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

doi:10.1093/nar/gkg305

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Nucleic Acids Research, 2003, Vol. 31, No. 8 2066-2076
© 2003 Oxford University Press

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

Matja $z$ Polak, Muthiah Manoharan¹, Gopal B. Inamati¹ and Janez Plavec

Slovenian NMR Center, National Institute of Chemistry, Hajdrihova 19, SI-1001 Ljubljana, Slovenia and ¹ Department of Medicinal Chemistry, Isis Pharmaceuticals Inc., Carlsbad, CA 92008, USA

*To whom correspondence should be addressed. Tel: +386 147 60 353; Fax: +386 147 60 300; Email: janez.plavec{at}ki.si

Conformational properties of trimeric and tetrameric 2',5'-linkedoligonucleotides, 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 ³J_HH, ³J_HP and ³J_CP coupling constants,acquired in the range of 273–343 K, gave insight intothe conformation of sugar rings in terms of a two-state North ${leftrightarrow}$ South (N ${leftrightarrow}$ S) pseudorotational equilibrium and into the conformationof the sugar–phosphate backbone in the model antisenseoligonucleotides 1–4. 2',5'-linked oligomers 3'-MOE-A₃^2'^,5^'(1) and 3'-MOE-A₄²^'^,5^' (2) show preference for N-type conformersand indication of A-type conformational features, which is prerequisitefor antisense hybridization. The drive of N ${leftrightarrow}$ S equilibrium in1–4 has been rationalized with the competing gauche effectsof 2'/3'-phosphodiester and 3'/2'-MOE groups, anomeric and stericeffects. Furthermore, the pairwise comparisons of 3'-MOE with3'-OH and 3'-deoxy 2',5'-linked adenine trimers emphasized thefine tuning of N ${leftrightarrow}$ S equilibrium in 3'-MOE-A₃²^'^,5^' (1) and 3'-MOE-A₄²^'^,5^'(2) by the steric effects of 3'-MOE group and the possibilityof water-mediated H-bonds with vicinal phosphodiester functionality.In full correspondence, the drive of N ${leftrightarrow}$ S equilibrium towardsN 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 correspondingribo analogs. ß^t, ${gamma}$ ⁺ and ${epsilon}$ ^– rotamers are preferredin both 2',5'- and in 3',5'-linked oligonucleotides 1–4.

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