2',5'-Oligoadenylates and related 2',5'-oligonucleotide analogues. 2. Effect on cellular proliferation, protein synthesis, and endoribonuclease activity.
A number of the new enzymatically synthesized 2',5'-oligonucleotide trimers, namely, those containing the nucleosides 8-azaadenosine, toyocamycin, sangivamycin, formycin, 8-bromoadenosine, tubercidin, and guanosine, were found to inhibit protein synthesis and cellular proliferation after uptake into intact L and HeLa cells. 2',5'-Oligonucleotide trimers containing cytidine, inosine, uridine, and 1,N6-ethenoadenosine had some effect while those containing 2-chloroadenosine, 3-ribosyladenine, ribavirin, and 2-beta-D-ribofuranosylthiazole-4-carboxamide had no detectable effect on protein synthesis or cellular proliferation after uptake into L or HeLa cells. All of these 2',5'-oligonucleotide analogues inhibited protein synthesis in the in vitro rabbit reticulocyte lysate system except for the trimer containing ribavirin. Such nucleoside substitutions have further defined the substrate-specificity requirements for the endoribonuclease and/or the inhibitors for the 2',5'-phosphodiesterase. Most of the 2',5'-analogues were degraded in L-cell extracts so the endogenous nucleases are not very specific. The 2',5'-trimers containing tubercidin and 2-beta-D-ribofuranosylthiazole-4-carboxamide were quite stable in comparison to the 2',5'-A trimer. The inhibition of protein synthesis and cellular proliferation observed correlated well with the degradation of rRNA and polyadenylated mRNA observed after uptake of the 2',5'-analogues into intact L cells. The degradation of the polyadenylated mRNA appeared to be a more sensitive test than inhibition of cellular protein synthesis for determining biological activities of the 2',5'-oligonucleotide analogues.
D000227:Adenine Nucleotides / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001692:Biological Transport; D002455:Cell Division / Q000187:drug effects; D004722:Endoribonucleases / Q000378:metabolism*; D006367:HeLa Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007700:Kinetics; D007739:L Cells / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009841:Oligonucleotides / Q000378:metabolism / Q000494:pharmacology*; D009843:Oligoribonucleotides / Q000378:metabolism / Q000494:pharmacology*; D014176:Protein Biosynthesis / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000227:Adenine Nucleotides; D009841:Oligonucleotides; D009843:Oligoribonucleotides; C023505:2',5'-oligoadenylate; D004722:Endoribonucleases