Title Promoter Affiliations Abstract "Development of a click chemistry based synthetic methodology for the synthesis of innovative potential lead compounds and/or chemical probes." "Koen Augustyns" "Medicinal Chemistry (UAMC)" "Several projects in the Laboratory for Medicinal Chemistry rely on click chemistry (1) as an essential aspect of bio-orthogonal derivatisation of proteins under physiological conditions or (2) as an efficient tool for the construction of innovative biologically active compounds. The candidate will apply his expertise in this domain to support and develop these ongoing projects. Additionally, novel approaches to overcome current boundaries in the domain of click chemistry will be investigated." "A novel electrochemical microreactor for the synthesis of fine chemicals" "Simon Kuhn" "Process Engineering for Sustainable Systems (ProcESS)" "Due to the advantages of small-scale flow reactors, such as better control over process conditions and intrinsic safety, there is an increased tendency to apply them to the continuous manufacturing of chemical products. These small-scale reactors also allow to intensify processes further by using alternative energy sources, such as ultrasound and electrochemistry. However, the industrial application of these small-scale flow reactors is significantly limited by their currently achieved throughput and productivity. In this project, we will overcome these productivity limitations by exploiting the synergistic effect of ultrasound on intensified electrochemical reactors. Hence, we will directly contribute to the electrification of the chemical industry promoting green and sustainable processes." "Chemical synthesis routes towards 3-dimensional metal oxide nano-architectures for energy generation and storage" "An HARDY" "Laboratory of Inorganic and Physical Chemistry" "The current project develops innovative routes for the synthesis of new materials systems with controlled nanoarchitectures in three dimensions. The multimetal oxides and phosphates selected here, have been recognized to show strong potential for improved electrochemical energy storage and generation in the most recent scientific literature. The project addresses three challenges: the synthesis of phase pure new material compositions, the formation of complex shaped powder materials and 3D ordered nanoarchitectures, and achieving of controlled interfaces in functional device environments. All of these issues are tackled by applying wet chemical synthesis routes. Sustainable, water based routes are preferred and new possibilities for obtaining the desired nanostructures are investigated. To achieve its goals, the project will develop new precursors for the synthesis of new materials with highly valent metal ions, requiring strong control over the oxidation states, it will develop hard or soft template based approaches, and it will realize deposition of ultrathin coatings onto active material components for devices. In this way, thorough insights are generated in the factors determining the realization of new, functional 3D materials by soft chemical syntheses." "Computational investigations of the catalytic mechanism of Staphylococcus aureus transglycosylase: design and chemical synthesis of novel mechanism-based inhibitors." "Hans De Winter" "Medicinal Chemistry (UAMC)" "Bacterial resistance against current medications is a growing problem that will pose significant health problems in the near future. Penicillins are a class of antibiotics that exert there effect by blocking the biosynthesis of the bacterial cell wall by means of inhibition of the transpeptidase protein, an enzyme responsible for the synthesis of the essential glycan chains in the cell wall. An alternative approach to inhibit the growth of the bacterial cell wall would be by inhibition of the transglycosylase enzyme, a protein involved in the polymerisation of the sugar chains that make up the backbone of these glycan chains. Currently there are no medications on the market or in clinical trials that have a mechanism of action of glycosyltransferase inhibition, but it has been shown that blocking the normal function of this enzyme leads to inhibition of bacterial cell growth. The main objective of the current project is to identify potent inhibitors against this transglycosylase enzyme using large-scale molecular dynamics simulations to study the catalytic mechanism of action and kinetics in large detail. Results of these simulations will be used to propose novel chemical compounds that will be synthesized through a collaboration with the University of Leuven. Biochemical testing of the antibacterial effects of these compounds will be performed at the University of Liège." "Isolation, structure elucidation and chemical synthesis of compounds with hypoglycemic activity from Gynura divaricata and G. bicolor" "Department of Sustainable Organic Chemistry and Technology" "Gynura divaricata and G. bicolor are two plants that are used in traditional Chinese medicine for the treatment of diabetes. In this project their hypoglycemic activity is investigated in pharmacological studies. Afterwards, attempts will be undertaken to isolate the active compounds and their derivatives." "Development of methods for enrichment and analysis for trace analysis of endocrine disrupting chemicals in water samples mediated by synthetic selective receptors" "Patrick Sandra" "Department of Organic and Macromolecular Chemistry" "A method will be developped allowing sorptive extraction of EDC's from contaminated water samples, based on immobilized peptidomimetics mimicking the estrogen receptor recognized by EDC's. Using smart thermoresponive polymers as solid support should pave the way to selective chromatographic analytical methods for determining EDC's." "Synthesis of diamino acid derivatives with a cyclopropane or aziridine skeleton and their application in the synthesis of potential physiologically active alpha, gamma-dimainobutyric acid derivatives" "Department of Sustainable Organic Chemistry and Technology" "The synthesis of constrained x, B- or x, Y-diamino acid derivatives as building blocks for new substituted 2,4-diaminobutyric acid derivatives is of great importance in medicinal and agricultural chemistry. This research concerns the development of stereoselective syntheses and biochemical evaluation of new derivatives of 1,2-diaminocyclopropane-1-carboxylic acid, 2-amino-2-aziridin-2-ylacetic acid and 2-amino-3-aziridin-2-ylpropionic acid and also the study of their ring opening reactions towards potentially physiologically active amino acid derivatives." "Visible-light photoredox catalysis: synthesis of sulfonylated heterocycles via thiosulfonates." "Pieter Mampuys" "Organic synthesis (ORSY)" "Visible light photocatalysis is an emerging technique in organic synthesis for the development of a wide range of previously inaccessible transformations. In this proposal the photoredox-catalyzed synthesis of sulfonylated heterocycles is described, making use of visible light and based on thiosulfonates (RSO2SR). The proposed method does not utilize (super)stoichiometric oxidants, required for the introduction of the sulfonyl group under classical conditions, and allows recycling of the resulting thiol (RSH) waste. Classical routes towards these heterocycles often require harsh reaction conditions for the incorporation of the sulfone moiety, which compromise the greenness of the process. The proposed method will therefore contribute to the development of more sustainable protocols for the production of pharmaceutical and biologically relevant sulfur-containing heterocycles." "Synthesis and application of probes for serine and cysteine hydrolases and the polyamine transport system" "Steven Verhelst" "Laboratory of Chemical Biology" "Activity-based probes (ABPs) are small molecular tools that allow the detection and monitoring of enzyme activity by covalently binding onto the active site of the enzyme. They consist of a warhead that binds the enzyme, a recognition element that alters the selectivity of the probe and a detection tag that allows the visualization, quantification or purification of probe-labeled enzymes. ABPs are applied to elucidate enzyme function, enzyme localization and the involvement of enzymes in health and disease. They can furthermore be used as screening tools for drug candidates.To monitor the activity a single enzyme, the selectivity of an ABP has to be steered towards this target. This often requires a difficult and time-consuming synthetic process, and as a result, selective ABPs have only been developed for relatively few enzymes expressed in human cells. One enzyme family of which only a few members have selective ABPs are the serine hydrolases. To speed up the process of ABP development for serine hydrolases, solid-phase synthesis procedures that allow a fast synthesis of six classes of serine-reactive probes were developed in Chapter III. The application of these procedures is shown by the combinatorial on-resin synthesis of a library of ABPs. These probes bear a recognition element made up of an aromatic moiety and a piperidine/piperazine ring, and a serine reactive warhead. Two probes with a triazole urea warhead were found to be reactive and selective for acyl-protein thioesterases 1 and 2 (APT-1/2) in a screening on serine hydrolases present in mouse brain.Chapter IV describes the use of the solid-phase synthesis procedures established in Chapter III to synthesize a library of triazole urea ABPs, based on the APT-1/2 reactive ABPs found in the previous chapter. In this library, changes were made in the recognition elements of the probes to drive their reactivity towards one of the APT-isoforms and creating isoform-selective ABPs. Although this yielded no selective probes, several probes with a higher reactivity for both APT-isoforms than the original probes were discovered.In Chapter V, the development of ABPs for the SARS-CoV-2 main protease (Mpro) is described. Mpro is a cysteine protease that is the key player in the proteolytic maturation of the non-structural proteins of the SARS-CoV-2 virus by cleavage of its polyproteins. It has gained a lot of attention as a potential target for antiviral drugs to combat the Covid-19 pandemic. In this chapter, azapeptidic ABPs for Mpro are synthesized that can be fully made on resin. The recognition element of these probes consists of the preferred P1, P2 and P3 substrates of Mpro, of which the P1 residue is an aza-amino acid. The ABPs are capped with a cysteine-reactive warhead on the P1 aza-residue. A probe with a chloroacetamide warhead was found to be very potent in labelling Mpro and to have a very low detection limit. This probe could furthermore inhibit cell death in SARS-CoV-2 infected cells and can potentially be used for labeling Mpro in live cells.The mammalian polyamine transport system was a mystery at the start of this research project, as no proteins had been identified as polyamine transporters. Chapter VI describes the synthesis of azide-functionalized polyamines, which were converted to fluorescent probes through “click” chemistry with an alkyne-BODIPY fluorophore. Through a SAR study with polyamine probes with different lengths, different positionings of the fluorophore and a different amount of positive charges, it was found that probes in which the fluorophore is attached to an outer amine of the polyamine get taken best into cells. These polyamine probes have since been used by other research groups in the identification of polyamine transporters.In summary, this thesis describes the synthesis and validation of probes that target APT-1/2, SARS-CoV-2 Mpro and the polyamine transport system. These probes can be synthesized efficiently via solid-phase synthesis or click chemistry. The developed solid-phase synthesis procedures are applicable for the synthesis of probes for other targets as well." "Multiscale modeling of complex kinetics on metal surfaces: Fischer-Tropsch Synthesis" "Department of Chemical engineering and technical chemistry" "Fischer-Tropsch synthesis offers the possibility to convert coal, natural gas or biomass to high-quality fuels or base chemicals. Complete control of the process is, however, only possible when the complex kinetics that take place on the metal surface are unraveled."