2′-N-Alkylaminocarbonyl-2′-amino-LNA: Synthesis, duplex stability, nuclease resistance, and in vitro anti-microRNA activity. (15th January 2023)

• Record Type: Journal Article
• Authors: Takegawa-Araki, Tomo; Yasukawa, Kai; Iwazaki, Norihiko; Utsugi, Masayuki; Furukawa, Hiroyuki; Kumagai, Shinji; Sawamoto, Hiroaki; Obika, Satoshi
• Is Part Of: Bioorganic & medicinal chemistry. Volume 78(2023)
• Publication Date: 2023-01-15
• Subjects: Anti-miRNA oligonucleotide -- miRNA -- Amino-LNA -- Bridged nucleic acid -- Locked nucleic acid; ON oligonucleotide -- AMO anti-miRNA oligonucleotide -- ASOs antisense oligonucleotides -- LNA locked nucleic acid -- ALNA 2′-amino LNA -- PEM post-elongation modification -- DMTr 4, 4′-dimethoxytrityl -- RP-HPLC reverse-phase high performance liquid chromatography -- GuNA guanidine-bridged nucleic acid; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2022.117148
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 2′-Amino-LNA has the potential to acquire various functions through chemical modification at the 2′-nitrogen atom. This study focused on 2′- N -alkylaminocarbonyl 2′-amino-LNA, which is a derivative of 2′-amino-LNA. We evaluated its practical usefulness as a chemical modification of anti-miRNA oligonucleotide. The synthesis of phosphoramidites of 2′- N -alkylaminocarbonyl substituted 2′-amino-LNA bearing thymine and 5-methylcytosine proceeded in good yields. Incorporating the 2′- N -alkylaminocarbonyl-2′-amino-LNA monomers into oligonucleotides improved the duplex stability for complementary RNA strands and robust nuclease resistance. Moreover, 2′- N -alkylaminocarbonyl-2′-amino-LNA is a promising scaffold that significantly increases the potency of anti-miRNA oligonucleotides.