title: 3-Deazaadenosine analogues of p5'A2'p5'A2'p5'A: synthesis, stereochemistry, and the roles of adenine ring nitrogen-3 in the interaction with RNase L.
abstract: Sequence-specific 3-deazaadenosine (c(3)A)-substituted analogues of trimeric 2',5'-oligoadenylate, p5'A2'p5'A2'p5'A, were synthesized and evaluated for their ability to activate human RNase L (EC 3.1.2.6) aiming at the elucidation of the nitrogen-3 role in this biochemical process. Substitution of either 5'-terminal or 2'-terminal adenosine with c(3)A afforded the respective analogues p5'(c(3)A)2'p5'A2'p5'A and p5'A2'p5'A2'p5'(c(3)A) that were as effective as the natural tetramer itself as activators of RNase L (EC(50)=1nM). In contrast, p5'A2'p5'(c(3)A)2'p5'A showed diminished RNase L activation ability (EC(50)=10nM). The extensive conformational analysis of the c(3)A-substituted core trimers versus the parent natural core trimer by the (1)H and (13)C NMR, and CD spectroscopy displayed close stereochemical similarity between the natural core trimer and (c(3)A)2'p5'A2'p5'A and A2'p5'A2'p5'(c(3)A) analogues, thereby strong evidences for the syn base orientation about the glycosyl bond of the c(3)A residue of the latter were found. On the contrary, an analogue A2'p5'(c(3)A)2'p5'A displayed rather essential deviations from the spatial arrangement of the parent natural core trimer.
authors.affiliation: Institute of Bioorganic Chemistry, National Academy of Sciences, 220141 Minsk, Belarus.
authors.forename: Elena N
authors.initials: EN
authors.lastname: Kalinichenko
authors.forename: Tatiana L
authors.initials: TL
authors.lastname: Podkopaeva
authors.forename: Elena V
authors.initials: EV
authors.lastname: Budko
authors.forename: Frank
authors.initials: F
authors.lastname: Seela
authors.forename: Beihua
authors.initials: B
authors.lastname: Dong
authors.forename: Robert
authors.initials: R
authors.lastname: Silverman
authors.forename: Jouko
authors.initials: J
authors.lastname: Vepsäläinen
authors.forename: Paul F
authors.initials: PF
authors.lastname: Torrence
authors.forename: Igor A
authors.initials: IA
authors.lastname: Mikhailopulo
mesh_terms: D000225:Adenine / Q000737:chemistry*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D004722:Endoribonucleases / Q000737:chemistry* / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D015394:Molecular Structure; D009584:Nitrogen / Q000737:chemistry*; D009841:Oligonucleotides / Q000138:chemical synthesis / Q000737:chemistry; D010710:Phosphates / Q000737:chemistry; D013237:Stereoisomerism; D014372:Tubercidin / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D009841:Oligonucleotides; D010710:Phosphates; C018258:3-deazaadenosine; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease; D000225:Adenine; D014372:Tubercidin; D009584:Nitrogen