Thiol-Specific Linkers for the Synthesis of Oligonucleotide Conjugates via Metal-Free Thiol–Ene Click Reaction

Abstract

Chemical conjugation of oligonucleotides is widely used to improve their delivery and therapeutic potential. A variety of strategies are implemented to efficiently modify oligonucleotides with conjugating partners. The linkers typically used for oligonucleotide conjugation have limitations in terms of stability or ease of synthesis, which generates the need for providing new improved linkers for oligonucleotide conjugation. Herein, we report the synthesis of novel vinylpyrimidine phosphoramidite building blocks, which can be incorporated into an oligonucleotide by standard solid-phase synthesis in an automated synthesizer. These linker-bearing oligonucleotides can be easily conjugated in a biocompatible manner with thiol-functionalized molecules leading to the efficient generation of oligonucleotide conjugates.