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Social policy --- Human rights --- Flanders

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Stevioside, a diterpenoid glycoside, is obtained from the leaves of the plant Stevia rebaudiana. The main components of the leaves are steviol glycosides, which consist out of a diterpene moiety(steviol) and sugar components. Amongst these steviol glycosides, stevioside is most commonly used. Apart from its intensely sweet properties, stevioside and its relatives are known to show a number of biological properties. It has been proven to be both anti-hyperglycemic and anti-hypertensive. Various other beneficial effects are attributed to stevioside. For these reasons, the raw extract of the leaves has been used in several countries as an alternativetreatment for type 2 diabetes. The same effects could later be observed for theaglycone steviol its acid-catalyzed rearrangement product isosteviol. Unfortunately, due to their low absorption in the human body, high doses of these products are needed to achieve asignificant effect. These doses can be reduced by using analogs with different polarities instead of (iso)steviol, thereby increasing the bioavailability. Furthermore, when a large collection of diterpene analogs is present, a structure-activity relationship could be devised. In this thesis, weconstructed a large collection of novel (iso)steviol derivatives. In a first chapter, isosteviol (the rearrangement product of steviol) was transformed into a 1,2,4-triazine via a series of reactions. This 1,2,4-triazine could easily be further reacted via alkylationsor metal-catalyzed cross-couplings, which resulted in a small library of heterocyclic compounds. In one specific case, the alkylated triazine was further transformed into a dihydrothieno[2,3-b]pyridine via a reverse electron demand Diels-Alder reaction. Since these triazine reactions wentsmoothly, we extended their use to the triterpene allobetulin, the rearrangement product of betulin. Similar results were obtained, and a small library of allobetulin derivatives was obtained. In the second chapter of this thesis, the application of pericyclic reactions on the (iso)steviol moiety was investigated. For steviol, the carbonyl ene reaction was used to obtain alfa-hydroxy esterderivatives. These compounds were then successfully transformed steviol analogs with an extra alfa-hydroxy lactone or 2-phenyldihydro-2H-pyran-3(4H)-one ring. For isosteviol, the potential of the Diels Alder reaction was investigated. Via an in situ synthesized diene, a novelheterocyclic ring was added. The stereochemistry of each derivative was determined. Finally, we investigated the possible reactions of the double bond of steviol. Severalnucleophiles were added to the previously known epoxide. When possible, these derivatives were reacted further, for example in the Click reaction. The double bond of steviol could be transformed into isoxazolidines using nitrones several nitrones. Each synthesized compound was tested for their biological activity on various targets. Out of these test results, two screenings are discussed in this PhD thesis. First, a general phenotypic screening on the zebrafish model was carried out. From these screenings, a clear structure-activity relationship was observed, and, via an identification of the phenotype a hypothesis of theunderlying cellular cause was constructed. Secondly, all compounds were tested for their activity as HIV replication inhibitors. For this purpose, the (iso)steviol and allobetulin analogs were tested in a tetrazolium-based colorimetric assay using MT-4 cells. Two derivatives were active, and the most active one was further derivatized. Unfortunately, we were unable to improvethe activity of the original lead compound.  

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