2',5'-Oligoadenylates and related 2',5'-oligonucleotide analogs. 2. Effect on cellular proliferation, protein synthesis, and endoribonuclease activity

• Published in: Biochemistry (Easton) 1983-04, Vol.22 (9), p.2127-2135
• Main Authors: Hughes, Bronwyn G, Robins, Roland K
• Format: Article
• Language: English
• Subjects: Adenine Nucleotides - metabolism; Adenine Nucleotides - pharmacology; Animals; Biological Transport; Cell Division - drug effects; Endoribonucleases - metabolism; HeLa Cells - drug effects; HeLa Cells - physiology; Humans; Kinetics; L Cells (Cell Line) - drug effects; L Cells (Cell Line) - physiology; Mice; Oligonucleotides - metabolism; Oligonucleotides - pharmacology; Oligoribonucleotides - metabolism; Oligoribonucleotides - pharmacology; Protein Biosynthesis - drug effects; Structure-Activity Relationship
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/bi00278a012

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.