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

Abstract

Keywords: Chimeric oligonucleotides / Chirality / Conformational analysis / Circular dichroism / Nucleic acids / Thermodynamic stability 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 (∆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

The role of nucleophilic catalysis in chemistry and stereochemistry of ribonucleosideH-phosphonate condensation

“…P-Chiral oligonucleotide analogues (e.g. phosphorothioates, 2 phosphoramidates, 3 methylphosphonates, 4 or boranophosphates 5 ) having defined configuration at the phosphorus atom find diverse applications in investigations of nucleic acid interactions with other biologically important molecules, for example proteins, RNA, and DNA. 6 Such P-chiral oligonucleotides may also be considered as potential drugs for nucleic acid-based therapies, 7 that could permit a more precise tuning of oligonucleotide interactions with the biological targets than is possible with the currently used pools of P-diastereomers.…”

Stereodefined dinucleoside (3′,5′)-propionamidophosphonates and β-cyanoethylphosphonates and their incorporation into modified oligonucleotides

“…19 Alternatively, 'solid phase' KOH/Al 2 O 3 was used for the addition of dinucleotides 1 to acrylonitrile, and the corresponding dinucleoside (3 0 ,5 0 )-b-cyanoethyl phosphonates 3 (B = Thy, 31 P NMR 27.4 ppm-FAST, and 28.5 ppm-SLOW) and 3 (B 1 = B 2 = Cyt Bz 27.54 ppm-FAST, 28.81 ppm-SLOW) 20 were obtained in good yields in a stereoretentive manner. 19 The phosphitylation of R P -2 with ClP(OCH 2 CH 2 CN)(iPr 2 N) and DIPEA, as reported previously, 21 chain elongation on synthesizer, yielded two chimeric oligonucleotides, d(TTTxTT 8 ) where x = CH 2 CH 2 C(O)NH 2 for R P -10 and S P -10, and x = P(O)CH 2 CH 2 CN for R P -11 and S P -11, respectively. 22 From the preliminary data given in Table 3, the relationship between the absolute configuration at the phosphorous atom of the internucleotide alkylphosphonate linkage and the stability of the hybrid duplexes with complementary DNA and RNA templates is apparent.…”

Stereospecific suppression of active site mutants by methylphosphonate substituted substrates reveals the stereochemical course of site-specific DNA recombination

“…Racemic mixtures of MeP-oligonucleotides were purchased from Trilink Technologies (San Diego, CA, USA). Stereochemically pure R P and S P forms of MeP-oligonucleotides were synthesized according to published protocols ( 29 , 30 ), as outlined in a previous study ( 26 ).…”