Non-nucleoside building blocks for copper-assisted and copper-free click chemistry for the efficient synthesis of RNA conjugates.
Novel non-nucleoside alkyne monomers compatible with oligonucleotide synthesis were designed, synthesized, and efficiently incorporated into RNA and RNA analogues during solid-phase synthesis. These modifications allowed site-specific conjugation of ligands to the RNA oligonucleotides through copper-assisted (CuAAC) and copper-free strain-promoted azide-alkyne cycloaddition (SPAAC) reactions. The SPAAC click reactions of cyclooctyne-oligonucleotides with various classes of azido-functionalized ligands in solution phase and on solid phase were efficient and quantitative and occurred under mild reaction conditions. The SPAAC reaction provides a method for the synthesis of oligonucleotide-ligand conjugates uncontaminated with copper ions.
Drug Discovery, Alnylam Pharmaceuticals, Cambridge, Massachusetts 02142, USA.
K N
KN
Jayaprakash
Chang Geng
CG
Peng
David
D
Butler
Jos P
JP
Varghese
Martin A
MA
Maier
Kallanthottathil G
KG
Rajeev
Muthiah
M
Manoharan
D003300:Copper / Q000737:chemistry*; D015394:Molecular Structure; D009705:Nucleosides / Q000737:chemistry*; D012313:RNA / Q000737:chemistry*
D009705:Nucleosides; D012313:RNA; D003300:Copper