Synthesis and hybridizing properties of P-stereodefined chimeric [PS]-{DNA:RNA} and [PS]-{DNA:(2′-OMe)-RNA} oligomers

Oxathiaphospholane derivatives of 2′-OMe-ribonucleosides and 2′-O-TBDMS-ribonucleosides ((M)N-OTP and (T)N-OTP, respectively; nucleobase protected) were synthesized and separated into pure P-diastereomers. X-ray analysis showed the R(P) absolute configuration of the phosphorus atom in the fast-eluting diastereomer of (T)A-OTP. The fast- and slow-eluting P-diastereomers of (M)N-OTP and (T)N-OTP were used in the solid-phase synthesis of phosphorothioate dinucleotides ((M)N(PS)T and N(PS)T, respectively), which were subsequently hydrolyzed with R(P)-selective phosphodiesterase svPDE and S(P)-selective nuclease P1 to determine the absolute configuration of the phosphorus atoms. P-Stereodefined phosphorothioate ([PS]) 10-mer chimeric oligomers [PS]-{DNA:(2′-OMe)-RNA} and isosequential [PS]-{DNA:RNA} containing two (M)N(PS) or N(PS) units were synthesized. Melting experiments performed for their complexes with Watson–Crick paired DNA matrix showed that (M)N(PS) or N(PS) units decrease the thermal stability of the duplexes (ΔT(m) = −0.5 ÷ −5.5 °C per modification) regardless of the absolute configuration of the P-atoms. When the (2′-OMe)-RNA matrix was used an increase in T(m) was noted in all cases (ΔT(m) = +1 ÷ +7 °C per modification). The changes in thermal stability of the duplexes formed by [PS]-chimeras with DNA and (2′-OMe)-RNA matrices do not correlate with the absolute configuration of the phosphorus atoms.