Browsing by Author "Redcliffe, James Leo"

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Synthesis and transformation of cyclic nitrones: new candidates for the inhibition of α-L-fucosidases
(2011) Redcliffe, James Leo; Jäger, Volker (Prof. Dr.)
The main themes of this PhD thesis entailed the synthesis of new candidates for glycosidase inhibition assays. Glycosidases catalyze the degradation (i.e. hydrolytic cleavage or transfer) of glycosidic bonds. The synthesis of suitable, selective inhibitors of glycosidases may be a tool to stop detrimental or disease-related cell processes and may be of therapeutic value. In particular, this work focused on the synthesis of alpha-L-fucosidase inhibitors. We choose to synthesise a library of polyhydroxylated pyrrolidines, bearing extended aglycon side-chains and to investigate the biological properties, i.e the inhibiton against fucosidases, in a systematic manner. The route to these pyrrolidines relied on the halogen-induced cyclisation of unsaturated hydroxylamines, which in turn can be derived from simple carbohydrates, such as D-ribose. The cyclisation leads to the formation of cyclic nitrones which are a class of synthetically versatile compounds. The key nitrone compound with L-lyxo configuration can be transformed in a few steps into actual fucosidase inhibitors, through a Grignard addition (to install the side-chain) followed by a simple reduction/deprotection protocol. This rapidly provided us with a library of polyhydroxylated pyrrolidines bearing several para-substituted aromatic side-chains. Several pyrrolidines as fucosidase inhibitor candidates were active in the low-micromolar range. The best candidates showed inhibition against fucosidase even at concentrations as low as 1.2 nM, resulting in some of the most potent inhibitors in this class currently known in the literature. Further elements of the dissertation involved the synthesis of six-membered nitrones with L-fuco configuration and their elaboration into fucosidase inhibitors (one example), according to a new route developed in this Thesis. This thesis also focused on an investigation of the oxidation selectivity of tri- and tetra-substituted N-hydroxypyrrolidines and, to a lesser extent, the subsequent reactions of the new nitrones that were created. Two oxidation reagents were compared, revealing striking kinetic - though hardly any regioisomeric - differences in the reaction outcomes. Special electronic effects of neighbouring substituents were found, in specific cases, to effect a drastic change in oxidation regioselectivity to provide some surprising results.