Monosaccharide Derivatives with Low-Nanomolar Lectin Affinity and High Selectivity Based on Combined Fluorine–Amide, Phenyl–Arginine, Sulfur–π, and Halogen Bond Interactions

Article abstract of DOI:10.1002/cmdc.201700744

The design of small and high-affinity lectin inhibitors remains a major challenge because the natural ligand binding sites of lectin are often shallow and have polar character. Herein we report that derivatizing galactose with un-natural structural elements that form multiple non-natural lectin–ligand interactions (orthogonal multipolar fluorine–amide, phenyl–arginine, sulfur–π, and halogen bond) can provide inhibitors with extraordinary affinity (low nanomolar) for the model lectin, galectin-3, which is more than five orders of magnitude higher than the parent galactose; moreover, is selective over other galectins.

Full text of DOI:10.1002/cmdc.201700744

Accepted Article
Title: Monosaccharide derivatives with low nM lectin affinity and high
selectivity based on combined fluorine-amide, phenyl-arginine,
sulfur-π, and halogen bond interactions
Authors: Fredrik Richard Zetterberg, Kristoffer Peterson, Richard
Johnsson, Thomas Brimert, Maria Håkansson, Derek T.
Logan, Hakon Leffler, and Ulf J Nilsson
This manuscript has been accepted after peer review and appears as an
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To be cited as: ChemMedChem 10.1002/cmdc.201700744
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10.1002/cmdc.201700744
ChemMedChem
COMMUNICATION
Monosaccharide derivatives with low nM lectin affinity and high
selectivity based on combined fluorine-amide, phenyl-arginine,
sulfur-π, and halogen bond interactions
Fredrik R. Zetterberg,*[a] Kristoffer Peterson,[b] Richard E. Johnsson,[c] Thomas Brimert,[c] Maria
Håkansson,[d] Derek T. Logan,[d,e] Hakon Leffler,[f] and Ulf J. Nilsson*[b]
Abstract: The design of small and high affinity lectin inhibitors
remains a major challenge because lectin natural ligand binding
sites often are shallow and have polar character. We report that
derivatizing galactose with un-natural structural elements that form
multiple non-natural lectin-ligand interactions (orthogonal multipolar
fluorine-amide, phenyl-arginine, sulfur-π, and halogen bond) can
provide inhibitors with extraordinary affinity (low nM) for the model
lectin, galectin-3, which is over 5 orders of magnitude higher than
the parent galactose, and, moreover, is selective compared to other
galectins.
by modifying natural carbohydrate core structures with unnatural
chemical groups,[2a] for example the heparin mimetic
Fondaparinux,[4] nM-affinity inhibitors of the uropathogeninic E.
coli adhesin FimH obtained by optimized interactions with CRD-
lining tyrosine side chains,[5] sodium glucose transporter
(SGLT2) inhibitors of the glifozin family,[6] influenza
neuramnidase inhibitors Zanamivir and Oseltamivir,[7] selectin
inhibitors,[8] siglec inhibitors based on optimized substituents on
a sialic acid core structure,[9] and galectins,[10] the topic of this
report.
Similar to other lectins, the galectin carbohydrate-binding site is
shallow, found along the concave side of the ~130 amino acid ß-
sandwich carbohydrate recognition domain (CRD).[11] The
carbohydrate binding site contains the galectin-defining
galactoside-binding site conferred by a conserved motif of about
7 amino acids. By itself, this subsite has weak binding to
galactosides, with Kd in the mM range. Addition of saccharides
on either side of the galactose can significantly enhance affinity,
but also decrease it. In the most commonly used galectin
saccharide inhibitors lactose, N-acetyl-lactosamine, and
thiodigalactoside the addition of a monosaccharide on the
reducing side of the galactose increases affinity by 10-100 fold,
to Kds in the mid µM range. Previously we achieved much higher
affinities (nM) by derivatizing such disaccharides with artificial
moieties that targets additional sites at either end, that is C3-
Lectin binding to glycoconjugates are rate-limiting in many
pathophysiological
processes[1]
including
host-pathogen
interaction, inflammation, immunity and cancer. Consequently,
the discovery of drug-like inhibitors of such interactions is
receiving significant attention.[2] However, finding small high
affinity lectin inhibitors is a major challenge because the lectin
carbohydrate-binding sites tend to be polar and shallow. Lectins
typically bind natural glycans with multiple hydrogen bonds,
sometimes enhanced by CH-π stacking of carbohydrate CH
onto aromatic amino acid side chains, and with recently
highlighted contributions from conformational entropy.[3] This
usually results in weak-medium-to-affinity (µM-mM) for a small
mono- or disaccharide, although exceptions are known. The
challenge then is to find lectin inhibitors with drug like affinities,
low nM, and pharmacological properties that are much better
than the natural ligands. This has been achieved in some cases
derivatization of N-acetyl-lactosamine and C3,C3'-derivatization
10b, 13]
of thiodigalactoside with aromatic ester,[12] amide,[10a,
or
14]
triazole[10c,
moieties. Recently we found that C3
multifluorinated phenyl groups providing orthogonal multipolar
fluorine-amide interactions strongly enhanced affinity for
galectin-3.[10c,
This inspired attempts to replace the
[a]
[b]
Dr. F. Zetterberg
14a]
Galecto Biotech AB Sahlgrenska Science Park
Medicinaregatan 8 A, SE-413 46 Gothenburg, Sweden
E-mail: fz@galecto.com
monosaccharide at the reducing side of galactose with a less
polar aglycon, with the aim of still reaching high affinity while
keeping the galactose derivatized with a C3 trifluorophenyl
group. Indeed, with 4-methylphenylthio as the aglycon 1a, single
digit µM affinity for galectin-3 was reached.[14a]
Mr. K. Peterson, Prof. U. J. Nilsson
Centre for Analysis and Synthesis, Department of Chemistry
Lund University, POB 124, SE-221 00 Lund, Sweden
E-mail: ulf.nilsson@chem.lu.se
Here we report further optimization of the thioglycosidic aglycon
[c]
[d]
[e]
Dr. R. Johnsson, Dr. T. Brimert
Red Glead Discovery AB, Medicon Village, SE-223 63 Lund,
Sweden
Dr. M. Håkansson
SARomics Biostructures AB, Medicon Village, SE-223 63 Lund,
Sweden
that affords galectin-3 inhibitors with low nM-affinities
–
unprecedented for a monosaccharide galectin inhibitor. Series of
β- (1b-c) and α-thio-D-galactopyranosides (2a-m) carrying the
same C3 4-(3,4,5-trifluorophenyl)-1H-triazole substituent were
synthesized (Scheme 1) and affinities compared with 1a using a
competitive fluorescence anisotropy assay (Tables 1-3).[10c]
Dr. D. T. Logan
Biochemistry and Structural Biology, Center for Molecular Protein
Science, Department of Chemistry, Lund University, Box 124, SE-
221 00 Lund, Sweden
[f]
Prof. H. Leffler
Department of Laboratory Medicine, Section MIG, Lund University
BMC-C1228b, Klinikgatan 28, SE-221 84 Lund, Sweden
Supporting information for this article is given via a link at the end of the
document.
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10.1002/cmdc.201700744
ChemMedChem
COMMUNICATION
OR2
OR2
O
N
N
F
R1
N
AcO
OAc
Table 1. Kd (µM) values for 1a-b and 2a-b for human galectin-3 determined by
competitive fluorescence polarization.[10c]
R2O
O
F
N3
R
AcO
Compound
Structure
Kd
F
a
4 R1=OAc, R2=Ac
3 R=OAc
5 R=Cl
OH
e
OH
O
N
N
F
R1
N
1b R1=ethylthio, R2=H
1c R1=3-chlorophenylthio, R2=H
d
f
b,c
HO
R2
F
AcO
N3
OAc
O
F
1a
2a
1b
2b
R1=4-methylphenylthio, R2=H
R1=H, R2=4-methylphenylthio
R1=ethylthio, R2=H
5.2[14a]
AcO
R1
0.33±0.033
5.1±0.53
1.0±0.087
via route e,f
via route d
6c R1=3-chlorophenylthio 6a R1=4-methylphenylthio
6e R1=phenylthio
6b R1=ethylthio
R1=H, R2=ethylthio
6f R1=3-bromophenylthio
6g R1=3-iodophenylthio
6h R1=3,4-dichlorophenylthio
6d R1=4-chlorophenylthio
6k R1=3,4-dichlorophenoxy
Influence of phenyl aglycon halogen substituents. To explore
these potential new interactions of the α-aglycon, we used the
phenyl 2e (similar affinity as 2a) as a scaffold and examined
different halogen substituents. The 3-chloro 2c enhanced affinity
for galectin-3 by another order of magnitude leading to Kd about
50 nM whereas the 4-chloro 2d did not. 3-Bromo (2f) and 3-iodo
(2g) also lead to enhanced affinity. Introduction of an electron-
withdrawing substituent, 4-chloro (2h) or 4-cyano (2i), next to
the 3-chloro enhanced affinity further by a factor of about two,
reaching a remarkable Kd of 23 nM for 2i. In contrast, addition of
a 2-chloro to the 3-chloro 2j decreased affinity by one order of
magnitude. The β-anomer 1c of 2c had 30-fold lower affinity (Kd
1.60±0.078 µM) for galectin-3, but was among the best β-
anomers (cf. 1a and 1b in Table 1).
6i R1=3-chloro-4-cyanophenylthio
6j R1=2,3-dichlorophenylthio
g,h
HO
OH
O
N
N
F
N
HO
R1
F
F
2a R1=4-methylphenylthio 2g R1=3-iodophenylthio
2b R1=ethylthio 2h R1=3,4-dichlorophenylthio
2c R1=3-chlorophenylthio 2i R1=3-chloro-4-cyanophenylthio
2d R1=4-chlorophenylthio 2j R1=2,3-dichlorophenylthio
Influence of the anomeric sulfur. The importance of the α-
anomeric sulfur is apparent since the O-glycoside 2k had about
15-fold lower affinity (Kd 0.49±0.024 µM) compared to the
corresponding S-glycoside 2h.
2e R1=phenylthio
2f R1=3-bromophenylthio
2k R1=3,4-dichlorophenoxy
Structural analysis. The structure activity relationships (SAR)
described above suggests that the strong affinity enhancement
of some compounds with α-linked aglycons is due to a subtle
combination of different types of sterically precise interactions
with galectin-3. To analyze these further, complexes of the
galectin-3 CRD (galectin-3C) with one of the best α-glycosides
(2h) and an analogous β-compound (1c) were compared by X-
ray crystallography. The crystals diffracted to 1.2 and 1.5Å,
respectively, and clear ligand density was observed for the
galactose residue and its 3C substituent. As expected, their
positions were essentially identical for the two compounds,
including the orthogonal multipolar ligand fluorine-amide
interaction with R144, I145, and S237, and the ligand phenyl-
R144 side-chain stacking, and similar as observed earlier for
disaccharide derivatives[10c] (Figure 1c and d). The electron
density maps were weaker for the aglycons replacing glucose
and these showed double conformations for 1c (Figure 1a),
modeled with 0.3 and 0.7 occupancy. Despite this, the key
affinity enhancing atoms - the 3-chloro substituent of the phenyl
aglycon and the glycosidic sulfur - could be clearly identified,
and the phenyl ring modeled.
Scheme 1. Synthesis of compounds 1a-c and 2a-k. Reagents and conditions:
(a) 3,4,5-trifluorophenylacetylene, CuI, DIPEA, toluene, 40°C, 49%; (b) R1-SH,
BF3 ·OEt2, mol. sieves, DCM, overnight, 29-50%; (c) NaOMe, MeOH, 2h, 25%-
87%; (d) R1–SH or R1-OH, BF3 ·OEt2, mol. sieves, DCM or 1,2-dichloroethane,
overnight., 0-r.t, 4 days, 21-48%; (e) PCl5, BF3 ·OEt2, DCM, 20 min., 91%; (f)
R1–SH, CsCO3 or NaH, 50°C, DMF 25-66%; (g) 1,2,3-trifluoro-5-[2-
(trimethylsilyl)ethynyl]benzen, CuI, DIPEA, toluene, 40°C; (h) NaOMe, MeOH,
2h, 23-91% over two steps.
Influence of the anomeric configuration. Much to our surprise, α-
D-thio-galactopyranoside 2a had one order of magnitude higher
affinity for galectin-3 compared to the reference β-D-thio-
galactopyranoside 1a. For an aliphatic aglycon, the α-anomer 2b
also had enhanced affinity over the corresponding β-anomer 1b,
albeit with a smaller 5-fold difference. Since the methyl α- and β-
D-galactopyranosides have similar affinities for galectin-3,[15] this
suggests that the larger α-aglycons finds new interactions with
the galectin that are not typically exploited by natural ligands and
that have not previously been explored for artificial ligand design.
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COMMUNICATION
Table 2. Kd (µM) values for 2c-j for human galectin-3 determined by
competitive fluorescence polarization.[10c]
Compound
Kd
OH
OH
O
N
N
F
N
R1
HO
S
R2
R3
F
F
2c
R1=R3=H, R2 =Cl
0.049±0.0027
2d
2e
2f
R1=R2=H, R3 =Cl
R1=R2=R3=H
0.38±0.022
0.52±0.038
R1=R3=H, R2 =Br
R1=R3=H, R2 =I
R1=H, R2=R3=Cl
0.031±0.0024
0.058±0.0043
0.037±0.0010
0.047±0.0063
0.85±0.031
2g
2h
2i
R1=H, R2= Cl, R3=CN
R1=R2=Cl, R3=H
2j
For both compounds 1c and 2h, the 3-chloro substituent has the
direction and position expected to form a halogen bond with the
backbone carbonyl oxygen of G182 in the protein, which
provides an explanation for the tenfold higher affinity of 2c and
2h over 2d and 2c over 2e. The 4-chloro of 2d and 2h points out
in solution and cannot form a halogen bond with the protein, and
does not enhance affinity by itself (cf. 2d/2e). Halogen bond
strengths can be enhanced by increasing the size of the halide
σ-hole.[16] One way is to replace the chloro substituent with a
larger halide; a small affinity enhancement was found here with
bromide 2f, but not with iodide 2g which may have been too
large to fit. Another way to increase the size of the halide σ-hole
is to introduce an electron withdrawing group in the vicinity.
Adding 4-chloro (2h) or a 4-cyano group (2i) enhanced affinity
compared to the 3-chloro 2c by about 2-fold. In contrast, adding
2-chloro 2j decreased affinity by 10-fold possibly due to steric
conflict with the protein.
Figure 1. A-B) Electron density map (grey mesh) 2|Fo| − |Fc| αc contoured at
1σ for 1c and 2h in complex with galectin-3C. Galectin-3C in complex with C)
1c revealing fluorine-amide carbonyl interactions with residues R144, I145,
and S237, and an X-bond interaction with G182 backbone carbonyl oxygen
and with D) 2h revealing fluorine-amide carbonyl interactions with residues
R144, I145, and S237,
a S-π interaction with W181, and an X-bond
interaction with G182 backbone carbonyl oxygen.
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The anomeric sulfur of the α-D-galactopyranoside 2h is
positioned near W181 suggesting
a
beneficial sulfur-π
interaction[17] not shared by the β-galactosides. This could be an
important contribution to the affinity differences in the α/β
anomeric pairs 1a/2a (10 fold), 1b/2b (5 fold), and 1c/2c (30
fold). In addition, the oxygen analog 2k has a 15-fold lower
affinity than the corresponding thio-galactoside 2h, which also
supports the hypothesis of affinity enhancing effects of the α-
anomeric sulfur. The longer C-S bonds and/or smaller C-S-C
bond angle of the α-thio-galactosides 2a-2j may also be
important to place the aglycon in a favorable position compared
to the equivalent values for O to interact with galectin-3,
particularly for 3-chloro to form an optimal halogen bond.
Conclusion. Derivatizing a low-affinity monosaccharide with
functionalities forming a combination of orthogonal multipolar
fluorine-amide, phenyl-arginine, sulfur-π, and halogen bond
interactions, results in lectin ligands with affinities far surpassing
those of common natural ligand fragments (e.g. about 100000
fold more potent than methyl β-D-galactoside[18] and 5000 fold
more potent than methyl β-lactoside[19]); removal of any of these
interactions results in significant loss of affinity. The compounds
are the smallest high affinity galectin-3 inhibitors described and
thus constitute a new class of promising drug lead structures.
We suggest that systematic introduction of interactions, as the
ones described here, can be a very useful strategy discovering
small ligands that target shallow and polar lectin carbohydrate-
binding sites, increasing the drugability for any such target. Polar
and sp3-rich monosaccharide scaffolds as drug discovery
starting points differ substantially from the small, aromatic, and
lipophilic starting scaffolds typically generated by fragment-
based lead generation or HTS strategies, and hence may also
provide a useful alternative strategy for a broader range of
targets.
The phenyl aglycon itself did not show evidence for any strong
interactions with the protein, which may explain why replacing it
with an aliphatic ethyl aglycon in 2b only led to a 2-fold
decrease in affinity (compared to 2a). Instead it may be more
important as
a scaffold to position the phenyl 3-chloro
substituent to form a halogen bond with G182.
Galectin selectivity. Having arrived at monosaccharide inhibitors
with exceptional affinities for galectin-3, the important question
of selectivity for different members of the galectin family was
addressed (Table 3). In comparison with galectin-3, compound
2h had >100-fold lower affinity for most of the tested human
galectins, and 20 and 4-fold lower affinity for galectin-2 and the
C-terminal CRD of galectin-4, respectively. In contrast, methyl
α-D-galactopyranoside shows both poor affinity and selectivity
for the galectins investigated. Hence, at least some of the
specific interactions of the artificial substituents contributing to
the high galectin-3 affinity also contribute to the selectivity over
other galectins.
Experimental Section
Synthetic procedures, crystallization experiments, and data collection
and refinement are described in the supplementary information.
Table 3. Kd (µM) values of 2h and methyl α-D-galactopyranoside for human
Acknowledgements
galectins determined by competitive fluorescence polarization.[10c]
This work was supported by the Swedish Research Council
(Grants No. 621-2012-2978), the Royal Physiographic Society,
Lund, a project grant awarded by the Knut and Alice Wallenberg
Foundation (KAW 2013.0022), and Galecto Biotech AB, Sweden.
Galectin
1
2h
Me α-gal
>10000[15]
>20000
2700[15]
3.7±0.15
0.64±0.11
0.037±0.0010
0.13±0.012
2.9±0.40
31±3.7
2
Keywords: lectin • galectin-3 • sulfur-π • halogen bond • fluorine
3
multipolar interaction • inhibitor
4Ca
4Nb
7
>20000
>20000
11000[15]
>20000
6300[15]
[1]
[2]
A. Varki, Glycobiology 2016, 27, 3-49.
a) B. Ernst, J. L. Magnani, Nat. Rev. Drug Disc. 2009, 8, 661-677; b) A.
Fernández-Tejada, F. J. Cañada, J. Jiménez-Barbero, Chem. Eur. J.
2015, 21, 10616-10628; c) J. E. Hudak, C. R. Bertozzi, Chem. Biol.
2014, 21, 16-37.
8Ca
8Nb
9Ca
9Nb
11±1.9
[3]
a) C. Diehl, O. Engström, T. Delaine, M. Håkansson, S. Genheden, K.
Modig, H. Leffler, U. Ryde, U. J. Nilsson, M. Akke, J. Am. Chem. Soc.
2010, 132, 14577-14589; b) C. MacRaild, A. Daranas, A. Bronowska, S.
Homans, J. Mol. Biol. 2007, 368, 822-832; c) I. V. Nesmelova, E.
Ermakova, V. A. Daragan, M. Pang, M. Menéndez, L. Lagartera, D.
Solís, L. G. Baum, K. H. Mayo, J. Mol. Biol. 2010, 397, 1209-1230.
M. Petitou, C. van Boeckel, Angew. Chem. Intl ed. Engl. 2004, 43,
3118-3133.
83±17
2.4±0.41
2.7±0.24
6200±220
2800[15]
[a] C-terminal domain. [b] N-terminal domain.
[4]
[5]
a) S. Kleeb, X. Jiang, P. Frei, A. Sigl, J. Bezençon, K. Bamberger, O.
Schwardt, B. Ernst, J. Med. Chem 2016, 59, 3163-3182; b) S. Kleeb, L.
Pang, K. Mayer, D. Eris, A. Sigl, R. C. Preston, P. Zihlmann, T. Sharpe,
R. P. Jakob, D. Abgottspon, A. S. Hutter, M. Scharenberg, X. Jiang, G.
This article is protected by copyright. All rights reserved.

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COMMUNICATION
Navarra, S. Rabbani, M. Smiesko, N. Lüdin, J. Bezençon, O. Schwardt,
[13] a) P. Sörme, P. Arnoux, B. Kahl-Knutsson, H. Leffler, J. M. Rini, U. J.
Nilsson, J. Am. Chem. Soc. 2005, 127, 1737-1743; b) P. Sörme, Y.
Qian, P.-G. Nyholm, H. Leffler, U. J. Nilsson, ChemBioChem 2002, 3,
183-189.
T. Maier, B. Ernst, J. Med. Chem 2015, 58, 2221-2239.
[6]
[7]
[8]
Y. Zhang, Z. P. Liu, Curr. Med. Chem. 2016, 23, 832-849.
E. De Clercq, Nat. Rev. Drug Discovery 2006, 5, 1015-1025.
J. Egger, C. Weckerle, B. Cutting, O. Schwardt, S. Rabbani, K. Lemme,
B. Ernst, J. Am. Chem. Soc. 2013, 135, 9820-9828.
[14] a) K. Peterson, R. Kumar, O. Stenström, P. Verma, P. R. Verma, M.
Håkansson, B. Kahl-Knutsson, F. Zetterberg, H. Leffler, M. Akke, D. T.
Logan, U. J. Nilsson, submitted 2017; b) B. A. Salameh, I. Cumpstey, A.
Sundin, H. Leffler, U. J. Nilsson, Bioorg. Med. Chem. 2010, 18, 5367-
5378.
[9]
a) S. Kelm, J. Exp. Med. 2002, 195, 1207-1213; b) H. Prescher, A.
Schweizer, E. Kuhfeldt, L. Nitschke, R. Brossmer, ACS Chem. Biol.
2014, 9, 1444-1450.
[10] a) I. Cumpstey, E. Salomonsson, A. Sundin, H. Leffler, U. J. Nilsson,
Chem. Eur. J. 2008, 14, 4233-4245; b) I. Cumpstey, A. Sundin, H.
Leffler, U. J. Nilsson, Angew. Chem. Int. Ed. 2005, 44, 5110-5112; cT.
Delaine, C. Collins, A. Mackinnon, G. Sharma, J. Stegmayr, V. K.
Rajput, S. Mandal, I. Cumpstey, A. Larumbe, B. A. Salameh, H. von
Wachenfeldt, B. Kahl-Knutsson, H. van Hattum, M. van Scherpenzeel,
R. J. Pieters, T. Sethi, H. Schambye, H. Leffler, H. Blanchard, U. J.
Nilsson, ChemBioChem 2016, 17, 1759-1770.
[15] V. K. Rajput, H. Leffler, U. J. Nilsson, B. Mukhopadhyay, Bioorg. Med.
Chem. Lett. 2014, 24, 3516-3520.
[16] G. Cavallo, P. Metrangolo, R. Milani, T. Pilati, A. Priimagi, G. Resnati,
G. Terraneo, Chem. Rev. 2016, 116, 2478-2601.
[17] a) B. R. Beno, K.-S. Yeung, M. D. Bartberger, L. D. Pennington, N. A.
Meanwell, J. Med. Chem. 2015, 58, 4383-4438; b) C. R. Forbes, S. K.
Sinha, H. K. Ganguly, S. Bai, G. P. A. Yap, S. Patel, N. J. Zondlo, J.
Am. Chem. Soc. 2017, 139, 1842-1855.
[11] a) S. Di Lella, V. Sundblad, J. Cerliani, C. M. Guardia, D. A. Estrin, G. R.
Vasta, G. A. Rabinovich, Biochemistry 2011, 50, 7842-7857; b) S. P. M.
Mendez-Huergo, A. G. Blidner, G. A. Rabinovich, Curr. Opin. Immun.
2017, 45, 8-15.
[18] I. Cumpstey, S. Carlsson, H. Leffler, U. J. Nilsson, Org. Biomol. Chem.
2005, 3, 1922-1932.
[19] I. Cumpstey, E. Salomonsson, A. Sundin, H. Leffler, U. J. Nilsson,
ChemBioChem 2007, 8, 1389-1398.
[12] T. Delaine, I. Cumpstey, L. Ingrassia, M. Le Mercier, P. Okechukwu, H.
Leffler, R. Kiss, U. J. Nilsson, J. Med. Chem. 2008, 51, 8109-8114.
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Fredrik R. Zetterberg,* Kristoffer
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Monosaccharide derivatives with low
nM lectin affinity and high selectivity
based on combined fluorine-amide,
phenyl-arginine, sulfur-π, and
Text for Table of Contents
halogen bond interactions
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