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.

Ausgangspunkt dieser vorliegenden Arbeit waren bisherige Untersuchungen unseres Arbeitskreises zum Memb-ranverankerungsverhalten (Phospholipidmembranen, LUV) von Nukleosiden und Oligonukleotiden, welche einen lipophilen Anker an der 5-Position der Pyrimidin- oder an der 8-Position der Purinbase tragen. Diese Nukleolipide ankern gut in der Membran, stehen aber nicht mehr für eine Watson-Crick-Basenpaarung an der Phasengrenzfläche zu Verfügung. Demnach wurde durch die Verwendung unterschiedlicher Reaktionen (Veresterung, Thioetherbildung, Carbamoylverknüpfung oder „Clickreaktion“ zu Triazolen) und verschiedener funktioneller Gruppen (Hydroxy, Thiohydroxy, Azid, Amin) an die 2´-Position der Nukleoside eine Reihe von lipophilen Resten (Alkylketten, Cholesterol, Pyren) eingeführt. Diese Konjugate verankerten ebenfalls gut in den Membranen und es zeigten sich erste Hinweise, dass durch die Einführung eines Spacers zwischen dem Nukleosid und dem lipophilen Anker, eine Basenpaarung an der Phasengrenzfläche möglich ist. Weiterhin zeigte es sich, dass Nukleolipide mit nur einem lipophilen Rest nicht stabil in Membranen verankern, vor allem, wenn dieser nicht verzweigt ist. Bei der Anwendung von Oligonukleotiden zum Ankern in Membranen ist es unbedeu-tend, an welcher Stelle der lipophile Rest am Nukleotid vorkommt, denn zum einen geht das entsprechende Nukleolipid selbst keine Basenpaarung ein und zum anderen erfolgt keine Basenpaarung über dieses hinweg. Für biotechnologische Anwendungen konnte mit Hilfe dieser synthetisierten lipophilen Oligonukleotide gezeigt werden, dass zwei vesikelmembranverankerte Oligonukleotide, welche komplementäre Enden tragen, eine Doppelhelix miteinander bilden und so diese beiden Vesikel auf einen definierten Abstand halten können. Da Nukleolipide einen amphiphilen Charakter aufweisen, sollte unter dem AFM untersucht werden, ob diese supramolekulare Strukturen zeigen. Dies wurde in der Tat auch beobachtet. Ebenso konnten mittels der LB-Technik LB-Schichten aus Nukleolipiden dargestellt werden. / The starting point of this work was found in our previous studies about anchoring behaviour of lipidated nucleo-sides and oligonucleotides in biocompatible phospholipid membranes (LUV). That nucleosides and oligonucleotides bear a lipophilic anchor at the 5-position of pyrimidine or at the 8-position of purinbases. This nucleolipi-des anchor well in such membranes, but were not longer available for a Watson-Crick base pairing at the interface to water. Therefore lipophilic groups (alkyl chain, cholesterol, Pyren etc.) were now connected to the 2''-position of nucleosides by several reactions (esterification, thioether binding, carbamoyl binding or "click reaction") and various functional groups (hydroxy, thiohydroxy, azide, amine) to the 2´-position of nucleosides. These nucleolipides also well anchored in the model membranes, and gave first evidence that by introducing a spacer between the nucleoside and the lipophilic anchor a base pairing at the interface to water is possible. However, only one anchor is not sufficient for a stable anchoring in the phospholipid membranes, especially if they are not branched. It was found out that it is insignifacant for the application of oligonucleotides in membrane anchoring, at which position of nucleotide the lipid is attached, because on the one hand, the corresponding nucleolipid can not form a pair with a corresponding nucleobase and secondly, there is no base pairing in the nucleotides situated between two lipidated positions. For biotechnology applications it might be interesting that two different vesicles each of it furnushed with a complementary lipidated oligonucleotide could be kept together in a defined distance by forming double strand DNA. Since nucleolipide possess amphiphilic character, there abillity to form supramolecular structures was investigated by atomic force microscope (AFM). In addition formation of LB-layers could be achieved by LB-technology.