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

ABSTRACT

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.