Development of Synthetic Routes to 2′-O,4′-C-Spirocyclopentylene-Bridged Nucleic Acids: Thymidine, Guanosine, and Adenosine

Kumagai, Riku; Yamada, Riko; Yamaguchi, Takao; Obika, Satoshi

doi:https://doi.org/10.1002/chem.202502995

Development of Synthetic Routes to 2′-O,4′-C-Spirocyclopentylene-Bridged Nucleic Acids: Thymidine, Guanosine, and Adenosine

Kumagai, Riku; Yamada, Riko; Yamaguchi, Takao et al.

Chemistry - A European Journal, 2025

アクセス数:99件（2026-02-15 21:36 集計）

固定URL: https://hdl.handle.net/11094/103466

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タイトル	Development of Synthetic Routes to 2′-O,4′-C-Spirocyclopentylene-Bridged Nucleic Acids: Thymidine, Guanosine, and Adenosine
著者	著者名 Kumagai, Riku
	著者名 Yamada, Riko
	NRID 1000080596601 1000080596601 ORCID 0000-0003-3180-0257 0000-0003-3180-0257 researchmap permalink takao-yamaguchi takao-yamaguchi Scopus Author ID 56322895500 56322895500 著者名 Yamaguchi, Takao
	NRID 1000080243252 1000080243252 ORCID 0000-0002-6842-6812 0000-0002-6842-6812 researchmap permalink read0014368 read0014368 Scopus Author ID 7003800550 7003800550 著者名 Obika, Satoshi
キーワード等	iodocyclization
	modified nucleic acid
	nucleoside synthesis
	oligonucleotide therapeutics
	transglycosylation
内容	Kumagai R., Yamada R., Yamaguchi T., et al. Development of Synthetic Routes to 2′-O,4′-C-Spirocyclopentylene-Bridged Nucleic Acids: Thymidine, Guanosine, and Adenosine. Chemistry - A European Journal , (2025); https://doi.org/10.1002/chem.202502995.
抄録	Modified nucleic acids are crucial for improving the efficacy and safety of antisense oligonucleotides (ASOs). We previously synthesized and evaluated 2′-O,4′-C-spirocyclopentylene-bridged nucleic acid (scpBNA2) bearing the pyrimidine nucleobases thymine (T) and 5-methylcytosine (mC). Oligonucleotides incorporating scpBNA2 exhibited strong binding affinity toward complementary single-stranded RNA (ssRNA) and high resistance to nuclease degradation. These favorable properties enabled ASOs containing scpBNA2-T and scpBNA2-mC in the wing regions to induce potent target RNA knockdown both in vitro and in vivo. Furthermore, replacing 2′-O,4′-C-methylene-bridged nucleic acid/locked nucleic acid (2′,4′-BNA/LNA) with scpBNA2 significantly reduced hepatotoxicity, underscoring its potential as a promising nucleic acid analog for ASO design. In this study, we established efficient synthetic routes to scpBNA2 nucleosides bearing the purine nucleobases guanine (G) and adenine (A), in addition to the previously reported scpBNA2-T. The scpBNA2-T nucleoside was synthesized via 2′,4′-lactonization followed by formation of a 2,2′-anhydropyrimidine intermediate. For scpBNA2-G and scpBNA2-A, we devised a robust strategy that combines late-stage transglycosylation—converting the thymine nucleobase into purines—with an iodocyclization reaction to construct the 2′,4′-bridged framework. This concise approach provides access to scpBNA2 nucleosides and supports their broader applications in ASO development.
出版者	John Wiley and Sons Inc
収録物名	Chemistry - A European Journal
刊行年月	2025-11-07
言語	英語
ハンドルURL	https://hdl.handle.net/11094/103466
PISSN	09476539
eISSN	15213765
関連情報 (isIdenticalTo)	DOI (出版社版) https://doi.org/10.1002/chem.202502995
アクセス権	open access
権利情報	This article is licensed under a Creative Commons Attribution 4.0 International License.
出版タイプ	Version of Record
カテゴリ	学術雑誌論文 Journal Article

資源タイプ	学術雑誌論文
ローカル資源タイプ	学術雑誌論文
DCMI資源タイプ	text
DCTERMS.bibliographicCitation	Chemistry - A European Journal. 2025
DC.title	Development of Synthetic Routes to 2′-O,4′-C-Spirocyclopentylene-Bridged Nucleic Acids: Thymidine, Guanosine, and Adenosine
DC.creator	Kumagai, Riku
	Yamada, Riko
	Yamaguchi, Takao
	Obika, Satoshi
DC.publisher	John Wiley and Sons Inc
DC.language' scheme='DCTERMS.RFC1766	英語
DC.type' scheme='DCTERMS.DCMIType	text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2025-11-07
DC.identifier	https://doi.org/10.1002/chem.202502995
DC.subject	iodocyclization
	modified nucleic acid
	nucleoside synthesis
	oligonucleotide therapeutics
	transglycosylation
DC.description	Kumagai R., Yamada R., Yamaguchi T., et al. Development of Synthetic Routes to 2′-O,4′-C-Spirocyclopentylene-Bridged Nucleic Acids: Thymidine, Guanosine, and Adenosine. Chemistry - A European Journal , (2025); https://doi.org/10.1002/chem.202502995.
DCTERMS.abstract	Modified nucleic acids are crucial for improving the efficacy and safety of antisense oligonucleotides (ASOs). We previously synthesized and evaluated 2′-O,4′-C-spirocyclopentylene-bridged nucleic acid (scpBNA2) bearing the pyrimidine nucleobases thymine (T) and 5-methylcytosine (mC). Oligonucleotides incorporating scpBNA2 exhibited strong binding affinity toward complementary single-stranded RNA (ssRNA) and high resistance to nuclease degradation. These favorable properties enabled ASOs containing scpBNA2-T and scpBNA2-mC in the wing regions to induce potent target RNA knockdown both in vitro and in vivo. Furthermore, replacing 2′-O,4′-C-methylene-bridged nucleic acid/locked nucleic acid (2′,4′-BNA/LNA) with scpBNA2 significantly reduced hepatotoxicity, underscoring its potential as a promising nucleic acid analog for ASO design. In this study, we established efficient synthetic routes to scpBNA2 nucleosides bearing the purine nucleobases guanine (G) and adenine (A), in addition to the previously reported scpBNA2-T. The scpBNA2-T nucleoside was synthesized via 2′,4′-lactonization followed by formation of a 2,2′-anhydropyrimidine intermediate. For scpBNA2-G and scpBNA2-A, we devised a robust strategy that combines late-stage transglycosylation—converting the thymine nucleobase into purines—with an iodocyclization reaction to construct the 2′,4′-bridged framework. This concise approach provides access to scpBNA2 nucleosides and supports their broader applications in ASO development.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	103466
citation_title	Development of Synthetic Routes to 2′-O,4′-C-Spirocyclopentylene-Bridged Nucleic Acids: Thymidine, Guanosine, and Adenosine
citation_author	Kumagai, Riku
	Yamada, Riko
	Yamaguchi, Takao
	Obika, Satoshi
citation_publisher	John Wiley and Sons Inc
citation_language	英語
citation_date	2025-11-07
citation_journal_title	Chemistry - A European Journal
citation_doi	https://doi.org/10.1002/chem.202502995
citation_public_url	https://hdl.handle.net/11094/103466

Development of Synthetic Routes to 2′-O,4′-C-Spirocyclopentylene-Bridged Nucleic Acids: Thymidine, Guanosine, and Adenosine

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