Synthesis and biological activity of tubercidin analogues of ppp5'A2'p(5'A2'p)n5'A.
A series of tubercidin (7-deazaadenosine) analogues of 2-5A of the general formula p5'(c7A)2'p[5'(c7A)-2'p]n5'(c7A) (n = 0-5) were prepared by lead ion catalyzed polymerization of the 5'-phosphoroimidazolidate of tubercidin. Through the corresponding imidazolidates, these oligonucleotide 5'-monophosphates were converted to the 5'-triphosphates. All reported structures were corroborated by enzyme digestion and 1H or 31P nuclear magnetic resonance. When evaluated for its ability to bind to the 2-5 A-dependent endonuclease of mouse L cells, the tubercidin analogue of trimeric 2-5A, namely, ppp5'(c7A)2'p5'(c7A)2'p5'(c7A), and the corresponding tetramer were bound as effectively as 2-5A itself; nonetheless, it and the corresponding tetramer, ppp5'-(c7A)2'p5'(c7A)2'p5'(c7A)2'p5'(c7A), failed to stimulate the 2-5A-dependent endonuclease as judged by its inability to inhibit translation in extracts of mouse L cells programmed with encephalomyocarditis virus RNA and to give rise to ribosomal RNA cleavage in the same cell system under conditions where 2-5A showed activity at 10(-9) M. The trimer, ppp5'(c7A)2'p5'(c7A)2'p5'(c7A), was an antagonist of 2-5A action in the L cell extract. In the lysed rabbit reticulocyte system, both the trimeric and tetrameric tubercidin 2-5A analogues were bound to the 2-5A-dependent endonuclease as well as 2-5A, but in this case, the tetramer triphosphate, ppp5'(c7A)2'p5'(c7A)2'p5'(c7A)2'p5'(c7A), was just as potent an inhibitor of translation as 2-5A tetramer triphosphate. Moreover, this inhibition was prevented by the established 2-5A antagonist p5'A2'p5'A2'p5'A.(ABSTRACT TRUNCATED AT 250 WORDS)
D000227:Adenine Nucleotides / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D002051:Burkitt Lymphoma; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D006801:Humans; D007202:Indicators and Reagents; D007739:L Cells / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009841:Oligonucleotides / Q000138:chemical synthesis*; D009843:Oligoribonucleotides / Q000138:chemical synthesis* / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects*; D011817:Rabbits; D012156:Reticulocytes / Q000378:metabolism; D012263:Ribonucleosides / Q000138:chemical synthesis*; D013329:Structure-Activity Relationship; D014372:Tubercidin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology
D000227:Adenine Nucleotides; D007202:Indicators and Reagents; D009841:Oligonucleotides; D009843:Oligoribonucleotides; D012263:Ribonucleosides; C023505:2',5'-oligoadenylate; D014372:Tubercidin