Efficient RNA-targeting by the introduction of aromatic stacking in the duplex major groove via 5-(l-phenyl-l,2,3-triazol-4-yl)-2'-deoxyuridines

摘要

Three pyrimidine nucleosides with differently substituted phenyltriazoles attached to the 5-position were prepared by Cu(I)-assisted azide-alkyne cycloadditions (CuAAC) and incorporated into oligonucle-otides. Efficient pai-pai-stacking between two or more phenyltriazoles in the major groove was found to increase the thermal stability of a DNA:RNA duplex significantly. The best stacking, and most stable duplex, was obtained by a sulfonamide substituted derivative.The nucleic acid duplex constitutes an excellent scaffold for chemically designed supramolecular chemistry.1 The duplex is formed between complementary oligonucleotide sequences on the basis of selective hydrogen-bonding and strong pai-pai-stacking of the nucleobases. With the aim of targeting RNA-sequences by synthetic oligonucleotides, following the so-called antisense approach,2 the idea of synthetically increasing the stability of the duplex by increasing the stacking has been approached in several ways including synthetic nucleobases with larger ring systems.3 A major example is a tricyclic phenoxazine replacing a cytosine and increasing the thermal stability of a DNA:RNA duplex with up to 5 degC per modification. Furthermore, the 5-position of pyrimidine nucleosides has been functionalised with the propyn-1-yl group5 as well as with five-membered heterocycles, and these modifications have been found to increase the duplex stability via increased pai-pai-stacking.