Development of a novel nucleoside analogue with S-type sugar conformation: 2′-deoxy-trans-3′,4′-bridged nucleic acids

Two novel trans-3′,4′-bridged nucleic acid (trans-3′,4′-BNA) monomers, one with a 3,5,8-trioxabicyclo[5.3.0]decane structure and the other with a 4,7-dioxabicyclo[4.3.0]nonane structure, were successfully synthesized from thymidine. The locked trans-fused ring structures of the nucleoside analogues were confirmed by X-ray crystallography, which also indicated that their furanose rings had a typical S-type conformation involving C_2′-endo or C_3′-exo sugar puckering, respectively, and the same ring conformation as that observed in the B-type helical structure of the DNA duplex.     

Synthesis and properties of trans-3',4'-bridged nucleic acids having typical S-type sugar conformation

The synthesis of nucleoside analogues with a conformationally restricted sugar moiety is of great interest. The present research describes the synthesis of BNA (bridged nucleic acid) monomers 1 and 2 bearing a 4,7-dioxabicyclo[4.3.0]nonane skeleton and a methoxy group at the C2' position. Conformational analysis showed that the sugar moiety of these monomers is restricted in a typical S-type conformation. It was difficult to synthesize the phosphoramidite derivative of the ribo-type monomer 1, while the phosphoramidite of the arabino-type monomer 2 was successfully prepared and incorporated into oligodeoxynucleotides (ODNs). The hybridization ability of the obtained ODN derivatives containing 2 with complementary strands was evaluated by melting temperature (T(m)) measurements. As a result, the ODN derivatives hybridized with DNA and RNA complements in a sequence-selective manner, though the stability of the duplexes was lower than that of the corresponding natural DNA/DNA or DNA/RNA duplex.