O 4-Thymidinyl functionalization to a solid support enables a versatile 3'-end oligonucleotide conjugation strategy
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Synthesis and Bioconjugation of Thiol-Reactive Reagents for the Creation of Site-Selectively Modified Immunoconjugates
Published on: March 6, 2019
Nicholas G Horton1, Evan Zakaria1, Dara V Grebennikova1
1Department of Chemistry, University of Guelph 50 Stone Rd. E Guelph N1G 2W1 ON Canada doflaher@uoguelph.ca.
Abstract:
Conjugation of ligands to oligonucleotides represents an effective strategy for modulating and enhancing the physicochemical and biological properties of nucleic acids, including cellular uptake and delivery, bioavailability, and capabilities for detection and tracking. Here, we report a straightforward conjugation methodology from a readily accessible unit containing a 3'-azido functional group and an alkylene linker from the O 4-position of a thymidinyl unit to a solid support. We showcase that this unit is compatible with efficient post-elongation on-column strain-promoted azide-alkyne cycloaddition (SPAAC) chemistry. Alternatively, it may be efficiently reduced to the corresponding amino group on-solid support, allowing for a variety of amidation reactions with model ligand handles. We show compatibility with both DNA and RNA. Ultimately, our newly developed strategy consists of a unified unit capable of pre- and post-strand assembly conjugation, and will find applications in multiple (bio)conjugation contexts.
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