Synthesis and thermodynamics of oligonucleotides containing chirally pure R_P methylphosphonate linkages

摘要

Methylphosphonate (MP) oligodeoxynucleotides (MPOs) are metaboiically stable analogs of conventional DNA containing a methyl group in place of one of the non-bonding phosphoryl oxygens. All 16 possible chiral R_P MP dinucleotides were synthesized andderivatized 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 (R-P chirally enriched MPOs) or (ii) alternating R_P MP/phosphodiesterbackbone oligonucleotides, depending on the composition of the 3'-coupfing 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.