Synthesis of 2′-O-[3-(N-methylsulfamoyl)propan-1-yl]ribothymidine as a potentially applicable 2′-modified nucleoside for antisense oligonucleotides

Abstract

A synthetic scheme was developed to derive a modified ribothymidine bearing a 3-(N-methylsulfamoyl)propyl group on 2′-oxygen (TMSP). For synthesis initiation, a nucleophilic attack of 1,2-ethanediol on 5′-protected 2,2′-anhydro-ribothymidine was performed to selectively modify the 2′-position. After protection of the 3′-hydroxy group, the hydroxyethyl group was oxidized to the aldehyde, which was coupled with isobutyl (diethoxyphosphinyl)methanesulfonate through the Horner–Wadsworth–Emmons reaction to yield the sulfonate intermediate. The intermediate was further converted to the desired TMSP. Using the phosphoramidite units derived from nucleosides, we synthesized oligonucleotides incorporating TMSP. Oligonucleotides modified with TMSP were found to have duplex stability, resistance toward 3′-exonuclease digestion, and antisense activity comparable to that of the oligonucleotide modified with a previously reported 2′-O-methylcarbamoylethyl group. Based on these results and the generality of the synthetic scheme, 2′-O-sulfamoylalkyl modification is expected to be used for the modulation of the properties of oligonucleotides by changing the substituents on the nitrogen, enabling the oligonucleotides to possess suitable properties for antisense oligonucleotides.