Role of the stereochemistry of 3'-fluoro-3'-deoxy analogues of 2-5A in binding to and activation of mouse RNase L

Article abstract of DOI:10.1002/recl.19951140202

The synthesis of two sets of analogues of 2-5A trimer containing 9-(3-fluoro-3-deoxy-β-D-xylo-furanosyl)adenine (A^F) 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 ribo and xylo isomeric pair of fluorodeoxy analogues of 2-5A (i) to compete with p₃(A2'p)₃A3'<32P>pC3'p for binding to RNase L in L₉₂₉ cell extracts, and (ii) to activate the partially purified RNase L from L₉₂₉ cell extracts to hydrolyze poly(U)<3H>, was compared to that of the related 3'-deoxy analogue and the parent trimer, p₃A₃, using radiobinding and RNase L-(2',5')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(A^F)A was found to be nine times more effective an activator of RNase L, whereas isomeric p₃A(A^F)A is 30 times less effective.