A Convergent Click Ligation Approach to the Synthesis of Triazole-incorporated PMOs and Evaluation of Hybridization Properties

The synthesis of Phosphorodiamidate Morpholino Oligonucleotides (PMOs) incorporating single triazole rings in the backbone has been achieved via Cu(I) catalyzed Azide-Alkyne cycloaddition reaction (CuAAC). The synthetic approach implemented, is convergent, involving the ligation of a 5'-azide PMO fragment to 3'-alkyne fragment both in solution and on solid support. To access the 3'-alkyne PMO fragment, we synthesized 3'-N-propargyl chlorophosphoramidate morpholino monomers for all four nucleobases. The resulting triazole-incorporated PMOs (TL-PMOs) have exhibited comparable or improved binding affinity towards complementary DNA/RNA strands compared to its regular analogs.