Synthesis and biological activity of uronic acid analogues of 2-5A[5'-O-triphosphoryladenylyl(2----5')adenylyl-(2'----5')adenosine].
The oligonucleotide ppp5'A2'p5'A2'p5'A, known as 2-5A, is a potent translational inhibitor involved in some aspects of interferon action. To explore the specific function of the charged 5'-triphosphate moiety, we prepared a series of congeners in which the 5' region was hypermodified. Thus, uronic acid derivatives were substituted for the 5' terminal adenosine residue of 2-5A. Compounds 9, 10, 11 and 12 carried adenosine 5'-uronic acid, ethyl adenosine 5'-uronate, adenosine 5'-uronamide, and adenosine 5'-(N-ethyl)uronamide, respectively, in place of the 5' terminal adenosine triphosphate moiety of 2-5A. While all the analogues showed some weak interaction with the 2-5A-dependent endonuclease (RNase L), compound 9 showed the strongest binding ability, and while unable to activate the mouse RNase L, could activate human RNase at a concentration 100-fold greater than that required for the parent 2-5A. This result suggests that the function of the 5'(poly)phosphate moiety of 2-5A may be fulfilled by some other anionic moiety.
Kinjo
J E
JE
Section of Biomedical Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
Pabuccuoglu
A
A
Alster
D K
DK
Lesiak
K
K
Torrence
P F
PF
D000227:Adenine Nucleotides / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D004722:Endoribonucleases / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008221:Lymphoid Tissue / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D009841:Oligonucleotides / Q000138:chemical synthesis* / Q000494:pharmacology; D009843:Oligoribonucleotides / Q000138:chemical synthesis* / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D014574:Uronic Acids / Q000138:chemical synthesis* / Q000494:pharmacology
D000227:Adenine Nucleotides; D009841:Oligonucleotides; D009843:Oligoribonucleotides; D011500:Protein Synthesis Inhibitors; D014574:Uronic Acids; C023505:2',5'-oligoadenylate; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease