title: 2-5A analogs as mechanistic probes of the 2-5A system: stereoconfiguration of phosphorothioate analogs of 2-5A markedly influences metabolic stability.
abstract: The stereoconfiguration of the diester bond of phosphorothioate analogs of 2-5A strongly influenced lability to enzymatic hydrolysis by cellular and serum phosphodiesterases. Bonds containing the Sp configuration were extremely resistant to hydrolysis compared to the corresponding Rp configuration linkages. The rate of hydrolysis of the diester bond was influenced by chain length of the adenylate oligomer, with a stability ranking of dimer greater than trimer greater than tetramer; as well as by the stereo-configuration of the diester bond adjacent to the one undergoing hydrolysis. The anti-proliferative and anti-viral activities of these various phosphorothioate 2-5A core analogs were assessed. The most stable analogs possessed the greatest biological activities (at 25-50 microM), which were not readily attributable to 2-5A degradation products or endonuclease activation. A 5'-triphosphate analog of 2-5A containing a phosphorothioate substituent in the gamma-position was obtained in good yield by enzymatic synthesis from ATP-gamma S. This gamma-thio 2-5A analog showed full biological activity.
mesh_terms: D000227:Adenine Nucleotides / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D006868:Hydrolysis; D051379:Mice; D009843:Oligoribonucleotides / Q000378:metabolism* / Q000494:pharmacology; D010755:Organophosphates / Q000378:metabolism* / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000378:metabolism*; D014176:Protein Biosynthesis; D018139:Simplexvirus / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000227:Adenine Nucleotides; D009843:Oligoribonucleotides; D010755:Organophosphates; D009943:Organophosphorus Compounds; C023505:2',5'-oligoadenylate