Synthesis and thermodynamics of oligonucleotides containing chirally pure R(p) methylphosphonate linkages

Abstract

Methylphosphonate (MP) oligodeoxynucleotides (MPOs) are metabolically stable analogs of conventional DNA containing a methyl group in place of one of the non-bonding phosphoryl oxygens. All 16 possible chiral Rp MP dinucleotides were synthesized and derivatized for automated oligonucleotide synthesis. These dimer synthons can be used to prepare (i) all-MP linked oligonucleotides having defined Rp chirality at every other position (Rp chirally enriched MPOs) or (ii) alternating Rp MP/phosphodiester backbone oligonucleotides, depending on the composition of the 3'-coupling group. Chirally pure dimer synthons were also prepared with 2'-O-methyl sugar modifications. Oligonucleotides prepared with these Rp chiral methylphosphonate linkage synthons bind RNA with significantly higher affinity than racemic MPOs.