Abstract
We report hybridization properties of new phosphate-modified α α α α-oligonucleoside analogs with non-ionic or cationic internucleotide linkages such as methoxy-ethylphosphoramidate (PNHME), phosphoromorpholi-date (PMOR) and dimethylaminopropylphosphor-amidate (PNHDMAP). First we evaluated the chirality effect of the phosphorus atom on the affinity of α α α α-or β β β β-dodecanucleoside phosphodiesters containing one chirally enriched N-alkylphosphoramidate linkage located in the middle of the sequence d(TCTT-AA*CCCACA). As for P-substituted β β β β-oligonucleo-tides, a difference in binding behavior between the two diastereoisomers (difference in ∆ ∆ ∆ ∆T m) exists in the hybridization properties of α α α α-analogs when DNA was the target but this effect was not detrimental to duplex stability. This effect was considerably reduced when RNA was the target. Secondly we studied the effect of steric hindrance around phosphorus on the affinity of fully modified β β β β-and α α α α-oligo-nucleoside N-alkylphosphoramidates for their DNA and RNA targets. This effect was very weak with α α α α-analogs whereas it was more pronounced with β β β β-oligos. PNHME-modified α α α α-oligonucleosides formed more stable duplexes with DNA (∆ ∆ ∆ ∆T m +9.6°°°°C) and RNA (∆ ∆ ∆ ∆T m +1.4°°°°C) targets than the 'parent' phosphodiester. Finally, base pairing specificity of these α α α α-oligonucleo-side N-alkylphosphoramidates for their targets was found to be as high as for natural oligonucleoside phosphodiesters.