Tuning of conformational preorganization in model 2′,5′- and 3′,5′-linked oligonucleotides by 3′- and 2′-O-methoxyethyl modification

AUTOR(ES)
FONTE

Oxford University Press

RESUMO

Conformational properties of trimeric and tetrameric 2′,5′-linked oligonucleotides, 3′-MOE-A32′,5′ (1) and 3′-MOE-A42′,5′ (2), and their 3′,5′-linked analogs, 2′-MOE-A33′,5′ (3) and 2′-MOE-A43′,5′ (4), were examined with the use of heteronuclear NMR spectroscopy. The temperature-dependent 3JHH, 3JHP and 3JCP coupling constants, acquired in the range of 273–343 K, gave insight into the conformation of sugar rings in terms of a two-state North ↔ South (N ↔ S) pseudorotational equilibrium and into the conformation of the sugar–phosphate backbone in the model antisense oligonucleotides 1–4. 2′,5′-linked oligomers 3′-MOE-A32′,5′ (1) and 3′-MOE-A42′,5′ (2) show preference for N-type conformers and indication of A-type conformational features, which is prerequisite for antisense hybridization. The drive of N ↔ S equilibrium in 1–4 has been rationalized with the competing gauche effects of 2′/3′-phosphodiester and 3′/2′-MOE groups, anomeric and steric effects. Furthermore, the pairwise comparisons of 3′-MOE with 3′-OH and 3′-deoxy 2′,5′-linked adenine trimers emphasized the fine tuning of N ↔ S equilibrium in 3′-MOE-A32′,5′ (1) and 3′-MOE-A42′,5′ (2) by the steric effects of 3′-MOE group and the possibility of water-mediated H-bonds with vicinal phosphodiester functionality. In full correspondence, the drive of N ↔ S equilibrium towards N by 2′-MOE in 3′,5′-linked analogs 2′-MOE-A33′,5′ (3) and 2′-MOE-A43′,5′ (4) is weaker in comparison with 3′-OH group in the corresponding ribo analogs. βt, γ+ and ε– rotamers are preferred in both 2′,5′- and in 3′,5′-linked oligonucleotides 1–4.

ACESSO AO ARTIGO

Documentos Relacionados