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.
Sawai
Hiroaki
H
Department of Applied Chemistry, Faculty of Engineering, Gunma University, Kiryu, Gunma 376-8515 Japan. sawai@chem.gunma-u.ac.jp
Hirano
Atushi
A
Mori
Hiroyuki
H
Shinozuka
Kazuo
K
Dong
Beihua
B
Silverman
Robert H
RH
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