New light labile linker for solid phase synthesis of 2′-O-acetalester oligonucleotides and applications to siRNA prodrug development

We report on the synthesis and properties of oligonucleotides containing 2′-O-(levulinic acid) and 2′-O-(amino acid) acetalesters. Given that esters serve as promoieties in several therapeutic prodrugs, we believe that these derivatives will have potential use as nucleic acid prodrugs. In addition, we report on the synthesis of a novel solid support with a photolabile linker that not only allows for the synthesis of oligonucleotides containing various 2′-O-acetalesters, but can be generally adopted to the synthesis of base-sensitive oligoribonucleotides. The release of oligonucleotides from this support is faster than with conventional linkers.

Graphical abstractA novel light labile linker for RNA synthesis was developed and used in the synthesis of acetalester conjugates.Figure optionsDownload full-size imageDownload as PowerPoint slide