Molecular architecture with carbohydrate functionalized ss-peptides adopting 3helical conformation

Article abstract of DOI:10.3762/bjoc.10.93

Carbohydrate recognition is essential in cellular interactions and biological processes. It is characterized by structural diversity, multivalency and cooperative effects. To evaluate carbohydrate interaction and recognition, the structurally defined attachment of sugar units to a rigid template is highly desired. ss-Peptide helices offer conformationally stable templates for the linear presentation of sugar units in defined distances. The synthesis and ss-peptide incorporation of sugar-ss-amino acids are described providing the saccharide units as amino acid side chain. The respective sugar-ss-amino acids are accessible by Michael addition of ammonia to sugar units derivatized as a,ss-unsaturated esters. Three sugar units were incorporated in ss-peptide oligomers varying the sugar (glucose, galactose, xylose) and sugar protecting groups. The influence of sugar units and the configuration of sugar-ss-amino acids on ss-peptide secondary structure were investigated by CD spectroscopy.

Full text of DOI:10.3762/bjoc.10.93

Molecular architecture with carbohydrate
functionalized β-peptides adopting
314-helical conformation
Nitin J. Pawar1,2, Navdeep S. Sidhu3, George M. Sheldrick3,
Dilip D. Dhavale*2 and Ulf Diederichsen*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 948–955.
1Institute for Organic and Biomolecular Chemistry, Georg-August
University Göttingen, Tammannstrasse 2, D-37077 Göttingen,
Germany, 2Department of Chemistry, Garware Research Centre,
University of Pune, Pune 411 007, India and 3Institute for Inorganic
Chemistry, Georg-August University Göttingen, Tammannstraße 4,
D-37077 Göttingen, Germany
doi:10.3762/bjoc.10.93
Received: 28 December 2013
Accepted: 31 March 2014
Published: 28 April 2014
Associate Editor: S. Flitsch
Email:
Dilip D. Dhavale* - ddd@chem.unipune.ac.in; Ulf Diederichsen* -
udieder@gwdg.de
© 2014 Pawar et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
carbohydrate recognition; conformation; glycopeptide; β-peptide;
sugar amino acid
Abstract
Carbohydrate recognition is essential in cellular interactions and biological processes. It is characterized by structural diversity,
multivalency and cooperative effects. To evaluate carbohydrate interaction and recognition, the structurally defined attachment of
sugar units to a rigid template is highly desired. β-Peptide helices offer conformationally stable templates for the linear presentation
of sugar units in defined distances. The synthesis and β-peptide incorporation of sugar-β-amino acids are described providing the
saccharide units as amino acid side chain. The respective sugar-β-amino acids are accessible by Michael addition of ammonia to
sugar units derivatized as α,β-unsaturated esters. Three sugar units were incorporated in β-peptide oligomers varying the sugar
(glucose, galactose, xylose) and sugar protecting groups. The influence of sugar units and the configuration of sugar-β-amino acids
on β-peptide secondary structure were investigated by CD spectroscopy.
Introduction
Synthetic biomimetic macromolecules, which are capable to peptidomimetic foldamers wherein the presence of β-amino
fold into well-defined three-dimensional structures in analogy acids rendered them to adopt a variety of conformational stable
to natural peptides and proteins, have been extensively studied secondary structures, even with short peptide sequences [4-6].
to increase the understanding of complex biomolecules [1-3]. Amongst them the 314-helix is the most significant helical sec-
In this respect, β-peptides are especially of interest as ondary structure in β-peptides requiring three amino acids per
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turn and orienting every third side chain (i and i+3) on the same well-defined tetravalent mannose glycoconjugates on a cyclic
side of the helix [7-11]. β-Peptide helices are stable in water or peptide which show specific binding with concanavalin A [29].
organic solvents and are highly resistant towards enzymatic de- Further, the ternary type-II polyproline helix is used for the
gradation [12]. Furthermore, they provide sheet-like structures structurally defined presentation of sugar units [34], and simi-
and can be used for helical self-association towards protein-like larly the β-peptides provide a suitable conformationally
assemblies mimicking secondary structures and eventually constrained and well-defined scaffold for sugar presentation on
acting as inhibitors for protein–protein interaction [13,14]. In a 314-helix [18-20] as well as on a β-peptide 312-helical scaf-
addition, β-peptide 314-helices furnish an ideal structural back- fold obtained by oligomerization of glycosylated pyrrolidine
bone for the well-organized presentation of recognition units β-amino acids [35].
since incorporation of artificial β-amino acids allows posi-
tioning of side chains on one side of the helix in equidistant 5 Å Glycopeptide or glycoprotein synthesis is challenged by
intervals. This concept was proven to be beneficial for base-pair different conditions required for carbohydrate and peptide
recognition of β-peptide nucleic acids leading to high duplex chemistry. Therefore, sugar units are introduced by side-chain
stabilities of entropically preorganized recognition units [15- ligation and labeling strategies on the peptide scaffold or were
17]. Further, the presentation of a sugar unit on a β-peptide established by incorporation of sugar-β-amino acids by solid-
helical topology was reported by Arvidsson and coworkers phase peptide synthesis (SPPS) [36,37]. Sugar amino acid
[18,19]. One D-galactose unit is positioned on the helical building blocks have attracted interest due to their use as struc-
surface taking advantage of peptide folding for biomolecular tural elements as peptidomimetics [38,39], oligosaccharide
interaction with corresponding lectins. Taillefumier and mimetics [40,41] and induction of secondary structures [42-46].
coworkers link sugar units to β-peptide amino acid side chains Carbohydrate-derived β-amino acids used in this study were
by azide–alkyne cycloaddition [20].
obtained by conjugate addition (Michael addition) of ammonia
to a carbohydrate derived α,β-unsaturated ester [47-50].
Following the concept of highly organized presentation of sugar
units on a β-peptide scaffold, we report on simultaneous In the present article, a new class of C-linked β-glycopeptide
incorporation of various sugars (glucose, galactose, xylose) as scaffolds 1–8 (Figure 2) were synthesized and investigated with
sugar-β-amino acids in a 314-helix. Up to three sugar units were respect to secondary structures, along with the influence of
linearly aligned with 5 Å distance (Figure 1). This kind of sugar glycan modifications on peptide conformation [24,25], and the
organization will be of later relevance, e.g., in lectin binding potential of defined sugar presentation on a template. The
studies and with respect to the investigation of multivalency β-glycopeptides are synthetically accessible by incorporation of
effects [21-23].
sugar amino acids in β-peptide helical secondary structures,
whereas sugar-β-amino acids were derived from a continuation
of our efforts in synthesis of sugar-amino acids [51,52].
β3-Amino acids were used in SPPS in order to get a conforma-
tionally stable and well-defined β-peptide 14-helix. The helix
propensity is further improved by incorporation of the
constrained cyclic amino acid trans-(1R,2R)-2-aminocyclo-
hexanecarboxylic acid (ACHC) [53]. β-Homolysine was used to
assure the peptide solubility in aqueous solution. Therefore, the
β-peptide design provides incorporation of D-glucose, D-galac-
tose and D-xylose derived sugar-β-amino acids at every third
position (i and i+3). The remaining positions were filled with
β-homolysine and ACHC. For ease of synthesis, β-homo-
glycine amide was chosen as C-terminal amino acid. Further the
C-glycosidic attachment of the sugar units at the peptide back-
bone was varied with respect to the configuration. As evident
Figure 1: Sketch of right-handed β-peptide helix functionalized in
every third amino acid by carbohydrates presenting equidistant sugar
units with uniform orientation in 5 Å intervals.
The use of peptide scaffolds for the presentation of sugar from CD spectroscopy, out of eight β-glycopeptides 1–8
epitopes has already some precedence. Complex saccharide (Figure 2), the five β-glycopeptides 2–6 were shown to adopt a
structures are linked to α-peptides, protein fragments [24-27] 314-helix conformation, thereby organizing the D-glucose,
and recently also to glycofoldamers [28]. Sugars are arranged D-galactose or D-xylose carbohydrate epitopes on one face of
on cyclopeptides [29-33], like Dumy and coworkers report the helix.
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Beilstein J. Org. Chem. 2014, 10, 948–955.
Thus, preparation of the glucose derived β3-amino acid, the
corresponding starting material ethyl (methyl 2,3,4-tri-O-
benzyl-6,7-dideoxy-α-D-gluco-oct-6-enopyranoside)uronate
(9a) was prepared from D-glucose as reported earlier [54].
Conjugate addition of ammonia to the α,β-unsaturated ester 9a
afforded a mixture of L- and D-glycero sugar-β-amino esters
10a and 10b in a 1:3 diastereomeric ratio as indicated by
1H NMR spectroscopy (Scheme 1).
The C6-epimers 10a and 10b were separated by column chro-
matography and obtained in 22% and 66% yield, respectively.
The major isomer 10b was crystallized and based on X-ray
data, the 6R absolute configuration and the formation of the
D-glycero-isomer were confirmed (Figure 3). Therefore, the
minor isomer 10a was assigned the 6S absolute configuration.
The formation of major isomer 10b can be explained based on
the Felkin–Anh model. Thus, the ammonia nucleophile prefer-
entially attacks from the re-face as shown in TS 1 (Figure 4) to
give 10b [48,55].
In the next step, ester saponification of 10a using lithium
hydroxide afforded D-glucose derived β-amino acid 11a in 84%
yield. Finally, N-terminal fluorenylmethoxycarbonyl (Fmoc)
protection of the β-amino acid using Fmoc N-hydroxysuccin-
imidyl carbonate (Fmoc-OSu) under basic conditions gave
sugar β-amino acid Fmoc-L-glycero-glucose(Bn)-OH 12a in
81% yield (Scheme 1). The C6-epimer Fmoc-D-glycero-
glucose(Bn)-OH 12b was obtained by analogous procedures as
performed for 12a.
Figure 2: Synthesized β-glycopeptides 1–8.
Results and Discussion
Synthesis of carbohydrate-β3-amino acids
The synthesis of Fmoc-D-glycero-galactose-OH 12c was
carried out in analogy to the preparation of 12a (Scheme 2).
Key step for the synthesis of β3-sugar amino acids is the Thus, Michael addition of ammonia to D-galactose derived α,β-
Michael addition of ammonia to α,β-unsaturated esters [47-50]. unsaturated ester 9c [56] afforded 10c (L-glycero) as a single
Scheme 1: Synthesis of sugar-amino acid building blocks 12a and 12b.
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Beilstein J. Org. Chem. 2014, 10, 948–955.
fold Fmoc-L-glycero-galactose-OH 12c (Scheme 2). The xylose
derived N-Fmoc protected β-amino acid 1,2-O-isopropylidene-
3-O-benzyl-5-deoxy-5-(N-9-fluorenylmethoxycarbonylamino)-
β-L-ido-heptofuranuronic acid (Fmoc-L-ido-xylose-OH 12d)
was prepared following a literature protocol [49].
Synthesis of β-glycopeptides 1–8
Fmoc-protected sugar β-amino acids 12a–d were found to be
compatible with SPPS conditions. Therefore, the sugar units
were introduced in the β-peptide like regular amino acids using
a modified Fmoc SPPS protocol on mild acid sensitive Sieber
amide resin. Simultaneous tert-butyloxycarbonyl (Boc)-depro-
tection and cleavage of the β-glycopeptides from solid support
using 5% trifluoroacetic acid (TFA) in dry dichloromethane
provided β-glycopeptides D-glucose(Bn) 1 and 7,
D-galactose(acetonide) 3, and D-xylose(Bn, acetonide) 5 with
all sugar hydroxy groups still being protected (Figure 2).
Further, oligomers 1 and 7 were debenzylated using H2, 10%
Pd/C to β-glycopeptides 2 and 8, respectively. The acetonide
groups in the galactosyl and xylosyl sugar units were depro-
tected simultaneously along with the Boc-groups and cleavage
from solid support using TFA/water (4:1) [58] provided
D-galactose and D-xylose derived β-glycopeptides 4 and 6. The
structural integrity of β-peptides 1–8 was ensured by high reso-
lution ESI mass spectrometry.
Figure 3: ORTEP diagram of compound 10b.
Figure 4: Preferential re-attack according to the Felkin–Anh model
(TS 1) yielding 10b (left) and si-attack (TS 2) providing 10c (right).
Conformational studies: carbohydrate influ-
diastereomer in 91% yield that was identified by spectral data ence on helical content
identical to the reported [57]. Formation of compound 10c is in β-Peptides can be characterized by CD spectroscopy providing
accordance with the Felkin–Anh model. In case of compound a positive Cotton effect at 215 nm for right-handed β3-peptides
9c, the TS 2 (Figure 4) is favourable with the attack of ammonia with 314-helix conformation. The helical content correlates with
to the C=C double bond from the si-face affording compound the signal intensity and can be enhanced especially by ACHC
10c as the only product.
incorporation at positions i and i+3; it is hardly sensitive to pH
and ionic strength [59]. The CD spectra of the β-glycopeptides
Ester hydrolysis with lithium hydroxide followed by primary 1–8 were measured at pH 7 in triethylammonium acetate buffer
amine protection using Fmoc-OSu afforded the required scaf- at various temperatures (Figure 5). A strong positive Cotton
Scheme 2: Synthesis of the galactosyl β-amino acid building block 12c.
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Figure 5: CD spectra of β-glycopeptides 1–8 (c = 20 μM) in triethylammonium acetate buffer (5 mM, pH 7) at various temperatures.
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effect at 215 nm for β-glycopeptides 2–6 indicates a right- group and an anomeric acetal are structurally well tolerated. An
handed 314-helix conformation [4-6]. Even at 80 °C the helical additional perspective emerged from the unprotected β-glyco-
content drops only about 20–40% depending on the kind of peptides since the equilibrium between hemiacetal and open-
sugar units incorporated. Oligomers 1–6 all have in common the chain aldehyde form also does not interfere with the 314-helix
(S)-configuration for the β3-sugar side chains; this is in agree- secondary structure and allows further functionalization with
ment with the right-handed 314-helix and a positive Cotton saccharides, e.g., by reductive amination.
effect.
Supporting Information
Nevertheless, β3-peptide 1 seems to provide a different struc-
ture and helical sense indicated by a negative and shifted
Supporting Information File 1
(204 nm) Cotton signal. This is likely due to the triple benzyl
protection on the sugar units and the resulting high sterical
demand in combination with hydrophobicity [60]. A similar
effect was noticed for β3-peptide 7 that differs from oligomer 1
only in the β3-sugar side chain configuration. The deprotected
oligomer 8 having the (6R)-configuration of sugar-β-amino
acids is not structured as expected for β-peptides with mixed
β3-side chain configurations. Overall, there is a indication for
the influence of the benzyl groups in β3-peptides 1 and 7 on the
secondary structure.
Experimental section and copies of 1H and 13C NMR
spectra of compounds 10a, 10b, 11a, 11b, 11c, 12a, 12b
and 12c, HPLC traces of purified β-glycopeptides 1–8 as
well as crystallographic data of compound 10b.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-10-93-S1.pdf]
Acknowledgements
Generous support of the European Commission by an Erasmus
Mundus EXPERTS program (stipend for N.P.) is gratefully
acknowledged.
In addition to the influence of side chain configuration and ster-
ically demanding sugar protecting groups on the β-peptide
helical content, a difference between glucose and galactose
containing peptides 2 and 4 was noticed by an increase in signal
intensity in case of the galactose 4 substitution. For the galac-
tosyl β-peptides, the hemiacetal form of the sugar units might
be in equilibrium with the aldehyde form. The non-protected
sugar units 4 seem to adopt better to the 314-helix conformation.
Nevertheless, the galactosyl β-peptide 3 with 1,2-3,4-acetonide
protection also seems sterically not demanding compared to the
benzyl groups. Similarly, the five-membered xylose derivatives
5 and 6 fit nicely into the 314-helix structure and even the
benzyl and isopropylidene protecting groups do not affect the
β-peptide conformation.
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