ROLE OF THE STEREOCHEMISTRY OF 3'-FLUORO-3'-DEOXY ANALOGS OF 2-5A IN BINDING TO AND ACTIVATION OF MOUSE RNASE L

The synthesis of two sets of analogues of 2-5A trimer containing 9-(3- fluoro-3-deoxy-beta-D-xylo-furanosyl)adenine (A(F)) or 3'-fluoro-3'-de oxyadenosine (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'[P-32]pC3' p for binding to RNase L in L929 cell extracts, an d (ii) to activate the partially purified RNase L from L929 cell extra cts to hydrolyze poly(U)[H-3], was compared to that of the related 3'- deoxy analogue [Torrence et al., J. Biol. Chem. 263, 1131 (1988)] and the parent trimer, p3A3, using radiobinding and RNase L-(2',5')pentaad enylate(core)-agarose assays, respectively. Evidence is presented to s how that the stereochemistry of the trimers plays an important role, s pecifically in the second process. The most striking observation is th at, compared to 2-5A, p3A(A(F))A was found to be nine times more effec tive an activator of RNase L, whereas isomeric p3A(A(F))A is 30 times less effective.