Solid-Phase Synthesis of Boranophosphate/Phosphorothioate/Phosphate Chimeric Oligonucleotides and Their Potential as Antisense Oligonucleotides.
Solid-Phase Synthesis of Boranophosphate/Phosphorothioate/Phosphate Chimeric Oligonucleotides and Their Potential as Antisense Oligonucleotides.
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DOI：
10.1021/acs.joc.1c01812
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发表时间：
2022-03-18
期刊：
影响因子：
--
通讯作者：
Wada T
中科院分区：
文献类型：
--
作者：
Takahashi Y;Sato K;Wada T
在这项研究中，我们成功地合成了硼磷酸（PB）、硫代磷酸（PS）和磷酸（PO）嵌合寡核苷酸（odn）作为反义寡核苷酸（ASOs）的候选物。利用h -硼膦酸盐、h -硫代膦酸盐和h -膦酸盐单体合成了PB/PS/PO-ODNs。每个单体与羟基缩合生成h -硼膦酸酯键、h -硫代膦酸酯键和h -膦酸二酯键，在合成的最后阶段分别氧化成PB键、PS键和PO键。对于h -硫代膦酸盐单体的缩聚，由于单体有两个亲核中心：S原子和O原子，因此调节化学选择性是必要的。为了解决这一问题，我们使用了可控制化学选择性的磷型冷凝试剂。在这种策略下，我们可以合成PB/PS/PO低聚物，包括2 ' -OMe间隙型十二聚体。并对合成的嵌合odn的生理生物学特性进行了评价。生理和生物学特性的评价表明，在odn的适当位点引入适当的p修饰和糖修饰可以控制其双相稳定性、核酸酶抗性、RNase h诱导能力和碱基错配识别能力，这些都是作为有效ASOs的关键特性。
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.
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影响因子：
14.9
作者：
Anderson BA;Freestone GC;Low A;De-Hoyos CL;Iii WJD;Østergaard ME;Migawa MT;Fazio M;Wan WB;Berdeja A;Scandalis E;Burel SA;Vickers TA;Crooke ST;Swayze EE;Liang X;Seth PP
通讯作者：
Seth PP
核苷 H-硼膦酸盐：一类新的含硼核苷酸类似物
影响因子：
4.9
作者：
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影响因子：
16
作者：
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通讯作者：
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影响因子：
2.1
作者：
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通讯作者：
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影响因子：
7.5
作者：
HALL, IH;BURNHAM, BS;SHAW, BR
通讯作者：
SHAW, BR