Synthesis and Properties of a Bridged Nucleic Acid with a Perhydro-1,2-oxazin-3-one Ring

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• 作者：Ajaya R. Shrestha ; Yoshiyuki Hari ; Aiko Yahara ; Takashi Osawa ; Satoshi Obika
• 刊名：Journal of Organic Chemistry
• 出版年：2011
• 出版时间：December 16, 2011
• 年：2011
• 卷：76
• 期：24
• 页码：9891-9899
• 全文大小：406K
• 年卷期：v.76,no.24(December 16, 2011)
• ISSN：1520-6904

文摘

A novel derivative of 2鈥?4鈥?bridged nucleic acid, named hydroxamate-bridged nucleic acid (HxNA), containing a six-membered perhydro-1,2-oxazin-3-one ring, was designed and synthesized. The introduction of a carbonyl function along with an N鈥揙 linkage in the six-membered bridged structure is the unique structural feature of the novel 2鈥?4鈥?bridged nucleic acid analogue. The design was carried out to restrict the flexibility of the sugar moiety through the trigonal planarity of carbonyl function, which would improve the properties of the modification. The synthesized monomer was incorporated into oligonucleotides, and their properties were examined. The HxNA-modified oligonucleotides exhibited selectively high affinity toward complementary ssRNA. Furthermore, the nuclease resistance of the HxNA-modified oligonucleotide was found to be higher than that of the corresponding natural and 2鈥?4鈥?BNA/LNA-modified oligonucleotides. Interestingly, exposure of HxNA modified oligonucleotide to 3鈥?exonuclease resulted in gradual opening of the bridge, which stopped further digestion. Moreover, ring-opening of only one modification at the 3鈥?end of the oligonucleotides was observed, even if two or three HxNA modifications were present in the sequence. The results demonstrate the strong potential of the HxNA modification as a switch for the generation of highly nuclease-resistant RNA selective oligonucleotide in situ, which could have potential applications in antisense technology.