glycoside 7 (0.1 mmol) in
CH2Cl2 were added methyl acrylate (0.3 mmol) and 5 mol% of
Grubbs 2nd generation catalyst. The reaction mixture was heated
under reflux (55 °C) under N2 for 3 h. The solution was evaporated
under reduced pressure and the residue was purified by flash col-
umn chromatography on silica gel to give 12 as a yellow oil in 94%
yield: 1H NMR (300 MHz, CDCl3, d ppm): 6.94–6.84 (m, 1H), 5.88
(d, J = 14.3 Hz, 1H), 5.36 (d, J = 3.3 Hz, 1H), 5.07 (t, J = 9.9 Hz, 1H),
4.98 (dd, J = 3.3, 9.9 Hz, 1H), 4.12–3.97 (m, 2H), 3.84 (t, J = 6.3 Hz,
1H), 3.68 (s, 3H), 3.54–3.47 (m, 1H), 2.41 (m, 2H), 2.11 (s, 3H),
2.00 (s, 6H), 1.93 (s, 3H); 13C NMR (75.5 MHz, CDCl3, d ppm):
170.3, 170.2, 169.9, 169.6, 166.4, 143.4, 123.3, 76.6, 74.0, 71.8,
68.9, 67.4, 61.4, 51.4, 34.2, 20.6, 20.5, 20.4, 20.3; ESI-MS m/z :
431.3 [M+H]+; HRMS m/z calcd C19H26O11 [M+H]+: 431.1555;
found: 431.1538.
5
2.5
2.5
2.5
2.5
>5
2.5
2.5
>5
5
>5
0.3
2.5
0.3
>5
0.16
>5
0.16
0.3
0.6
2.5
56
61
62
1.3
<10
20
64c
66c
68c
70c
75c
76c
77c
78c
2.6 (1.3)
20 (10)
2.6 (1.3)
10 (5)
2.6 (1.3)
1.3 (0.7)
2.6 (1.3)
<10
2.6 (1.6)
<10
5 (2.5)
<10
5 (2.5)
2.6 (1.3)
1.3 (0.7)
20 (10)
0.3
0.6
0.3
>5
5.1.4. (E)-Methyl 4-(b-D-galactopyranosyl)-but-2-enoate (13)
Synthesis according to the typical de-O-acetylation procedure
obtained in quantitative yield as a yellow solid: mp = 53–54 °C
(ethanol); 1H NMR (300 MHz, CDCl3, d ppm): 6.92–6.87 (m, 1H),
5.82 (d, J = 15.6 Hz, 1H), 3.93–3.75 (m, 1H), 3.52 (s, 1H), 3.37–
3.05 (m, 6H), 2.58–2.38 (m, 2H); 13C NMR (75.5 MHz, CDCl3, d
ppm): 174.8, 147.0, 122.5, 78.7, 78.4, 74.1, 71.0, 69.1, 61.3, 52.4,
a
All compounds were compared to galactose except for compounds 64, 68, and
75 which were compared to lactose.
b
Lactose is ꢁ50ꢂ better than galactose.
c
Numbers in parentheses express the relative potency of each lactose unit in the
C
11H18O7 [M+H]+: 263.1132; found:
divalent derivative compare to lactose for compounds 64, 68, and 75 and galactose
for compounds 17, 66, 70, 76, 77, and 78.
38.7 HRMS m/z calcd
263.1125.
5.1.5. (E)-Methyl 2-phenyl-4-(2,3,4,6-tetracetyl-b-D-galactopyr
5. Experimentals
5.1. Chemistry
anosyl)-but-2-enoate (14)
To a 0.16 M solution of 12 (0.1 mmol) in DMF were added phe-
nyl iodide (0.2 mmol), 10% palladium(II) acetate, tetrabutylammo-
nium bromide (0.1 mmol), and sodium bicarbonate (0.3 mmol).
The reaction mixture was heated at 85 °C under N2 overnight.
The solution was evaporated under reduced pressure, and the res-
idue was purified by flash column chromatography on silica gel to
5.1.1. General
All reactions in organic medium were carried out under nitro-
gen atmosphere using freshly distilled solvents. CH2Cl2 was dried
over P2O5, THF and toluene were dried over sodium and benzophe-
none. Evolution of the reaction was monitored by analytical thin-
layer chromatography using silica gel 60 F254 precoated plates (E.
Merck). Purifications by column chromatography were performed
give 14 as a yellow oil; [
a
]
25: ꢀ4.8° (c 1.0 in CHCl3); 1H NMR
D
(300 MHz, CDCl3, d ppm): 7.44–7.40 (m, 2H), 7.36–7.33 (m, 3H),
6.09 (s, 1H), 5.33 (d, J = 3.3 Hz, 1H), 5.15 (t, J = 9.9 Hz, 1H), 4.95
(dd, J = 3.3, 10.2 Hz, 1H), 3.85 (d, J = 6.6 Hz, 2H), 3.74 (s, 3H),
3.65–3.49 (m, 3H), 3.21 (dd, J = 9.3, 14.0 Hz, 1H), 2.13 (s, 3H),
2.11 (s, 3H), 1.96 (s, 3H), 1.92 (s, 3H); 13C NMR (75.5 MHz, CDCl3,
d ppm): 170.3, 170.2, 170.1, 166.5, 156.9, 141.5, 128.8, 128.2,
126.9, 118.8, 78.3, 73.8, 71.9, 69.4, 67.6, 61.3, 51.2, 33.2, 20.9,
using silica gel Si 60 (40–63 lM) with the indicated eluent. Optical
rotations were measured with a JASCO P-1010 polarimeter. Melt-
ing points were measured on an Electrothermal MEL-TEMP appa-
ratus. NMR spectra were recorded on a Varian Gemini 300
spectrometer. Proton and carbon chemical shifts (d) are reported
in ppm downfield from CHCl3, CH3OH, or DMSO. Coupling con-
stants (J) are reported in Hertz (Hz) with singlet (s), doublet (d),
doublet of doublet (dd), triplet (t), multiplet (m), and broad (br).
Infrared were measured with a Bomem MB-series. Low-resolution
(ESI-MS) and high-resolution mass spectra (HRMS) were achieved
using a LC-MSD-TOF instrument from Agilent Technologies (by Dr.
Alexandra Furtos and Karine Venne; Mass Spectrometry Labora-
tory, Université de Montréal, Québec, Canada or at the Université
20.7, 20.6; ESI-MS m/z
:
507.3 [M+H]+; HRMS m/z calcd
C
25H30O11 [M+H]+: 507.1868; found: 507.1855.
5.1.6. (E)-Methyl 2-phenyl-4-(b-D-galactopyranosyl)-but-2-
enoate (15)
Synthesis according to the typical de-O-acetylation procedure
obtained in quantitative yield as a yellowish solid: mp = 57–58 °C
(ethanol); 1H NMR (300 MHz, CDCl3, d ppm): 7.21–7.17 (m, 5H),
5.84 (s, 1H), 3.64 (s, 1H), 3.52 (s, 3H), 3.51–3.27 (m, 6H), 3.24–

7818
D. Giguère et al. / Bioorg. Med. Chem. 16 (2008) 7811–7823
2.96 (m, 2H); 13C NMR (75.5 MHz, CDCl3, d ppm): 169.1, 157.9,
140.6, 129.3, 128.8, 127.1, 118.9, 78.8, 78.3, 74.1, 71.7, 69.1, 60.9,
51.9, 33.1; HRMS m/z calcd C17H22O7 [M+H]+: 339.1445; found:
339.1438.
5.1.10. 5-(2,3,4,6-Tetraacetyl-b-D-galactopyranosyl)-4-methyl-
2-(4-bromophenyl)sulfonylaminothiazole (28)
Synthesis according to the same procedure as for the synthesis
of 27 obtained in 91% yield as a white solid: mp = 95–96 °C (etha-
nol); [
a
]
D
25: ꢀ21.8° (c 1.1 in CHCl3); 1H NMR (300 MHz, CDCl3, d
ppm): 7.61 (d, J = 9.0 Hz, 2H), 7.49 (d, J = 9.0 Hz, 2H), 5.44 (d,
J = 3.0 Hz, 1H), 5.19 (dd, J = 10.0 Hz, 1H), 5.08 (dd, J = 10.0, 3.5 Hz,
1H), 4.46 (dd, J = 9.5 Hz, 1H), 4.14–3.95 (m, 3H), 2.27 (s, 3H), 2.18
(s, 3H), 1.99 (s, 3H), 1.94 (s, 3H), 1.88 (s, 3H); 13C NMR
(75.5 MHz, CDCl3, d ppm): 170.6, 170.4, 170.2, 169.8, 169.1,
140.7, 133.0, 132.2, 128.0, 127.3, 115.3, 75.1, 73.6, 71.7, 69.5,
67.5, 61.8, 21.0, 20.8, 12.5; IR (KBr, cmꢀ1): 1751, 1540, 1221,
742; HRMS m/z calcd C24H27BrN2O11S2 [M+H]+: 663.0319; found:
663.0298.
5.1.7. 1-(2,3,4,6-Tetracetyl-b-
2,4-Pentanedione (0.62 mL, 6.0 mmol) was added to a mixture
-galactose (900 mg, 5.0 mmol) and NaHCO3 (630 mg,
D-galactopyranosyl)-ace-tone (18)
of
D
7.5 mmol) in water (20 mL). The mixture was stirred overnight
at 90 °C, and then cooled to room temperature. The solution
was washed with DCM (3ꢂ 20 mL), and the combined organic
solutions were dried over Na2SO4, filtered, and concentrated un-
der reduced pressure. To the crude C-galactoside in pyridine
(15 mL) at 0 °C was added dropwise Ac2O (7.5 mL) and the mix-
ture was stirred at room temperature overnight. In the morning,
ice (30 mL) and EtOAc (30 mL) were added to the solution, and
the organic layer was washed with aqueous NH4Cl (2ꢂ 30 mL),
aqueous NaHCO3 (2ꢂ 30 mL), brine (2ꢂ 30 mL), and water (2ꢂ
30 mL). The organic solution was dried over Na2SO4, filtered, con-
centrated, and chromatographed using a mixture of Et2O/CHCl3
(1:5) to give 18 in 90% yield over two steps as a colorless oil
(1.523 g): 1H NMR (300 MHz, CDCl3, d ppm): 5.33 (dd, J = 3.0,
1.0 Hz, 1H), 5.04–4.91 (m, 2H), 4.04–3.78 (m, 4H), 2.69 (dd,
J = 16.5, 9.0 Hz, 1H), 2.40 (dd, J = 16.5, 3.0 Hz, 1H), 2.09 (s, 3H),
2.06 (s, 3H), 1.95 (s, 3H), 1.94 (s, 3H), 1.89 (s, 3H); 13C NMR
(75.5 MHz, CDCl3, d ppm): 205.4, 170.5, 170.3, 170.2, 170.1,
74.5, 74.4, 72.0, 69.1, 67.8, 61.6, 45.6, 31.2, 20.9, 20.8, 20.7; HRMS
m/z calcd C17H24O10 [M+H]+: 389.1449; found: 389.1435.
5.1.11. 5-(2,3,4,6-Tetraacetyl-b-D-galactopyranosyl)-4-methyl-
2-(b-naphthyl)sulfonylaminothiazole (29)
Synthesis according to the same procedure as for the synthesis
25
of 27 obtained in 76% yield as a white solid: mp = 92–93 °C; [
a]
:
D
ꢀ19.3° (c 1.2 in CHCl3); 1H NMR (300 MHz, CDCl3, d ppm): 8.36 (s,
1H), 7.82 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.64–7.43 (m,
4H), 5.43 (d, J = 3.5 Hz, 1H), 5.23 (dd, J = 10.0 Hz, 1H), 5.07 (dd,
J = 10.0, 3.5 Hz, 1H), 4.46 (dd, J = 9.5 Hz, 1H), 4.14–3.94 (m, 3H),
2.31 (s, 3H), 2.19 (s, 3H), 1.97 (s, 3H), 1.94 (s, 3H), 1.79 (s, 3H);
13C NMR (75.5 MHz, CDCl3, d ppm): 170.6, 170.5, 170.2, 169.8,
169.1, 138.6, 134.8, 133.2, 132.2, 129.5, 129.3, 128.6, 127.9,
127.4, 127.2, 122.2, 115.0, 75.1, 73.7, 71.8, 69.4, 67.6, 61.8, 21.0,
20.9, 20.8, 20.7, 12; IR (KBr, cmꢀ1): 1751, 1540, 1221, 770; HRMS
m/z calcd C28H30N2O11S2 [M+H]+: 635.1370; found: 635.1351.
5.1.8. 2-Amino-5-(2,3,4,6-tetraacetyl-b-D-galactopyranosyl)-4-
methylthiazole (26)
5.1.12. 5-(2,3,4,6-Tetraacetyl-b-D-galactopyranosyl)-4-methyl-
2-(2-chlorophenyl)sulfonylaminothiazole (30)
Bromoketone 21 (47.16 mmol), thiourea (3.58 g, 47.16 mmol)
and DIPEA (15.78 mL, 94.32 mmol) were dissolved in propionitrile
(300 mL) and the mixture was stirred under reflux for 4 h. After
this time, the mixture was evaporated and chromatographed using
a mixture of t-BuOH/CHCl3 (1:9) to give 26 in 65% yield as a yellow
Synthesis according to the same procedure as for the synthesis
25
of 27 obtained in 83% yield as a white solid: mp = 91–92 °C; [
a]
:
D
+16.0° (c 1.0 in CHCl3); 1H NMR (300 MHz, CDCl3, d ppm): 8.12–
8.07 (m, 1H), 7.44–7.27 (m, 3H), 5.41 (d, J = 3.5 Hz, 1H), 5.16 (dd,
J = 10.0 Hz, 1H), 5.06 (dd, J = 10.0, 3.5 Hz, 1H), 4.46 (dd, J = 9.5 Hz,
1H), 4.13–3.92 (m, 3H), 2.31 (s, 3H), 2.16 (s, 3H), 1.97 (s, 3H),
1.91 (s, 3H), 1.86 (s, 3H); 13C NMR (75.5 MHz, CDCl3, d ppm):
170.6, 170.4, 170.2, 170.0, 169.0, 138.6, 133.4, 133.2, 132.4,
131.8, 130.7, 126.8, 115.4, 75.1, 73.7, 71.7, 69.4, 67.5, 61.8, 21.0,
20.9, 20.8, 20.7, 12.6; IR (KBr, cmꢀ1): 1752, 1542, 1228, 1046,
753; HRMS m/z calcd C24H27ClN2O11S2 [M+H]+: 619.0824; found:
619.0805.
oil (13.6 mg); [
a
]
D
25: ꢀ8.0° (c 1.0 in CHCl3); 1H NMR (300 MHz,
CDCl3, d ppm): 5.48 (d, J = 3.5 Hz, 1H), 5.35 (t, J = 10.0 Hz, 1H),
5.13 (dd, J = 3.5, 10.0 Hz, 1H), 4.63 (d, J = 9.5 Hz, 1H), 4.09 (m,
3H), 2.20 (s, 3H), 2.01 (s, 3H), 1.99 (s, 3H), 1.96 (s, 3H), 1.87 (s,
3H); 13C NMR (75.5 MHz, CDCl3, d ppm): 170.3, 170.2, 170.0,
169.3, 158.0, 144.4, 120.6, 74.6, 74.2, 71.7, 70.3, 67.4, 61.5, 20.6,
20.5, 20.5, 20.5, 15.3; IR (neat NaCl, cmꢀ1): 3735, 3400, 3118,
3020, 2962, 1749, 1521, 1371, 1226, 1051, 753; ESI-MS m/z :
445.1 [M+H]+; HRMS m/z calcd C18H24N2O9S [M+H]+: 445.1282;
found: 445.1265.
5.1.13. 5-(2,3,4,6-Tetraacetyl-b-D-galactopyranosyl)-4-methyl-
2-(4-tert-buthylphenyl)sulfonylaminothiazole (31)
Synthesis according to the same procedure as for the synthesis
25
5.1.9. 5-(2,3,4,6-Tetraacetyl-b-D-galactopyranosyl)-4-methyl-2-
(4-methyl-phenyl)sulfonylaminothiazole (27)
of 27 obtained in 80% yield as a white solid: mp = 97–98 °C; [
a]
:
D
ꢀ32.1° (c 1.4 in CHCl3); 1H NMR (300 MHz, CDCl3, d ppm): 7.78 (d,
J = 8.5 Hz, 2H), 7.46 (d, J = 8.8 Hz, 2H), 7.27 (dd, J = 3.3 Hz, 1H), 5.49
(dd, J = 10.0 Hz, 1H), 5.14 (dd, J = 3.3, 10.0 Hz, 1H), 4.50 (d, J = 9.5
Hz, 1H), 4.19–4.00 (m, 3H), 2.35 (s, 3H), 2.24 (s, 3H), 2.05 (s, 3H),
2.00 (s, 3H), 1.94 (s, 3H), 1.33 (s, 9H); 13C NMR (75.5 MHz, CDCl3,
d ppm): 170.4, 170.3, 170.1, 169.6, 168.8, 155.9, 138.5, 132.9,
126.2, 125.7, 114.3, 74.9, 73.5, 71.6, 69.1, 67.3, 61.6, 35.04, 31.1,
20.8, 20.7, 20.6, 12.4; IR (KBr, cmꢀ1): 1752, 1540, 1222, 1086,
754; HRMS m/z calcd C28H36N2O11S2 [M+H]+: 641.1840; found:
641.1821.
Tosyl chloride (19 mg, 0.10 mmol) and DMAP (13 mg,
0.10 mmol) were added to a solution of aminothiazole 26 (45 mg,
0.10 mmol) in 3 mL of DCM. The mixture was stirred under reflux
overnight, then concentrated. Flash chromatography was done
using a mixture of t-BuOH/CHCl3 (1:9). Sulfonamide 27 was ob-
tained as a white solid in 86% yield (51 mg): mp = 91–92 °C;
[a
]
D
25: ꢀ27.4° (c 1.3 in CHCl3); 1H NMR (300 MHz, CDCl3, d
ppm): 7.64 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 8.5 Hz, 2H), 5.43 (d,
J = 3.0 Hz, 1H), 5.21 (dd, J = 10.0 Hz, 1H), 5.07 (dd, J = 10.0, 3.5 Hz,
1H), 4.46 (dd, J = 9.5 Hz, 1H), 4.14–3.95 (m, 3H), 2.34 (s, 3H), 2.28
(s, 3H), 2.18 (s, 3H), 2.00 (s, 3H), 1.94 (s, 3H), 1.88 (s, 3H); 13C
NMR (75.5 MHz, CDCl3, d ppm): 170.6, 170.5, 170.3, 169.8, 169.1,
143.0, 138.9, 133.1, 129.6, 126.5, 114.7, 75.1, 73.7, 71.8, 69.4,
67.5, 61.8, 21.7, 21.0, 20.9, 20.78, 12.5; IR (KBr, cmꢀ1): 1751,
5.1.14. 5-(2,3,4,6-Tetraacetyl-b-D-galactopyranosyl)-4-methyl-
2-(2,5-dibromophenyl)sulfonylaminothiazole (32)
Synthesis according to the same procedure as for the synthe-
sis of 27 obtained in 67% yield as a white solid: mp = 90–91 °C;
1541, 1225, 1088; HRMS m/z calcd
C
25H30N2O11S2 [M+H]+:
[a]
25: ꢀ17.0° (c 1.0 in CHCl3); 1H NMR (300 MHz, CDCl3, d
D
599.1370; found: 599.1364.
ppm): 8.30–8.27 (m, 1H), 7.46–7.41 (m, 2H), 5.44 (d, J = 3.0 Hz,

D. Giguère et al. / Bioorg. Med. Chem. 16 (2008) 7811–7823
7819
1H), 5.18 (dd, J = 10.0 Hz, 1H), 5.08 (dd, J = 10.0, 3.5 Hz, 1H), 4.47
5.1.18. 5-(2,3,4,6-Tetraacetyl-b-
D-galactopyranosyl)-4-methyl-
(dd, J = 9.5 Hz, 1H), 4.15–3.95 (m, 3H), 2.33 (s, 3H), 2.18 (s, 3H),
2.00 (s, 3H), 1.94 (s, 3H), 1.91 (s, 3H); 13C NMR (75.5 MHz,
CDCl3, d ppm): 170.6, 170.4, 170.2, 169.9, 169.1, 141.9, 136.7,
136.1, 133.6, 133.2, 121.2, 119.6, 115.9, 75.1, 73.7, 71.7, 69.4,
67.5, 61.8, 21.0, 20.8, 12.7; IR (KBr, cmꢀ1): 1752, 1540, 1222,
2-p-nitrobenzamidothiazole (36)
Synthesis according to the same procedure as for the synthesis
of 35 obtained in 80% yield as a yellow oil; [
a
]
25: ꢀ27.1° (c 1.6 in
D
CHCl3); 1H NMR (300 MHz, CDCl3, d ppm): 8.27 (d, 2 H, J = 9.0 Hz,
2H), 8.09 (d, J = 9.0 Hz, 2H), 5.49 (d, J = 3.5 Hz, 1H), 5.32 (dd,
J = 10.0 Hz, 1H), 5.16 (dd, J = 3.5, 10.0 Hz, 1H), 4.65 (d, J = 9.5 Hz,
1H), 4.10 (m, 3H), 2.18 (s, 3H), 2.03 (s, 3H), 1.97 (s, 3H), 1.96 (s,
3H), 1.95 (s, 3H); 13C NMR (75.5 MHz, CDCl3, d ppm): 170.3,
170.1, 169.9, 169.8, 163.3, 158.0, 149.9, 144.3, 137.5, 129.0,
123.6, 121.6, 74.5, 73.9, 71.5, 70.3, 67.4, 61.5, 20.6, 20.4, 20.4,
20.4, 14.,9; IR (neat NaCl, cmꢀ1): 3298, 3022, 2982, 1751, 1675,
1547, 1369, 1229, 1052, 756; ESI-MS m/z : 594.1 [M+H]+; HRMS
m/z calcd C25H27N3O12S [M+H]+: 594.1395; found: 594.1382.
1054, 756; HRMS m/z calcd
740.9424; found: 740.9407.
C
24H26Br2N2O11S2 [M+H]+:
5.1.15. 5-(2,3,4,6-Tetraacetyl-b-D-galactopyranosyl)-4-methyl-
2-(benzyl)sulfonylaminothiazole (33)
Aminothiazole 26 (120 mg, 0.27 mmol) was heated in a sealed
tube at 140 °C in presence of benzaldehyde (0.81 mmol) for 1 h.
After this time, crude imine was dissolved in THF (2 mL) and
NaBH4 (40 mg, 1.08 mmol) was added. The mixture was stirred
at room temperature for 30 min. Aqueous NH4Cl (5 mL) and EtOAc
(5 mL) were added, and the aqueous layer was extracted with
EtOAc (3ꢂ 5 mL). The combined organic solutions were dried over
Na2SO4, filtered, and concentrated. Flash chromatography was
done using a mixture of EtOAc/toluene (1:1). Benzyl 33 was ob-
5.1.19. 2-p-Anisamido-5-(2,3,4,6-tetraacetyl-b-D-
galactopyranosyl)-4-methylthiazole (37)
Synthesis according to the same procedure as for the synthesis of
35 obtained in 44% yield as a yellow oil; [
a]
25: ꢀ21.5° (c 1.6 in
D
CHCl3); 1H NMR (300 MHz, CDCl3, d ppm): 7.86 (d, J = 9.0 Hz, 2H),
6.94 (d, J = 9.0 Hz, 2H), 5.48 (d, J = 3.5 Hz, 1H), 5.35 (dd, J = 10.0 Hz,
1H), 5.14 (dd, J = 3.5, 10.0 Hz, 1H), 4.64 (d, J = 9.5 Hz, 1H), 4.09 (m,
3H), 3.84 (s, 3H), 2.20 (s, 3H), 2.00 (s, 3H), 1.99 (s, 3H), 1.96 (s, 3H),
1.87 (s, 3H); 13C NMR (75.5 MHz, CDCl3, d ppm): 170.3, 170.2,
170.1, 168.8, 164.6, 158.8, 144.8, 129.8, 128.8, 128.1, 125.1, 124.3,
120.1, 114.0, 74.5, 74.1, 70.2, 67.5, 61.6, 55.4, 20.6, 20.5, 20.5, 20.4,
14.9; IR (neat NaCl, cmꢀ1): 3313, 3022, 2941, 1756, 1664, 1608,
1516, 1373, 1256, 1225, 1056, 766; ESI-MS m/z : 579.1 [M+H]+;
HRMS m/z calcd C26H30N2O11S [M+H]+: 579.1650; found: 579.1631.
tained as
a
colorless oil in 42% yield (61 mg): 1H NMR
(300 MHz, CDCl3, d ppm): 7.32–7.22 (m, 5H), 5.41 (d, J = 3.0 Hz,
1H), 5.19 (dd, J = 10.0 Hz, 1H), 5.07 (dd, J = 10.0, 3.5 Hz, 1H), 4.52
(d, J = 9.5 Hz, 1H), 4.41 (d, J = 14.5 Hz, 1H), 4.33 (d, J = 14.5 Hz,
1H), 4.13–3.94 (m, 3H), 2.13 (s, 3H), 2.08 (s, 3H), 1.98 (s, 3H),
1.93 (s, 3H), 1.85 (s, 3H); 13C NMR (75.5 MHz, CDCl3, d ppm):
170.6, 170.5, 170.3, 169.5, 169.1, 147.6, 147.3, 137.49, 128.9,
127.9, 127.7 (2C), 74.8, 74.7, 72.2, 70.3, 67.8, 61.8, 50.0, 20.9,
20.7, 15.5; HRMS m/z calcd
C
25H30N2O9S [M+H]+: 535.1751;
found: 535.1812.
5.1.20. 2-p-Bromobenzamido-5-(2,3,4,6-tetraacetyl-b-D-
5.1.16. 5-(2,3,4,6-Tetraacetyl-b-
D
-galactopyranosyl)-4-methyl-
galactopyranosyl)-4-methylthiazole (38)
2-(4-nitrobenzyl)sulfonylaminothiazole (34)
Synthesis according to the same procedure as for the synthesis
Synthesis according to the same procedure as for the synthesis
of 33 obtained in 47% yield as a colorless oil; 1H NMR (300 MHz,
CDCl3, d ppm): 8.13 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 8.5 Hz, 2H),
5.40 (d, J = 2.5 Hz, 1H), 5.14 (dd, J = 10.0 Hz, 1H), 5.05 (dd,
J = 10.0, 3.5 Hz, 1H), 4.54–4.45 (m, 3H), 4.10–3.94 (m, 3H), 2.10
(s, 3H), 2.03 (s, 3H), 1.96 (s, 3H), 1.91 (s, 3H), 1.82 (s, 3H); 13C
NMR (75.5 MHz, CDCl3, d ppm): 170.6, 170.4, 170.3, 169.3, 169.1,
147.6, 147.3, 128.1, 124.1, 114.9, 74.8, 74.6, 72.1, 70.3, 67.7, 61.8,
of 35 obtained in 77% yield as a yellow oil; [
a
]
D
25: ꢀ25.2° (c 1.1 in
CHCl3); 1H NMR (300 MHz, CDCl3, d ppm): 7.77 (d, J = 9.0 Hz, 2H),
7.60 (d, J = 9.0 Hz, 2H), 5.50 (d, J = 3.5 Hz, 1H), 5.35 (dd,
J = 10.0 Hz, 1H), 5.16 (dd, J = 3.5, 10.0 Hz, 1H), 4.63 (d, J = 9.5 Hz,
1H), 4.11 (m, 3H), 2.20 (s, 3H), 2.03 (s, 3H), 2.01 (s, 3H), 1.98 (s,
3H), 1.91 (s, 3H); 13C NMR (75.5 MHz, CDCl3, d ppm): 170.4,
170.3, 170.1, 169.0, 164.4, 158.6, 144.7, 132.9, 131.1, 129.4,
128.9, 128.1, 127.7, 121.6, 74.7, 74.2, 71.8, 70.3, 67.5, 61.6, 20.7,
20.6, 20.6, 20.6, 14.9; IR (neat NaCl, cmꢀ1): 3303, 2971, 1751,
1669, 1540, 1369, 1225, 1053, 750; ESI-MS m/z : 627.1 [M+H]+
(Br79); 629.0 [M+H]+ (Br81); HRMS m/z calcd C25H27N2O10SBr
[M+H]+: 627.0649; found: 627.0633.
49.0, 20.9, 20.8, 20.7, 15.6; HRMS m/z calcd
C25H29N3O11S
[M+H]+: 580.1602; found: 580.15849.
5.1.17. 2-Benzamido-5-(2,3,4,6-tetraacetyl-b-D-galactopyrano-
syl)-4-methylthiazole (35)
Aminothiazole 26 (226 mg, 0.509 mmol) and DMAP (93 mg,
0.764 mmol) were dissolved in 2 mL of THF at 0 °C. Benzoyl chlo-
ride (0.764 mmol) was added, and the mixture was stirred at 0 °C
overnight. After this time, saturated NaHCO3 (6 mL) was added
and the mixture was extracted with ethyl acetate (3ꢂ 6 mL).
The combined organic solution was dried over Na2SO4, filtered,
concentrated, and chromatographed using a mixture of t-BuOH/
CHCl3 (1:9). Amide 35 was obtained as a yellow oil in 58% yield
5.1.21. 5-(2,3,4,6-Tetraacetyl-b-
2-phenylacetamidothiazole (39)
Synthesis according to the same procedure as for the synthesis
of 35 obtained in 59% yield as a yellow oil; [
D-galactopyranosyl)-4-methyl-
a
]
D
25: ꢀ17.0° (c 1.2 in
CHCl3); 1H NMR (300 MHz, CDCl3, d ppm): 5.47 (d, J = 3.5 Hz, 1H),
5.31 (dd, J = 9.5 Hz, 1H), 5.14 (dd, J = 3.5, 10.0 Hz, 1H), 4.64 (d,
J = 9.5 Hz, 1H), 4.09 (m, 3H), 3.76 (s, 3H), 2.25 (s, 3H), 2.18 (s,
3H), 2.00 (s, 3H), 1.97 (s, 3H), 1.88 (s, 3H); 13C NMR (75.5 MHz,
CDCl3, d ppm): 170.4, 170.3, 170.1, 168.9, 168.6, 157.1, 144.8,
132.9, 129.5, 129.2, 127.8, 121.3, 74.7, 74.3, 71.8, 70.3, 67.5, 61.6,
43.2, 20.7, 20.6, 20.5, 20.5, 15.3; IR (neat NaCl, cmꢀ1): 3277,
2952, 2926, 2868, 1750, 1541, 1371, 1225, 1052, 758; ESI-MS m/z
(162 mg); [
a
]
D
25: ꢀ27.1° (c 1.6 in CHCl3); 1H NMR (300 MHz,
CDCl3, d ppm): 7.89 (d, J = 7.0 Hz, 2H), 7.57 (t, J = 7.5 Hz, 3H),
7.46 (t, J = 7.5 Hz, 2H), 5.49 (d, J = 3.5 Hz, 1H), 5.36 (dd,
J = 10.0 Hz, 1H), 5.14 (dd, J = 3.5, 10.0 Hz, 1H), 4.63 (d, J = 9.5 Hz,
1H), 4.09 (m, 3H), 2.21 (s, 3H), 2.01 (s, 3H), 1.97 (s, 3H), 1.91 (s,
3H), 1.88 (s, 3H); 13C NMR (75.5 MHz, CDCl3, d ppm): 170.7,
170.6, 170.4, 169.1, 165.6, 159.0, 145.1, 132.9, 129.2, 128.3,
125.5, 121.5, 74.9, 74.4, 72.2, 70.5, 67.7, 61.9, 21.6, 20.9, 20.9,
20.8, 15.0; IR (neat NaCl, cmꢀ1): 3303, 3032, 2956, 1751, 1671,
1537, 1370, 1294, 1225, 1054, 756; ESI-MS m/z : 549.1 [M+H]+;
:
563.1 [M+H]+; HRMS m/z calcd C25H28N2O10
S
[M+H]+:
563.1700; found: 563.1684.
5.1.22. 2-Acetamido-5-(2,3,4,6-tetraacetyl-b-D-galactopyranosyl)-
4-methylthiazole (40)
Synthesis according to the same procedure as for the synthesis
HRMS m/z calcd
C25H28N2O10
S
[M+H]+: 549.1544; found:
of 35 obtained in 92% yield as a yellow oil; [
a
]
D
25: ꢀ9.9° (c 1.6 in
549.15243.
MeOH); 1H NMR (300 MHz, CDCl3, d ppm): 5.46 (d, J = 3.0 Hz,

7820
D. Giguère et al. / Bioorg. Med. Chem. 16 (2008) 7811–7823
1H), 5.29 (dd, J = 10.0 Hz, 1H), 5.13 (dd, J = 3.5, 10.0 Hz, 1H), 4.62 (d,
J = 9.5 Hz, 1H), 4.06 (m, 3H), 2.25 (s, 3H), 2.16 (s, 3H), 2.15 (s, 3H),
1.98 (s, 3H), 1.94 (s, 3H), 1.89 (s, 3H); 13C NMR (75.5 MHz, CDCl3, d
ppm): 170.3, 170.2, 170.0, 169.3, 167.9, 158.0, 144.4, 120.6, 74.6,
74.2, 71.7, 70.3, 67.4, 61.5, 22.8, 20.6, 20.5, 20.5, 20.5, 15.3; IR (neat
NaCl, cmꢀ1): 3287, 3028, 2977, 1751, 1692, 1543, 1370,1228, 1053,
J = 9.1 Hz, 1H), 3.79 (dd, J = 3.0 Hz, 1H), 3.60–3.40 (m, 5H), 1.96
(s, 3H); 13C NMR (75.5 MHz, D2O, d ppm): 167.4, 136.8, 134.5,
134.1, 132.2, 131.6, 130.5, 127.5, 117.3, 79.3, 74.8, 73.4, 71.6,
69.2, 61.2, 11.5; IR (KBr, cmꢀ1): 3467, 1652, 1438, 1063; HRMS
m/z calcd C16H19ClN2O7S2 [M+H]+: 451.0401; found: 451.0395.
756; ESI-MS m/z : 487.1 [M+H]+; HRMS m/z calcd C20H26N2O10
S
5.1.28. 5-(b-D-Galactopyranosyl)-4-methyl-2-(4-tert-Butyl-
phenyl)sulfonylaminothiazole (46)
[M+H]+: 487.1388; found: 487.1387.
Synthesis according to the typical de-O-acetylation procedure
obtained in 74% yield as a white solid: mp = 164–165 °C (ethanol);
5.1.23. 5-(2,3,4,6-Tetraacetyl-b-
carbamate-4-methylthiazole (41)
D-galactopyranosyl)-2-methyl-
[a]
25: +1.1° (c 1.0 in DMSO); 1H NMR (300 MHz, CD3OD, d ppm):
D
Synthesis according to the same procedure as for the synthesis
7.77 (d, J = 8.5 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 4.95 (s, 4H), 4.28 (d,
J = 8.8 Hz, 1H), 3.91 (dd, J = 2.7 Hz, 1H), 3.76–3.54 (m, 5H), 2.09 (s,
3H), 1.26 (s, 9H); 13C NMR (75.5 MHz, CD3OD, d ppm): 169.7,
156.9, 140.5, 133.2, 127.2, 126.7, 118.6, 80.7, 76.5, 75.9, 73.0, 70.6,
62.8, 35.8, 31.4, 12.2; IR (KBr, cmꢀ1): 3480, 1660, 1439, 1045; HRMS
m/z calcd C20H28N2O7S2 [M+H]+: 473.1417; found: 473.1408.
of 35 obtained in 73% yield as a yellow oil; [
a
]
D
25: ꢀ8.2° (c 1.4 in
MeOH); 1H NMR (300 MHz, CDCl3, d ppm): 5.48 (d, J = 3.5 Hz,
1H), 5.32 (dd, J = 10.0 Hz, 1H), 5.15 (dd, J = 3.5, 10.0 Hz, 1H), 4.66
(d, J = 9.5 Hz, 1H), 4.09 (m, 3H), 3.82 (s, 3H), 2.30 (s, 3H), 2.20 (s,
3H), 2.03 (s, 3H), 1.98 (s, 3H), 1.90 (s, 3H); 13C NMR (75.5 MHz,
CDCl3, d ppm): 170.4, 170.3, 170.2, 168.7, 160.8, 154.0, 145.2,
120.3, 74.7, 74.3, 71.9, 70.3, 67.5, 61.6, 52.9, 20.7, 20.7, 20.6, 20.4,
14.9; IR (neat NaCl, cmꢀ1): 3180, 2961, 1751, 1559, 1370, 1230,
1086, 1053, 760; ESI-MS m/z : 503.1 [M+H]+; HRMS m/z calcd
5.1.29. 5-(b-D-Galactopyranosyl)-4-methyl-2-(2,5-dibromophe-
nyl)sulfonylaminothiazole (47)
Synthesis according to the typical de-O-acetylation procedure
C
20H26N2O11S [M+H]+: 503.1337; found: 503.1330.
obtained in 83% yield as a yellow oil; [
a
]
25: ꢀ3.9° (c 1.2 in DMSO);
D
1H NMR (300 MHz, D2O, d ppm): 7.92 (s, 1H), 7.17 (d, J = 7.7 Hz,
1H), 7.05 (d, J = 8.2 Hz, 1H), 4.21 (d, J = 8.2 Hz, 1H), 3.82–3.81 (m,
1H), 3.54–3.44 (m, 5H), 2.00 (s, 3H); 13C NMR (75.5 MHz, D2O, d
ppm): 168.3, 141.2, 137.0, 136.9, 136.4, 132.9, 121.0, 118.5,
117.9, 78.9, 75.0, 73.9, 71.8, 68.9, 60.9, 12.3; IR (Neat NaCl)
cmꢀ1: 3476, 1653, 1437, 1061; HRMS m/z calcd C16H18BrN2O7S2
[M+H]+: 572.9002; found: 572.8985.
5.1.24. 5-(b- -Galactopyranosyl)-4-methyl-2-(4-methyl-phenyl)
D
sulfonylaminothiazole (42)
Synthesis according to the typical de-O-acetylation procedure
obtained in 61% yield as a white solid: mp = 131–132 °C (ethanol);
[a
]
25: ꢀ13.9° (c 1.0 in DMSO); 1H NMR (300 MHz, D2O, d ppm):
D
7.49 (d, J = 7.1 Hz, 2H), 7.01 (d, J = 7.8 Hz, 2H), 4.21 (d, J = 8.8 Hz,
1H), 3.79–3.78 (m, 1H), 3.58–3.41 (m, 5H), 2.04 (s, 3H), 1.99 (s,
3H); 13C NMR (75.5 MHz, D2O, d ppm): 169.3, 144.5, 137.3,
134.8, 129.9, 126.4, 117.1, 79.2, 74.9, 73.9, 71.7, 69.1, 61.3, 20.8,
11.9; IR (KBr, cmꢀ1): 3462, 1655, 1432, 1060; HRMS m/z calcd
5.1.30. 5-(b-
D-Galactopyranosyl)-4-methyl-2-benzylamino-
thiazole (48)
Synthesis according to the typical de-O-acetylation procedure
obtained in 69% yield as a yellow solid: mp = 83–84 °C (ethanol);
C
17H22N2O7S2 [M+H]+: 431.0947; found: 431.0938.
[
a
]
25: ꢀ5.0° (c 0.1 in DMSO); 1H NMR (300 MHz, D2O, d ppm):
D
5.1.25. 5-(b-
D
-Galactopyranosyl)-4-methyl-2-(4-bromophenyl)
7.22–7.18 (m, 4H), 4.29 (s, 3H), 4.27 (d, J = 7.7 Hz, 1H), 3.81 (d,
J = 3.0 Hz, 1H), 3.62–3.42 (m, 5H), 1.96 (m, 3H); 13C NMR
(75.5 MHz, D2O, d ppm): 170.4, 146.5, 138.0, 129.2, 128.1, 127.8,
115.8, 79.2, 75.7, 74.3, 72.5, 69.4, 61.5, 48.9, 14.2; IR (KBr, cmꢀ1):
3470, 1657, 1455, 1009; HRMS m/z calcd C17H22N2O5S [M+H]+:
367.1328; found: 367.1319.
sulfonylaminothiazole (43)
Synthesis according to the typical de-O-acetylation procedure
obtained in 64% yield as a white solid: mp = 149–150 °C (ethanol);
[a]
25: +14.0° (c 1.0 in DMSO); 1H NMR (300 MHz, D2O, d ppm):
D
7.49 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.5 Hz, 2H), 4.23 (d, J = 9.1 Hz,
1H), 3.81 (dd, J = 2.3 Hz, 1H), 3.58–3.46 (m, 5H), 2.00 (s, 3H); 13C
NMR (75.5 MHz, D2O, d ppm): 168.7, 139.1, 132.5, 128.1, 127.5,
117.2, 116.1, 79.6, 76.6, 75.9, 73.9, 71.7, 61.3, 11.6; IR (KBr,
cmꢀ1): 3473, 1657, 1428, 1061; HRMS m/z calcd C16H19BrN2O7S2
[M+H]+: 494.9896; found: 494.9889.
5.1.31. 5-(b-D-Galactopyranosyl)-4-methyl-2-4-nitrobenzyla-
minothiazole (49)
Synthesis according to the typical de-O-acetylation procedure
obtained in 75% yield as a yellow solid: mp = 127–128 °C (ethanol);
[a]
25: +19.6° (c 0.2 in DMSO); 1H NMR (300 MHz, D2O, d ppm):
D
5.1.26. 5-(b-
sulfonylaminothiazole (44)
D
-Galactopyranosyl)-4-methyl-2-(b-naphthyl)
8.01 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 4.42 (s, 2H), 4.30
(d, J = 9.6 Hz, 1H), 3.83 (d, J = 3.0 Hz, 1H), 3.64–3.41 (m, 5H), 1.95
(s, 3H); 13C NMR (75.5 MHz, D2O, d ppm): 147.7, 146.6, 128.4,
127.5, 124.3, 116.2, 79.2, 75.7, 74.3, 72.6, 69.4, 61.5, 48.0, 14.5;
IR (KBr, cmꢀ1): 3459, 1653, 1447, 1071; HRMS m/z calcd
Synthesis according to the typical de-O-acetylation procedure
obtained in 92% yield as a white solid: mp = 126–127 °C (ethanol);
[a]
25: +41.0° (c 1.0 in DMSO); 1H NMR (300 MHz, CD3OD, d ppm):
D
8.40 (s, 1H), 7.92–7.79 (m, 4H), 7.55–7.47 (m, 2H), 4.86 (s, 4H), 4.26
(d, J = 9.1 Hz, 1H), 3.89 (dd, J = 3.0 Hz, 1H), 3.76–3.51 (m, 5H), 2.06
(s, 3H); 13C NMR (75.5 MHz, D2O, d ppm): 169.8, 140.3, 135.9,
133.4, 133.0, 130.1, 130.0, 129.4, 128.8, 128.4, 127.8, 123.3,
118.7, 80.8, 76.5, 75.9, 73.0, 70.7, 62.9, 12.1; IR (KBr, cmꢀ1):
3492, 1675, 1437, 1067; HRMS m/z calcd C20H22N2O7S2 [M+H]+:
467.0947; found: 467.0937.
C
17H21N3O7S [M+H]+: 412.1179; found: 412.1169.
5.1.32. 2-Benzamido-5-(b-D-galactopyranosyl)-4-methylthiazole
(50)
Synthesis according to the typical de-O-acetylation procedure
obtained in 93% yield as a yellow oil; [
a
]
D
25: +13.0° (c 1.1 in
MeOH); 1H NMR (300 MHz, CDCl3, d ppm): 8,03 (d, J = 7,5 Hz,
2H), 7,51 (m, 3H), 4,80 (m, 2H), 4,54 (m, 2H), 4,25 (m, 1H), 3,71
(m, 1H), 3,40 (m, 5H), 2,22 (s, 3H); 13C NMR (75.5 MHz, CDCl3, d
ppm): 166.8, 158.0, 144.6, 133.4, 132.7, 129.4, 128.5, 124.4, 79.6,
75.7, 74.9, 73.1, 69.3, 61.5, 15.4; IR (neat NaCl, cmꢀ1): 3410,
2921, 2858, 1653, 1541, 1293, 1091, 894, 706; ESI-MS m/z :
381.2 [M+H]+; HRMS m/z calcd C17H20N2O6S [M+H]+: 381.1122;
found: 381.11095.
5.1.27. 5-(b-D-Galactopyranosyl)-4-methyl-2-(2-chloro-phenyl)
sulfonylaminothiazole (45)
Synthesis according to the typical de-O-acetylation procedure
obtained in 85% yield as a white solid: degrade at 217–218 °C (eth-
anol); [
a
]
25: ꢀ4.4° (c 1.0 in DMSO); 1H NMR (300 MHz, D2O, d
D
ppm): 7.82 (d, J = 8.5 Hz, 1H), 7.29–7.16 (m, 3H), 4.23 (d,

D. Giguère et al. / Bioorg. Med. Chem. 16 (2008) 7811–7823
7821
5.1.33. 5-(b-
dothiazole (51)
D
-Galactopyranosyl)-4-methyl-2-p-nitro-benzami-
NMR (75.5 MHz, CDCl3, d ppm): 158.9, 155.2, 145.0, 123.9, 79.6,
75.7, 74.9, 73.1, 69.3, 61.5, 53.5, 15.49; IR (neat NaCl, cmꢀ1):
3468, 3402, 2927, 2858, 1733, 1559, 1315, 1245, 1079, 764; ESI-
MS m/z : 335.1 [M+H]+; HRMS m/z calcd C12H18N2O7S [M+H]+:
335.0914; found: 335.0903.
Synthesis according to the typical de-O-acetylation procedure
obtained in 74% yield as a yellow oil; [a]
25: +0.8° (c 1.0 in MeOH);
D
1H NMR (300 MHz, CDCl3, d ppm): 8.27 (m, 4H), 4.79 (m, 2H), 4.52
(m, 2H,), 4.27 (m, 1H), 3.71 (m, 1H), 3.43 (m, 5H), 2.22 (s, 3H); 13C
NMR (75.5 MHz, CDCl3, d ppm): 166.3, 160.1, 149.9, 142.0, 139.3,
130.0, 124.1, 123.9, 79.6, 75.7, 74.9, 72.9, 69.3, 61.6, 14.7; IR (neat
NaCl, cmꢀ1): 3413, 2924, 2890, 1670, 1525, 1346, 1052, 851, 714;
ESI-MS m/z : 426.2 [M+H]+; HRMS m/z calcd C17H19N3O8S [M+H]+:
426.0972; found: 426.0962.
5.1.39. Dimeric lactoside (64)
Synthesis according to the typical de-O-acetylation procedure
obtained in 95% yield as a orange solid: mp = 173–174 °C (etha-
nol); [
a
]
25: ꢀ93.2° (c 1.0 in DMSO); 1H NMR (300 MHz, CD3OD,
D
d ppm): 7.64–7.53 (m, 4H), 4.50 (d, J = 9.6 Hz, 2H), 4.32 (d,
J = 7.7 Hz, 2H), 3.86–3.36 (m, 28H); 13C NMR (75.5 MHz, CD3OD,
d ppm): 131.9, 131.4, 128.7, 103.9, 84.5, 79.6, 76.8, 75.9, 73.7,
72.9, 71.3, 71.2, 69.2, 61.3, 60.9, 23.0; IR (KBr, cmꢀ1): 3406, 1576,
1419, 1088; HRMS m/z calcd C36H50O20S2 [M+Na]+: 889.2235;
found: 889.2223.
5.1.34. 2-p-Anisamido-5-(b-D-galactopyranosyl)-4-
methylthiazole (52)
Synthesis according to the typical de-O-acetylation procedure
obtained in 62% yield as a yellow oil; [
a]
25: +10.5° (c 1.3 in
D
MeOH); 1H NMR (300 MHz, CDCl3, d ppm): 8.03 (d, J = 9.5 Hz,
2H), 7.00 (d, J = 9.5 Hz, 2H), 4.75 (m, 2H), 4.47 (m, 2H), 4.26 (m,
1H), 3.78 (s, 3H), 3.70 (m, 1H), 3.32 (m, 5H), 2.20 (s, 3H); 13C
NMR (75.5 MHz, CDCl3, d ppm): 165.5, 163.2, 157.7, 144.2, 130.5,
124.9, 124.3, 114.5, 79.6, 75.9, 75.0, 73.0, 69.3, 61.5, 55.9, 15.5;
IR (neat NaCl, cmꢀ1): 3439, 2922, 2842, 1655, 1606, 1547, 1514,
1311, 1260, 1177, 1025, 845, 761; ESI-MS m/z : 411.1 [M+H]+;
HRMS m/z calcd C18H22N2O7S [M+H]+: 411.1227; found: 411.1214.
5.1.40. Dimeric galactoside (66)
Synthesis according to the typical de-O-acetylation procedure
obtained in quantitative yield as a brown solid: mp = 172–173 °C
(ethanol); [
a
]
25: ꢀ117.8° (c 1.0 in DMSO); 1H NMR (300 MHz,
D
CD3OD, d ppm): 7.33–7.26 (m, 4H), 4.52 (d, J = 9.8 Hz, 2H), 3.85–
3.28 (m, 16H); 13C NMR (75.5 MHz, CD3OD, d ppm): 131.4, 116.2,
85.2, 79.6, 75.2, 70.2, 69.4, 61.5, 23.0; IR (KBr, cmꢀ1): 3339, 1576,
1410, 1085; HRMS m/z calcd C24H30O10S2 [M+Na]+: 565.1178;
found: 565.1167.
5.1.35. 2-p-Bromobenzamido-5-(b-D-galactopyranosyl)-4-
methylthiazole (53)
Synthesis according to the typical de-O-acetylation procedure
5.1.41. Dimeric lactoside (68)
obtained in 80% yield as a yellow oil; [
a]
25: +7.2° (c 1.4 in MeOH);
Synthesis according to the typical de-O-acetylation procedure
D
1H NMR (300 MHz, CDCl3, d ppm): 7.96 (d, J = 8.5 Hz, 2H), 7.72 (d,
J = 8.5 Hz, 2H), 4.78 (m, 2H), 4.51 (m, 2H), 4.26 (m, 1H), 3.71 (m,
1H), 3.37 (m, 5H), 2.21 (s, 3H); 13C NMR (75.5 MHz, CDCl3, d
ppm): 166.1, 158.5, 143.5, 132.4, 132.1, 130.8, 127.1, 124.5, 79.8,
75.9, 75.1, 73.2, 69.4, 61.6, 15.5; IR (neat NaCl, cmꢀ1): 3411,
2922, 2858, 1664, 1591, 1547, 1313, 1070, 893, 747; ESI-MS m/z :
459.1 [M+H]+ (Br79); 461.1 [M+H]+ (Br81); HRMS m/z calcd
obtained in 95% yield as a brown solid: mp = 160–161 °C (ethanol);
[a
]
D
25: ꢀ68.6° (c 1.0 in DMSO); 1H NMR (300 MHz, D2O, d ppm):
4.53 (d, J = 9.8 Hz, 2H), 4.25 (d, J = 7.7 Hz, 2H), 3.79–3.62 (m, 6H),
3.59–3.22 (m, 24H); 13C NMR (75.5 MHz, D2O, d ppm): 102.9,
84.4, 78.8, 78.1, 75.9, 75.4, 75.2, 72.6, 71.8, 71.0, 70.7, 68.7, 61.1,
60.3, 18.1; IR (KBr, cmꢀ1): 3477, 1576, 1421, 1078; HRMS m/z calcd
C
30H46O20S2 [M+Na]+: 813.1922; found: 813.1912.
C
17H19N2O6S [M+H]+: 459.0227; found: 459.0211.
5.1.42. Dimeric galactoside (70)
5.1.36. 5-(b- -Galactopyranosyl)-4-methyl-2-
phenylacetamidothiazole (54)
D
Synthesis according to the typical de-O-acetylation procedure
obtained in 90% yield as a brown solid: mp = 76–77 °C (ethanol);
Synthesis according to the typical de-O-acetylation procedure
[
a
]
25: ꢀ110.4° (c 1.0 in DMSO); 1H NMR (300 MHz, D2O, d
D
obtained in 46% yield as a yellow oil; [
a
]
25: +17.0° (c 0.5 in MeOH);
ppm): 4.45 (d, J = 9.0 Hz, 2H), 3.80–3.35 (m, 16H); 13C NMR
(75.5 MHz, D2O, d ppm): 85.5, 79.4, 75.9, 74.5, 69.9, 69.3, 67.4,
61.5, 18.5; IR (KBr, cmꢀ1): 3548, 1560, 1437; HRMS m/z calcd
D
1H NMR (300 MHz, CDCl3, d ppm): 7.21 (m, 5H), 4.75 (m, 2H), 4.50
(m, 2H), 4.21 (m, 1H), 3.69 (m, 1H), 3.36 (m, 5H), 2.44 (s, 2H), 2.16
(s, 3H); IR (neat NaCl, cmꢀ1): 3402, 2922, 2858, 1678, 1551, 1312,
1282, 1052, 788, 728, 698; ESI-MS m/z : 395.1 [M+H]+; HRMS m/z
calcd C18H22N2O6S [M+H]+: 395.1278; found: 395.1270.
C
18H26O10S2 [M+H]+: 467.1046; found: 467.1037.
5.1.43. Dimeric lactoside (71)
Alkyne lactoside 57 (0.302 mmol) was dissolved in THF (0.1 M)
and CuI (0.03 mmol), DIPEA (0.606 mmol) and azide 59
(0.332 mmol) were added and stirred, at room temperature. The
green solution was stirred until disappearance of the starting
material (maximum 3 h), and then evaporated under reduced pres-
sure, dissolved with ethyl acetate, and filtered through a pad of
Celite. The organic solution was washed with aqueous HCl (10%),
dried over sodium sulfate, filtered, evaporated under reduced pres-
sure, and chromatographed using a mixture of ethyl acetate/hex-
ane (2:1) to give 71 in 81% yield as a white solid: mp = 125–
5.1.37. 2-Acetamido-5-(b-D-galactopyranosyl)-4-methylthiazole
(55)
Synthesis according to the typical de-O-acetylation procedure
obtained in 60% yield as a yellow oil; [a]
25: +10.6° (c 1.1 in
D
MeOH); 1H NMR (300 MHz, CDCl3, d ppm): 4.70 (m, 2H), 4.42 (m,
2H), 4.20 (m, 1H), 3.69 (m, 1H), 3.39 (m, 5H), 2.15 (s, 3H), 2.05
(s, 3H); 13C NMR (75.5 MHz, CDCl3, d ppm): 169.8, 156.7, 144.9,
124.2, 79.6, 75.8, 74.9, 73.1, 69.3, 61.5, 22.9, 15.6; IR (neat NaCl,
cmꢀ1): 3497, 3318, 2922, 2854, 1690, 1551, 1288, 1036, 785;
ESI-MS m/z
:
319.1 [M+H]+; HRMS m/z calcd C12H18N2O6S
126 °C (EtOAc/hexanes); [
a]
25: ꢀ41.4° (c 1.0 in CHCl3); 1H NMR
D
[M+H]+: 319.0965; found: 319.0957.
(300 MHz, CDCl3, d ppm): 7.64 (s, 1H), 5.79 (d, J = 8.8 Hz, 1H),
5.43–5.31 (m, 3H), 5.19 (dd, J = 9.3 Hz, 1H), 5.10 (dd, J = 8.2 Hz,
2H), 4.97–4.88 (m, 2H), 4.55–4.40 (m, 4H), 4.17–3.73 (m, 17H),
3.68–3.65 (m, 1H), 2.14 (s, 3H), 2.12 (s, 3H), 2.11 (s, 3H), 2.07 (s,
3H), 2.06 (s, 3H), 2.05 (s, 3H), 2.03 (s, 6H), 2.02 (s, 3H), 2.00 (s,
3H), 1.96 (s, 3H), 1.95 (s, 3H), 1.94 (s, 3H), 1.88 (s, 3H); 13C NMR
(75.5 MHz, CDCl3, d ppm): 170.4, 170.2, 170.1, 170.0, 169.9,
169.6, 169.5, 169.4, 169.3, 168.9, 144.9, 120.7, 100.9, 85.5, 81.8,
5.1.38. 5-(b-D-Galactopyranosyl)-2-methylcarbamate-4-
methylthiazole (56)
Synthesis according to the typical de-O-acetylation procedure
obtained in 60% yield as a yellow oil; [a]
25: +6.5° (c 0.3 in MeOH);
D
1H NMR (300 MHz, CDCl3, d ppm): 4.72 (m, 2H), 4.,42 (m, 2H), 4.20
(m, 1H), 3.69 (m, 1H), 3.65 (s, 3H,), 3.38 (m, 5H), 2.12 (s, 3H); 13C

7822
D. Giguère et al. / Bioorg. Med. Chem. 16 (2008) 7811–7823
76.2, 76.1, 75.9, 75.5, 73.5, 72.3, 70.8, 70.6, 70.3, 68.9, 66.5, 62.0,
61.6, 60.8, 24.1, 20.9, 20.7, 20.6, 20.5, 20.4, 20.0; IR (neat NaCl)
(ethanol); [
a
]
25: ꢀ12.6° (c 0.5 in DMSO); 1H NMR (300 MHz,
D
D2O, d ppm): 8.06 (s, 1H), 5.49 (d, J = 9.1 Hz, 1H), 4.33 (d,
J = 9.6 Hz, 1H), 4.25 (d, J = 7.7 Hz, 1H), 4.03–3.83 (m, 5H), 3.73–
3.72 (m, 2H), 3.67–3.19 (m, 13H); 13C NMR (75.5 MHz, D2O, d
ppm): 146.1, 123.7, 103.3, 88.5, 85.1, 78.7, 76.2, 75.8, 73.5, 73.0,
72.3, 71.4, 70.1, 69.0, 61.4, 61.3, 60.7, 24.1; IR (KBr, cmꢀ1): 3547,
1566, 1442; HRMS m/z calcd C21H35N3O15S [M+H]+: 602.1868;
found: 602.1855.
cmꢀ1: 1752, 1371, 1237, 1055; HRMS m/z calcd C55H73N3O34
S
[M+H]+: 1352.3875; found: 1352.3848.
5.1.44. Heterodimer (72)
Synthesis according to the same procedure as for the synthesis
of 71 obtained in 89% yield as a yellow solid: mp = 108–109 °C
25
(EtOAc/hexanes);
[
a]
:
ꢀ35.6° (c 1.0 in CHCl3); 1H NMR
D
(300 MHz, CDCl3, d ppm): 7.76 (s, 1H), 5.83 (d, J = 9.1 Hz, 1H),
5.57 (dd, J = 3.0, 1H), 5.50 (dd, J = 9.3 Hz, 1H), 5.34 (dd, J = 2.5 Hz,
1H), 5.29–5.21 (m, 2H), 5.11 (dd, J = 7.9 Hz, 1H), 4.99–4.93 (m,
2H), 4.57–4.46 (m, 3H), 4.24–4.06 (m, 7H), 3.89–3.75 (m, 4H),
2.22 (s, 3H), 2.16 (s, 3H), 2.15 (s, 3H), 2.07 (s, 3H), 2.06 (s, 3H),
2.05 (s, 3H), 2.04 (s, 3H), 2.03 (s, 3H), 1.99 (s, 3H), 1.97 (s, 3H),
1.94 (s, 3H); 13C NMR (75.5 MHz, CDCl3, d ppm): 170.3, 170.1,
169.9, 169.8, 169.6, 169.4, 169.1, 147.7, 120.8, 101.2, 86.4, 81.3,
76.4, 76.2, 74.1, 73.7, 71.0, 70.7, 70.6, 70.4, 69.1, 67.8, 66.8, 66.6,
62.2, 61.1, 60.7, 23.9, 20.9, 20.8, 20.6, 20.5, 20.2; IR (neat NaCl)
5.1.49. Heterodimer (77)
Synthesis according to the typical de-O-acetylation procedure
obtained in 75% yield as a white solid: mp = 161–162 °C (ethanol);
[
a
]
25: ꢀ14.4° (c 1.0 in DMSO); 1H NMR (300 MHz, D2O, d ppm):
D
8.05 (s, 1H), 5.59 (d, J = 9.3 Hz, 1H), 4.32 (d, J = 7.7 Hz, 1H), 4.23
(d, J = 6.6 Hz, 1H), 3.99–3.37 (m, 21H); 13C NMR (75.5 MHz, D2O,
d ppm): 145.9, 123.8, 103.3, 87.6, 85.6, 79.2, 77.9, 75.8, 74.9,
74.3, 72.9, 72.3, 71.4, 69.8, 68.9, 61.3, 60.2; IR (KBr, cmꢀ1): 3535,
1498, 1413; HRMS m/z calcd C21H35N3O15S [M+H]+: 602.1868;
found: 602.1859.
cmꢀ1: 1752, 1371, 1233, 1056; HRMS m/z calcd C43H57N3O26
S
[M+H]+: 1064.3030; found: 1064.3006.
5.1.50. Dimeric galactoside (78)
Synthesis according to the typical de-O-acetylation procedure
obtained in quantitative yield as a white solid: mp = 60–61 °C (eth-
5.1.45. Heterodimer (73)
Synthesis according to the same procedure as for the synthesis
anol); [
a
]
D
25: ꢀ20.4° (c 1.0 in DMSO); 1H NMR (300 MHz, D2O, d
of 71 obtained in 77% yield as a white solid: mp = 112–113 °C
ppm): 8.07 (s, 1H), 5.49 (d, J = 8.2 Hz, 1H), 4.24 (d, J = 6.3 Hz, 1H),
4.07–3.42 (m, 14H); 13C NMR (75.5 MHz, D2O, d ppm): 146.0,
123.6, 88.4, 85.6, 79.2, 78.6, 74.3, 73.4, 70.1, 69.9, 69.2, 68.9,
61.3, 61.2, 24.0; IR (KBr, cmꢀ1): 3548, 1559, 1432; HRMS m/z calcd
(EtOAc/hexanes);
[a
]
D
:
ꢀ40.9° (c 1.0 in CHCl3); 1H NMR
25
(300 MHz, CDCl3, d ppm); 1H NMR (300 MHz, CDCl3, d ppm): 7.62
(s, 1H), 5.76 (d, J = 9.1 Hz, 1H), 5.36–5.21 (m, 4H), 5.12–4.96 (m,
3H), 4.87 (dd, J = 3.0, 10.4 Hz, 1H), 4.46 (d, J = 7.7 Hz, 1H), 4.39–
4.35 (m, 1H), 4.27 (d, J = 9.3 Hz, 1H), 4.13–3.83 (m, 8H), 3.74–
3.69 (m, 1H), 2.03 (s, 6H), 1.96 (s, 9H), 1.94 (s, 3H), 1.92 (s, 3H),
1.85 (s, 3H), 1.83 (s, 6H), 1.76 (s, 3H); 13C NMR (75.5 MHz, CDCl3,
d ppm): 170.1, 169.9, 169.8, 169.7, 169.6, 169.2, 169.0, 168.6,
144.1, 120.6, 100.6, 85.3, 81.4, 75.7, 75.3, 73.7, 72.0, 71.3, 70.6,
68.9, 67.2, 67.1, 66.5, 61.5, 61.2, 60.6, 23.3, 20.3, 20.2, 19.7; IR (neat
C
15H25N3O10S [M+H]+: 440.1334; found: 440.1333.
5.2. Biological assay
5.2.1. General procedure for glycoside inhibition experiments
Recombinant galectins-1 and -3 were purified using a lactose-
agarose affinity column (Sigma–Aldrich).11a,43 Hemagglutination
assays were performed using human O-type red blood cells (RBCs)
as described previously.41 RBCs (final concentration at 0.0025%),
which were fixed with 3% glutaraldehyde (around 0.625% in PBS),
NaCl) cmꢀ1: 1754, 1457, 1263; HRMS m/z calcd C43H57N3O26
S
[M+H]+: 1064.3030; found: 1064.3016.
5.1.46. Dimeric galactoside (74)
were incubated with 1 lM of galectin in the presence or absence
Synthesis according to the same procedure as for the synthesis
of 71 obtained in 88% yield as a white solid: mp = 81–82 °C (EtOAc/
of the various concentrations of inhibitors in U-shaped 96-well
plate. After incubation at 37 °C for 30 min, aggregation of RBCs
was evaluated and performed in triplicate.
hexanes); [
a
]
25: ꢀ48.4° (c 1.1 in CHCl3); 1H NMR (300 MHz, CDCl3,
D
d ppm): 7.71 (s, 1H), 5.82 (d, J = 9.1 Hz, 1H), 5.48–5.34 (m, 3H),
5.25–5.04 (m, 3H), 4.32 (d, J = 9.3 Hz, 1H), 4.25–4.10 (m, 1H),
4.08–3.97 (m, 4H), 3.78–3.73 (m, 1H), 2.12 (s, 3H), 2.06 (s, 3H),
1.99 (s, 3H), 1.93 (s, 6H), 1.85 (s, 3H), 1.86 (s, 3H), 1.83 (s, 3H);
13C NMR (75.5 MHz, CDCl3, d ppm): 169.9, 169.6, 169.5, 169.4,
169.2, 144.2, 120.6, 86.1, 81.2, 73.9, 71.4, 70.4, 67.9, 67.4, 67.3,
Acknowledgments
This work was supported from Natural Sciences and Engineer-
ing Research Council of Canada (NSERC) and a Canadian Research
Chair in Therapeutic Chemistry to R.R. and from Canadian Insti-
tutes for Health Research to S.S. D.G. thanks FQRNT (Québec) for
a postgraduate fellowship.
66.8, 61.6, 60.9, 23.4, 20.3, 20.2, 20.1, 19.8; IR (neat NaCl) cmꢀ1
1757, 1372, 1251; HRMS m/z calcd C31H41N3O18
:
S
[M+H]+:
776.2185; found: 776.2176.
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Synthesis according to the typical de-O-acetylation procedure
obtained in 92% yield as a white solid: mp = 122–123 °C (ethanol);
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a
]
25: ꢀ6.3° (c 1.0 in DMSO); 1H NMR (300 MHz, D2O, d ppm): 8.02
D
(s, 1H), 5.57 (d, J = 9.1 Hz, 1H), 4.30 (d, J = 8.5 Hz, 2H), 4.23 (d,
J = 7.7 Hz, 1H), 3.97–3.16 (m, 26H); 13C NMR (75.5 MHz, D2O, d
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5.1.48. Heterodimer (76)
Synthesis according to the typical de-O-acetylation procedure
obtained in quantitative yield as a white solid: mp = 118–119 °C

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