SYNTHESIS AND THERMODYNAMICS OF OLIGONUCLEOTIDES CONTAINING CHIRALLY PURE R(P) METHYLPHOSPHONATE LINKAGES

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 R(p) MP dinucleotides were synthesized and derivatized for automated o ligonucleotide synthesis. These dimer synthons can be used to prepare (i) all-MP linked oligonucleotides having defined R(p) chirality at ev ery other position (R(p) chirally enriched MPOs) or (ii) alternating R (p) MP/phosphodiester backbone oligonucleotides, depending on the comp osition of the 3'-coupling group, Chirally pure dimer synthons were al so prepared with 2'-O-methyl sugar modifications. Oligonucleotides pre pared with these R(p) chiral methylphosphonate linkage synthons bind R NA with significantly higher affinity than racemic MPOs.