Cordycepin analogues of 2-5A and its derivatives. Chemical synthesis and biological activity.
Cordycepin (3'-deoxyadenosine) analogues of 2-5A were prepared by dicyclohexylcarbodiimide-induced polymerization of cordycepin 5'-monophosphate. A series of oligomers of the general formula p5'(3'dA)-2'[p5'(3'dA)]n (n = 1-5) was obtained. Cordycepin trimer 5'-monophosphate (n = 2) and cordycepin tetramer 5'-monophosphate (n = 3) were converted to the corresponding 5'-di- and triphosphates via the phosphorimidazolide method. Confirmation of assigned structures was provided through enzyme digestions, 1H and 31P NMR, and comparison with material which was synthesized by a completely independent route. Neither the cordycepin trimer triphosphate, ppp5'(3'dA)-2'p5'(3'dA)2'p5'(3'dA), nor the cordycepin tetramer triphosphate, ppp5'(3'dA)2'p5'(3'dA)2'p5'(3'dA)2'p5'-(3'dA), were inhibitors of translation in cell-free extracts of mouse L-cells programmed with encephalomyocarditis virus. In rabbit reticulocyte lysates, the cordycepin trimer triphosphate was devoid of activity, whereas the cordycepin tetramer triphosphate had approximately 1/100th the activity of 2-5A tetramer triphosphate, ppp5'A2'p5'A2'p5'A2'p5'A. Even though the cordycepin analogues were unable to activate the 2-5A-dependent endoribonuclease, they were able to bind to the endonuclease, thereby antagonizing the translational inhibitory effects of 2-5A. Thus, replacement of the 3'-hydroxyl groups of all the ribose moieties of 2-5A results in an analogue which can bind to the 2-5A-dependent endoribonuclease but is incapable of activating the enzyme. The 3'-hydroxyl groups of 2-5A, therefore, are critical for activation of the 2-5A-dependent endonuclease.
D000818:Animals; D003838:Deoxyadenine Nucleotides / Q000138:chemical synthesis* / Q000494:pharmacology; D003839:Deoxyadenosines / Q000494:pharmacology; D004686:Encephalomyocarditis virus / Q000235:genetics; D007739:L Cells / Q000378:metabolism; D051379:Mice; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis* / Q000494:pharmacology; D009841:Oligonucleotides / Q000138:chemical synthesis*; D014176:Protein Biosynthesis / Q000187:drug effects*; D012367:RNA, Viral / Q000235:genetics; D011817:Rabbits; D012156:Reticulocytes / Q000378:metabolism; D013329:Structure-Activity Relationship
D003838:Deoxyadenine Nucleotides; D003839:Deoxyadenosines; D009838:Oligodeoxyribonucleotides; D009841:Oligonucleotides; D012367:RNA, Viral