Syntheses and properties of conformationally restrained nucleosides and oligonucleotides analogues

Abstract

This review summarizes our efficient syntheses of novel bicyclic nucleoside analogues, 3'-O,4'-C-methyleneribonucleosides (1) (4-BC type nucleoside analogue), 2'-O,4'-C-methyleneribonucleosides (2) (5-BC), 3'- amino-3'-deoxy-3'-N,4'-C-methyleneribonucleosides (3) (aza 4-BC), and 3'- azido- and 3'-amino-3'-deoxy-2'-O,4'-C-methyleneribonucleosides (4, 5) (aza 5-BC). From 1H-NMR and X-ray crystallographic analyses, the 4-BC and aza 4- BC type nucleoside analogues (1, 3) were found to have a S-conformation predominantly, while the conformations of 5-BC and aza 5-BC type nucleoside analogues (2, 4, 5) were exclusively locked in N-form. The 4-BC and 5-BC type nucleoside analogues (1, 2) were effectively introduced into oligonucleotides using a DNA synthesizer. Furthermore, unprecedented hybridizing ability towards complementary RNA and DNA, RNA selectivity, potent triplex forming ability, and sufficient enzymatic stability of these modified oligonucleotides were also confirmed. These results should reveal a promising route to the development of antisense/antigene methodology.