Nucleolipids and Lipo-Oligonucleotides of 5-Fluorouridine: Synthesis, Biological Applications and Immobilization

The thesis comprises the synthesis and spectroscopic characterization of novel lipid derivatives mainly of the cancerostatic 5-fluorouridine (5-FU). The chemical structure of the lipid residues resembles naturally occurring compounds, namely acyclic terpenes, waxes, and large ring ketones. They are positioned either at N(3) or at the O-2’,3’ cis-glycolic moiety of the nucleoside. The introduction of the lipophilic residues was performed either by ketalization of the glyconic hydroxyls or by direct alkylation as well as by Mitsunobu reaction at N(3) of the aglycone. The resulting nucleolipids were further converted to 2-(cyanoethyl) phosphoramidites as building blocks for automated solid phase nucleic acid synthesis. The latters were used for the preparation of a series of lipo-oligonucleotides which were studied with respect to their immobilization within artificial lipid bilayers and compared concerning immobilization rate and stability. Moreover, selected 5-FU nucleolipids were fluorophore-labelled and tested with respect to their cancerostatic activity towards human colon carcinoma cells (HT-29). Additionally, O-2’,3’-functionalized 5-FU ketals were covalently bound either to soluble chitosanes of various molecular weight or to chitosane foils. The latters were studied towards their enzymatic degradability. Last, the reaction of lipophilic phosphoramidites with the blood volume expander hydroxyethyl starch yielding enzymatically hydrolysable phosphodiester bonds was investigated