title: Oligodeoxynucleotides containing 2'-O-modified adenosine: synthesis and effects on stability of DNA:RNA duplexes.
abstract: Hybridization thermodynamics were compared for oligonucleotide sequences containing 2'-fluoro dA, 2'-O-methyl A, 2'-O-ethyl A, 2'-O-propyl A, 2'-O-butyl A, 2'-O-pentyl A, 2'-O-nonyl A, 2'-O-allyl A, and 2'-O-benzyl A in place of deoxyadenosine. Although the effect of 2'-modified adenosine on duplex stability is sequence dependent, a clear trend is apparent. For six sequences containing a few 2'-modified adenosines in a background of unmodified deoxynucleotides, the average delta TM per substitution ranged from +1.3 degrees C for 2'-fluoro dA to -2.0 degrees C for 2'-O-nonyl A. For the 2'-O-alkyl series, the average delta TM per substitution correlates well with size of the substituent; the order of stability is 2'-O-methyl A > 2'-O-ethyl A > 2'-O-propyl A > 2'-O-butyl A > 2'-O-pentyl A > 2'-O-nonyl A. This correlation also extends to 2'-fluoro dA, 2'-O-allyl A, and 2'-O-benzyl A if chain length is measured by number of carbon atoms. When examined in the background of 2'-O-methyl ribonucleotides, all 2'-modified adenosines with a substituent no larger than 2'-O-pentyl stabilized the duplex nearly 2 degrees C per substitution compared to unmodified dA. These thermodynamic results and CD spectra of modified and unmodified hybrids support a model of DNA:RNA hybrids in which the geometry is between that of B-form and A-form.
authors.affiliation: Department of Molecular, Cellular and Structural Biology, ISIS Pharmaceuticals, Carlsbad, California 92008.
authors.forename: E A
authors.initials: EA
authors.lastname: Lesnik
authors.forename: C J
authors.initials: CJ
authors.lastname: Guinosso
authors.forename: A M
authors.initials: AM
authors.lastname: Kawasaki
authors.forename: H
authors.initials: H
authors.lastname: Sasmor
authors.forename: M
authors.initials: M
authors.lastname: Zounes
authors.forename: L L
authors.initials: LL
authors.lastname: Cummins
authors.forename: D J
authors.initials: DJ
authors.lastname: Ecker
authors.forename: P D
authors.initials: PD
authors.lastname: Cook
authors.forename: S M
authors.initials: SM
authors.lastname: Freier
mesh_terms: D000241:Adenosine / Q000737:chemistry*; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry*; D009693:Nucleic Acid Hybridization; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis / Q000737:chemistry*; D012313:RNA / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D009838:Oligodeoxyribonucleotides; D012313:RNA; D004247:DNA; D000241:Adenosine