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Synthesis of Orthogonally Functionalized Oligosaccharides for Self-assembled Monolayers and as Multimodal Tools in Chemical Biology
Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis covers different topics in the field of synthetic organic chemistry combined with the field of surface science and glycobiology.

First, the text presents a series of orthogonally protected oligosaccharides (tri-, penta-, and heptasaccharides) of varying length and structures, which are synthesized with the aim of developing novel heterobifunctional biocompatible cross-linkers. Successful conjugation with different chemical handles is also described and used to illustrate the potential implementation of defined carbohydrate based compounds have potential use in biosensing applications. The results of incubation experiments using living cells indicate that the linker is incorporated into cell surfaces and enriched in microdomains.

Second, synthesis of various saccharide-terminated alkane thiols immobilized on gold surfaces is reported. The protein adsorption and antifouling characteristics of these surfaces were investigated using model proteins and the common fouling organisms, Ulva linza and Balanus amphitrite.

Further, oligo(lactose)-based thiols (di-, tetra-, and hexasaccharides) were synthesized and immobilized on gold nanoparticles to investigate how well these rigid, rod-like oligosaccharides can stabilize such nanoparticles for future use in constructing hybrid nanoparticles.

Finally, the thesis describes synthesis of a systematic series of oligo(ethylene) glycols possessing either hydrogen- or methyl-terminated groups. Investigation of the fundamental characteristics of self-assembled monolayers, will give important insights into the design of protein repellant surfaces.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2012. , 65 p.
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1442
Keyword [en]
Oligosaccharide synthesis, glycosylation, thioglycosides, orthogonally protected, oligo(lactosides), spacer molecule, heterobifunctional, surface plasmon resonance, lipid anchor, self-assembled monolayers, glyconanoparticles
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:liu:diva-76733ISBN: 978-91-7519-906-1 (print)OAI: oai:DiVA.org:liu-76733DiVA: diva2:516513
Public defence
2012-05-11, Planck, Fysikhuset, Campus Valla, Linköpings universitet, Linköping, 10:15 (English)
Opponent
Supervisors
Available from: 2012-04-18 Created: 2012-04-18 Last updated: 2017-01-11Bibliographically approved
List of papers
1. Synthesis of tri-, penta-, and hepta-saccharides, functionalized with Orthogonally N-Protected Amino residues at the reducing and non-reducing ends
Open this publication in new window or tab >>Synthesis of tri-, penta-, and hepta-saccharides, functionalized with Orthogonally N-Protected Amino residues at the reducing and non-reducing ends
2012 (English)In: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 68, no 33, 6712-6720 p.Article in journal (Refereed) Published
Abstract [en]

The synthesis of four bifunctionalized orthogonally N-protected oligosaccharides derived from lactose and mannose, intended as cross-linking derivatives, is described. The amino sugar at the non-reducing end is derivatized with an N-Boc-protected glycine moiety, and further connected to either a mannose (1→6) disaccharide or (1→3) lactose units (one, two or three) resulting in tri-, penta-, or heptasaccharides. All of the synthesized oligosaccharides have an Nbenzyloxycarbonyl-aminoethyl residue at the reducing end. The fully orthogonal N-Boc/N-Cbz protection group pattern enables further conjugation/derivatization and results in a hydrophilic cross-linking molecule. It was found that the order of the final synthetic steps were crucial to avoid acyl migration. A suitable amide coupling protocol has been applied to introduce the NBoc-protected glycine moiety in alcoholic solvent. The synthesized oligosaccharides will provide a model system to investigate the influence of length, structure and flexibility. The function of the cross-linked substituents thereby provide valuable insights into the role as a spacer molecule.

Keyword
Glycosylation, glycosidation, oligosaccharide synthesis, spacer molecules, orthogonally protected, carbohydrates, bifunctionalized
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-76730 (URN)10.1016/j.tet.2012.05.118 (DOI)000306618400009 ()
Available from: 2012-04-18 Created: 2012-04-18 Last updated: 2017-12-07Bibliographically approved
2. Derivatization of a bioorthogonal protected trisaccharide linker: towards multimodal tools for chemical biology
Open this publication in new window or tab >>Derivatization of a bioorthogonal protected trisaccharide linker: towards multimodal tools for chemical biology
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2012 (English)In: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 23, no 6, 1333-1340 p.Article in journal (Refereed) Published
Abstract [en]

When cross-linking biomolecules to surfaces or to other biomolecules, the use of appropriate spacer molecules is of great importance. Mimicking the naturally occurring spacer molecules will give further insight into their role and function, possibly unveil important issues regarding the importance of the specificity of carbohydrate-based anchor moieties, in e.g., glycoproteins and glycosylphosphatidylinositols. Herein, we present the synthesis of a lactoside-based trisaccharide, potentially suitable as a heterobifunctional bioorthogonal linker molecule whereon valuable chemical handles have been conjugated. An amino-derivative having thiol functionality shows promise as novel SPR-surfaces. Furthermore, the trisaccharide has been conjugated to a cholesterol moiety in combination with a fluorophore which successfully assemble on the cell surface in lipid microdomains, possibly lipid-rafts. Finally, a CuI-catalyzed azide-alkyne cycloaddition reaction (CuAAC) confirms the potential use of oligosaccharides as bioorthogonal linkers in chemical biology.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2012
Keyword
spacer molecule, oligosaccharide-based, cholesterol anchor, SPR, lipid rafts, click-chemistry
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-76735 (URN)10.1021/bc300160a (DOI)000305358700027 ()
Available from: 2012-04-18 Created: 2012-04-18 Last updated: 2017-12-07
3. Saccharide-Functionalized Alkanethiols for Fouling-Resistant Self-Assembled Monolayers: Synthesis, Monolayer Properties, and Antifouling Behavior
Open this publication in new window or tab >>Saccharide-Functionalized Alkanethiols for Fouling-Resistant Self-Assembled Monolayers: Synthesis, Monolayer Properties, and Antifouling Behavior
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2011 (English)In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 27, no 24, 15034-15047 p.Article in journal (Refereed) Published
Abstract [en]

We describe the synthesis of a series of mono-, di-, and trisaccharide-functionalized alkanethiols as well as the formation of fouling-resistant self-assembled monolayers (SAMs) from these. The SAls,,Is were characterized using ellipsometry, wetting measurements, and infrared reflection absorption spectroscopy (WAS). We show that the structure of the carbohydrate moiety affects the packing density and that this also alters the alkane chain organization. Upon increasing the size of the sugar moieties (from mono- to di- and trisaccharides), the structural qualities of the monolayers deteriorated with increasing disorder, and for the trisaccharide, slow reorganization dynamics in response to changes in the environmental polarity were observed. The antifouling properties of these SAMs were investigated through protein adsorption experiments from buffer solutions as well as settlement (attachment) tests using two common marine fouling species, zoospores of the green macroalga Ulva linza and cypris larvae of the barnacle Balanus amphitrite. The SAMs showed overall good resistance to fouling by both the proteins and the tested marine organisms. To improve the packing density of the SAMs with bulky headgroups, we employed mixed SAMs where the saccharide-thiols are diluted with a filler molecule having a small 2-hydroxyethyl headgroup. This method also provides a means by which the steric availability of sugar moieties can be varied, which is of interest for specific interaction studies with surface-bound sugars. The results of the surface dilution study and the low nonspecific adsorption onto the SAMs both indicate the feasibility of this approach.

Place, publisher, year, edition, pages
American Chemical Society, 2011
National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-75120 (URN)10.1021/la202774e (DOI)000298118500040 ()
Note

Funding Agencies|AMBIO|NMP-CT-2005-011827|European Commission||

Available from: 2012-02-21 Created: 2012-02-17 Last updated: 2017-05-31Bibliographically approved
4. Synthesis of oligo(lactose)-based thiols and their self-assembly onto gold surfaces
Open this publication in new window or tab >>Synthesis of oligo(lactose)-based thiols and their self-assembly onto gold surfaces
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2013 (English)In: Colloids and Surfaces B: Biointerfaces, ISSN 0927-7765, E-ISSN 1873-4367, Vol. 105, 187-193 p.Article in journal (Refereed) Published
Abstract [en]

The ability to produce monomolecular coatings with well-defined structural and functional properties is of key importance in biosensing, drug delivery, and many recently developed applications of nanotechnology. Organic chemistry has proven to be a powerful tool to achieve this in many research areas. Herein, we present the synthesis of three oligo(lactosides) glycosylated in a (1 → 3) manner, and which are further functionalized with amide-linked short alkanethiol spacers. The oligosaccharides (di-, tetra-, and hexasaccharide) originate from the inexpensive and readily available lactose disaccharide. These thiolated derivatives were immobilized onto gold surfaces, and the thus formed self-assembled monolayers (SAMs) on planar gold were characterized by wettability, ellipsometry and infrared reflection–absorption spectroscopy. Further, the ability of these SAMs to stabilize gold nanoparticles in saline solutions was also demonstrated, indicating that the oligosaccharides may be used as stabilizing agents in gold nanoparticle-based assays.

Place, publisher, year, edition, pages
Elsevier, 2013
Keyword
Oligosaccharides, Lactose, Self-assembled monolayers, Gold nanoparticles
National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-92697 (URN)10.1016/j.colsurfb.2013.01.002 (DOI)000316589500027 ()
Note

The previous status of this article was Manuscript.

Available from: 2013-05-16 Created: 2013-05-16 Last updated: 2017-05-31Bibliographically approved
5. Spectroscopic Characterization and Modeling of Methyl- and Hydrogen-Terminated Oligo (ethylene glycol) Self-Assembled Monolayers
Open this publication in new window or tab >>Spectroscopic Characterization and Modeling of Methyl- and Hydrogen-Terminated Oligo (ethylene glycol) Self-Assembled Monolayers
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2012 (English)In: The Journal of Physical Chemistry C, ISSN 1932-7447, E-ISSN 1932-7455, Vol. 116, no 22, 12008-12016 p.Article in journal (Refereed) Published
Abstract [en]

Two series of oligo (ethylene glycol) (OEG) thiol compounds HS-(CH2CH2O)nR with R = CH3, H and n = 5, 6, 7, have been synthesized and used to form self-assembled monolayers (SAMs) on gold. The data from null ellipsometry, infrared reflection-absorption spectroscopy and ab initio calculations of this type of OH- and CH3-terminated OEG SAMs are used to examine the rarely addressed in-SAM orientation of oligo (ethylene glycols) and to provide detailed assignments of infrared bands in the fingerprint and CH-stretching regions. Based on these results, a new spectral band has been observed at 2947 cm-1 and identified by the firstprinciple calculations as localized vibrations that are specific for hydrogen-terminated OEG thiolate SAMs. This band can be used as an indicator of a high crystalline like ordering. It is further more stressed that theory agrees with the experimentally obtained CH-stretching spectra remarkably well if, and only if, the OEG helix axis within studied SAMs is tilted by about 20o with respect to the surface normal.

Keyword
Oligo(ethylene glycol) self-assembled monolayers, infrared reflection absorption spectroscopy, first-principle calculations
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-77052 (URN)10.1021/jp212400z (DOI)000304888700021 ()
Available from: 2012-05-03 Created: 2012-05-03 Last updated: 2017-12-07Bibliographically approved

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