Consequences of P ‐Chirality in Chimeric 2′‐ O ‐Methyloligoribonucleotides with Stereoregular Methylphosphonothioate Linkages

Stereoregular chimeric oligonucleotides modified with diastereomerically pure methylphosphonothioate linkages interact with complementary DNA or RNA templates in a stereodependent manner. There is an unprecedented large difference in the stability of duplexes of oligonucleotides modified with alternating methylphosphonothioate linkages (Δ T m = 34 °C) that is dependent only on the stereochemistry of the methylphosphonothioate phosphorus centres. The nature of these interactions was studied by circular dichroism and NMR spectroscopy, and a thermodynamic analysis was performed. The collected data indicate that the absolute configuration at the P ‐chiral methylphosphonothioate linkages in chimeric 2′‐ O ‐methylribonucleotides could, in some cases, determine the global conformation of single–strand oligonucleotides and constrain the conformation of hybrid duplexes formed with RNA. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)