Peptoids and polyamines going sweet: Modular synthesis of glycosylated peptoids and polyamines using click chemistry

Article abstract of DOI:10.3762/bjoc.9.7

Sugar moieties are present in a wide range of bioactive molecules. Thus, having versatile and fast methods for the decoration of biomimetic molecules with sugars is of fundamental importance. The glycosylation of peptoids and polyamines as examples of such biomimetic molecules is reported here. The method uses Cu-catalyzed azide alkyne cycloaddition to promote the reaction of azidosugars with either polyamines or peptoids. In addition, functionalized nucleic acids were attached to polyamines via the same route. Based on a modular solid-phase synthesis of peralkynylated peptoids with up to six alkyne groups, the latter were modified with azidosugar building blocks by using copper-catalyzed azide alkyne cycloadditions. In addition, the up-scaling of some particular azide-modified sugars is described.

Full text of DOI:10.3762/bjoc.9.7

Peptoids and polyamines going sweet:
Modular synthesis of glycosylated peptoids and
polyamines using click chemistry
Daniel Fürniss1, Timo Mack2, Frank Hahn2, Sidonie B. L. Vollrath1,
Katarzyna Koroniak1, Ute Schepers*3 and Stefan Bräse*1,3
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 56–63.
1Institute of Organic Chemistry, Karlsruhe Institute of Technology
doi:10.3762/bjoc.9.7
(KIT), Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany, 2Kekulé
Institute of Organic Chemistry and Biochemistry, Rheinische Friedrich
Wilhelms University of Bonn, Germany and 3Institute of Toxicology
and Genetics, Karlsruhe Institute of Technology (KIT),
Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen,
Germany
Received: 21 April 2012
Accepted: 10 December 2012
Published: 10 January 2013
This article is part of the Thematic Series "Synthesis in the
glycosciences II".
Email:
Ute Schepers* - ute.schepers@kit.edu; Stefan Bräse* -
braese@kit.edu
Guest Editor: T. K. Lindhorst
©
2013 Fürniss et al; licensee Beilstein-Institut.
*
Corresponding author
License and terms: see end of document.
Keywords:
click chemistry; glycans; peptoids; polyalkynes; polyamines;
solid-phase chemistry
Abstract
Sugar moieties are present in a wide range of bioactive molecules. Thus, having versatile and fast methods for the decoration of
biomimetic molecules with sugars is of fundamental importance. The glycosylation of peptoids and polyamines as examples of such
biomimetic molecules is reported here. The method uses Cu-catalyzed azide alkyne cycloaddition to promote the reaction of azido-
sugars with either polyamines or peptoids. In addition, functionalized nucleic acids were attached to polyamines via the same route.
Based on a modular solid-phase synthesis of peralkynylated peptoids with up to six alkyne groups, the latter were modified with
azidosugar building blocks by using copper-catalyzed azide alkyne cycloadditions. In addition, the up-scaling of some particular
azide-modified sugars is described.
Introduction
To date, oligosaccharides have gained more and more interest or a chemical coupling reaction that permits the selective and
as potential drugs in the treatment of a variety of diseases. simple formation of covalent adducts. Some modifications
However, the rendering of nucleic acids and oligosaccharides as permit the attachment to other molecules through a variety of
therapeutically active substances often requires a derivatization functional groups, such as amines (–NH2) and carboxylic acids
56

Beilstein J. Org. Chem. 2013, 9, 56–63.
(
–COOH) resulting in peptide bonds, thiols (–SH) resulting in mammalian cells [11]. They have also been shown to function
disulfides, thioethers or thioesters, aldehydes (–CHO) and in the recognition of biomacromolecules. Likewise, other poly-
hydroxy (–OH) groups. Nonetheless, coupling to these groups cationic species, such as the N-alkylated glycine oligomers
often requires a laborious protection of other reactive func- (peptoids) [14-25], have emerged as powerful tools in the
tional groups as they can compete in the coupling step. A context of drug delivery [26-29], peptidomimetics and other
matched pair of groups, which are selective in reacting with biologically relevant applications [28,30-32] as well as ma-
each other while being unreactive with other functional groups terials science [33,34].
in the molecule would, therefore, be highly useful in the prepar-
ation of functional structures. Likewise, the coupling reaction During the last decade the synthesis of polyamines and peptoids
should be permitted in hydrophilic solvents such as water or has been well established on solid phases [26,27,29,35-39].
DMSO, since both unprotected nucleic acids and oligo- However, the on-bead addition of oligosaccharide or monosac-
saccharides, as well as many other biomacromolecules, prefer a charide modifications are not known so far. The modification of
hydrophilic reaction environment.
polyamines or peptoids is usually achieved by alternation of the
termini [36,40] or by direct use of different side-chain function-
With the advent of mild and biocompatible conjugation alities. For peptoids, CuAAC has already been used success-
methods such as the Staudinger ligation [1] or the copper- fully to introduce diverse side-chain functionalities directly
catalyzed alkyne azide cycloaddition (CuAAC) [2,3], a large during solid-phase synthesis of peptoids starting from both,
number of versatile and functional bioconjugates are accessible azido- and alkyne-functionalized side chains [41,42]. In addi-
for various applications in chemical biology [4].
tion CuAAC has also been used in order to constrain peptoid
secondary structures [43].
To date, many therapeutically active molecules are synthetic
derivatives of biomacromolecules that have to be soluble in CuAAC reactions for the attachment of sugar residues to
hydrophilic environments to be taken up in vivo or in cell cul- peptoid backbones have been reported for some cases [44,45];
ture. Common solubilizers that enhance the cellular uptake are however, a fully glycosylated structure is unknown (for glyco-
polyamines and other polycationic moieties such as particular dendrons see [46]). In this study, we describe the first solid-
peptoids.
phase synthesis of glycosylated polyamines and a fully glyco-
sylated hexapeptoid.
Recently, polycationic polyamines have been shown to be effi-
cacious in the cellular delivery of oligonucleotides such as
Results and Discussion
DNA [5-7] and RNA [8-11]. Conjugates of polyamines with ali- Synthesis of azidosugars
phatic lipids or cholesterol yielding, i.e., dioctadecylamino- Although the syntheses of the azidosugars 1–3 and 5 (Figure 1)
glycylspermine (DOGS, transfectam) are well established were described before [47], we optimized and revised the proce-
reagents for the transfection of DNA and oligonucleotides dure reported by Laughlin and Bertozzi [48] due to some diffi-
[
5-7,11-13] displaying only very little toxicity towards culties in obtaining reproducible results.
Figure 1: Azidosugars used in this study. The synthesis of the azidosugars 1–3 was modified from [47,48], compounds 4, 6 and 7 were commercially
available.
57

Beilstein J. Org. Chem. 2013, 9, 56–63.
Instead of 5.00 equiv of chloroacetic anhydride only 1.10 equiv the solid support. To avoid a degradation of the coupled
were used. A change from LiN3 to NaN3, which is more stable biomacromolecules at high concentrations of strong acids, a
and cheaper, in conjunction with lowering the amount of the polystyrene resin was chosen that contains a tritylchloride
azide salt from 5.00 equiv to less than 3.60 equiv gave similar linker. The resin was obtained by treatment of Merrifield resin
results. The solvent was changed from DMF to MeOH. By with p-hydroxytriphenylmethyl alcohol and subsequent chlori-
applying revised conditions 55% yield (on a 4.64 mmol scale) nation [49,50]. This tritylchloride linker allowed a mild
was obtained with a comparable yield on a 1.16 mmol scale cleavage of the acid labile products using less than 0.5% tri-
(
61%). In contrast to the originally reported procedure, the fluoroacetic acid (TFA) in dichloromethane. The loading of the
purification and isolation of intermediates could be omitted. We Merrifield resin occurred in pretty good yields as the ratio of the
tried to use fewer equivalents of sodium azide during the scale- measured to the calculated loading value was 0.70 mmol/g to
up of the reaction but this caused a decrease of the overall reac- 0.78 mmol/g (Scheme 1).
tion yields.
The synthesis started with the assembly of the 2-nitrobenzene-
In all cases, the test reactions were performed starting from sulfonyl-(Nosyl, further abbreviated with Ns)-protected sper-
D-glucosamine hydrochloride as a model compound for the mine backbone 8 on a solid phase via Fukuyama Ns strategy
synthesis of 1,3,4,6-tetra-O-acetyl-N-azidoacetyl-D- [51]. The next step was the Ns protection of the residual prima-
glucosamine (Ac4GlcNAz = 1). Optimal variations from ry amine with 6.00 equiv of Ns-chloride and 12.0 equiv 2,4,6-
Bertozzi’s protocol for this model compound were the use of collidine in CH2Cl2 followed by N-alkylation with
1
3
.10 equiv chloroacetic anhydride in the first step and 5-chloropent-1-yne to insert the terminal alkyne moiety. To
.50 equiv sodium azide as well as methanol in the second step accomplish that, we used 10.0 equiv of alkyne and 15.0 equiv of
(
for further details, see Table 1). Eventually, we applied these K2CO3 in DMF; the reaction led to resin 9 with virtually quanti-
optimized reaction conditions to synthesize also 1,3,4,6-tetra-O- tative yield, as shown in Scheme 1. For the CuAAC with the
acetyl-N-azidoacetyl-D-galactosamine (Ac4GalNAz = 2) and azides moieties 4, 6 and 7, respectively, we used 0.500 equiv of
1
,3,4,6-tetra-O-acetyl-N-azidoacetyl-D-mannosamine CuSO4·5H2O and 5.00 equiv sodium ascorbate as the catalytic
(
Ac4ManNAz = 3) with similar yields under these optimized system, which is a slightly higher catalyst concentration than
conditions (see Supporting Information File 1).
reported for the reaction in solution [52]. To ensure, that the
reaction proceeds completely we chose 2 days of agitation at
ambient temperature and obtained resin 10−12.
Click reaction on alkynylated polyamines and
peptoids
The covalent coupling of many biomacromolecules to solid- Finally, the Ns deprotection was achieved in 18 h with
phase-bound polycationic moieties, such as polyamines or 20.0 equiv of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and
peptoids, often requires a hydrophilic reaction environment as 20.0 equiv of β-mercaptoethanol. The cleavage from the resin
well as very mild cleaving conditions of the final product from was carried out with 1% TFA in dichloromethane at 10 min
Table 1: Optimization of the synthesis of azide 1.
Entry
Reaction scale
Solvent (2nd step)
MN3
Overall reaction yield (over 3 steps)
1
2
3
4
5
6
1.16 mmol
4.64 mmol
4.64 mmol
4.64 mmol
13.4 mmol
23.2 mmol
DMF
5.00 equiv (M = Li)
5.00 equiv (M = Na)
2.10 equiv (M = Na)
3.50 equiv (M = Na)
2.10 equiv (M = Na)
2.00 equiv (M = Na)
61%
23%
35%
55%
38%
42%
DMF
MeOH
MeOH
MeOH
MeOH
58

Beilstein J. Org. Chem. 2013, 9, 56–63.
Scheme 1: Reaction conditions and reagents: (a) Ns-chloride (6.00 equiv), 2,4,6-collidine (12.0 equiv), CH2Cl2, rt, 16 h; (b) 5-chloropent-1-yne
(10.0 equiv), K2CO3 (15.0 equiv), DMF, 60 °C, 16 h; (c) azidosugars 6, 7 or AZT (4) (2.00 equiv/1.86 equiv), CuSO4·5H2O (0.500 equiv), sodium
ascorbate (5.00 equiv), DMF/H2O (6:1), rt, 2 d; (d) DBU (20.0 equiv), β-mercaptoethanol (20.0 equiv), DMF, rt, 18 h; (e) 1% TFA in CH2Cl2, rt, 10 min.
residence time. The products 13–15 were obtained with >90% As a model compound we started with the synthesis of a
yield, calculated on the initial loading of the resin hexaglycosylated peptoid hexamer. Therefore, we synthesized a
(
0.70 mmol/g). The 1H NMR data clearly showed the aromatic hexaalkynated peptoid structure 26,27 on resin (Scheme 3).
shift of the triazole proton at 8.02 ppm, 8.03 ppm and 7.94 ppm
for 13–15, respectively. The 13C NMR spectra indicated the The synthesis of a hexaalkynated peptoid backbone 26,27 was
presence of the anomeric carbon atoms at 89.70 ppm for 13 as carried out on Rink or Barlos resin containing a 2-chlorotrityl
well as at 89.41 ppm and 105.47 ppm for 14.
chloride linker by standard methods using the submonomer
strategy [14]. By using this method, the peptoid backbone is
In a different approach, we synthesized glycosylated spermine assembled in two subsequently repeated steps: In the first step
derivatives by our optimized procedure on a 2-chlorotrityl chlo- (acylation), bromoacetic acid is reacted with the resin, and in
ride resin [35,37-39]. The reaction of the resin 16 and 17 with the second step (amination) a primary amine is used to substi-
the Ac4GlcNAz derivative 1 proceeded smoothly in the pres- tute the bromine to give the peptoid residue. This approach
ence of copper ions. In some cases, changing the base from avoids the use of N-terminally protected monomers, which have
DIPEA to DBU was beneficial (Scheme 2).
to be synthesized in advance.
After these encouraging results, we turned our attention to For the incorporation of the alkyne side chains we chose propar-
peptoids. For the glycosylation of peptoids, we envisaged the gylamine as building block. A sixfold repetitive coupling
generation of a fully glycosylated peptoid in order to investi- sequence resulted in the peptoids, which were further modified
gate the compatibility of peptoid synthesis and decoration with with rhodamine B (Rho-CO2H) as an easily accessible and
sugars.
versatile fluorescent tag.
59

Beilstein J. Org. Chem. 2013, 9, 56–63.
Scheme 2: Synthesis of spermine conjugates 20,21 and 24,25. 2-chlorotrityl chloride resin was used as a solid support.
Scheme 3: Synthesis of hexaalkynyl peptoids 26 and 27 on solid supports.
60

Beilstein J. Org. Chem. 2013, 9, 56–63.
Rhodamine B was coupled to the N-terminus in order to provide carried out by using Cu(CH3CN)4PF6 in THF with 2,6-lutidine
a label for future biological applications, such as the study of as base. Only 1.60 equiv of the azidosugar were necessary to
the cellular uptake. For both resins, the peptoid synthesis was achieve full conversion after 18 h, and no shorter oligomers
successful; the only differences are the functional groups on the were observed in the MALDI–TOF spectrum. Cleavage from
C-terminus. After cleavage from Rink-amide resin with tri- the resin by treatment with 33% hexafluoroisopropanol (HFIP)
fluoroacetic acid, an amide is obtained, whereas cleavage from in dichloromethane and subsequent HPLC purification resulted
2
-chlorotrityl chloride resin with hexafluoroisopropanol (HFIP) in the fully glycosylated hexameric product 28 (Scheme 4).
gives the carboxylic acid. The mild cleavage conditions of the
-chlorotrityl linker did not harm the sugar moieties of the final Conclusion
glycosylated compound, and this linker was therefore favored In conclusion, we were able to improve protocols for the syn-
2
over the Rink linker.
thesis of tetra-O-acetyl protected sugars. Applying this, better
yields as well as upscaling was possible. With these sugar
For the conjugation of Ac4GalNAz (2), the same conditions building blocks, functionalization of polyamine derivatives was
were used as described for the spermine conjugation possible directly on solid supports by using copper-catalyzed
(
Scheme 2) with minor modifications. The CuAAC was alkyne azide cycloaddition conditions. In addition to that, the
Scheme 4: Synthesis of a hexa-glycosylated peptoid 28.
61

Beilstein J. Org. Chem. 2013, 9, 56–63.
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