The evaluation of 2′- and 6′-substituted carbocyclic nucleosides as building blocks for antisense oligonucleotides

Oligodeoxyribonucleotides incorporating 2′- or 6′-alkoxy substituted carbocyclic nucleotide units are shown to bind to complementary RNA with lower affinity than their unmodified parent compounds, while the presence of stretches of contiguous 6′-hydroxy substituted building blocks enhances RNA-binding affinity. 6′-substituted carbocyclic nucleotides are generally found to increase oligonucleotide resistance to enzymatic degradation, the effect being more pronounced for larger substituents.