Synthesis of the antisense oligonucleotides carrying the modified 2-5A molecules at their 5′-termini and their properties

• Published in: Nucleic Acids Symposium Series 2002-11, Vol.2 (1), p.45-46
• Main Authors: Ueno, Yoshihito, Kato, Yoichiro, Okatani, Shusaku, Kitade, Yukio
• Format: Article
• Language: English
• ISSN: 0261-3166; 1746-8272
• DOI: 10.1093/nass/2.1.45

The synthesis of 8-methyladenosine (l)-substituted 2-5A tetramers with hydroxyalkyl groups at the 5′-phosphates and the corresponding 2-5A-antisense chimeras is described. These oligonucleotides were synthesized by the phosphoramidite method with a DNA/RNA synthesizer. These 2-5A tetramers, 8 and 9, with hydroxyethyl and hydroxybutyl groups at their 5′-phosphates were more resistant to hydrolysis by alkaline phosphatase than those without the hydroxyalkyl groups. Incorporation of the hydroxyethyl group into the 2-5A tetramer and 2-5A-antisense chimera slightly reduced the abilities of their analogs to activate recombinant human RNase L, but the abilities of the 2-5A tetramer, 11, and the 2-5A-antisense chimera, 15, with the hydroxyethyl group and 1 returned to 80 and 50% relative to those of the un-modified oligonucleotides, 7 and 12, respectively. Furthermore, the enzyme activated by 2-5A-antisense chimera 15 cleaved the complementary RNA as efficiently as that activated by 2-5A-antisense chimera 12 without the hydroxyethyl group and 1. Thus, the 2-5A-antisense chimera carrying the hydroxyethyl group and 1 was found to be a good candidate for an antisense molecule.