The synthesis of phosphorodiamidate morpholino oligonucleotides
(PMOs) incorporating single or double triazole rings in the backbone
has been achieved via Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC).
The synthetic approach implemented is fundamentally convergent, involving
the ligation of a 5′-azide PMO fragment to a 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 (TzPMOs) have exhibited comparable
or improved binding affinity toward complementary deoxyribonucleic
acid (DNA)/ribonucleic acid (RNA) strands compared to its regular
analogues. Finally, a full-length TzPMO was designed to target the
Nanog gene, demonstrating almost identical hybridization properties
when compared to its regular version. Circular dichroism studies revealed
a B-type helical conformation for the duplexes formed by TzPMOs.