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

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• 作者：Takashi Hara ; Tetsuya KodamaYumi Takegaki ; Kunihiko Morihiro ; Kosuke Ramon Ito ; Satoshi Obika
• 刊名：Journal of Organic Chemistry
• 出版年：2017
• 出版时间：January 6, 2017
• 年：2017
• 卷：82
• 期：1
• 页码：25-36
• 全文大小：637K
• ISSN：1520-6904

文摘

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.