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Carbohydrate Synthesis and Study of Carbohydrate-Lectin Interactions Using QCM Biosensors and Microarray Technologies
KTH, School of Chemical Science and Engineering (CHE), Chemistry.
2006 (English)Doctoral thesis, comprehensive summary (Other scientific)
Abstract [en]

Interactions between carbohydrates and proteins are increasingly being recognized as crucial in many biological processes, such as cellular adhesion and communication. In order to investigate the interactions of carbohydrates and proteins, the development of efficient analytic technologies, as well as novel strategies for the synthesis of carbohydrates, have to be explored. To date, several methods have been exploited to analyze interactions of carbohydrates and proteins, for example, biosensors, nuclear magnetic resonance (NMR); enzyme-linked immunosorbent assays (ELISA), X-ray crystallography and array technologies. This thesis describes the development of novel strategies for the synthesis of carbohydrates, as well as new efficient strategies to Quartz Crystal Microbalance- (QCM-) biosensors and carbohydrate microarrays technologies. These methodologies have been used to probe carbohydrate-lectin-interactions for a range of plant and animal lectins.

Place, publisher, year, edition, pages
Stockholm: KTH , 2006. , 106 p.
Series
Trita-IOK, ISSN 1100-7974 ; 2006:106
Keyword [en]
Lectins; Carbohydrates; Molecular recognition; Biosensors; Quartz crystal microbalance; Carbohydrate microarrays.
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-4177ISBN: 91-7178-503-5 (print)OAI: oai:DiVA.org:kth-4177DiVA: diva2:11091
Public defence
2006-12-01, D3, Lindstedtsvägen 5, Stockholm, 10:00
Opponent
Supervisors
Note
QC 20100915Available from: 2006-11-22 Created: 2006-11-22 Last updated: 2011-09-05Bibliographically approved
List of papers
1. Quartz crystal microbalance bioaffinity sensor for rapid identification of glycosyldisulfide lectin inhibitors from a dynamic combinatorial library
Open this publication in new window or tab >>Quartz crystal microbalance bioaffinity sensor for rapid identification of glycosyldisulfide lectin inhibitors from a dynamic combinatorial library
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2006 (English)In: Biosensors & bioelectronics, ISSN 0956-5663, E-ISSN 1873-4235, Vol. 22, no 1, 42-48 p.Article in journal (Refereed) Published
Abstract [en]

Carbohydrate-lectin,interactions were probed with dynamic combinatorial libraries, using the plant lectin Concanavalin A as target species. The dynamic combinatorial libraries were generated from a pool of thiol components through reversible thiol-disulfide interchange, and screened using a simple and efficient method based on a quartz crystal microbalance setup. It was found that dimers based on 1-thio- and 6-thin-mannose analogues were the most active inhibitors. Furthermore, the results clearly show that the 6-thio-mannose possess unique characteristics compared to its oxygen-containing counterpart.

Keyword
quartz crystal microbalance; dynamic combinatorial chemistry; glycochemistry; carbohydrates; lectins; molecular recognition
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-8269 (URN)10.1016/j.bios.2005.11.024 (DOI)000241040600006 ()2-s2.0-33746607715 (Scopus ID)
Note
QC 20100818Available from: 2008-04-25 Created: 2008-04-25 Last updated: 2017-12-14Bibliographically approved
2. Glycosyldisulfides from Dynamic Combinatorial Libraries as O-Glycoside Mimetics for Plant and Endogenous Lectins: Their Reactivities in Solid-Phase and Cell Assays and Conformational Analysis by Molecular Dynamics Simulations
Open this publication in new window or tab >>Glycosyldisulfides from Dynamic Combinatorial Libraries as O-Glycoside Mimetics for Plant and Endogenous Lectins: Their Reactivities in Solid-Phase and Cell Assays and Conformational Analysis by Molecular Dynamics Simulations
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2006 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, Vol. 14, 6314-6326 p.Article in journal (Refereed) Published
Abstract [en]

Dynamic combinatorial library design exploiting the thiol-disulfide exchange readily affords access to glycosyldisulfides. In order to reveal lectin-binding properties of this type of non-hydrolyzable sugar derivative, libraries originating from a mixture of common building blocks of natural glycans and thiocompounds were tested against three plant agglutinins with specificity to galactose, fucose or N-acetylgalactosamine, respectively, in a solid-phase assay. Extent of lectin binding to matrix-immobilized neoglycoprotein presenting the cognate sugar could be reduced, and evidence for dependence on type of carbohydrate was provided by dynamic deconvolution. Glycosyldisulfides also maintained activity in assays of increased physiological relevance, that is, using native tumor cells and also adding to the test panel an endogenous lectin (galectin-3) involved in tumor spread and cardiac dysfunction. N-Acetylgalactosamine was pinpointed as the most important building block of libraries for the human lectin and the digalactoside as most potent compound acting on the toxic mistletoe agglutinin which is closely related to the biohazard ricin. Because this glycosyldisulfide, which even surpasses lactose in inhibitory capacity, rivals thiodigalactoside as inhibitor, their degrees of intramolecular flexibility were comparatively analyzed by computational calculations. Molecular dynamics runs with explicit consideration of water molecules revealed a conspicuously high degree of potential for shape alterations by the disulfide's three-bond system at the interglycosidic linkage. The presented evidence defines glycosyldisulfides as biologically active ligands for lectins

Keyword
agglutinin, combinatorial chemistry, drug design, galectin, glycosyldisulfide, neoglycoprotein, dynamic chemistry
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-6387 (URN)10.1016/j.bmc.2006.05.045 (DOI)000240615300018 ()2-s2.0-33747134305 (Scopus ID)
Note
QC 20100915Available from: 2006-11-22 Created: 2006-11-22 Last updated: 2010-09-15Bibliographically approved
3. Stereospecific Ester Activation in Nitrite-Mediated Carbohydrate Epimerization
Open this publication in new window or tab >>Stereospecific Ester Activation in Nitrite-Mediated Carbohydrate Epimerization
2006 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 71, no 8, 3306-3309 p.Article in journal (Refereed) Published
Abstract [en]

The Lattrell-Dax method of nitrite-mediated substitution of carbohydrate triflates is an efficient method to generate structures of inverse configuration. In the present study, epimerization of gluco- and galactopyranoside derivatives to the corresponding allo- and gulopyranoside structures by triflation/nitrite treatment has been investigated. It was found that a neighboring ester group was essential for the reactivity of the nitrite-mediated triflate, inversion. Furthermore, a good inversion yield also depended on the relative configuration of the neighboring ester group to the triflate. Only with the ester group in the equatorial position, whatever the configuration of the triflate, did the reaction proceed smoothly, whereas a neighboring axial ester group proved largely inefficient. The results were subsequently used to predict the inversion of glucopyranoside derivatives to the mannopyranoside epimers.

Keyword
stereoselective-synthesis, glycosides, benzoate, anions, sugars
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-9883 (URN)10.1021/jo052662i (DOI)000236678100053 ()2-s2.0-33645773127 (Scopus ID)
Note
QC 20100709Available from: 2009-01-27 Created: 2009-01-27 Last updated: 2017-12-14Bibliographically approved
4. Solvent-dependent, kinetically controlled stereoselective synthesis of 3- and 4- thioglycosides
Open this publication in new window or tab >>Solvent-dependent, kinetically controlled stereoselective synthesis of 3- and 4- thioglycosides
2005 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 70, no 17, 6952-6955 p.Article in journal (Refereed) Published
Abstract [en]

Facile approaches to prepare 3- and 4-thioglycosides of the galacto, gulo, and gluco type from the parent triflates are presented. The dependencies of the solvent and the protecting group pattern, as well as the configuration of the neighboring and leaving groups, have been studied for these reactions. The results clearly show that the efficient stereo-selective synthesis of methyl 3-thin-galactoside depends highly on the solvent and the nucleophile concentration.

Keyword
Derivatives, Solvents, Stereochemistry, Synthesis (chemical)
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-6395 (URN)10.1021/jo050650r (DOI)000231183000054 ()2-s2.0-23644434820 (Scopus ID)
Note
QC 20100915Available from: 2006-11-22 Created: 2006-11-22 Last updated: 2017-12-14Bibliographically approved
5. Study of Real-time Lectin–Carbohydrate Interactions on the Surface of a Quartz Crystal Microbalance
Open this publication in new window or tab >>Study of Real-time Lectin–Carbohydrate Interactions on the Surface of a Quartz Crystal Microbalance
2005 (English)In: Biosensors & bioelectronics, ISSN 0956-5663, E-ISSN 1873-4235, Vol. 21, no 1, 60-66 p.Article in journal (Refereed) Published
Abstract [en]

A quartz crystal microbalance (QCM) biosensor system for lectin-carbohydrate interactions has been developed. Yeast mannan was immobilised on polystyrene-coated quartz crystals, and interactions tested with the lectin concanavalin A (Con A). The biosensor could be easily operated, where mannan immobilisation and all binding analyses were performed in real-time using a flow-through system. The apparent binding constant for yeast mannan to Con A was estimated to be 0.4 μM, well in accordance to reported literature values. In addition, the effective concentration values (EC50-values) for a series of mannose/mannoside ligands, acting as competitors to the mannan/Con A interaction, were determined to range from 0.18 to 5.3 mM, in good correlation with a related enzyme-labelled lectin assay (ELLA) protocol

Keyword
Carbohydrates, Glycochemistry, Lectins; Molecular recognition, Quartz crystal microbalance
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-6389 (URN)10.1016/j.bios.2004.10.006 (DOI)000232268900006 ()2-s2.0-20444439074 (Scopus ID)
Note
QC 20100915Available from: 2006-11-22 Created: 2006-11-22 Last updated: 2017-12-14Bibliographically approved
6. Redox-Responsive and Calcium-Dependent Switching of Glycosyldisulfide Interactions with Concanavalin A
Open this publication in new window or tab >>Redox-Responsive and Calcium-Dependent Switching of Glycosyldisulfide Interactions with Concanavalin A
2005 (English)In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 15, 2707-2710 p.Article in journal (Refereed) Published
Abstract [en]

Glycosyldisulfides can interact efficiently with carbohydrate-binding entities. This has been shown for a range of thiosaccharide dimers when tested for their effects against the lectin Concanavalin A using a modified quartz crystal microbalance-technique. Contrary to the thiosaccharide monomers, showing no significant binding up to 10 mM, several of the dimers showed IC50-values in the low millimolar range. Three of the glycosyldisulfides tested also displayed very high positive apparent cooperativity effects that were found to be both calcium-dependent and redox-responsive.

Keyword
dynamic chemistry, glycochemistry, molecular recognition, lectins, thiosaccharides, quartz crystal microbalance
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-6391 (URN)10.1016/j.bmcl.2005.04.024 (DOI)000229665600001 ()2-s2.0-19544365923 (Scopus ID)
Note
QC 20100915Available from: 2006-11-22 Created: 2006-11-22 Last updated: 2017-12-14Bibliographically approved
7. Photogenerated Carbohydrate Microarrays
Open this publication in new window or tab >>Photogenerated Carbohydrate Microarrays
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2007 (English)In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 8, no 2, 166-168 p.Article in journal (Refereed) Published
Abstract [en]

Chemical Equation Presented) Sugars in a row. A new strategy for carbohydrate microarrays based on photochemical ligation of perfluorophenylazide-derivatized carbohydrates to PEO surfaces is presented. It constitutes a controllable and robust method of array fabrication, on the carbohydrate chemistry and on the surface-chemistry levels, and the resulting carbohydrate arrays can be efficiently used to reveal the recognition patterns of carbohydrate-binding proteins.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2007
Keyword
carbohydrates, lectins, microarrays, photochemistry, surfaces
National Category
Inorganic Chemistry
Identifiers
urn:nbn:se:kth:diva-6392 (URN)10.1002/cbic.200600447 (DOI)000243810000003 ()17154195 (PubMedID)2-s2.0-33846914211 (Scopus ID)
Note

QC 20100915

Available from: 2006-11-22 Created: 2006-11-22 Last updated: 2017-12-14Bibliographically approved
8. Photoderivatized QCM Surfaces for the Study of Real-Time Lectin-Carbohydrate Interactions
Open this publication in new window or tab >>Photoderivatized QCM Surfaces for the Study of Real-Time Lectin-Carbohydrate Interactions
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(English)Article in journal (Refereed) Submitted
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-6393 (URN)
Note
QC 20100915Available from: 2006-11-22 Created: 2006-11-22 Last updated: 2010-09-15Bibliographically approved
9. Synthesis of Positional Thiol Analogs of β-D-Galactopyranose
Open this publication in new window or tab >>Synthesis of Positional Thiol Analogs of β-D-Galactopyranose
2007 (English)In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, Vol. 29, 4927-4934 p.Article in journal (Refereed) Published
Abstract [en]

Approaches toward the synthesis of thio- beta -D -galactose derivatives are described. These compounds were prepared from the parent carbohydrates: D-galactose, methyl P-D-galactoside and methyl P-D-glucoside, respectively. It was found that not only the strategies of protecting group introduction and selective deprotection, but also the choices of solvent and nucleophilic reagent concentration were crucial to allow the efficient introduction of sulfur at different positions of the galactose ring. The effects from the solvent, the nucleophilic reagent concentration, and the protecting group patterns have been investigated. The results clearly show that ester protecting groups play highly important roles for the synthesis of thio-containing carbohydrates, requiring nonpolar solvents to suppress the neighboring group participation. For the Lattrell-Dax (nitrite -mediated) inversion reaction, employed in the synthetic route to the 2-thio-beta-D-galactoside, intramolecular nucleophilic attack, as well as stronger stereospecific ester activation, are necessary to overcome hindrance from 4,6-O-benzylidene protection.

Keyword
thiosaccharides, galactose, lattrell-dax, inversion
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-9887 (URN)10.1002/ejoc.200700364 (DOI)000250367600015 ()2-s2.0-35349025393 (Scopus ID)
Note
QC 20100709. Tidigare titel: Synthesis of Thiogalactose derivatives for S-linked OligosaccharidesAvailable from: 2009-01-27 Created: 2009-01-27 Last updated: 2017-12-14Bibliographically approved

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