Conformation analysis of 3'-fluorinated A(2'-5')A(2'-5')A fragments. Relation between conformation and biological activity.

A one- and two-dimensional NMR study has been performed on seven A(2'-5')A(2'-5')A fragments containing 9-(3'-fluoro-3'-deoxy-beta-D-xylofuranosyl)-adenine (AF) or 3'-fluoro-3'-deoxyadenosine (AF) residues at different positions, and on the corresponding monomers. A(2'-5')A(2'-5')A served as a reference compound. The fluoro substituent governs the conformation of the sugar ring: an AF residue displays mainly N-type sugar and the ring is considerably flattened (phi N approximately 30 degrees) compared to AF residues (phi S approximately 40 degrees), which exhibit almost pure S-type conformation. Moreover, in AF moieties the rotamer distribution around torsion angle gamma (O5'-C5'-C4'-C3') and the base orientation are influenced to a large extent by the presence of the fluorine substituent. The sugar rings of nonfluorinated residues in the trimers appear rather flexible. A possible correlation between the conformational characteristics of the fluorinated fragments and their biological activity has been found: the fragments that meet the prerequisites for binding to RNase L indeed show enhanced binding to this endonuclease. Furthermore, substitution of the 3'-OH group of the second residue by hydrogen or of the 3'-OH group of the 2'-terminal residue by fluorine or hydrogen results in increased resistance towards 2'-5'-phosphodiesterase.