Synthesis, characterization, and biological properties of 8-azido- and 8-amino-substituted 2',5'-oligoadenylates.
A series of 8-azido- and 8-amino-substituted 2',5'-oligoadenylatyes was prepared by a uranyl-ion catalyzed polymerization of the corresponding 8-substituted adenosine phosphorimidazolide. Subsequent 5'-dephosphorylation of the resulting 5'-phosphoryl 2',5'-linked oligomers with alkaline phosphatase gave the corresponding core oligomers. The CD spectra indicated that the 8-aminoadenosine analogue of the 2',5'-linked trimer has an anti-orientation as in naturally occurring 2',5'-oligoadenylates, while 8-azido-substituted 2',5'-oligoadenylates have a syn-orientation. The 8-substituted oligomers showed enhanced resistance against digestion by snake venom phosphodiesterase. The 2',5'-linked 8-azidoadenylate trimer and tetramer displayed strong RNase L binding and activating ability, although the corresponding dimer is devoid of such activities. In contrast, very low or no RNase L binding and activating ability were observed in the 8-aminoadenosine analogue of 2',5'-oligoadenylates. Results indicate that the bulkiness and ionic character of the 8-substituting group have significant effects on the ability of these analogues to bind and activate RNase L. Furthermore, the orientation of the glycosidic base in the 2-5A analogues may change from syn to anti during binding to RNase L. The 8-azidoadenosine analogues of 2-5A will be useful tools in the photoaffinity labeling of RNase L, due to their strong RNase L binding ability. In addition, these 8-azidoadenosine compounds may be considered as candidates for experimental therapeutic agents because they have enhanced stability to enzyme degradation while retaining the ability to activate RNase L.
Department of Applied Chemistry, Faculty of Engineering, Gunma University, Kiryu, Gunma 376-8515 Japan. sawai@chem.gunma-u.ac.jp
Hiroaki
H
Sawai
Atushi
A
Hirano
Hiroyuki
H
Mori
Kazuo
K
Shinozuka
Beihua
B
Dong
Robert H
RH
Silverman
D000227:Adenine Nucleotides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000469:Alkaline Phosphatase / Q000737:chemistry; D000588:Amines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001386:Azides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002942:Circular Dichroism; D004355:Drug Stability; D004722:Endoribonucleases / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008968:Molecular Conformation; D009843:Oligoribonucleotides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D043264:Phosphodiesterase I / Q000737:chemistry; D019920:Photoaffinity Labels / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D012910:Snake Venoms / Q000737:chemistry; D013329:Structure-Activity Relationship; D014020:Tissue Extracts / Q000378:metabolism
D000227:Adenine Nucleotides; D000588:Amines; D001386:Azides; D009843:Oligoribonucleotides; D019920:Photoaffinity Labels; D012910:Snake Venoms; D014020:Tissue Extracts; C023505:2',5'-oligoadenylate; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease; D000469:Alkaline Phosphatase; D043264:Phosphodiesterase I; C470790:phosphodiesterase I, snake venom