Synthesis of mannose and galactose oligonucleotide conjugates by bi-click chemistry

Glyco oligonucleotide conjugates, each exhibiting two mannose and two galactose residues, were efficiently synthesized by two successive 1,3-dipolar cycloadditions (click chemistry). Two phosphoramidite derivatives were used: one bearing a bromoalkyl group as a precursor to azide functionalization and another bearing a propargyl group. After a first cycloaddition with a mannosyl-azide derivative, the bromine atoms were substituted with NaN(3) and a second click reaction was performed with a 1'-O-propargyl galactose, affording the heteroglyco oligonucleotide conjugate.