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Review | Regular issue | Vol 100, No. 5, 2020, pp.681-717
Published online, 22nd January, 2020
DOI: 10.3987/REV-19-922
Bridged Nucleosides as Building Blocks of Oligonucleotides: Synthesis and Properties

Yoshiyuki Hari*

*Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan

Abstract

Bridging between the 2ʹ- and 4ʹ-carbons in a nucleoside restricts the furanose ring to C3ʹ-endo conformation, which coincides with the sugar conformation in an oligonucleotide forming a duplex with single-stranded RNA (ssRNA) and a triplex with double-stranded DNA (dsDNA). Therefore, oligonucleotides modified by 2ʹ,4ʹ-bridged nucleosides generally increase hybridization ability with ssRNA and dsDNA when compared with the natural oligonucleotide. Till date, a large number of 2ʹ,4ʹ-bridged nucleosides with additional two-atom to four-atom bridges between 2ʹ- and 4ʹ-carbons have been developed by many research groups including our group. For this, ionic cyclization, ring-closing metathesis, and radical cyclization have been used so far as the synthetic strategies of bridge constructions. Based on such a background, we recently proposed a 2ʹ,4ʹ-bridged nucleoside possessing 6ʹ-oxygen founded on a new design concept and several types of analogs including 2ʹ-O,4ʹ-C-ethyleneoxy-bridged 5-methyluridine with a four-atom bridge have been developed. In addition, as a new strategy of bridge construction, radical cyclization using the 4ʹ-carbon radical of a nucleoside was exemplified and a promising 2ʹ,4ʹ-bridged nucleoside, the 6ʹ-methyl analog of 2ʹ-O,4ʹ-C-ethylene-bridged 5-methyluridine, was found. This review mainly focuses on our recent results on bridged nucleosides used for chemically modified oligonucleotides. It describes the design and synthesis of the bridged nucleosides, along with the properties of oligonucleotides including bridged nucleosides.