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Abstract. The synthesis of two sets of analogues of 2-5A trimer containing 943-fluoro-3-deoxy-P-D-xylo-furanosy1)adenine (AF) or 3'-fluoro-3'-deoxyadenosine (A F) at different positions of the chain is described, along with the preparation of the corresponding 5'-monophosphates and 5'-diphosphorylated (core) trimers. The ability of each rib0 and xylo isomeric pair of fluorodeoxy analogues of 2-5A ( i ) to compete with p3(A2'p),A3'[32P]pC3'p for binding to RNase L in L929 cell extracts, and (ii) to activate the partially purified RNase L from L,, cell extracts to hydrolyze p~l y ( U ) [~H ] , was compared to that of the related 3'-deoxy analogue [Torrence et al., J . Biol. Chem. 263, 1131(1988] and the parent trimer, p3A,, using radiobinding and RNase L-(2'Jr)pentaadenylate(core)-agarose assays, respectively. Evidence is presented to show that the stereochemistry of the trimers plays an important role, specifically in the second process. The most striking observation is that, compared to 2-5A, p3A(AF)A was found to be nine times more effective an activator of RNase L, whereas isomeric p3A(AF)A is 30 times less effective.

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 (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 (øN∼ 30°) compared to AF residues (øS∼ 40°), which exhibit almost pure S‐type conformation. Moreover, in AF 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.