Synthesis and DNA binding affinity of irregular sequence oligonucleotides with triazole internucleotide linkages.

Abstract

A novel class of backbone-modified oligonucleotide analogs has emerged since the discovery of CuI-catalyzed [3+2] azide-alkyne cycloaddition. These are oligonucleotide analogs with 1,4-substituted 1,2,3-triazoles in internucleotide linkages. Of all such analogs known to date, only the triazole-linked deoxythymidine decamer has been reported to show enhanced binding affinity to complementary DNA. Importantly, it is a fully modified (dT)10 analog. Irregular oligonucleotides bearing the same backbone modification have not been described so far. With a goal of investigating sequence and regularity dependence of the effect of this modification on duplex stability, we have designed sequentially heterogenous modified oligonucleotides, which can be prepared using a modified dinuleoside block. In this paper we report on the synthesis of the dithymidine phosphoramidite block with the triazole linker, its utilization in oligonucleotide synthesis and hybridization data of thus obtained oligonucleotide analogs. The effect of single and multiple modifications on stability of irregular sequence duplexes is assessed and compared with published data for the oligo(T)/oligo(A) duplex. We also compare the effect of the linker concerned with that of a shorter triazole linker.