title: Chiral and steric effects in the efficient binding of alpha-anomeric deoxyoligonucleoside N-alkylphosphoramidates to ssDNA and RNA.
abstract: We report hybridization properties of new phosphate-modified alpha-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 alpha- or beta-dodecanucleoside phosphodiesters containing one chirally enriched N -alkylphosphoramidate linkage located in the middle of the sequence d(TCTT-AA*CCCACA). As for P-substituted beta-oligonucleo-tides, a difference in binding behavior between the two diastereoisomers (difference in Delta T (m)) exists in the hybridization properties of alpha-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 beta- and alpha-oligonucleoside N -alkylphosphoramidates for their DNA and RNA targets. This effect was very weak with alpha-analogs whereas it was more pronounced with beta-oligos. PNHME-modified alpha-oligonucleosides formed more stable duplexes with DNA (Delta T (m)+9.6 degrees C) and RNA (Delta T (m)+1.4 degrees C) targets than the 'parent' phosphodiester. Finally, base pairing specificity of these alpha-oligonucleo-side N -alkylphosphoramidates for their targets was found to be as high as for natural oligonucleoside phosphodiesters.
authors.affiliation: Laboratoire de Chimie Organique Biomoléculaire de Synthèse, UMR 5625 CNRS-UM II, CC 008, Université Montpellier II, Place Eugène Bataillon, 34095 Montpellier Cedex 5, France.
authors.forename: A
authors.initials: A
authors.lastname: Laurent
authors.forename: M
authors.initials: M
authors.lastname: Naval
authors.forename: F
authors.initials: F
authors.lastname: Debart
authors.forename: J J
authors.initials: JJ
authors.lastname: Vasseur
authors.forename: B
authors.initials: B
authors.lastname: Rayner
mesh_terms: D000478:Alkylation; D020137:Base Pair Mismatch; D020029:Base Pairing / Q000235:genetics*; D001483:Base Sequence; D004277:DNA, Single-Stranded / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015696:Gene Products, tat / Q000235:genetics; D015497:HIV-1 / Q000235:genetics; D009691:Nucleic Acid Denaturation; D009693:Nucleic Acid Hybridization; D009841:Oligonucleotides / Q000138:chemical synthesis / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D009994:Osmolar Concentration; D010758:Phosphorus / Q000737:chemistry / Q000378:metabolism; D012313:RNA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013237:Stereoisomerism; D013696:Temperature; D013816:Thermodynamics; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: D004277:DNA, Single-Stranded; D015696:Gene Products, tat; D009841:Oligonucleotides; D054322:tat Gene Products, Human Immunodeficiency Virus; D010758:Phosphorus; D012313:RNA