title: 2'-O-[2-[2-(N,N-dimethylamino)ethoxy]ethyl] modified oligonucleotides: symbiosis of charge interaction factors and stereoelectronic effects.
abstract: [structure: see text] Oligonucleotides with a novel, 2'-O-[2-[2-(N,N-dimethylamino)ethoxy]ethyl] (2'-O-DMAEOE) modification have been synthesized. This modification, a cationic analogue of the 2'-O-(2-methoxyethyl) (2'-O-MOE) modification, exhibits high binding affinity to target RNA (but not to DNA) and exceptional resistance to nuclease degradation. Analysis of the crystal structure of a self-complementary oligonucleotide containing a single 2'-O-DMAEOE modification explains the importance of charge factors and gauche effects on the observed antisense properties. 2'-O-DMAEOE modified oligonucleotides are ideal candidates for antisense drugs.
authors.affiliation: Department of Medicinal Chemistry, Isis Pharmaceuticals, Inc., Carlsbad, California 92008, USA.
authors.forename: Marija
authors.initials: M
authors.lastname: Prhavc
authors.forename: Thazha P
authors.initials: TP
authors.lastname: Prakash
authors.forename: George
authors.initials: G
authors.lastname: Minasov
authors.forename: P Dan
authors.initials: PD
authors.lastname: Cook
authors.forename: Martin
authors.initials: M
authors.lastname: Egli
authors.forename: Muthiah
authors.initials: M
authors.lastname: Manoharan
mesh_terms: D000818:Animals; D001483:Base Sequence; D004355:Drug Stability; D004980:Ethane / Q000031:analogs & derivatives / Q000737:chemistry*; D004987:Ethers / Q000737:chemistry*; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D009692:Nucleic Acid Heteroduplexes / Q000737:chemistry; D009693:Nucleic Acid Hybridization; D016376:Oligonucleotides, Antisense / Q000737:chemistry* / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D018075:RNA, Complementary / Q000378:metabolism; D012910:Snake Venoms / Q000201:enzymology; D021241:Spectrometry, Mass, Electrospray Ionization; D055672:Static Electricity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C478253:2'-O-(2-(2-(N,N-dimethylamino)ethoxy)ethyl); D004987:Ethers; D009692:Nucleic Acid Heteroduplexes; D016376:Oligonucleotides, Antisense; D009943:Organophosphorus Compounds; D018075:RNA, Complementary; D012910:Snake Venoms; D010727:Phosphoric Diester Hydrolases; D004980:Ethane