Cordycepin analogues of 2-5A and its derivatives. Chemical synthesis and biological activity

• Published in: The Journal of biological chemistry Vol. 258; no. 3; pp. 1671 - 1677
• Main Authors: Sawai, H, Imai, J, Lesiak, K, Johnston, M I, Torrence, P F
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.02.1983; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Deoxyadenine Nucleotides - chemical synthesis; Deoxyadenine Nucleotides - pharmacology; Deoxyadenosines - pharmacology; Encephalomyocarditis virus - genetics; L Cells - metabolism; Mice; Oligodeoxyribonucleotides - chemical synthesis; Oligodeoxyribonucleotides - pharmacology; Oligonucleotides - chemical synthesis; Protein Biosynthesis - drug effects; Rabbits; Reticulocytes - metabolism; RNA, Viral - genetics; Structure-Activity Relationship
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/S0021-9258(18)33038-2

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.