Mitsunobu Reactions of 5-Fluorouridine with the Terpenols Phytol and Nerol: DNA Building Blocks for a Biomimetic Lipophilization of Nucleic Acids

Abstract

The cancerostatic 5-fluorouridine (5-FUrd; 1) was sequentially sugar-protected by introduction of a 2,3-O-heptylidene ketal group (2), followed by 5-O-monomethoxytritylation (3). This fully protected derivative was submitted to Mitsunobu reactions with either phytol ((Z and E)-isomer) or nerol ((Z)-isomer) to yield the nucleoterpenes 4a and 4b. Both were 5-O-deprotected with 2% Cl2CHCOOH in CH2Cl2 to yield compounds 5a and 5b, respectively. These were converted to the 5-O-cyanoethyl phosphoramidites 6a and 6b, respectively. Moreover, the 2,3-O-(1-nonyldecylidene) derivative, 7a, of 5-fluorouridine was resynthesized and labelled at C(5) with an Eterneon-480 fluorophor((R)) (7b). The resulting nucleolipid was studied with respect to its incorporation in an artificial bilayer, as well as to its aggregate formation. Additionally, two oligonucleotides carrying terminal phytol-alkylated 5-fluorouridine tags were prepared, one of which was studied concerning its incorporation in an artificial lipid bilayer.