To design the ideal water oxidation catalyst, understanding of the catalytic mechanism and decomposition pathways is essential. The aim of the research described in this thesis is to provide... Show moreTo design the ideal water oxidation catalyst, understanding of the catalytic mechanism and decomposition pathways is essential. The aim of the research described in this thesis is to provide mechanistic insight on the water oxidation reaction catalyzed by homogeneous electrocatalysts and topostulate design criteria for the ideal water oxidation catalyst. Show less
Supramolecular polymers are class of materials that are formed by non-covalent interactions such as hydrogen bonding, π-π interactions, electrostatic interactions and the hydrophobic effect. The... Show moreSupramolecular polymers are class of materials that are formed by non-covalent interactions such as hydrogen bonding, π-π interactions, electrostatic interactions and the hydrophobic effect. The design and development of supramolecular polymers in aqueous solution gained a particular attention for the wide variety of applications in the biomedical field. In water, the self-assembly of well-defined nanostructures is mainly determined by the combination of hydrophobic effect with hydrogen bonding interactions in the monomer design. When squaramide-based monomer self-assemble, the formation of stable nanostructures in water is determined by the formation of directional hydrogen bonds which are strengthened by the partial aromatic character of the squaramide. In this thesis, the self-assembly properties of a panel of squaramide-based monomers is examined in aqueous solution through modulating the monomer chemical structure, co-assembly and introduction of light responsive chemistries. Show less
Ice, the solid state of water, plays an important role on our planet as well as the entire universe.Despite the fact that an individual water molecule has a very simple structure, its chemical... Show moreIce, the solid state of water, plays an important role on our planet as well as the entire universe.Despite the fact that an individual water molecule has a very simple structure, its chemical bonding in the solid phase can be surprisingly complex.Nowadays, atomistic computational models allow to describing and understanding these properties in a way that has not been possible for a long time.Chemical interactional potentials are at the heart of these atomistic models.In increasing order of complexity, these potentials range from simple pair potentials over polarizable force fields up to density functional theory (DFT).It is an ongoing scientific challenge is to improve and test these potentials.This thesis attempts to provide some answers to the following research questions:(i) How important is the contribution of zero-point energy to thermodynamical properties of ice phases?(ii) How accurately do available interaction potentials allow to model (small) differences between H2O and D2O ices related to nuclear quantum effects?(iii) Do interaction potentials need to be improved when nuclear quantum effects in ice are taken into account? Show less
Het proefschrift omschrijft de chemische synthese van fenolische glycolipiden van verschillende mycobacteriën met het doel om deze te kunnen gebruiken voor immunologisch onderzoek.
Glycoside hydrolases (glycosidases/GHs) are widely abundant enzymes in all kingdoms of life and are important biocatalysts that catalyze the hydrolysis of glycosidic linkages in oligo... Show moreGlycoside hydrolases (glycosidases/GHs) are widely abundant enzymes in all kingdoms of life and are important biocatalysts that catalyze the hydrolysis of glycosidic linkages in oligo/polysaccharides, glycoproteins and glycolipids with tremendous efficiency. Abnormal glycosidase activity is intimately associated with a variety of human diseases. Overexpression of heparanase, for example, is implicated in almost all cancers examined, and correlates with increased tumor size, tumor angiogenesis, enhanced metastasis and poor prognosis. Specific inhibitors of glycosidases are of great value, not only because they can serve as useful biological tools to study the catalytic machinery, mechanism and itinerary of target enzymes by crystal structure analysis of (covalent) inhibitor-enzyme complexes, but also because they may act as starting points for the development of therapeutic drugs for the treatment of glycosidase-mediated diseases. Additionally, covalent mechanism-based inhibitors have been used as scaffolds for the development of activity-based probes (ABPs) which allow profiling of glycosidases in complex biological systems. The research described in this dissertation focus on the development and biochemical evaluation of covalent inhibitors and ABPs for retaining endo- and exo-glycosidases including starch-degrading enzymes and human lysosomal β-glucocerebrosidase (GBA), as well as the synthesis of a panel of uronic acid-type 1-N-iminosugars as potential competitive heparanase inhibitors. Show less
The 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... Show moreThe 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. Show less
Artificial photosynthesis has recognised potential to produce green and sustainable fuels from earth-abundant resources such as water, carbon dioxide (CO2), and sunlight. In an artificial... Show moreArtificial photosynthesis has recognised potential to produce green and sustainable fuels from earth-abundant resources such as water, carbon dioxide (CO2), and sunlight. In an artificial photosynthetic system, two half-reactions, such as water oxidation and proton reduction or CO2 reduction, have to be combined. To achieve such a system, it is crucial to have: a) efficient light-harvesting by the photosensitiser, b) stable catalysts for the oxidation and the reduction reaction, c) unidirectional proton and electron transport between the oxidation and the reduction site, ideally by a recyclable electron relay, d) efficient charge separation, and e) a strong, photostable membrane that does not leak molecular components. In natural photosynthesis, these requirements are achieved altogether using compartmentalisation, which consists in embedding the key components of the system, i.e. for green plants the oxygen evolving complex, photosystem I and II, and the natural electron relays, around the lipid bilayer of the thylakoid membrane. The use of spherical lipid membranes (such as liposomes) as biological mimics of the thylakoid membrane is a promising approach to confine half-reactions, facilitate charge separation, and avoid charge recombination and other undesired side-reactions. In the research described in this thesis, it was attempted to realise a full artificial photosynthetic system based on liposomes and several of the key intermediate steps were achieved: 1) unidirectional electron transfer across a liposomal membrane from an electron donor encapsulated in the interior of the liposome to an electron acceptor located outside (Chapter 2), and 2) photocatalytic reduction of CO2 (Chapter 3) and of protons (Chapter 4) at the surface of liposomes. Special attention was paid in Chapter 2 and Chapter 5 to the question of the (photo)stability of the membrane and light-induced leakage. Show less
This thesis presents the first synthetic peptides ADP-ribosylated on serine, threonine, tyrosine, arginine and cysteine. Besides synthetic peptides, this thesis discusses the first synthetic route... Show moreThis thesis presents the first synthetic peptides ADP-ribosylated on serine, threonine, tyrosine, arginine and cysteine. Besides synthetic peptides, this thesis discusses the first synthetic route towards ADP-ribosylated nucleic acids. Furthermore, two photoaffinity probes for PARP1 have been developed and assessed in living cells and two activity based probes have been synthesized, designed for CD38. Show less
The redox-conversion reaction of metal-disulfide and metal-thiolate complexes are important, as they may shed light on electron-transfer reactions that often occur in Nature. Despite their... Show moreThe redox-conversion reaction of metal-disulfide and metal-thiolate complexes are important, as they may shed light on electron-transfer reactions that often occur in Nature. Despite their importance, very few examples have been reported. In addition to that, there is a limited understanding of how the coordination environment of the metal ion affects this reaction. In this thesis, our investigation was set based on the ligand-field theory to determine its correlation with the redox-conversion reactions in cobalt-based systems. Our experiments revealed that using an exogenous ligand with a strong ligand-field character may induce the redox conversion from cobalt(II)-disulfide complexes to cobalt(III)-thiolate complexes. Using this knowledge, the possibility of the redox-conversion reaction was also extended from cobalt(II)-diselenide to cobalt(III)-selenolate complexes.Finally, we have come up with several conclusions about the redox-conversion reactions of the cobalt(II)-dichalcogenide complexes. It was revealed that the conversion is affected by the ligand-field strength of the dichalcogenide ligand. The smaller ligand-field strength can be counterbalanced with the introduction of the strong auxiliary ligand. Lastly, the cleanliness of the conversion depends on the magnitude of the overall ligand-field splitting energy of the complex. Show less
Artificial photosynthesis (AP) is one of the scientific challenges that could help us achieving a global “carbon neutral” society. Photocatalytic water splitting is considered as the first... Show moreArtificial photosynthesis (AP) is one of the scientific challenges that could help us achieving a global “carbon neutral” society. Photocatalytic water splitting is considered as the first challenge of AP, which contains two half reactions: water oxidation and hydrogen evolution. It is widely accepted that a photocatalytic system needs a minimum of three components: a photosensitizer (PS), a catalyst (Cat) and a sacrificial electron donor or acceptor (SE). In such a photocatalytic system, at least three electron-transfer steps can be identified: one between the SE and the excited PS (PS*), one between the photo-reduced or photo-oxidized PS and the Cat, and one between the Cat and its substrate. This thesis on the one hand focused on developing improved molecular components for the two half reactions of water splitting in purely homogeneous systems. On the other hand optimized photocatalytic systems with balances between the driving force of electron transfer from the SE to the PS*, and that of electron transfer between the catalyst and the oxidized or reduced photosensitizer (PS+ or PS–). Show less
The research described in this Thesis was aimed at designing and synthesizing nature-inspired compounds as part of TB vaccine discovery. A variety of synthetic analogues of mycobacterial cell wall... Show moreThe research described in this Thesis was aimed at designing and synthesizing nature-inspired compounds as part of TB vaccine discovery. A variety of synthetic analogues of mycobacterial cell wall components, from peptide and glycolipid antigens to glycolipid PAMPs has been accessed. Evaluation of the immune stimulatory activity of the novel compounds in combination with preliminary immunization studies in vivo, suggested the potential of selected synthetic conjugates as single molecule vaccines against TB. Further research is needed to verify the efficacy of these vaccine modalities. Show less
Evolution acts via mutations in amino acid sequences. Substitution of essential amino acids leads to a nonfunctional protein. Thus, the number of essential residues is limited by evolutionary... Show moreEvolution acts via mutations in amino acid sequences. Substitution of essential amino acids leads to a nonfunctional protein. Thus, the number of essential residues is limited by evolutionary pressure. The roles of all non-catalytic essential residues in class A β-lactamases are described with a large-scale experiments, as well as specific functions of a few residues. The results show that residues close to the active site and farther away have different reasons for being essential. Show less
This thesis focuses on the synthesis, characterization and performance towards CO2 electroreduction of mono and bi-metallic particles based on p-block metals. With an industrial perspective in mind... Show moreThis thesis focuses on the synthesis, characterization and performance towards CO2 electroreduction of mono and bi-metallic particles based on p-block metals. With an industrial perspective in mind, we try to synthesize particulate, high surface area materials with clean, scalable synthesis methods where possible and test their performance in H-Cell and gas diffusion electrode flow cell configurations. With a combination of characterization techniques, we find possible explanations for the catalytic behaviors. Show less
This thesis has shed light on some of the ways in which the local electrolyte composition can differ from the bulk and how these changes in the local reaction environment can determine the activity... Show moreThis thesis has shed light on some of the ways in which the local electrolyte composition can differ from the bulk and how these changes in the local reaction environment can determine the activity and/or selectivity of two important electrocatalytic reactions, namely, electrochemical CO2 reduction reaction (CO2RR) and hydrogen evolution reaction (HER). Show less
Monoacylglycerol lipase (MAGL) is the principal enzyme responsible for hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-AG). MAGL inhibition provides several potential therapeutic... Show moreMonoacylglycerol lipase (MAGL) is the principal enzyme responsible for hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-AG). MAGL inhibition provides several potential therapeutic opportunities, including anti-nociceptive, anti-inflammatory and anti-cancer activity. This thesis describes the discovery of LEI-515 as peripherally restricted, reversible MAGL inhibitor. A library of 233.820 compounds was screened at the Pivot Park Screening Center and 7 hits were confirmed. Over 100 analogues of the most promising hit were designed, synthesized and evaluated in a natural substrate assay and activity-based protein profiling. This resulted in the identification of LEI-515, which has subnanomolar inhibitory potency, high selectivity and good metabolic stability. LEI-515 is a reversible inhibitor that forms a hemiketal with catalytic Ser122, stabilized by hydrogen bonds with Ala53 and Met123. LEI-515 is > 100-fold selective over a panel of 44 ion channels, receptors and enzymes, including the cannabinoid CB1 and CB2 receptor, hERG and cyclooxygenases. Targeted lipidomics revealed that LEI-515 increased cellular 2-AG levels in a concentration and time-dependent manner. Pharmacokinetic studies indicated that LEI-515 has excellent oral bioavailability, but does not penetrate the brain. Show less
With increasing carbon dioxide levels in the atmosphere and their detrimental effect on the global climate, modern society needs to push for more renewable energy sources. Storing widely accessible... Show moreWith increasing carbon dioxide levels in the atmosphere and their detrimental effect on the global climate, modern society needs to push for more renewable energy sources. Storing widely accessible and abundant solar energy in chemical bonds in the form of molecular fuel via artificial photosynthesis can support this endeavour. Dye-sensitized Photoelectrochemical Cells are promising candidates for Solar-to-fuel conversion; however, their efficiency is still lacking and needs further improvement. Computational Simulations can provide insight in fundamental mechanisms and guide the search for suitable molecular components and interfaces to improve the performance of such devices. In this thesis, a wide range of computational tools are applied to investigate the photoinduced processes and catalytic intermediates involved in dye-sensitized photoanodes for water oxidation. Through combination of semi-empirical methods with DFT and quantum-classical approaches, large scale molecular simulations of extended photoanode systems including electrode, dye and water oxidation catalyst become feasible. The insights gained from these fundamental processes are used to evaluate and optimize molecular components in silico. Show less
Phospholipase A/acyltransferase 3 (PLAAT3) and PLAAT4 are enzymes involved in the synthesis of bioactive lipids. Despite sequential and structural similarities, the two enzymes differ in activity... Show morePhospholipase A/acyltransferase 3 (PLAAT3) and PLAAT4 are enzymes involved in the synthesis of bioactive lipids. Despite sequential and structural similarities, the two enzymes differ in activity and specificity. The relation between the activity and dynamics of the N-terminal domains of PLAAT3 and PLAAT4 was studied. PLAAT3 has a much higher melting temperature and exhibits less nanosecond and millisecond dynamics in the active site, in particular in loop L2(B6), as shown by NMR spectroscopy and molecular dynamics calculations. Swapping the L2(B6) loops between the two PLAAT enzymes results in strongly increased phospholipase activity in PLAAT3 but no reduction in PLAAT4 activity, indicating that this loop contributes to the low activity of PLAAT3. The results show that, despite structural similarity, protein dynamics differ substantially between the PLAAT variants, which can help to explain the activity and specificity differences. Show less
This thesis systematically studies the physicochemical properties of non-planar, propeller-shaped, polycyclic aromatic hydrocarbons. The synthesis of several so-called propellerenes is described on... Show moreThis thesis systematically studies the physicochemical properties of non-planar, propeller-shaped, polycyclic aromatic hydrocarbons. The synthesis of several so-called propellerenes is described on a gram scale, using optimized procedures aimed at using less hazardous reagents and reducing the amount of organic solvent used. The conformational behavior of several propellerenes is studied experimentally using variable temperature NMR, and findings corroborated using high-level DFT computations. The origin of the conformational preference of propellerenes is elucidated using a novel adaptation of the activation-strain model. By computationally dissecting propellerenes into its constituent parts, the preference of these parts can be analyzed. The spectroscopic properties of conformationally pure propellerenes are studied experimentally, and experimental findings explained on a molecular orbital level, using time dependent DFT computations. Lastly, the supramolecular behavior of propellerenes is studied by the production of molecularly thin films, using the Langmuir-Blodgett technique. These thin films are imaged using electron microscopy, the molecular dynamics at the air-water interface studied computationally, and the physical properties of the thin films quantified using AFM nanoindentation. These propellerene-based thin films are, for the first time, found able to be free-standing over nanometer distances. Combined, this thesis establishes propeller-shaped, polycyclic aromatic hydrocarbons as an independent field of study. Show less
Electrocatalysis allows for storing electricity or converting it into chemical bonds, producing chemical building blocks and fuels using renewable resources. Therefore, it plays an important role... Show moreElectrocatalysis allows for storing electricity or converting it into chemical bonds, producing chemical building blocks and fuels using renewable resources. Therefore, it plays an important role in the transition towards a more sustainable future for our society through electrification. Still, to bring electrochemical technologies to industrial scale and make them competitive, optimization of various aspects of electrocatalytic reactions are needed. Many fundamental studies focus on understanding the catalyst surface, however, different components of the electrolyte, as pH and cations, have also shown to significantly affect the reaction activity and selectivity. In view of that, in this thesis, various aspects of the electrode-electrolyte interface are studied at different scales, using Scanning Electrochemical Microscopy (SECM), stationary and rotating-disc electrode voltammetry techniques, and bulk electrolysis. Show less
