Schistosomiasis is an acute and chronic disease caused by blood dwelling parasitic trematodes of the genus Schistosoma, and it is classified as the second most socioeconomically devastating... Show moreSchistosomiasis is an acute and chronic disease caused by blood dwelling parasitic trematodes of the genus Schistosoma, and it is classified as the second most socioeconomically devastating parasitic disease, second only to malaria. Currently the wormload is determined by the Kato-Katz method, which is not always reliable. In order to prepare diagnostic tools able to capture specific anti-carbohydrate antibodies or develop conjugate vaccines targeting these carbohydrate structures, sufficient amounts of well-defined fragments are needed. This thesis describes the synthesis of several glycans of these glycans present on the S. mansoni parasite, focusing mainly on the Circulating Anodic Antigen (CAA) and glycans bearing the unique α-(1-2)-L-Fucose-α-(1-2)-L-Fucose motifs. These glycans have been attached to gold nanoparticles and these particles were screened against several monoclonal antibodies and sera of individuals suffering from schistosomiasis. Show less
This Thesis focuses on the design and synthesis of ADP-ribosylated compounds that can be applied in biological studies.The limitations of the contemporary methods of chemical ADP-ribosylation and a... Show moreThis Thesis focuses on the design and synthesis of ADP-ribosylated compounds that can be applied in biological studies.The limitations of the contemporary methods of chemical ADP-ribosylation and a relative scarcity of the well-defined synthetic ADP-ribosylated derivative was an incentive to undertake synthetic studies to further advance the methodologies in the bioorganic chemistry of ADP-ribosylated molecules. This Thesis aims specifically at the developing of new and improved synthetic methodologies and to synthesize advanced mono- or oligo-ADP-ribosylated biomolecules. The target compounds that are described in this Thesis are not only represent a synthetic challenge but also have great value in biology for a better understanding of ADP-ribosylation. Show less
Wang, L.; Overkleeft, H.S.; Marel, G.A. van der; Codee, J.D.C. 2019
Pre‐activation based glycosylations have become a very powerful tool in the assembly of oligosaccharides and the use of nucleophilic additives allows for the in situ generation of reactive... Show morePre‐activation based glycosylations have become a very powerful tool in the assembly of oligosaccharides and the use of nucleophilic additives allows for the in situ generation of reactive intermediates with tailored reactivity. We here use a glycosylation strategy that is based on the use of per‐benzylated imidate building blocks for the fully stereoselective construction of a spacer equipped Aspergillus fumigatus α‐1,3‐octaglucan. We have used the trimethylsilyl iodide (TMSI)‐triphenylphosphine oxide (Ph3P=O) for the stereoselective installation of an azidopropanol spacer and triflic acid (TfOH)‐dimethyl formamide (DMF) enabled glycosylations for the coupling reactions with the secondary glucosyl C‐3‐alcohols. An operationally simple in situ activation coupling procedure is introduced and used for the final glycosylation events towards the octasaccharide. Show less
The post-translational modification of proteins known as adenosine diphosphate ribosylation (ADPr) is involved in a wide variety of important biological processes and is also associated with... Show moreThe post-translational modification of proteins known as adenosine diphosphate ribosylation (ADPr) is involved in a wide variety of important biological processes and is also associated with carcinogenesis and the process of aging. Therefore, a better understanding of the biology of ADP-ribosylation is crucial for the development of novel therapeutics. To facilitate this research, the availability of well-defined fragments of mono- and poly-ADP-ribose is essential. This Thesis describes the development of new synthetic methodologies to achieve this and the successful synthesis of well-defined ADP-ribosylated biomolecules. Show less
The glycosylation, the reaction which forms a bond between sugar molecules (the donor and the acceptor), is the central reaction in carbohydrate chemistry. Despite tremendous advances in... Show more The glycosylation, the reaction which forms a bond between sugar molecules (the donor and the acceptor), is the central reaction in carbohydrate chemistry. Despite tremendous advances in the past decades, however, the glycosylation reaction remains relatively poorly understood. Especially the formation of 1,2-cis glycosidic linkages remains a significant challenge. This thesis describes an investigation of the influence of reactivity and selectivity of several classes of carbohydrate donors and –acceptors on the selectivity in glycosylation reactions. Special emphasis was placed on the influence of protecting groups on the donor, and nucleophilicity of the acceptor, two major factors that play a tremendous role in the outcome of a glycosylation reaction. The obtained knowledge has been applied in the synthesis of complex carbohydrate molecules, native to pathogens such as Staphylococcus aureus, of which antibiotic-resistant forms such as MRSA present significant danger in hospitals, and the parasite Schistosoma mansoni, causative agent of the neglected tropical disease schistosomiasis. The synthesis of these molecules can play a part in the development of vaccines targeted against these pathogens. Show less
Volbeda, A.G.; Reintjens, N.R.M.; Overkleeft, H.S.; Marel, G.A. van der; Codée, J.D.C. 2016
This thesis describes the development and application of different methods for the construction of 1,2-cis glycosidic bonds, which remains one of the most challenging aspects in synthetic... Show moreThis thesis describes the development and application of different methods for the construction of 1,2-cis glycosidic bonds, which remains one of the most challenging aspects in synthetic carbohydrate chemistry. In Chapter 2 a synthesis of an orthogonally protected 2-acetamido-4-amino-2,4,6-trideoxy-D-galactose (AAT) building block starting from D-glucosamine is outlined. Chapter 3 describes a modular approach towards the synthesis of all possible trimer repeating units of the type 1 capsular polysaccharide of Streptococcus pneumonia, Sp1. The difficulty associated with the efficient stereoselective introduction of _-galacturonic acid bonds was overcome by employing galacturonic acid-[3,6]-lactone building blocks. Chapter 4 describes a study of the reactivity and stereoselectivity of a galacturonic acid-3,6-lactone thioglycosyl donor in comparison with protected galacturonic acid and galactose donors using a series of competition experiments and condensation reactions with different thiophilic activator systems. Chapter 5a describes the application of a panel of C-6 thioether mannosyl donors, a C-6-selenoether donor and a C-6-iodide N-phenyltrifluoroacetimidate mannosyl donor in a series of condensation reactions. The applicability of one of these 1,2-cis-mannosylating agents is the subject of Chapter 5b. Upon condensation of 6-thio-6-deoxy-mannosyl donors reductive removal of the 6-thio functionality provides 1,2-cis rhamnosides. Following this methodology a backbone tetrasaccharide containing alternating _- and _-D-rhamnosides was synthesized. Show less
Carbohydrate 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... Show moreCarbohydrate 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. Show less
