Single-entity heparan sulfate glycomimetic clusters for therapeutic applications

Article abstract of DOI:10.1002/anie.201410251

Heparan sulfate (HS) is a highly sulfated glycosaminoglycan with a variety of critical functions in cell signaling and regulation. HS oligosaccharides can mimic or interfere with HS functions in biological systems; however, their exploitation has been hindered by the complexity of their synthesis. Polyvalent displays of small specific HS structures on dendritic cores offer more accessible constructs with potential advantages as therapeutics, but the synthesis of single-entity HS polyvalent compounds has not previously been described. Herein we report the synthesis of a novel targeted library of single-entity glycomimetic clusters capped with varied HS saccharides. They have the ability to mimic longer natural HS saccharides in their inhibition of the Alzheimer's disease (AD) protease BACE-1. We have identified several single-entity HS clusters with IC50 values in the low-nanomolar range. These HS clusters are drug leads for AD and offer a novel framework for the manipulation of heparan sulfate-protein interactions in general.

Full text of DOI:10.1002/anie.201410251

Angewandte
Chemie
DOI: 10.1002/anie.201410251
Glycomimetics
Single-Entity Heparan Sulfate Glycomimetic Clusters for Therapeutic
Applications**
Peter C. Tyler, Scott E. Guimond, Jeremy E. Turnbull, and Olga V. Zubkova*
Dedicated to Professor Richard H. Furneaux on the occasion of his 65th birthday
Abstract: Heparan sulfate (HS) is a highly sulfated glycos-
aminoglycan with a variety of critical functions in cell signaling
and regulation. HS oligosaccharides can mimic or interfere
with HS functions in biological systems; however, their
exploitation has been hindered by the complexity of their
synthesis. Polyvalent displays of small specific HS structures on
dendritic cores offer more accessible constructs with potential
advantages as therapeutics, but the synthesis of single-entity HS
polyvalent compounds has not previously been described.
Herein we report the synthesis of a novel targeted library of
single-entity glycomimetic clusters capped with varied HS
saccharides. They have the ability to mimic longer natural HS
saccharides in their inhibition of the Alzheimerꢀs disease (AD)
protease BACE-1. We have identified several single-entity HS
clusters with IC50 values in the low-nanomolar range. These HS
clusters are drug leads for AD and offer a novel framework for
the manipulation of heparan sulfate–protein interactions in
general.
tive disorders.[10] However, the potentially numerous thera-
peutic applications of HS oligosaccharides have not been
realized, largely because of the difficulty and complexity of
the synthesis of these compounds. Fondaparinux (Arixtra),
a pharmaceutical anticoagulant, is an example of a synthetic
sulfated oligosaccharide.[11] However, the synthetic route to
this compound involves more than 40 steps.
A decade ago, HS was identified as a natural regulator of
the protease b-secretase (BACE-1), which generates toxic b-
amyloid (Ab) peptides as products; these peptides aggregate
into plaques in the brains of patients with Alzheimerꢀs disease
(AD).[12] Inhibitors of BACE-1 are expected to block this
process, thus providing a disease-modifying treatment by
preventing the formation of plaques and the degeneration of
neurons in the disease process.
Recently, we developed a novel synthetic approach to HS
oligosaccharides and prepared a targeted library of HS
fragments (ranging in size from 6- to 12-mers).[13] We have
shown these compounds to be promising BACE-1 inhibitors
with low-nanomolar IC50 values that could be used to prevent
the accumulation of Ab peptides. The complex synthesis of
HS oligosaccharides has been investigated by a number of
research groups,[14] but despite many useful modifications and
improved glycosylation protocols, the syntheses of HS targets
still require multiple steps (> 50 steps)[15] and remain cum-
bersome and costly. In this study, with the aim of greatly
simplifying the synthetic process while retaining the desired
bioactivity of target HS structures, we decorated tetravalent
dendritic cores with multiple short, readily synthesized HS
sequences (Scheme 1).
H
eparan sulfate (HS) and heparin belong to the glycos-
aminoglycan family. These linear polysaccharides are made of
repeating disaccharide units, which can be differentially
sulfated at the 2-O position of the d-glucuronic acid or l-
iduronic acid and/or the 6-O and, rarely, 3-O positions of the
glucosamine. The glucosamine amino group can be N-sulfated
and N-acetylated. The multiple biological functions of HS are
due to ionic interactions between negatively charged sulfates
and carboxylate groups with a variety of proteins, such as
growth factors,[1] proteases,[2] and cytokines.[3] HS plays crucial
roles in cancer,[4] inflammation,[5] bone repair,[6] angiogene-
sis,[7] anticoagulation,[8] viral invasion,[9] and neurodegenera-
[*] Dr. P. C. Tyler, Dr. O. V. Zubkova
The Ferrier Research Institute, Victoria University of Wellington
Gracefield Research Centre
Lower Hutt (New Zealand)
E-mail: Olga.Zubkova@vuw.ac.nz
Scheme 1. Synthetic targets.
Dr. S. E. Guimond, Prof. J. E. Turnbull
Institute of Integrative Biology, University of Liverpool
Liverpool L69 3BX (UK)
Dendritic cores[16] and dendrimers[17] provide a framework
to exploit polyvalency, a key principle in nature for the
establishment of strong yet reversible “Velcro”-type inter-
actions for biomolecular recognition.[18] Traditional drug
discovery has focused on small-molecule drugs that attach
to a single binding site;[19] however, biological targets are
large molecules which often rely on polyvalent interactions at
multiple sites in their binding cascades.[20] The weak inter-
[**] We acknowledge Dr. Herbert Wong and Dr. Yinrong Lu for an
excellent NMR and mass spectrometry service. We thank Dr. Ralf
Schwçrer for the synthesis of a monosaccharide intermediate, and
Eizabeth Edwards for technical assistance with the bioassays. J.E.T.
gratefully acknowledges the financial support of the Biotechnology
and Biological Sciences Research Council UK and the Medical
Research Council UK.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201410251.
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actions of individual subunit
structures are often enhanced
by their specific repetition,
known as a synergistic cluster-
ing effect.[21] However, many
polyvalent compounds and
polymers synthesized for
potential therapeutic applica-
tions are not single chemical
entities and it is difficult to
manufacture such mixtures for
FDA approval. Several studies
have been directed towards
the synthesis of HS glycomi-
metics. The multivalent pre-
sentation of heparin hexasac-
charides on PAMAM (poly-
amidoamine) dendrimers fur-
nished
potent
fibroblast
growth factor (FGF) regula-
tors and demonstrated the
ability of hyperbranched mac-
romolecules to amplify the
binding affinity of heparin
fragments. However, the
inability to fully cap the den-
drimers led to mixtures of
glycoconjugates.[22] A synthe-
sis of selectively sulfated HS
glycopolymers of controllable
length was recently reported
for the targeting of chemo-
kines and their receptor inter-
actions, but the products were
mixtures of polymers deco-
rated with heparin frag-
ments.[23] Herein we report
the synthesis of single-entity
tetravalent
glycomimetics
end-capped with short specific
HS sequences and their ability
to mimic much longer poly-
and oligosaccharide chains of
natural HS in their inhibition
of BACE-1.
A Michael reaction of pen-
taerythritol (1) with acryloni-
trile, followed by treatment
with concentrated HCl, gave
the known tetraacid 2,[24] the
treatment of which with N-
Scheme 2. Preparation of tetramer dendritic cores and glycomimetic clusters with monosaccharides
attached. a) Preparation of tetramer dendritic cores: i) NHS, EDC, DMF, DIPEA, room temperature;
ii) Et3N, DMF, room temperature; iii) H2, Pd(OH)2/C, aqueous MeOH, room temperature. b) Preparation of
glycomimetic clusters with GlcNAc(6S) attached through linkers: ii) Et3N, DMF, room temperature; iii) H2,
Pd(OH)2/C, aqueous MeOH, room temperature; iv) AgOTf, NIS, toluene, ꢀ308C!RT; v) AcSH, pyridine,
room temperature; vi) NaOMe, MeOH, room temperature; vii) SO3·NMe3, DMF, 608C. Bn=benzyl,
Cbz=carboxybenzyl, DIPEA=diisopropylethylamine, DMF=N,N-dimethylformamide, NIS=N-iodosuccin-
imide, Tf=trifluoromethanesulfonyl, Tol=tolyl.
hydroxysuccinimide
(NHS)
and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)
afforded the “short-armed” tetra-N-hydroxysuccinimide-acti-
vated ester 3 as a crystalline material. 8-Aminooctanoic acid
(4) was converted into the benzyl ester 5[25] and coupled with 3
to give the tetravalent dendritic core 6. Hydrogenolysis of 6
gave the tetraacid 7, the treatment of which with NHS/EDC
furnished the “long-armed” N-hydroxysuccinimide ester 8
(Scheme 2a).
To evaluate the coupling methodology, we prepared two
model glycomimetic clusters, 9 and 10 (Scheme 2b). The six-
carbon-atom linker 11 was attached to the glucosamine
building block 12[13] to give 13, which was converted into the
N-acetate 14. Zemplen deacetylation followed by sulfation
2
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and unmasking of the amino functionality by hydrogenolysis
afforded the sulfated monomer 15. Coupling of 15 to the
short-armed active ester core 3 led to complex mixtures of
starting material, some di- and trisubstituted clusters, and the
tetrasubstituted cluster 9, all of which had similar Rf values on
TLC plates. Repeated chromatography on silica gel produced
9 in 40% yield. We reasoned that electrostatic repulsion of
anionic sulfo groups led to only partial substitution and
formation of the product 9 in moderate yield. In an attempt to
improve the coupling yield, we attached the fully protected
monosaccharide 16 to the dendritic core 3. This reaction
successfully afforded cluster 17 in almost quantitative yield.
Deacetylation followed by O-sulfation furnished a “short-
armed” cluster 19. Hydrogenolysis then gave a pure cluster 9
in excellent yield (Scheme 2b). Encouraged by these results,
we prepared a “long-armed” tetramer cluster 10 in the same
manner. Again, the coupling yield, in this case for the
formation of the tetramer 20, was almost quantitative.
Derivatization steps gave the sulfated cluster 10 as a pure
single product.
afforded only the fully protected tetrasaccharides 35 and 36,
respectively, in 85 and 87% yield (Scheme 3). These di- and
tetrasaccharides were then partially processed to a stage
suitable for coupling to the cores. Selective removal of the
chloroacetate groups and oxidation of the resulting primary
hydroxy groups in 37–40, followed by ester formation,
provided the methyl esters 41–44 in excellent yield. Treatment
with thioacetic acid in pyridine then produced the N-acetates
45–47, and the linker amino groups were unmasked by
treatment with Zn in AcOH (N-Troc) or by hydrogenolysis
(N-Cbz) to afford the fully protected N-acetylated di- and
tetrasaccharide HS fragments 48–50. The N-Fmoc group in 44
was removed selectively with piperidine to furnish the
tetrasaccharide 51. The sulfated disaccharide monomer 54
was prepared from 46 in three steps: Zemplen deacetylation,
selective O-sulfation, and brief hydrogenolysis. Compound 54
was compared to the tetravalent compounds as BACE-
1 inhibitors to assess the clustering effect in these glycomi-
metics.
Coupling of four equivalents of the N-acetylated HS
fragments 48–51 with the tetra-N-hydroxysuccinimide active
ester 8 afforded tetramer clusters 55–58 in 93–95% yield after
chromatography (Scheme 4). Acidic hydrolysis selectively
removed the O-acetate groups to give 59–62 in high yield, and
sulfation of the primary hydroxy groups furnished 63–66,
which were purified by chromatog-
When assessed as inhibitors of BACE-1, the potency of
these compounds clearly increased from the monomer 15 to
the “short-armed” cluster 9 to the “long-armed” cluster 10
(Table 1). For this reason, the long-armed dendritic core was
used to prepare a targeted library of HS glycomimetics.
raphy. Simultaneous saponification
Table 1: Inhibitory activity of synthetic HS glycomimetics and heparin for the cleavage of FRET peptide
of the benzoate and methyl esters
then generated tetramers 67–70.
Hydrogenolysis of 67–69 in aqueous
THF basified with aqueous ammo-
nia gave the targeted 6-O-sulfated
N-acetylated tetramers 71–73,
which were isolated as their
sodium salts. Sulfation of the tetra-
mer clusters 67–70 afforded 74–77.
Hydrogenolysis then furnished the
targeted N-acetylated tetramers 78–
80 with two sulfate groups per
disaccharide unit as well as the
amino tetramer 81. N-Sulfation of
81 under aqueous conditions gave
the desired octa-N-sulfated hexa-
deca-O-sulfated HS tetramer 82.
The ability of the target com-
by BACE-1 enzyme.
Compound IC50 [nm]
IC50 [mgmLꢀ1
]
End-capping saccharide[a]
Molecular weight
heparin
15
0.2
94600
0.002
ca. 40
ca. 100
50
mixtures
GlcNAc6S
GlcNAc6S-IdoA2S
GlcNAc6S
GlcNAc6S
GlcNAc6S-GlcA
GlcNAc6S-IdoA
GlcNAc6S-GlcA-GlcNAc6S-GlcA
GlcNAc6S-GlcA2S
GlcNAc6S-IdoA2S
12000[b]
422.4
722.5
2042.0
2606.8
3399.3
3399.3
5412.7
3807.5
3807.5
54
138000
24720
760
9[c]
10
5
10
10
0.2
0.05
0.2
0.01
0.01
71
2940
72
2940
73
78
79
80
36.9
13.1
52.5
1.6
GlcNAc6S-GlcA2S-GlcNAc6S-GlcA2S 6229.1
GlcNS6S-IdoA2S-GlcNS6S-IdoA2S 6709.1
82
1.5
[a] GlcNAc: N-acetylated glucosamine; GlcA: glucuronic acid; IdoA: iduronic acid; 6S: 6-O-sulfate;
GlcNS: N-sulfated glucosamine; the numbered synthetic compounds have a six-carbon-atom linker (not
shown). [b] Average molar mass of heparin: 12 kDa. [c] “Short-armed” dendritic core (3).
pounds to inhibit the BACE-1 pro-
We previously prepared a library of hexa- to dodecasac-
charide fragments of HS and showed that 6-O-sulfation of the
GlcNAc residues was essential for BACE-1 inhibition,
whereas 2-O-sulfation of the uronic acids (UAs) increased
activity (especially in shorter saccharides, such as octasac-
charides) and N-acetylation was well-tolerated.[13] These
results provided a template for the HS structures to cap the
tetravalent cores.
tease was next investigated by the use of fluorescence
resonance energy transfer (FRET) peptide-cleavage assays
(see the Supporting Information). All glycomimetic clusters
inhibited BACE-1 with IC50 values in the micromolar to low-
nanomolar range (Table 1). Tetramers 9 and 10 with O-
sulfated GlcNAc (GlcNAc6S) attached showed low potency.
We found that the potency increased from an IC50 value of
25 mm for the sulfated “short-armed” small cluster 9 to a value
of 0.76 mm for the larger “long-armed” cluster 10. The clusters
with 6-O-sulfated GlcNAc in disaccharide fragments
(GlcNAc6S-UA) 71 and 72 were only micromolar inhibitors,
and the presence of d-glucuronic acid or l-iduronic acid as
the end-capping saccharide led to no difference in potency.
The glycosylation of donors 23–26[13] variously with the
linkers 11, 27, and 28 afforded only the b-disaccharides 29, 30,
33, and 34 in 80–90% yield (Scheme 3). The O-Fmoc-
protected derivatives 29 and 30 were converted into acceptors
31 and 32, and then coupling of 25 with 31 and 26 with 32
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GlcNAc6S-GlcA, displayed
an IC50 value of 37 nm. This
bioactivity was increased with
sulfation of the 2-O position of
the UA: Inhibitor 80 capped
with
GlcNAc6S-GlcA2S-
GlcNAc6S-GlcA2S tetrasac-
charides showed an IC50 value
of 1.6 nm. It is notable that this
potency is similar to that
observed for the most potent
8–12-mer synthetic HS saccha-
rides previously described as
BACE-1 inhibitors.[13] The N-
sulfation of glucosamine units
to produce GlcNS6S-IdoA2S-
GlcNS6S-IdoA2S capping sac-
charides in 82 led to only
a slight increase in potency
(IC50 = 1.5 nm).
Importantly, none of the
compounds displayed any sig-
nificant anticoagulant activity
towards factor Xa (< 0.1% of
the activity of unfractionated
heparin). Furthermore, in
regard to potential off-target
effects, all compounds dis-
played very low abilities to
inhibit the structurally related
aspartyl protease cathepsin D;
known inhibitors of this
enzyme, such as pepstatin A,
are
potent
(IC50 ꢁ 1 nm),
whereas the most inhibitory
GlcNAc6S-containing cluster
80, the N-sulfated cluster 82,
and
heparin
displayed
IC50 values of > 1 mm, 24 nm,
and 3.3 nm, respectively (see
Table 2 in the Supporting
Information). All compounds
also proved incapable of acti-
vating fibroblast growth factor
(FGF) signaling by either
FGF-1 or FGF-2 through
FGF receptor 1 at concentra-
tions up to 10 mgmLꢀ1,
Scheme 3. Synthesis of di- and tetrasaccharide building blocks with linkers. i) TMSOTf, CH2Cl2, ꢀ308C!
RT; ii) Et3N, CH2Cl2, room temperature; iii) DABCO, MeCN/EtOH, 708C; iv) TEMPO, BAIB, aqueous
MeCN, room temperature, then CH2N2, 08C!RT; v) HSAc, pyridine, room temperature; vi) H2, Pd(OH)2/C,
aqueous MeOH, room temperature; vii) Zn, AcOH, THF, room temperature; viii) piperidine, DMF, room
temperature; ix) NaOH, aqueous MeOH, 08C!RT; x) SO3·NMe3, DMF, 608C. The descriptors ido/gluco are
used to describe the configuration of the carbohydrate residues representing uronic acids in the target
molecule (ido- for a (GlcNAc-IdoA)n=0–1 and gluco- for a (GlcNAc-GlcA)n=0–1 saccharide). BAIB=bis-
(acetoxy)iodobenzene, Bz=benzoyl, DABCO=1,4-diazabicyclo[2.2.2]octane, Fmoc=fluorenyl-9-methoxy-
carbonyl, TEMPO=(2,2,6,6-tetramethylpiperidin-1-yl)oxy, TMS=trimethylsilyl, Troc=2,2,2-trichloroethoxy-
carbonyl.
whereas
EC50 values of 500 and
30 ngmLꢀ1
respectively, in
heparin
has
,
these assays (see Table 3 in
the Supporting Information).
To summarize, we have for
the first time prepared single-
The potency increased when the 2-O position of the UA was
sulfated (GlcNAc6S-UA2S); thus, tetramers 78 and 79 had
IC50 values of 13 and 52 nm. Tetramer 73 with larger HS
saccharides attached, tetrasaccharides GlcNAc6S-GlcA-
entity compounds presenting polyvalent displays of HS
saccharides. We have shown that these clusters can mimic
longer HS oligosaccharides in their ability to inhibit BACE-1,
an Alzheimerꢀs disease drug target, and lack off-target
4
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Glycomimetics
P. C. Tyler, S. E. Guimond, J. E. Turnbull,
O. V. Zubkova*
&&& — &&&
Single-Entity Heparan Sulfate
Glycomimetic Clusters for Therapeutic
Applications
A four-legged copycat: Heparan sulfate
(HS) has a variety of critical functions in
cell signaling, but the exploitation of HS
oligosaccharides as mimetic agents has
been hindered by the complexity of their
synthesis. Polyvalent displays of specific
HS structures on dendritic cores are
more accessible constructs (see exam-
ple). Such HS glycomimetic clusters
mimicked natural HS saccharides in their
inhibition of the Alzheimer’s disease
protease BACE-1.
Angew. Chem. Int. Ed. 2015, 54, 1 – 7
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7
These are not the final page numbers!