1,721,075 research outputs found
A bitter sweet symphony
Full text linkOratie uitgesproken door Prof.dr. Jeroen D.C. Codée bij de aanvaarding van het ambt van hoogleraar Organische Chemie aan de Universiteit Leiden op vrijdag 22 september 2023Oratie uitgesproken door Prof.dr. Jeroen D.C. Codée bij de aanvaarding van het ambt van hoogleraar Organische Chemie aan de Universiteit Leiden op vrijdag 22 september 2023Bio-organic Synthesi
Synthetic methods to glycerol teichoic acids
Full text linkSynthetic methods to glycerol teichoic acidsUBL - phd migration 201
Stereoelectronic and conformational effects in carbohydrate derived oxocarbenium, iminium and ammonium ions
Full text linkCarbohydrates or sugars, the most diverse class of biopolymers, are involved in many different biological processes. To be able to study these processes, well defined sugar structures are required. The synthesis of these sugar structures is at this moment far from ideal and therefore requires fundamental research, in particular towards the glycosylation reaction. In this reaction a positively charged oxocarbenium ion can be considered as the product forming intermediate, the cation is however commonly reasoned to lead to non-selective reactions and product mixtures. Chemical calculations on the oxocarbenium ion combined with model glycosylations proved the contrary, namely that these oxocarbenium ions are in fact selective. With these results, insight into the glycosylation mechanism is improved. The orientation of specific substituents on the sugar ring proved to have a profound influence on the stability of the oxocarbenium ion and thereby on the stereochemical outcome of glycosylations.UBL - phd migration 201
Design and synthesis of NLR and TLR based ligand-antigen conjugates
Full text linkThe mammalian immune system protects, amongst others, against invading pathogens and consists of an innate and adaptive component. The innate system is the first line of defense in which pattern recognition receptors, like TLR2, NOD1 and NOD2 receptors, detect pathogen associated molecular patterns (PAMPS) that are specific for pathogens. PAMPs exhibit a broad structural variety and the exact molecular structures of ligands that bind to the corresponding PRRs are mostly unknown. The research presented in this Thesis is directed to the design, synthesis and immunological evaluation of new NOD1, NOD2 and TLR2 ligands as well as conjugates in which these ligands are covalently bound to an antigenic OVA-derived peptide. The designed NLR and TLR ligand-antigen conjugates contribute to the insight of the processes of the mammalian immune system at molecular level. Further elucidation of pattern recognition receptor acti vation and antigen presentation with these conjugates may eventually result in synthetic vaccine modalities.UBL - phd migration 201
Protective group strategies in carbohydrate and peptide chemistry
Full text linkProtecting groups play a key role in the synthesis of complex natural products.This holds especially true for the synthesis of oligosaccharides, of which the monomeric carbohydrate building blocks usually contain up to five different hydroxyl functions. The discrimination of these hydroxyl functions requires a careful protecting group strategy and typically involves multistep protocols.This thesis describes the prepartion, installation, their use in the synthesis of stereoselective glycosidic bonds. Although protecting groups primarily function to mask a given functionality on the carbohydrate core, they also have a profound effect on the overall reactivity of a carbohydrate building block and can control the stereochemical outcome of a glycosylation reaction. Furthermore protecting groups can be used to introduce extra functionality on the carbohydrate core, such as visualization and/or purification handles. Fluorous solid phase extraction (FSPE) is an emerging tecnique, in which compounds are seperated on the basis of flourous content. The compound bearing fluorous tags which are difficult to purify by routine methods can easily be purified.Higher Education Commision of Pakistan (HEC) Leiden Institute of Chemistry (LIC)UBL - phd migration 201
Synthesis & biological applications of glycosylated iminosugars
Full text linkThe ongoing research in the field of lysosomal storage diseases (LSD), and more specific Gaucher disease is the basis for the research described in this thesis. The progress of Gaucher disease and the effect of therapeutic intervention is correlated to the level of chitotriosidase (CHIT1), the first identified human chitinase. Mea- surement of plasma CHIT1 activity in man is done by an assays using a fluorogenic substrate. The ability of CHIT1 to transglycosylate can complicate the enzyme assay, however umbelliferone 4__-deoxychitobioside is not prone to be transglycosylated. And gives a proportional fluorophore to active enzyme ratio read-out. Because of this umbelliferone 4__-deoxychitobioside has become a popular fluorogenic substrate for the measurement of human chitinases, an improved scalable route towards this compound is described in Chapter 2. Chapter 3 describes the synthesis and biological evaluation of three novel fluorogenic substrates, containing substituents of different sizes on the 4__-OH of the non-reducing sugar. The locally elevated activity of CHIT1 allows sitespecific drug delivery via the prodrug approach. Chapter 4 describes the design and synthesis of novel prodrugs in which a chitobiose core, the substrate for CHIT1, is coupled to known inhibitors of GCS which are able to restore the influx/efflux balance of GC in Gaucher cells. It is known that some iminosugars and N-alkylated derivatives thereof have a taste bitter. In Chapter 5 attempts are made to palliated this bitter taste by appending a galactosyl moiety to DNJ. Aside from potentially masking the bitter taste this modification will also help to direct the inhibitors to the colon were they will be processed by lactase. Cholesteryl-_-glucoside and cholesteryl-_ -glucoside, the synthesis of which is described in Chapter 6, will be used as as internal standards to get a better insight in the biosynthesis of the potentially neurotoxic steryl-glucosides, which are potentially linked to a high level of glycosylceramide. Chapter 7 summarizes the research described in chapters 2 to 6 and future prospects based on these results are presented.J.E. Jurriaanse StichtingUBL - phd migration 201
On the reactivity and selectivity of donor glycosides in glycochemistry and glycobiology
Full text linkThe processes of glycosidic bond formation and destruction are a central theme in glycochemistry and glycobiology, and form the basis of the research described in this Thesis. In the first part, studies towards the stereoselective construction of two complex bacterial oligosaccharide fragments are described. These fragments contain mannuronic acid residues connected through a beta-linkage, which is amongst the most challenging linkages to construct synthetically. In the second part, the use of mannuronic acid building blocks in the automated synthesis of alginates using solid-phase chemistry is presented. Using a second-generation carbohydrate synthesizer, alginate fragments up to 12 residues were assembled with high stereoselectivity. Using the same automated set-up, fragments of hyaluronic acid of up to 15 residues were synthesized. In the third part, 2-deoxy-2-fluoroglucosides are investigated as activity-based probes for glucocerebrosidase, a retaining beta-glucosidase enzyme.NWO, TI PharmaUBL - phd migration 201
Tools and reagents to study polysaccharide and glycolipid matabolism
Full text linkCarbohydrate processing enzymes are essential for a plethora of biological functions and processes. This thesis has focussed on the development of synthetic procedures for the synthesis of molecules that have the potential of being used for either the monitoring or modification of some of these processes. An effective synthesis of globotriaosylsphingosine has been developed. The stereoselective synthesis of an isotopically labeled D-erythro-sphingosine was then utilized for the formation of a labeled globotriaosylsphingosine, which was used as an internal standard in the monitoring of Fabry patients. Furthermore, a series of non-reducing end modified hyaluronan substrates bearing an anomeric fluorogenic leaving group was synthesized. These substrates were synthesized with the aim of being potential probes for the monitoring of the human hyaluronidase Hyal2. Finally, a new methodology was developed for a straightforward synthesis of sugar nucleotides. This methodology is well suited for the synthesis of modified sugar nucleotides, which can be utilized for the investigation of glycosyltransferases.B-BASICUBL - phd migration 201
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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