A New Nucleic Acid Prodrug Responsive to High Thiol Concentration: Synthesis of 2′-O-Methyldithiomethyl-Modified Oligonucleotides by Post-Synthetic Modification

This unit describes the synthesis of 2′-O-methyldithiomethyluridine-containing oligonucleotides, which can be deprotected to yield the parental oligoribonucleotides under high concentrations of glutathione similar in cytoplasm. The 2′-O-methyldithiomethyl group is sensitive to reductive conditions, so that it is incompatible to 3′-O-phosphoramidite modification in nucleosides. Thus, a novel post-synthetic approach to obtain 2′-O-methyldithiomethyluridine-containing oligonucleotides was developed, in which 2′-O-(2,4,6-trimethoxybenzylthiomethyl)uridine-modified oligonucleotides are readily converted by treatment with dimethyl(methylthio)sulfonium tetrafluoroborate to the 2′-O-methyldithiomethyluridine-modified oligonucleotides. The 2′-O-methyldithiomethyluridine-modified oligonucleotides are readily and cleanly converted to the parental oligonucleotides under high thiol conditions, such as 10 mM glutathione and dithiothreitol. © 2015 by John Wiley & Sons, Inc.