Mitsunobu reactions of 5-fluorouridine with the terpenols phytol and nerol: DNA building blocks for a biomimetic lipophilization of nucleic acids.

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% Cl2 CHCOOH in CH2 Cl2 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(®) (→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.