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

Conformational properties of trimeric and tetrameric 2',5'-linked oligonucleotides, 3'-MOE-A3(2',5') (1) and 3'-MOE-A4(2',5') (2), and their 3',5'-linked analogs, 2'-MOE-A3(3',5') (3) and 2'-MOE-A4(3',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-A3(2',5') (1) and 3'-MOE-A4(2',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-A3(2',5') (1) and 3'-MOE-A4(2',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-A3(3',5') (3) and 2'-MOE-A4(3',5') (4) is weaker in comparison with 3'-OH group in the corresponding ribo analogs. Beta(t), gamma+ and epsilon- rotamers are preferred in both 2',5'- and in 3',5'-linked oligonucleotides 1-4.