title: Synthesis and antisense properties of 2'-O-(2S-methoxypropyl)-RNA-modified gapmer antisense oligonucleotides.
abstract: To ascertain whether increasing hydrophobicity can enhance the activity of second-generation antisense oligonucleotides (ASOs) in muscle, we investigated the antisense properties of 2'-O-(2S-methoxypropyl)-RNA (2S-MOP)-modified ASOs. Synthesis of the 2S-MOP 5-methyl uridine phosphoramidite was accomplished on a multi-gram scale by Lewis-acid-catalyzed ring opening of 5'-O-tert-butyldiphenylsilyl ether-protected 2,2'-anhydro-5-methyl uridine with 2S-methoxy-1-propanol. Synthesis of the 2S-MOP 5-methyl cytidine nucleoside from the corresponding 5-methyl uridine nucleoside was accomplished by formation and displacement of a 4-triazolide intermediate with aqueous ammonia. 2S-MOP-modified oligonucleotides were prepared on an automated DNA synthesizer and showed similar enhancements in duplex thermal stability as 2'-O-methoxyethyl RNA (MOE)-modified oligonucleotides. 2S-MOP-containing antisense oligonucleotides were evaluated in Balb-c mice and showed good activity for decreasing the expression levels of scavenger receptor B1 (Srb1) and phosphatase and tensin homologue (PTEN) mRNA in liver and muscle tissue.
authors.affiliation: Isis Pharmaceuticals, Inc. 2855 Gazelle Court, Carlsbad, CA 92010 (USA).
authors.forename: Jinghua
authors.initials: J
authors.lastname: Yu
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Pandey
authors.forename: Hetal
authors.initials: H
authors.lastname: Khatri
authors.forename: Thazha P
authors.initials: TP
authors.lastname: Prakash
authors.forename: Eric E
authors.initials: EE
authors.lastname: Swayze
authors.forename: Punit P
authors.initials: PP
authors.lastname: Seth
mesh_terms: D000641:Ammonia / Q000737:chemistry; D000818:Animals; D008099:Liver / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018482:Muscle, Skeletal / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000138:chemical synthesis* / Q000494:pharmacology*; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis; D016372:RNA, Antisense / Q000138:chemical synthesis* / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051122:Scavenger Receptors, Class B / Q000096:biosynthesis
chemical_list: D016376:Oligonucleotides, Antisense; D016372:RNA, Antisense; D012333:RNA, Messenger; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D000641:Ammonia; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: antisense oligonucleotides; gapmers; methoxyethyl RNA derivatives; methylation