Conformational 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‐β‐D‐xylofuranosyl)‐adenine (A F ) or 3′‐fluoro‐3′‐deoxyadenosine (A F ) 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 A F residue displays mainly N ‐type sugar and the ring is considerably flattened (ø N ∼ 30°) compared to A F residues (ø S ∼ 40°), which exhibit almost pure S ‐type conformation. Moreover, in A F moieties the rotamer distribution around torsion angle γ (O5′‐C5′‐C4′‐C3′) and the base orientation are influenced to a large extent by the preseñce 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.