Synthesis and properties of oligodiaminogalactoses that bind to A-type oligonucleotide duplexes

Abstract

Recently, double-stranded oligonucleotide therapeutics with A-type duplex structures such as short interfering RNAs have gained considerable attention. We have reported the synthesis of cationic oligosaccharides that selectively bind to A-type oligonucleotide duplexes. In particular, oligodiaminogalactose (ODAGal) has a strong stabilizing effect on A-type oligonucleotide duplexes. However, an efficient synthetic method has not been established for ODAGals and the properties of ODAGals have been investigated only up to 4mer. The most crucial problem of the synthesis was side reactions on a p-methoxybenzyl (PMB) protecting group of a 3-hydroxy group. In this paper, the benzyl (Bn) group was chosen as a protecting group of the 3-hydroxy group to suppress the side reactions on protecting groups, and the yields of glycosylation reactions were significantly improved. Moreover, optimization of the conditions for the deprotection of the Bn groups allowed the efficient synthesis of fully deprotected ODAGals, and ODAGal 5mer and 6mer were synthesized for the first time. In addition, we systematically investigated the effects of these ODAGals on the properties of several oligonucleotide duplexes. It was found that ODAGal 4–6mers stabilized the A-type oligonucleotide duplexes thermally and biologically, typically without their structural changes and the effect was notable with longer ODAGals.