Total Synthesis of a Partial Structure from Arabinogalactan and Its Application for Allergy Prevention

Article abstract of DOI:10.1002/chem.202002287

Arabinogalactan, a microheterogeneous polysaccharide occurring in plants, is known for its allergy-protective activity, which could potentially be used for preventive allergy treatment. New treatment options are highly desirable, especially in a preventive manner, due to the constant rise of atopic diseases worldwide. The structural origin of the allergy-protective activity of arabinogalactan is, however, still unclear and isolation of the polysaccharide is not feasible for pharmaceutical applications due to a variation of the activity of the natural product and contaminations with endotoxins. Therefore, a pentasaccharide partial structure was selected for total synthesis and subsequently coupled to a carrier protein to form a neoglycoconjugate. The allergy-protective activity of arabinogalactan could be reproduced with the partial structure in subsequent in vivo experiments. This is the first example of a successful simplification of arabinogalactan with a single partial structure while retaining its allergy-preventive potential.

Full text of DOI:10.1002/chem.202002287

Accepted Article
Accepted Article
Title: Total Synthesis of a Partial Structure from Arabinogalactan and
its Application for Allergy-Prevention
Authors: Matthias Krumb, Maximilian Jäger, Alice Voss, Loreen Immig,
Karin Peters, Danuta Kowalczyk, Albrecht Bufe, Till Opatz,
Otto Holst, Christian Vogel, and Marcus Peters
This manuscript has been accepted after peer review and appears as an
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To be cited as: Chem. Eur. J. 10.1002/chem.202002287
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01/2020

10.1002/chem.202002287
Chemistry - A European Journal
COMMUNICATION
Total Synthesis of a Partial Structure from Arabinogalactan and
Its Application for Allergy Prevention
Matthias Krumb,[b] Maximilian Jäger,[a] Alice Voss,[c] Loreen Immig,[a] Karin Peters,[a] Danuta
Kowalczyk,[b] Albrecht Bufe,[a] Till Opatz,*[b] Otto Holst,[d] Christian Vogel,[c] and Marcus Peters*[a]
[a]
Dr. M. Jäger, MSc L. Immig, Dr. K. Peters, Prof. Dr. A. Bufe, Dr. M. Peters
Department of Experimental Pneumology
Ruhr-University Bochum
Universitätsstr. 150, 44801 Bochum, Germany
E-mail: marcus.peters@rub.de
[b]
MSc M. Krumb, D. Kowalczyk, Prof. Dr. T. Opatz
Department of Chemistry
Johannes Gutenberg-University
Duesbergweg 10-14, 55128 Mainz, Germany
E-mail: opatz@uni-mainz.de
[c]
[d]
A. Voss, Prof. Dr. C. Vogel
Department of Chemistry
University of Rostock
Albert-Einstein-Str. 3a, 18051 Rostock, Germany
Prof. Dr. O. Holst
Division of Structural Biochemistry
Research Center Borstel, Leibniz Lung Center, Airway Research Center North (ARCN)
Parkallee 1-40, 23845 Borstel, Germany
Supporting information for this article is given via a link at the end of the document.
Abstract: Arabinogalactan, a microheterogeneous polysaccharide
occurring in plants, is known for its allergy-protective activity, which
could potentially be used for preventive allergy treatment. New
treatment options are highly desirable, especially in a preventive
manner, due to the constant rise of atopic diseases worldwide. The
structural origin of the allergy-protective activity of arabinogalactan is,
however, still unclear and isolation of the polysaccharide is not
feasible for pharmaceutical applications due to a variation of the
activity of the natural product and contaminations with endotoxins.
Therefore, a pentasaccharide partial structure was selected for total
synthesis and subsequently coupled to a carrier protein to form a
neoglycoconjugate. The allergy-protective activity of arabinogalactan
could be reproduced with the partial structure in subsequent in vivo
experiments. This is the first example of a successful simplification of
arabinogalactan with a single partial structure while retaining its
allergy-preventive potential.
arabinose containing epitopes by the immune system, since it is
known that a cleavage of these significantly reduced the allergy-
protective activity of the polysaccharide.[6] Moreover, it was shown
in the same work that AG from other plants, namely Acacia or
Larix, does not show allergy-protective activity. This is probably
based on a differing molecular structure, however, the exact
chemical structure of the different AG is unknown. Fortunately,
pioneering work by Brecker et al. shed light on the structural
composition of AG isolated from Timothy grass (Phleum
pratensis) by deciphering arabinose and galactose containing
partial structures (Figure 1, A).[7] The latter consist of a -(1→6)-
linked D-galactopyranosyl backbone with L-arabinofuranosyl--
(1→5)- or -(1→3)- and -(1→3)-linked side chains. It was
revealed in previous studies that isolated AG from meadow foxtail
(Alopecurus pratensis), which contains these partial structures, is
allergy-protective.[6]
The negative impact on human health of allergic diseases, often
overrepresented in first world countries, has been increasing
unimpededly. However, studies have shown that growing up and
living in a traditional farming environment can decrease the risk of
developing these allergies significantly, which is known as the
“farm effect” in literature.[1-4] Nevertheless, the connection
between living in a farming environment and allergy protection is
not yet fully understood.[5] Arabinogalactan (AG), an immune-
modulating natural polysaccharide, has recently received
considerable attention as one potential origin for this
phenomenon.[5, 6]
The polysaccharide occurs frequently in grasses that are
present in a farming environment and can be isolated therefrom.[6,
7]
Unfortunately, the composition of the structurally
microheterogeneous AG is very complex and difficult to analyse.[8,
9] There is literature evidence that the allergy-protective activity of
AG could originate from recognition of particular (terminal)
1
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10.1002/chem.202002287
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deacetylation in the presence of benzoyl groups (Scheme 1). An
orthogonally stable Fmoc-protecting group was introduced to
enable glycosylation of the Araf2-disaccharide later in the
synthesis. In detail, the synthetic route for Galp3 (9) started from
peracetylated D-galactose (1) to give the 6-O-acetyl-protected
thioglycoside 2 through a reaction with thiophenol, Zemplén
deprotection and regioselective acetylation using a lipase to
selectively furnish the 6-O-protected galactose 2 in an 83 % yield
over three steps.[22] Subsequently, galactose 2 was benzoylated
and glycosylated with spacer 4, which was synthesized in six
steps from 5-phenylvaleric acid (3, details can be found in the SI).
The 6-O-acetyl group was then removed using methanolic HCl to
give intermediate 5. The free hydroxyl group obtained in 5 was
then glycosylated with an orthogonally protected galactose 6. The
latter was synthesized from galactose 2 through orthoester
formation with triethyl orthobenzoate, benzoylation, regioselective
cleavage of the orthoester intermediate 2a and, subsequent
Fmoc-protection in a 40 % yield over three steps.[23] Both building
blocks, galactose
5 and galactose 6, were glycosylated,
6-O-deprotected and again glycosylated with thioglycoside 8 to
synthesize a Galp3 building block 9 in four further steps.
Figure 1. Illustration of partial structures of AG identified by Brecker and co-
10]
workers using symbol nomenclature for glycans (A).[7,
Partial structure of
arabinogalactan selected for total synthesis and its retrosynthetic analysis (B).
Preventive and prophylactic approaches with a promising
perspective are still rare, despite a huge research effort in the
search for new treatment options for allergic diseases.[11] While
the use of natural polysaccharides for prophylaxis could be
envisioned, the size and complexity of AG precludes the
production of chemically well-defined species with consistent
biological activity. In addition, the separation of natural
polysaccharides from other immune-modulating contaminants,
such as endotoxins, is, at least, highly challenging, especially
under the good manufacturing practice conditions required for
pharmaceutical applications. Gratifyingly, the prime example of
fondaparinux,
a
synthetic pentasaccharide used as an
anticoagulant, showcases that the total synthesis of carbohydrate
pharmaceuticals can be cost-effective, despite their intrinsic high
complexity and polyfunctionality.[12-15] In terms of AG, there are a
few examples for the synthesis of related oligosaccharides but
structure-activity relationships are unfortunately missing.[16-21]
Thus, we selected a partial structure of arabinoglactan,
namely a pentasaccharide containing two L-arabinose and three
D-galactose units (Araf2Galp3) as the target for total synthesis to
match one of the partial structures in AG (Figure 1, A (structure II)
and Figure 1, B)[7] which were shown to be biologically active in
earlier studies.[6] Our overall goal for this project was to gain a
better understanding of the role of glyco-epitopes in AG and to
achieve a strategic simplification of the polysaccharide while the
useful allergy-protective activity is retained.
Scheme 1. Synthesis of Galp3 intermediate 9 over nine linear steps starting
from peracetylated D-Galactose (1).
The synthesis of the Araf2 side chain 14 required a (1→5) linkage
between the L-arabinose units, which was furnished using the
established tritylation-detritylation approach (Scheme 2).[24] The
cis-glycosidic linkage in the first galactose-connected arabinose
required the use of non-participating O-protection, while the latter
arabinose has a trans-glycosidic linkage and, therefore, requires
participating O-protection for synthesis.[25] According to a report
by Lowary and co-workers, the cis-glycosylation is possible when
The pentasaccharide selected requires construction of a
trigalactose (Galp3) backbone with two -(1→6)-glycosylations
and an additional -(1→3)-glycosylation for the attachment of the
arabinose side chain. The latter required the construction of an -
(1→5)-glycosidic linkage. Additionally, a reactive isothiocyanate
spacer was needed for covalent coupling to a carrier protein. The
synthesis of the pentasaccharide Araf2Galp3 started with the
construction of the trigalactose (Galp3) backbone; the (1→6)-
connections desired were furnished using a combination of
regioselective enzymatic acetylation and chemoselective
a
conformationally restricted O-xylylene-protected donor is
used.[26, 27] We adapted this approach and started the synthesis
from L-arabinose (10) in a Fischer glycosylation in methanol, the
product of which was subsequently benzoylated. Thioarabinoside
11 was subsequently prepared from a 1-O-acetyl-intermediate in
four steps and
a 26 % yield. Next, the 5-O-deprotected
2
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Scheme 3. Synthesis of the AG partial structure Araf2Galp3 15 over four linear
steps from the key intermediates Galp3 8 and Araf2 13.
arabinose 12 was produced in a sequence of debenzoylation,
5-O-tritylation, introduction of the 2,3-O-xylylene ether, according
to Lowary et al., and detritylation to give glycosyl acceptor 12 in a
31 % yield over four steps. The thioglycoside in arabinose 12
should be used afterwards for glycosylation to trigalactose 9.
Thus, an orthogonal glycosylation, which leaves the thioglycoside
untouched, was required to introduce the second arabinose unit.
Gratifyingly, using the N-phenyltrifluoroacetimidate donor 13,[28]
synthesized through cleavage of thioglycoside 11 to its hemi-
acetal and reaction with 2,2,2-trifluoro-N-phenylacetimidoyl
chloride, furnished the Araf2 intermediate 14 desired in a 62 %
yield in a modified procedure based on Andersen et al.[29]
The pentasaccharide was coupled to bovine serum albumin
(BSA) as the carrier protein to create a neoglycoconjugate
(Araf2Galp3-BSA, Figure S1) for biological evaluation. Coupling
was accomplished using the reactive isothiocyanate group, which
reacts readily with BSA’s free amino groups. The
neoglycoconjugate created was subsequently evaluated for
allergy-protective activity in a mouse model of allergic asthma
(Figure 2). The treatment of mice with Araf2Galp3-BSA led to
reduced allergic inflammation in the airways upon sensitization
and challenge with ovalbumin (OVA) as a model allergen. This
can be seen by the reduction of eosinophilic granulocytes,
lymphocytes and macrophages (Figure 2, A). Moreover,
immunoglobulin E (IgE) production (Figure 2, B) and the Th2
response determined by measuring the in vitro production of
interleukin (IL)-5 and IL-13 by spleen cells is significantly reduced
(Figure 2, C), as well as the goblet cell metaplasia (Figure 2, D
and Figure S2). The efficacy of treatment was comparable to AG,
shown to be allergy-protective in former studies.[6] Another
hallmark of allergic asthma is airway hyperreactivity (AHR)
towards provocation with cholinergic stimuli, such as
methacholine. Therefore, the AHR of mice was tested in the
asthma model by measuring the airway mechanics. As seen for
airway inflammation, the AHR is also significantly reduced in mice
treated with Araf2Galp3-BSA (Figure S4).
Scheme 2. Synthesis of Araf2 intermediate 13 over eight linear steps starting
from L-arabinose (9).
The final steps of the synthesis started with the glycosylation of
Araf2 donor 14 with Galp3 acceptor 9 (Scheme 3). After a
successful cis-glycosylation and Zemplén deprotection, protected
Araf2Galp3 15 was synthesized in a 27 % yield. In the two final
steps, the 2,3-O-xylylene protecting group was removed under
Birch conditions using liquid ammonia and sodium. This also led
to the reduction desired of the azide to an amino group at the
same time. Conversion of the latter to the reactive isothiocyanate
with thiophosgene under mildly basic conditions using BaCO3 as
a mild base in a water/ethanol mixture gave the target structure
Araf2Galp3 16 in a 71 % yield over two steps.
3
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Next, a neutral control structure was needed to clarify that the
biological activity of pentasaccharide 16 observed results from
the actual recognition of the structure by the immune system and
not from unspecific glycosylation. Hence, we synthesized a
glucose pentamer (Glcp5) equal in size and presence of
multivalent carbohydrate ligands to pentasaccharide 12 to form a
robust control structure (Scheme 4). D-glucose (17) was
converted to intermediate 18 over five steps in a 21 % yield using
standard operations. Glycosylation with thioglycoside 19 and
deprotection gave disaccharide 20 over two steps. This process
was repeated to obtain the pentaglucose 21 over five steps in
46 % in an iterative manner (details can be found in the SI). After
global deprotection, reduction and conversion of the amine to the
isothiocyanate using the established procedure, pentaglucose 22
was synthesized in a 39 % yield. It was subsequently coupled to
BSA to give the neoglycoconjugate Glcp5-BSA (Figure S1). No
significant protection against allergic airway disease was found
using Glcp5-BSA as a neutral control structure (Figure S3). These
results underline that the allergy-protective activity depends on
the specific composition of the pentasaccharide and is not due to
the unspecific glycosylation of BSA.
Scheme 4. Synthesis of the glucose pentamer (22, Glcp5).
Following the initial observation of the allergy-protective effect
of Araf2Galp3-BSA, the mechanism of protection was
investigated. During the treatment of mice with Araf2Galp3-BSA, a
significant increase of BSA-specific immunoglobin G 1 (IgG1) in
serum was observed, which was absent when mice were treated
with unmodified BSA. By contrast, treatment with Glcp5-BSA did
not lead to a significantly increased antibody production (Figure
3, A). Interestingly, the titre of BSA-specific IgG1 shows a strong
negative correlation with the number of eosinophilic granulocytes
and OVA-specific IgE, suggesting a causative relationship
Figure 2. Araf2Galp3-BSA reduces the allergic airway inflammation and
sensitization. (A). immunoglobulin E (IgE) was measured in BAL fluid (B).
Production of IL-5 and IL-13 was determined in spleen cell supernatants after
the restimulation of cells with OVA (C). Goblet cells were counted from five
different bronchi of each mouse and expressed as the number of cells per 100
µm basement membrane (D). One-way ANOVA was used to analyse the data
for statistical differences. * p < 0.05 and ** p < 0.01.
between these parameters (Figure 3,
B
and C). The
galactosylation of the IgG produced was analysed since it is
4
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10.1002/chem.202002287
Chemistry - A European Journal
COMMUNICATION
known that the modification of the Fc-part of IgG with galactose
confers immune-regulatory properties,[30-32]. It was found that the
treatment of mice with Araf2Galp3-BSA causes a significant
increase of galactosylated IgG1 (Figure 3, D). The IgG produced
was, therefore, suspected of being involved in the regulation of
airway inflammation. However, an interference with the induction
of eosinophilic airway inflammation by adoptive transfer of IgG1
was not observed (details can be found in the SI, Figure S5),
which hints at a more complex mechanism. In addition to
antibodies, B-lymphocytes produce cytokines that may affect
immune regulation. The so-called regulatory B cells are releasing
IL-10 and provide several other mechanisms of down-regulation
of inflammatory immune responses.[33, 34] Thus, IL-10 production
of B cells from the lung tissue of mice treated with Araf2Galp3-BSA
was confirmed (Figure S6). The activity of IL-10 was blocked by
intranasal administration of a blocking antibody binding to the
IL-10 receptor to analyse whether the IL-10 produced is involved
in the regulation of the allergic immune response. As expected,
mice that were treated with Araf2Galp3-BSA and an isotype control
antibody showed a significantly reduced allergic inflammation
(Figure 3, E). By contrast, the allergic airway inflammation and
sensitization in mice that received Araf2Galp3-BSA and an IL-10R
blocking antibody showed no significant difference from the
phenotype observed in mice that were not treated with the
glycoconjugate. This shows that IL-10 signalling is probably
involved in the mechanism of immune modulation mediated by
Araf2Galp3-BSA- (discussion can be found in the SI).
Figure 3. Araf2Galp3-BSA-induced production of specific IgG1. The BSA-
specific IgG1 antibodies were detected by ELISA (A). Antibody titre was
5
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10.1002/chem.202002287
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COMMUNICATION
correlated to the number of eosinophilic granulocytes (B) and the concentration
of IgE (C). Galactose modification of IgG was measured in a lectin-binding test
by using the galactose-specific Erythrina crista-galli lectin (D). The immune-
regulatory activity of IL-10 is also involved in Araf2Galp3-BSA-mediated allergy
protection. This was shown by blocking the IL-10 receptor by using an antibody,
leading to the inhibition of the anti-inflammatory action of Araf2Galp3-BSA (E).
One-way ANOVA was used to analyse the data for statistical differences.
Correlation analysis was done by Spearman’s rank correlation. * p < 0.05, ** p
< 0.01 and *** p < 0.001.
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In summary, a convergent total synthesis of a partial structure
of AG was accomplished by synthesis of a trigalactose backbone
and an arabinose disaccharide sidechain and their subsequent
combination. Late-stage introduction of a reactive isothiocyanate
and covalent coupling to BSA led to a neoglycoconjugate. It was
shown for the first time that this construct can reduce the allergic
airway inflammation in a mouse model of allergic asthma in
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Acknowledgements
This study was supported by Deutsche Forschungsgemeinschaft
(INST 213/950-1 FUGG, PE 1813/2-1), collaborative research
centre 1066 of Johannes Gutenberg-University, intramural
research funding of Ruhr-University Bochum F659-2009 and
F797-2013 and a grant provided by the Gesellschaft für
Pädiatrische Allergologie. We thank Dr. Johannes C. Liermann
(Mainz) for NMR Spectroscopy, Dr. Christopher Kampf (Mainz)
for mass spectrometry, and Petra Bonowitz (Bochum) and Sandra
Busse (Bochum) at Experimental Pneumology, Ruhr-University
Bochum, for excellent technical assistance. We like to thank Mr.
Philip Saunders (Language Support Services, Berlin) for
proofreading our manuscript.
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Keywords: Arabinogalactan • Total Synthesis • Carbohydrates •
Allergy Protection • Airway Inflammation
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Entry for the Table of Contents
Total synthesis of a pentasaccharide containing L-arabinose- and D-galactose was accomplished and covalently coupled to a carrier
protein to form a neoglycoconjugate that mimics partial structures of allergy-preventive arabinogalactan. Inhalative treatment of mice
with the neoglycoconjugate protects them against allergic inflammation by the induction of immune regulation involving antibodies and
interleukin-10.
7
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