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Solid-Phase Synthesis of Boranophosphate/Phosphorothioate/Phosphate Chimeric Oligonucleotides and Their Potential as Antisense Oligonucleotides

[Image: see text] In this study, we successfully synthesized boranophosphate (PB), phosphorothioate (PS), and phosphate (PO) chimeric oligonucleotides (ODNs) as a candidate for the antisense oligonucleotides (ASOs). The PB/PS/PO-ODNs were synthesized utilizing H-boranophosphonate, H-phosphonothioate...

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Detalles Bibliográficos
Autores principales: Takahashi, Yuhei, Sato, Kazuki, Wada, Takeshi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2021
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8938928/
https://www.ncbi.nlm.nih.gov/pubmed/34908418
http://dx.doi.org/10.1021/acs.joc.1c01812
Descripción
Sumario:[Image: see text] In this study, we successfully synthesized boranophosphate (PB), phosphorothioate (PS), and phosphate (PO) chimeric oligonucleotides (ODNs) as a candidate for the antisense oligonucleotides (ASOs). The PB/PS/PO-ODNs were synthesized utilizing H-boranophosphonate, H-phosphonothioate, and H-phosphonate monomers. Each monomer was condensed with a hydroxy group to create H-boranophosphonate, H-phosphonothioate, and H-phosphonate diester linkages, which were oxidized into PB, PS, and PO linkages in the final stage of the synthesis, respectively. As for condensation of an H-phosphonothioate monomer, regulating chemoselectivity was necessary since the monomer has two nucleophilic centers: S and O atoms. To deal with this problem, we used phosphonium-type condensing reagents, which could control the chemoselectivity. In this strategy, we could synthesize PB/PS/PO oligomers, including a 2′-OMe gapmer-type dodecamer. The physiological and biological properties of the synthesized chimeric ODNs were also evaluated. Insights from the evaluation of physiological and biological properties suggested that the introduction of suitable P-modification and sugar modification at proper sites of ODNs would control the duplex stability, nuclease resistance, RNase H-inducing ability, and one base mismatch discrimination ability, which are critical properties as potent ASOs.