Synthesis and Antisense Properties of 2′‐ O ‐(2 S ‐Methoxypropyl)‐RNA‐Modified Gapmer Antisense Oligonucleotides

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 ‐(2 S ‐methoxypropyl)‐RNA (2 S ‐MOP)‐modified ASOs. Synthesis of the 2 S ‐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 2 S ‐methoxy‐1‐propanol. Synthesis of the 2 S ‐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. 2 S ‐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. 2 S ‐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.