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
| Autor: | Elena N. Kalinichenko, Beihua Dong, Jouko Vepsäläinen, Paul F. Torrence, Igor A. Mikhailopulo, Tatiana L Podkopaeva, Elena V Budko, Robert H. Silverman, Frank Seela |
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| Rok vydání: | 2004 |
| Předmět: |
Circular dichroism
Ribonucleotide Magnetic Resonance Spectroscopy Stereochemistry RNase P Nitrogen Clinical Biochemistry Oligonucleotides Pharmaceutical Science Trimer Biochemistry Chemical synthesis Tubercidin Phosphates chemistry.chemical_compound Mice Tetramer Drug Discovery Endoribonucleases Animals Humans Glycosyl Ribonuclease Molecular Biology Chromatography High Pressure Liquid biology Molecular Structure Chemistry Adenine Circular Dichroism Organic Chemistry Stereoisomerism Enzyme Activation biology.protein Molecular Medicine |
| Zdroj: | Bioorganicmedicinal chemistry. 12(13) |
| ISSN: | 0968-0896 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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