TK-112690

We describe herein a straightforward and efficient preparation of 2',3'-dideoxy-2'-(2''-(trimethylsilyl)ethylthio)thymidine, which allows the preparation of diverse potentially antiviral and/or anticancer nucleosides (disulfides, thiols, sulfides, thiocyanates).

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.