The ongoing research in the field of lysosomal storage diseases (LSD), and more specific Gaucher disease is the basis for the research described in this thesis. The progress of Gaucher disease and... Show moreThe ongoing research in the field of lysosomal storage diseases (LSD), and more specific Gaucher disease is the basis for the research described in this thesis. The progress of Gaucher disease and the effect of therapeutic intervention is correlated to the level of chitotriosidase (CHIT1), the first identified human chitinase. Mea- surement of plasma CHIT1 activity in man is done by an assays using a fluorogenic substrate. The ability of CHIT1 to transglycosylate can complicate the enzyme assay, however umbelliferone 4__-deoxychitobioside is not prone to be transglycosylated. And gives a proportional fluorophore to active enzyme ratio read-out. Because of this umbelliferone 4__-deoxychitobioside has become a popular fluorogenic substrate for the measurement of human chitinases, an improved scalable route towards this compound is described in Chapter 2. Chapter 3 describes the synthesis and biological evaluation of three novel fluorogenic substrates, containing substituents of different sizes on the 4__-OH of the non-reducing sugar. The locally elevated activity of CHIT1 allows sitespecific drug delivery via the prodrug approach. Chapter 4 describes the design and synthesis of novel prodrugs in which a chitobiose core, the substrate for CHIT1, is coupled to known inhibitors of GCS which are able to restore the influx/efflux balance of GC in Gaucher cells. It is known that some iminosugars and N-alkylated derivatives thereof have a taste bitter. In Chapter 5 attempts are made to palliated this bitter taste by appending a galactosyl moiety to DNJ. Aside from potentially masking the bitter taste this modification will also help to direct the inhibitors to the colon were they will be processed by lactase. Cholesteryl-_-glucoside and cholesteryl-_ -glucoside, the synthesis of which is described in Chapter 6, will be used as as internal standards to get a better insight in the biosynthesis of the potentially neurotoxic steryl-glucosides, which are potentially linked to a high level of glycosylceramide. Chapter 7 summarizes the research described in chapters 2 to 6 and future prospects based on these results are presented. Show less