Het proefschrift omschrijft de chemische synthese van fenolische glycolipiden van verschillende mycobacteriën met het doel om deze te kunnen gebruiken voor immunologisch onderzoek.
The work in this thesis has been focused on two subjects. The first is the assembly of alginate oligosaccharides and the generation of building blocks for the enzymatic synthesis of alginate,... Show moreThe work in this thesis has been focused on two subjects. The first is the assembly of alginate oligosaccharides and the generation of building blocks for the enzymatic synthesis of alginate, and the second is the total synthesis of large fragments of the zwitterionic SP1 polysaccharide. With these fragments, details about alginate biosynthesis can be obtained through binding studies with biosynthesis enzymes, conjugate vaccines can be generated and binding studies with major histocompatibility complex II molecules can be studied. Show less
This thesis describes the synthesis of various teichoic acid (TA)-fragments, capsular polysaccharide (CPS)-mimics and a toolbox of glycerol phosphate probes. Most of these molecules feature one or... Show moreThis thesis describes the synthesis of various teichoic acid (TA)-fragments, capsular polysaccharide (CPS)-mimics and a toolbox of glycerol phosphate probes. Most of these molecules feature one or more phosphodiester functions, the introduction of which has been accomplished with phosphoramidite chemistry. The versatility of glycerol- and carbohydrate building blocks provided with a 2-cyanoethyl-protected phosphoramidite is illustrated by their application both in solution and in automated solid phase syntheses of TA and CPS oligomers as well as probes. The CPS-mimics are based on a polysaccharide present in the capsule of the gram negative bacterium Neisseria meningitidis, the pathogen that is the major cause of bacterial meningitis. The TA-fragments described in this thesis correspond to lipoteichoic acids (LTA) and wall teichoic acids (WTA) from Enterococcus faecalis and Enterococcus faecium, two commensal Gram-positive bacteria inhabiting the gastrointestinal tract. In both these bacterial families multi-drug-resistant strains have evolved and they are responsible for the majority of hospital-acquired infections. Enterococcal LTA generally consists of sn-glycerol-1-phosphate repeating units that can be decorated with carbohydrate- or D-alanyl appendages on the 2-OH of the glycerol moieties. The biosynthetic machinery of WTA is more complicated and can result in completely different structures. Show less
Kv11.1-induced cardiotoxicity has emerged as an unanticipated adverse effect of many pharmacological agents and has become a major obstacle in drug development over the past decades. In this thesis... Show moreKv11.1-induced cardiotoxicity has emerged as an unanticipated adverse effect of many pharmacological agents and has become a major obstacle in drug development over the past decades. In this thesis, allosteric modulation of the Kv11.1 channel has been extensively explored, and negative allosteric modulators were shown to relieve the proarrhythmic effects of structurally and therapeutically diverse Kv11.1 blockers. The most potent modulators may be developed as a new class of antiarrhythmic medications in the future. On the other hand, kinetic binding parameters of a wide range of Kv11.1 blockers at the channel have been thoroughly investigated in this thesis. Association and dissociation rates or residence times are strongly suggested to be integrated with equilibrium affinity values into the future paradigms for a better and more comprehensive evaluation of Kv11.1 liability of drug candidates. The __kon-koff-KD__ kinetic map provides a first and promising classification of Kv11.1 blockers, which could be beneficial and indicative for drug researchers to design compounds with less Kv11.1-mediated cardiac side effects in the early stage of drug development. Hopefully, all findings in this thesis have brought new insights into Kv11.1-induced cardiac arrhythmias, and will offer opportunities for restoring or preventing this kind of arrhythmias in the near future. Show less
Photosynthesis is the physico-chemical process by which plants, algae and photosynthetic bacteria use light energy to drive the synthesis of organic compounds. Light-induced electron transfer in... Show morePhotosynthesis is the physico-chemical process by which plants, algae and photosynthetic bacteria use light energy to drive the synthesis of organic compounds. Light-induced electron transfer in photosynthetic reaction centers (RCs) is highly efficient, having a quantum yield close to unity. In RCs of Rhodobacter (R.) sphaeroides wild type (WT), the primary electron donor is a bacteriochlorophyll a (BChl) dimer, called the Special Pair P, comprising two dimer halves PL and PM. Two additional BChl cofactors called accessory BChls (BA and BB), two bacteriopheophytins (_A and _B), two quinones and a non-heme iron are organized into two pseudo-symmetric branches named A and B. After the photo excitation the electron is transferred only via the active __A__ branch. On the other hand, in structurally similar RCs, as that of photosystem I, the electron transfer occurs equally over both branches. Neither the reason for the high efficiency nor that of the directionality of the electron transfer has been elucidated so far. To solve these questions, the solid-state photo-chemically induced nuclear polarization (photo-CIDNP) effect with its dramatic enhancement of local NMR signals provides an analytical tool especially suited for studying electron transfer in photosynthetic RCs. In fact, photo-CIDNP MAS NMR has been applied to explore electronic structures of the electron donors and acceptors in RCs Show less
In this talk, we address the problem of synthesizing Process Network specifications to FPGA execution platforms. The process networks we consider are special cases of Kahn Process Networks. We call... Show moreIn this talk, we address the problem of synthesizing Process Network specifications to FPGA execution platforms. The process networks we consider are special cases of Kahn Process Networks. We call them COMPAAN Data Flow Process Networks (CDFPN) because they are provided by a translator called the COMPAAN compiler that automatically translates affine nested loop programs to input-output equivalent (COMPAAN) process network specifications. The objective is to provide an effective and efficient implementation of CDFPNs in an FPGA execution platform, where our implementation is close to a one-to-one mapping of the originating CDFPN. The execution platform emerges as part of the mapping process resulting in a dedicated multi-processor execution platform for a given CDFPN specification. Show less
Porphyrins are essential in living organisms. E.g. in the red oxygen carrying blood protein hemoglobin oxygen binds to the Fe2+-containing heme and in plants the green pigment chlorophyll is... Show morePorphyrins are essential in living organisms. E.g. in the red oxygen carrying blood protein hemoglobin oxygen binds to the Fe2+-containing heme and in plants the green pigment chlorophyll is responsible for the initial steps in photosynthesis. The absorption of light by a porphyrin, followed by energy transfer to oxygen can lead to the formation of highly toxic but short living singlet oxygen. When such a porphyrin localizes in a tumor it is possible to destroy the tumor locally by the irradiating it with light. This treatment is known as photodynamic therapy and the pigment is called a photosensitizer. However a major drawback of current photosensitizers is that they do not show strong absorption in the far-red part of the spectrum where light penetrates tissue optimal. Besides patients treated with these photosensitizers remain light sensitive for 3-8 weeks. This thesis describes the preparation of new photosensitizers with strong absorption of light at 680-690 nm. The preparation of these porphyrin derivatives takes place via unprecedented chemical reactions and an explanation for the chemistry involved is given. Tests on mice showed that the lifetime of these new porphyrin derivatives in their body is reduced to less then 3 days, which makes them very interesting candidates as new generation photosensitizers for photodynamic therapy Show less
This research describes the quest to create 'super-caffeines', substances that only produce the desired effects of caffeine, and unlike caffeine, substances that should only have to be taken in... Show moreThis research describes the quest to create 'super-caffeines', substances that only produce the desired effects of caffeine, and unlike caffeine, substances that should only have to be taken in measured, minute, controlled amounts to achieve these effects. Unless particular steps are taken to avoid it, caffeine is a very prevalent substance in our society, which almost all of us ingest in some manner on a daily basis. It is an integral part of coffee, tea and chocolate-based products, cola drinks and is even used as a supplement in painkillers. Most people recognise caffeine as a stimulant; however, have you ever wondered how and why we get not only the pick-me-up effect, but also less desirable ones, for example, the need to go to the toilet more often and the racing heart? Caffeine is an example of a ligand (a chemical compound) that acts via certain anchor points in the body, the adenosine receptors. These receptors are located throughout the body in a number of different tissues. There are four different categories of this receptor that respond specifically to a substance called adenosine, which is produced within the body when and where it is needed. Once a substance like caffeine enters the body the majority of its effects are as a result of blocking these receptors, thereby not allowing the body's own chemical compound, adenosine, to occupy the receptors. The often welcome stimulatory effects of caffeine have been found to be as a consequence of blocking a particular adenosine receptor, known as the adenosine A1 receptor. The unwelcome sideeffects mentioned earlier are often a result of caffeine's interaction with one or more of the other three adenosine receptors. The therapeutic potential for new __super-caffeines__ (so called adenosine A1 receptor antagonists) are great, for instance as cognition enhancers in the elderly. This thesis describes the design and development of several series of new compounds which help us to define, understand and further the research into adenosine receptor antagonists. The substances themselves are novel in chemical structure, have excellent affinity for the adenosine A1 receptor (very much better than that measured for caffeine) and are selective for this particular receptor above the rest of the adenosine receptor family. Show less
This thesis describes a variety of asymmetric cis- and trans-platinum(II) complexes. The major aim of this research has been the design of complexes with high antitumor activity that may overcome... Show moreThis thesis describes a variety of asymmetric cis- and trans-platinum(II) complexes. The major aim of this research has been the design of complexes with high antitumor activity that may overcome cisplatin resistance, and to establish a comparison between complexes with both geometries. These new type of asymmetric platinum complexes contain in all cases the iPram ligand and in addition either aliphatic amines or azole ligands. Furthermore, a strong emphasis on asymmetric trans-Pt(II) complexes with azole ligands is presented in this research. Show less
Synthesis of 13C-enriched carotenoids. Carotenoids are natural colorants, ranging in color from pale yellow to deep purple, with important biological functions. Carotenoids in the human diet have a... Show moreSynthesis of 13C-enriched carotenoids. Carotenoids are natural colorants, ranging in color from pale yellow to deep purple, with important biological functions. Carotenoids in the human diet have a beneficial health effect, playing a role in the prevention of cardiovascular disease and cancer. To get more insight in the beneficial health effects of carotenoids, sensitive and accurate analysis is essential. The combination of 13C-enrichment of carotenoids and isotope-sensitive analysis allows the determination of small amounts of metabolites in the human body. To obtain the required 13C-enriched carotenoids, the development of efficient synthetic routes is described in this thesis. The color of lobsters. In nature, many carotenoids are bound to proteins, to form carotenoproteins. Often this binding is accompanied by a remarkable change in color, as the example of the carotenoprotein that is responsible for the deep blue color of the lobster shell. When the lobster is cooked, the protein denatures and the red carotenoid is released, which gives the lobster it__s striking red color after cooking. To understand this color change, 13C-enriched carotenoid was made and bound in the lobster protein. Using a combination of isotope-sensitive analyses and computational methods, we found that the color change is predominantly caused by intermolecular interactions between the carotenoids that are in close proximity when bound in the protein. Show less
