title: Synthesis and Properties of 7-Deazapurine- and 8-Aza-7-deazapurine-Locked Nucleic Acid Analogues: Effect of the Glycosidic Torsion Angle.
abstract: Conformationally restricted nucleoside analogues 2',4'-BNA/LNA-7-deazaguanine (LNA-7cG) and 2',4'-BNA/LNA-8-aza-7-deazaguanine (LNA-8n7cG), which avoid extra hydrogen bond formation at the 7-position of the guanine nucleobase, were successfully synthesized and incorporated into oligonucleotides. While the LNA-7cG-containing oligonucleotides show high duplex-forming ability with complementary DNA and RNA similar to LNA-G, the LNA-8n7cG-containing oligonucleotide has lower binding affinity than that of natural 2'-deoxyguanosine. This disparity in thermostability is also observed in 7-deazaadenosine analogues (LNA-7cA, LNA-8n7cA). Thermodynamic parameters and computational chemistry revealed that an inappropriate glycosidic torsion angle χ of 2',4'-BNA/LNA-8-aza-7-deazapurine analogues destabilizes duplex formation in contrast to 2',4'-BNA/LNA-7-deazapurine analogues. This result indicates that the nucleobase rotation angle plays an important role in duplex binding affinity. In addition, LNA-7cG-modified oligonucleotide effectively suppresses aggregation even in a guanine-rich sequence.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Osaka University , 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Hara
authors.affiliation: Graduate School of Pharmaceutical Sciences, Nagoya University , Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8601, Japan.
authors.forename: Tetsuya
authors.identifier: 0000-0002-5470-5896
authors.initials: T
authors.lastname: Kodama
authors.affiliation: Graduate School of Pharmaceutical Sciences, Osaka University , 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Takegaki
authors.affiliation: Graduate School of Pharmaceutical Sciences, Osaka University , 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Morihiro
authors.affiliation: Graduate School of Pharmaceutical Sciences, Osaka University , 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Kosuke Ramon
authors.initials: KR
authors.lastname: Ito
authors.affiliation: Graduate School of Pharmaceutical Sciences, Osaka University , 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Satoshi
authors.identifier: 0000-0002-6842-6812
authors.initials: S
authors.lastname: Obika