Expanding the Scope of 2′-SCF(3) Modified RNA

The 2′-trifluoromethylthio (2′-SCF(3)) modification endows ribonucleic acids with exceptional properties and has attracted considerable interest as a reporter group for NMR spectroscopic applications. However, only modified pyrimidine nucleosides have been generated so far. Here, the syntheses of 2′-SCF(3) adenosine and guanosine phosphoramidites of which the latter was obtained in highly efficient manner by an unconventional Boc-protecting group strategy, are reported. RNA solid-phase synthesis provided site-specifically 2′-SCF(3)-modified oligoribonucleotides that were investigated intensively. Their excellent behavior in (19)F NMR spectroscopic probing of RNA ligand binding was exemplified for a noncovalent small molecule–RNA interaction. Moreover, comparably to the 2′-SCF(3) pyrimidine nucleosides, the purine counterparts were also found to cause a significant thermodynamic destabilization when located in double helical regions. This property was considered beneficial for siRNA design under the aspect to minimize off-target effects and their performance in silencing of the BASP1 gene was demonstrated.