Thiol-Specific\nLinkers for the Synthesis of Oligonucleotide\nConjugates via Metal-Free Thiol–Ene Click Reaction

Chemical conjugation of oligonucleotides is widely used\nto improve\ntheir delivery and therapeutic potential. A variety of strategies\nare implemented to efficiently modify oligonucleotides with conjugating\npartners. The linkers typically used for oligonucleotide conjugation\nhave limitations in terms of stability or ease of synthesis, which\ngenerates the need for providing new improved linkers for oligonucleotide\nconjugation. Herein, we report the synthesis of novel vinylpyrimidine\nphosphoramidite building blocks, which can be incorporated into an\noligonucleotide by standard solid-phase synthesis in an automated\nsynthesizer. These linker-bearing oligonucleotides can be easily conjugated\nin a biocompatible manner with thiol-functionalized molecules leading\nto the efficient generation of oligonucleotide conjugates.