Journal Article Synthesis and Properties of 7-Deazapurine- and 8-Aza-7-deazapurine-Locked Nucleic Acid Analogues: Effect of the Glycosidic Torsion Angle

Hara, Takashi  ,  Kodama, Tetsuya  ,  Takegaki, Yumi  ,  Morihiro, Kunihiko  ,  Ito, Ramon Kosuke  ,  Obika, Satoshi

82 ( 1 )  , pp.25 - 36 , 2016-12-13 , ACS Publications
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.

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