Synthesis and biological activities of oligo(8-bromoadenylates) as analogues of 5'-O-triphosphoadenylyl(2'----5')adenylyl(2'----5')adenosine.

The 8-bromoadenosine analogue of 5'-O-triphosphoadenylyl(2'----5')adenylyl(2'----5')adenosine (2-5A) and its derivatives were synthesized, and their biological activity was evaluated in mouse L cell extracts. All compounds, except 5'-dephosphorylated "cores" bound to the 2-5A-dependent endonuclease with a relative activity, depending on the derivative, of 1 to 0.035 of that of 2-5A trimer. 8-Bromoadenylate trimer 5'-mono-, -di, and -triphosphates inhibited protein synthesis with a relative activity of 0.0023, 0.050, and 0.015 compared to 2-5A. Tetramer 5'-monophosphate also inhibited protein synthesis (relative activity 0.0033). The corresponding pentamer 5'-monophosphate did not; however, the pentamer 5'-diphosphate was able to inhibit translation (relative activity 0.0092). All compounds that possessed inhibitory activity in the protein synthesis inhibition assay gave ribosomal RNA cleavage patterns characteristic of the action of 2-5A-dependent endonuclease. Thus, 8-bromination of the all of the adenine rings of 2-5A leads to 20- to 70-fold reduction in the biological activity of the corresponding 5'-di- and -triphosphate, respectively; however, this same alteration of the three adenine moieties gives rise to a 5'-monophosphate with much enhanced translational inhibitory activity compared to the parent 2-5A trimer 5'-monophosphate.