Insertion of Chemical Handles into the Backbone of DNA during Solid‐Phase Synthesis by Oxidative Coupling of Amines to Phosphites

Author:

Hansen Rikke A.1,Märcher Anders1,Pedersen Kristian Nørgaard1,Gothelf Kurt V.1ORCID

Affiliation:

1. sDepartment of Chemistry and Interdisciplinary Nanoscience Centre (iNANO) Aarhus University Gustav Wieds Vej 14 8000 Aarhus Denmark

Abstract

AbstractConjugation of molecules or proteins to oligonucleotides can improve their functional and therapeutic capacity. However, such modifications are often limited to the 5′ and 3′ end of oligonucleotides. Herein, we report the development of an inexpensive and simple method that allows for the insertion of chemical handles into the backbone of oligonucleotides. This method is compatible with standardized automated solid‐phase oligonucleotide synthesis, and relies on formation of phosphoramidates. A unique phosphoramidite is incorporated into a growing oligonucleotide, and oxidized to the desired phosphoramidate using iodine and an amine of choice. Azides, alkynes, amines, and alkanes have been linked to oligonucleotides via internally positioned phosphoramidates with oxidative coupling yields above 80 %. We show the design of phosphoramidates from secondary amines that specifically hydrolyze to the phosphate only at decreased pH. Finally, we show the synthesis of an antibody‐DNA conjugate, where the oligonucleotide can be selectively released in a pH 5.5 buffer.

Funder

Novo Nordisk Fonden

Danmarks Frie Forskningsfond

Publisher

Wiley

Subject

General Medicine

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