Synthesis, Duplex-Forming Ability, and Nuclease Resistance of Oligonucleotides Containing a Thymidine Derivative with a 1-Oxaspiro[4.5]decane Skeleton

• Published in: Chemical & pharmaceutical bulletin Vol. 70; no. 10; pp. 699 - 706
• Main Authors: Osawa, Takashi, Yano, Natsumi, Aoyama, Hiroshi, Obika, Satoshi
• Format: Journal Article
• Language: English
• Published: TOKYO The Pharmaceutical Society of Japan 01.10.2022; Pharmaceutical Soc Japan; Japan Science and Technology Agency
• Subjects: 6′-C-spiro-DNA; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Conformation; Conformational analysis; duplex-forming ability; enzymatic stability; Life Sciences & Biomedicine; Monomers; Nuclease; Nucleic acids; Oligonucleotides; Pharmacology & Pharmacy; Physical Sciences; Ribonucleic acid; RNA; Science & Technology; sugar conformation; Synthesis; Thymidine; torsion angle γ; NUCLEOSIDE ANALOGS; ACIDS; STABILITY; torsion angle y; 6'-C-spiro-DNA; duplex-forming ability; enzymatic stability; sugar conformation; NUCLEOTIDES; DNA; DIVERSITY; CONFORMATIONAL-ANALYSIS; SUGAR RING
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.c22-00458

Chemically modified nucleic acids are essential for the therapeutic application of oligonucleotides. In this study, 6′-C-spiro-thymidine exhibiting a fixed torsion angle γ was designed, synthesized, and incorporated into oligonucleotides. The conformational analysis of the 6′-C-spiro-thymidine monomer revealed that its torsion angle γ was in the +synclinal range (approx. 60°), which is similar to that in a natural RNA duplex, as expected. On the other hand, the sugar conformation of the RNA duplex is known to be predominantly an N-type, whereas that of the synthesized monomer was an S-type. The results of the UV melting analysis demonstrated that the duplex-forming ability of 6′-C-spiro-thymidine was inferior to that of natural DNA. Contrarily, 6′-C-spiro-thymidine could enhance the stability of oligonucleotides toward nucleases. Particularly, the incorporation of 6′-C-spiro-thymidine on the 3′-ends of the oligonucleotides significantly increased the nuclease resistance of the oligonucleotides.