Analogs of (A2'p)nA. Correlation of structure of analogs of ppp(A2'p)2A and (A2'p)2A with stability and biological activity.
Analogs of (A2'p)2A core and ppp(A2'p)2A were chemically synthesized and their susceptibility to phosphodiesterase degradation and ability to either activate an endonuclease or to inhibit cell growth were determined. The absence of the internal 3'-OH groups ((3'dA2'p)2A) resulted in a 5-fold increase in stability, but also in a 10-fold decrease in activity, as measured by (a) activation of an endonuclease in cell-free extracts and inhibition of protein synthesis in intact cells by the 5'-triphosphate species and (b) inhibition of DNA synthesis in synchronized cells by the core analogs. An uncharged derivative of this analog containing two methylphosphotriesters, although significantly more stable, was even less active. Additional deletion of the terminal 3'-OH ((3'd A2'p)23'dA) resulted in a further 6-fold increase in stability (30-fold overall increase in stability), as well as approximately a 2-fold increase in ability to inhibit cell growth, as compared to the natural 2'5' A core. The analog lacking a terminal 2'-OH as well as lacking the internal 3'-OH group ((3'dA2'p)22'dA) showed an overall 15-fold increased stability, yet showed very little activity in inhibiting cell growth. The most stable (120-fold increased overall stability) as well as most active analog was a xyloadenosine analog of 2'5' A core, (xyloA2'p)2xyloA. These results show that modification of the 3'-terminal OH appears to be most important in increasing 2'-5' A core stability as well as biological activity. However, the mechanism of cell growth inhibition by these 2'-5' A core analogs may involve pathways different from those utilized by the 2'-5' A-dependent endonuclease.
D000227:Adenine Nucleotides / Q000096:biosynthesis / Q000494:pharmacology*; D000818:Animals; D001681:Biological Assay; D002478:Cells, Cultured; D004261:DNA Replication / Q000187:drug effects; D004355:Drug Stability; D007739:L Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009841:Oligonucleotides / Q000494:pharmacology*; D009843:Oligoribonucleotides / Q000096:biosynthesis / Q000494:pharmacology*; D014176:Protein Biosynthesis / Q000187:drug effects; D013329:Structure-Activity Relationship
D000227:Adenine Nucleotides; D009841:Oligonucleotides; D009843:Oligoribonucleotides; C018445:adenosine triphosphate-2',5'-adenosine monophosphate; C023505:2',5'-oligoadenylate