Rapid routes of synthesis of oligonucleotide conjugates from non-protectedoligonucleotides and ligands possessing different nucleophilic or electrophilic functional groups

Optimized methods are described for post-synthetic conjugation of non-prote cted oligodeoxyribonucleotides tol different ligands. Methods for the termi nal functionalization of oligonucleotides by amino, sulfhydryl, thiophospha te or carboxyl groups using different chemical reactions and linkers in bot h organic and aqueous media are described and compared. Experimental condit ions for subsequent coupling of ligands containing aliphatic and aromatic a mines, aromatic alcohols, carboxylic, sulfhydryl, alkylating, aldehydic and other reactive nucleophilic and electrophilic groups to oligonucleotides w ere established, including covalent linkage to other oligonucleotides.