Synthesis of Oligonucleotides Containing 2′-Difluorophosphonylated Thioether Adenosine Derivatives and Study of Their Physicochemical Properties

Efficient introduction of a difluorophosphonylated allyl or propyl thioether onto the 2'-position of adenosine is described. Following the preparation of phosphoramidites derived from these compounds, oligonucleotides incorporating these new chemical modifications were prepared successfully using a 12-mer model sequence. UV-melting experiments revealed a significant decrease in the thermal stability of modified RNA/RNA duplexes. In contrast, enzymatic degradation studies showed that the difluoromethylphosphonate group slows down enzymatic degradation while simultaneously increasing lipophilicity.