title: Zwitterionic oligodeoxyribonucleotide N3'-->P5' phosphoramidates: synthesis and properties.
abstract: Zwitterionic, net neutral oligonucleotides containing alternating negatively charged N3'-->P5' phosphoramidate monoester and positively charged phosphoramidate diester groups were synthesized. The ability of zwitterionic phosphoramidates to form complexes with complementary DNA and RNA was evaluated. Stoichiometry and salt dependency of these complexes were determined as a function of the nature of the heterocyclic bases of the zwitterionic compounds. Unlike the melting temperatures of the natural phosphodiester-containing oligomers, the T m of the duplexes formed with the zwitterionic oligothymidylates was salt concentration independent. The thermal stability of these duplexes was much higher with Delta T m values of 20-35 degrees C relatively to phosphodiester counterparts at low salt concentrations. The zwitterionic oligoadenylate formed only 2Py:1Pu triplexes with complementary poly(U) or poly(dT) strands. The thermal stability of these complexes was dependent on salt concentration. Also, the T m values of the complexes formed by the zwitterionic oligoadenylate with poly(U) were 6-41 degrees C higher than for the natural phosphodiester counterpart. Triplexes of this compound with poly(dT) were also more stable with a Delta T m value of 22 degrees C at low salt concentrations. Complexes formed by the zwitterionic oligonucleotides with complementary RNAs were not substrates for RNase H. Surprisingly, the duplex formed by the all anionic alternating N3'-->P5'phosphoramidate-phosphodiester oligothymidylate and poly(A) was a good substrate for RNase H.
authors.affiliation: Lynx Therapeutics Inc., 3832 Bay Center Place, Hayward, CA 94545, USA.
authors.forename: N
authors.initials: N
authors.lastname: Mignet
authors.forename: S M
authors.initials: SM
authors.lastname: Gryaznov
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000378:metabolism*; D018076:DNA, Complementary / Q000378:metabolism; D019281:Dimerization; D004355:Drug Stability; D004563:Electrochemistry; D006358:Hot Temperature; D007477:Ions; D015394:Molecular Structure; D009693:Nucleic Acid Hybridization; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis* / Q000378:metabolism*; D010756:Phosphoric Acids / Q000138:chemical synthesis* / Q000378:metabolism*; D018075:RNA, Complementary / Q000378:metabolism; D016914:Ribonuclease H / Q000378:metabolism
chemical_list: D000577:Amides; D018076:DNA, Complementary; D007477:Ions; D009838:Oligodeoxyribonucleotides; D010756:Phosphoric Acids; D018075:RNA, Complementary; C011067:phosphoramidic acid; D016914:Ribonuclease H