139 research outputs found
The synthesis of mannose-derived bioconjugates and enzyme inhibitors
No full textBioconjugates are involved in many biological processes. Glycoconjugates can bind to lectin receptors based on their specific carbohydrate structure. The mannose receptor, a C-type lectin, makes an interesting target to induce selective uptake by dendritic cells and macrophages. This thesis focus on the design and synthesis glycoconjugates linked with oligomannosides and artificial mannose clusters as homing device for the mannose receptor and other mannose binding lectins.UBL - phd migration 201
Mono-ADP-Ribosylation of peptides: an overview of synthetic and chemoenzymatic methodologies
No full textBio-organic Synthesi
The Hospital back in the City: A public function for the regeneration of Zaandam Kogerveld
No full textThe regeneration of the area Zaandam Kogerveld was initiated by a Hospital. The Hospital reintegrates with the city and is placed on a central location - next to the station Kogerveld. By placing the Hospital, the area receives a new identity and a dwelling character. The Hospital is altered to connect with it's surrounding urban structure and fit in with the dwelling neighbourhood. The public character of the Hospital is expressed in the open and public layout of the plan. In the research the consequences of integrating the Hospital with the city are analized.Hybrid BuildingsArchitectur
Elucidating the role of N-acetylglucosamine in Group A Carbohydrate for the development of an effective glycoconjugate vaccine against Group A Streptococcus
No full textGroup A Carbohydrate (GAC), conjugated to an appropriate carrier protein, has been proposed as an attractive
vaccine candidate against Group A Streptococcus infections. Native GAC consists of a polyrhamnose (polyRha)
backbone with N-acetylglucosamine (GlcNAc) at every second rhamnose residue. Both native GAC and the
polyRha backbone have been proposed as vaccine components. Here, chemical synthesis and glycoengineering
were used to generate a panel of different length GAC and polyrhamnose fragments. Biochemical analyses were
performed confirming that the epitope motif of GAC is composed of GlcNAc in the context of the polyrhamnose
backbone. Conjugates from GAC isolated and purified from a bacterial strain and polyRha genetically expressed
in E. coli and with similar molecular size to GAC were compared in different animal models. The GAC conjugate
elicited higher anti-GAC IgG levels with stronger binding capacity to Group A Streptococcus strains than the
polyRha one, both in mice and in rabbits.
This work contributes to the development of a vaccine against Group A Streptococcus suggesting GAC as
preferable saccharide antigen to include in the vaccine
Formation of glycosyl trichloroacetamides from trichloroacetimidate donors occurs through an intermolecular aglycon transfer reaction
No full textTo probe the reaction mechanism, underlying the rearrangementofoft-used trichloroacetimidate glycosyl donors into the correspondinganomeric trichloroacetamides, we have used a combination of C-13- and N-15-labeled glycosyl trichloroacetimidate donorsin a series of crossover experiments. These unambiguously show thattrichloroacetamides are formed via an intermolecular aglycon transfermechanism. This insight enables the design of more effective glycosylationprotocols, preventing the formation of dead-end side products.Bio-organic Synthesi
Towards near-infrared light-activated combination chemotherapy
No full textThe goal of the research presented in this thesis was to explore the chemical space of ruthenium(II) photocages, investigate their ability to host potent chemotherapy drugs, and to red shift the activation wavelength of the most promising PACT candidates to conduct biological studies. At first, we developed a method for the ortho-amination of pyridine N-oxides, providing an easy access to valuable building blocks based on quinoline, bipyridine, naphthyridine, phenanthroline, biisoquinoline and terpyridine. We then used this tool to construct a family of the new pentadentate ligands and respective ruthenium complexes capable of caging different approved and experimental anticancer medications. The resulting prodrugs showed good response to longwave visible light, efficiently releasing drug moieties based on primary amines, thioethers, nitriles, pyridines, imidazo[1.2-b]pyridazines, β-carbolines, and imidazoles. The follow up in vitro studies confirmed the potential of this construct to be used against cancer. Additionally, we performed the modification of previously developed ruthenium based agent to be tested with red light in vivo, which demonstrated the convincing applicability of PACT in actual tumor treatment and set the ground for further preclinical development.Metals in Catalysis, Biomimetics & Inorganic Material
Synthesis of chemical tools to study the immune system
No full textThis thesis describes the synthesis and biological evaluation of TLR2/6, TLR4, TLR7/8 and TLR9 ligands, of which the activity can be conditionally controlled. Trans-cyclooctenes are used to shield the ligand's moiety critical for TLR activation, which can be removed fast and quantitatively by the addition of tetrazine derivatives. Photocages are used in parallel for the same purpose, which can be removed by exposure to low-energetic UV-light. A new photocage has been developed that can be decorated on two positions, i.e. it is bifunctional. This photocage has been used to synthesize a proteasome inhibitor-doxorubicin conjugate, in which the photocage bisects the two groups, which induces apoptosis in targeted multiple myeloma cells with an acquired resistance for proteasome inhibitors. The photocage was also used to synthesize a probe that enables targeting and isolation of CD8+ T cells in viable human melanoma and non-squamous cell lung cancer tissues. </p
Discovery of BUB1 kinase inhibitors for the treatment of cancer
No full textThe spindle-assembly checkpoint (SAC) is a safety mechanism which secures accurate chromosome segregation during mitosis. BUB1, a serine/threonine kinase, is one of the proteins involved in this checkpoint and its inhibition is thought to have therapeutic potential for the treatment of cancer. Although the exact role of BUB1 in the SAC remains controversial, inhibition of its kinase function has previously been shown to reduce tumor size in mouse xenograft models when combined with paclitaxel. The research described in this thesis aimed to develop novel BUB1 kinase inhibitors for which high-throughput screening was used as starting point for drug discovery. Medicinal chemistry efforts were performed to improve potency after which the obtained inhibitors were further evaluated in cellular assays. In addition, the development of a cellular BUB1 target engagement assay is described. Hit optimization led to the discovery of two lead compounds with good physicochemical properties, subnanomolar affinity for BUB1, good cellular BUB1 target engagement, acceptable selectivity over other kinases and a favorable in vitro ADME profile.Molecular Physiolog
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