Synthesis of oligonucleotide 2′-conjugates via amide bond formation in solution

An efficient method for synthesis of 2′-O-carboxymethyl oligonucleotides is described. Fully deprotected oligonucleotides containing a carboxymethyl group at the 2′-position of sugar residue were obtained by a two-step procedure by periodate cleavage of an oligonucleotide containing 1,2-diol group followed by oxidation of the 2′-aldehyde resulted with sodium chlorite. 2′-O-Carboxymethyl oligonucleotides prepared were efficiently coupled in aqueous solution in the presence of a water-soluble carbodiimide to a number of amino acid derivatives or short peptides to afford novel 2′-conjugates of high purity in good yield. The method is thus shown to be suitable in principle for preparation of oligonucleotide–peptide conjugates containing an amide linkage between the 2′-carboxy group of a modified oligonucleotide and the amino terminus of a peptide.