Manual and automated synthesis of modified oligonucleotides on core–shell solid supports

• Oligonucleotides were prepared using a hybrid core–shell solid support made of PS and PEG through phosphoramidite chemistry. • The core–shell supports provided good yields when phosphoramidites were dissolved in dichloromethane. • Oligonucleotides with natural phosphate, phosphorothioate, lipid conjugates and mesyl phosphoramidate dimers were synthesized. • This is the first use of core–shell particles to prepare chemically modified oligonucleotide of therapeutic significance. A critical step in the manufacturing of oligonucleotides is the selection of ideal solid supports. Herein, we evaluate a hybrid core–shell solid support made of polystyrene and polyethyleneglycol, for the preparation of oligonucleotides using phosphoramidite chemistry. The results were compared with those obtained using conventional solid supports including controlled-pore glass and polystyrene NittoPhase®. The core–shell supports provided good yields when phosphoramidites were dissolved in dichloromethane. Automatic DNA synthesizer was used to prepare several oligonucleotides carrying natural phosphate, phosphorothioate linkages, lipid conjugates and mesyl phosphoramidate dimers in acceptable yields. This study represents the first reported use of core–shell particles for the synthesis of chemically modified oligonucleotide sequences of therapeutic significance.