• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

含有立体纯硫代磷酸酯键和C-5修饰脱氧尿苷衍生物的DNA寡聚物的合成与性质

Synthesis and properties of DNA oligomers containing stereopure phosphorothioate linkages and C-5 modified deoxyuridine derivatives.

作者信息

Hara Rintaro Iwata, Yoshino Reijiro, Nukaga Yohei, Maeda Yusuke, Sato Kazuki, Wada Takeshi

机构信息

Faculty of Pharmaceutical Sciences, Tokyo University of Science 2641 Yamazaki Noda Chiba 278-8510 Japan

Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University 1-5-45, Yushima Bunkyo-Ku Tokyo 113-8519 Japan.

出版信息

RSC Adv. 2020 Sep 15;10(56):34006-34013. doi: 10.1039/d0ra06970a. eCollection 2020 Sep 10.

DOI:10.1039/d0ra06970a
PMID:35519073
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9056737/
Abstract

Phosphorothioate (PS) modification, where a non-bridging oxygen atom in a phosphodiester linkage is replaced by a sulfur atom, is widely used to improve the properties of nucleic acid drugs. Each PS linkage can be found in two stereoisomers, p and p. Since one non-bridging oxygen or sulfur atom in p-PS or p-PS, respectively, is located close to the C-5 substituent of uracil in a DNA/RNA hybrid duplex, the combination of the stereochemistry of the PS linkages and the type of the C-5 modification of uracil bases is expected to affect the properties of the hybrid duplexes. Herein, DNA oligomers containing both stereopure phosphorohioate linkages and C-5 modified deoxyuridine derivatives were synthesized. The thermodynamic stability of the DNA/RNA and DNA/DNA duplexes and RNase H activity of the DNA/RNA duplexes were evaluated. The combination of 5-propynyluracil and (p)-PS linkages in a DNA strand could significantly increase the thermal stability of a DNA/RNA hybrid duplex without reducing its RNase H activity.

摘要

硫代磷酸酯（PS）修饰是指磷酸二酯键中的一个非桥连氧原子被硫原子取代，这种修饰被广泛用于改善核酸药物的性质。每个PS键都有两种立体异构体，p型和p型。由于在DNA/RNA杂交双链体中，p-PS或p-PS中的一个非桥连氧原子或硫原子分别靠近尿嘧啶的C-5取代基，因此PS键的立体化学与尿嘧啶碱基C-5修饰类型的组合预计会影响杂交双链体的性质。在此，合成了同时含有立体纯硫代磷酸酯键和C-5修饰脱氧尿苷衍生物的DNA寡聚物。评估了DNA/RNA和DNA/DNA双链体的热力学稳定性以及DNA/RNA双链体的RNase H活性。DNA链中5-丙炔基尿嘧啶和（p）-PS键的组合可以显著提高DNA/RNA杂交双链体的热稳定性，而不会降低其RNase H活性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0445/9056737/008313025cdb/d0ra06970a-f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0445/9056737/e181d2472b2a/d0ra06970a-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0445/9056737/3bc6bf990c1f/d0ra06970a-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0445/9056737/b70d061d4f0c/d0ra06970a-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0445/9056737/2a9a8c31831c/d0ra06970a-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0445/9056737/1c66978e9bd0/d0ra06970a-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0445/9056737/e8c36f8592f7/d0ra06970a-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0445/9056737/1875268c5fca/d0ra06970a-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0445/9056737/008313025cdb/d0ra06970a-f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0445/9056737/e181d2472b2a/d0ra06970a-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0445/9056737/3bc6bf990c1f/d0ra06970a-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0445/9056737/b70d061d4f0c/d0ra06970a-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0445/9056737/2a9a8c31831c/d0ra06970a-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0445/9056737/1c66978e9bd0/d0ra06970a-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0445/9056737/e8c36f8592f7/d0ra06970a-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0445/9056737/1875268c5fca/d0ra06970a-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0445/9056737/008313025cdb/d0ra06970a-f8.jpg

相似文献

1
Synthesis and properties of DNA oligomers containing stereopure phosphorothioate linkages and C-5 modified deoxyuridine derivatives.含有立体纯硫代磷酸酯键和C-5修饰脱氧尿苷衍生物的DNA寡聚物的合成与性质
RSC Adv. 2020 Sep 15;10(56):34006-34013. doi: 10.1039/d0ra06970a. eCollection 2020 Sep 10.
2
Thermal stability and conformation of antiparallel duplexes formed by P-stereodefined phosphorothioate DNA/LNA chimeric oligomers with DNA and RNA matrices.由具有DNA和RNA基质的P-立体定向硫代磷酸酯DNA/LNA嵌合寡聚物形成的反平行双链体的热稳定性和构象。
Org Biomol Chem. 2015 Oct 21;13(39):10032-40. doi: 10.1039/c5ob01474c.
3
Stereo-enriched phosphorothioate oligodeoxynucleotides: synthesis, biophysical and biological properties.立体富集硫代磷酸酯寡脱氧核苷酸：合成、生物物理及生物学性质
Bioorg Med Chem. 2000 Jan;8(1):275-84. doi: 10.1016/s0968-0896(99)00275-8.
4
CD, absorption and thermodynamic analysis of repeating dinucleotide DNA, RNA and hybrid duplexes [d/r(AC)]12.[d/r(GT/U)]12 and the influence of phosphorothioate substitution.重复二核苷酸DNA、RNA及杂交双链体[d/r(AC)]12.[d/r(GT/U)]12的CD、吸收及热力学分析以及硫代磷酸酯取代的影响
Nucleic Acids Res. 1997 Oct 15;25(20):4098-105. doi: 10.1093/nar/25.20.4098.
5
Helix-stabilizing compounds CC-1065 and U-71,184 bind to RNA-DNA and DNA-DNA duplexes containing modified internucleotide linkages and stabilize duplexes against thermal melting.螺旋稳定化合物CC-1065和U-71,184与含有修饰核苷酸间连接的RNA-DNA和DNA-DNA双链体结合，并使双链体对热解链具有稳定性。
Antisense Res Dev. 1995 Spring;5(1):49-57. doi: 10.1089/ard.1995.5.49.
6
Interactions of oligonucleotide analogs containing methylphosphonate internucleotide linkages and 2'-O-methylribonucleosides.含膦酸甲酯核苷酸间连接和2'-O-甲基核糖核苷的寡核苷酸类似物的相互作用。
Nucleic Acids Res. 1994 Oct 25;22(21):4497-503. doi: 10.1093/nar/22.21.4497.
7
Impact of guanidine-containing backbone linkages on stereopure antisense oligonucleotides in the CNS.胍基连接基团对 CNS 中立体纯反义寡核苷酸的影响。
Nucleic Acids Res. 2022 Jun 10;50(10):5401-5423. doi: 10.1093/nar/gkac037.
8
Spermine moiety attached to the C-5 position of deoxyuridine enhances the duplex stability of the phosphorothioate DNA/complementary DNA and shows the susceptibility of the substrate to RNase H.连接在脱氧尿苷C-5位的精胺部分增强了硫代磷酸酯DNA/互补DNA的双链稳定性，并显示出底物对RNase H的敏感性。
Chem Pharm Bull (Tokyo). 2008 Sep;56(9):1259-63. doi: 10.1248/cpb.56.1259.
9
Efficient stabilization of phosphodiester (PO), phosphorothioate (PS), and 2'-O-methoxy (2'-OMe) DNA·RNA hybrid duplexes by amino sugars.通过氨基糖高效稳定磷酸二酯（PO）、硫代磷酸酯（PS）和 2'-O-甲氧基（2'-OME）DNA·RNA 杂交双链体。
Biochemistry. 2012 Jul 10;51(27):5496-505. doi: 10.1021/bi3004507. Epub 2012 Jun 28.
10
Structure and stability of the consecutive stereoregulated chiral phosphorothioate DNA duplex.连续立体规整手性硫代磷酸酯DNA双链体的结构与稳定性
Biochemistry. 1999 Dec 7;38(49):16058-66. doi: 10.1021/bi9909344.

引用本文的文献

1
Chemically modified aptamers for improving binding affinity to the target proteins enhanced non-covalent bonding.用于提高与靶蛋白结合亲和力的化学修饰适配体增强了非共价键合。
Front Cell Dev Biol. 2023 Feb 23;11:1091809. doi: 10.3389/fcell.2023.1091809. eCollection 2023.

本文引用的文献

1
Understanding the effect of controlling phosphorothioate chirality in the DNA gap on the potency and safety of gapmer antisense oligonucleotides.了解控制 DNA 间隙中硫代磷酸酯手性对 gapmer 反义寡核苷酸效力和安全性的影响。
Nucleic Acids Res. 2020 Feb 28;48(4):1691-1700. doi: 10.1093/nar/gkaa031.
2
Chemical modification of PS-ASO therapeutics reduces cellular protein-binding and improves the therapeutic index.对 PS-ASO 治疗药物进行化学修饰可降低细胞内蛋白质结合，提高治疗指数。
Nat Biotechnol. 2019 Jun;37(6):640-650. doi: 10.1038/s41587-019-0106-2. Epub 2019 Apr 29.
3
RNA-Targeted Therapeutics.
RNA 靶向治疗药物。
Cell Metab. 2018 Apr 3;27(4):714-739. doi: 10.1016/j.cmet.2018.03.004.
4
Control of phosphorothioate stereochemistry substantially increases the efficacy of antisense oligonucleotides.控制硫代磷酸酯立体化学可显著提高反义寡核苷酸的疗效。
Nat Biotechnol. 2017 Sep;35(9):845-851. doi: 10.1038/nbt.3948. Epub 2017 Aug 21.
5
Synthesis and cellular activity of stereochemically-pure 2'-O-(2-methoxyethyl)-phosphorothioate oligonucleotides.立体化学纯的2'-O-(2-甲氧基乙基)-硫代磷酸酯寡核苷酸的合成与细胞活性
Chem Commun (Camb). 2017 Jan 3;53(3):541-544. doi: 10.1039/c6cc08473g.
6
Stereocontrolled Solid-Phase Synthesis of Phosphate/Phosphorothioate (PO/PS) Chimeric Oligodeoxyribonucleotides on an Automated Synthesizer Using an Oxazaphospholidine-Phosphoramidite Method.使用恶唑磷烷-磷酰胺方法在自动合成仪上进行磷酸酯/硫代磷酸酯（PO/PS）嵌合寡脱氧核糖核苷酸的立体控制固相合成。
J Org Chem. 2016 Apr 1;81(7):2753-62. doi: 10.1021/acs.joc.5b02793. Epub 2016 Mar 14.
7
Stereochemical bias introduced during RNA synthesis modulates the activity of phosphorothioate siRNAs.RNA合成过程中引入的立体化学偏向性调节硫代磷酸酯siRNA的活性。
Nat Commun. 2015 Mar 6;6:6317. doi: 10.1038/ncomms7317.
8
Synthesis, biophysical properties and biological activity of second generation antisense oligonucleotides containing chiral phosphorothioate linkages.含手性硫代磷酸酯键的第二代反义寡核苷酸的合成、生物物理性质及生物活性
Nucleic Acids Res. 2014 Dec 16;42(22):13456-68. doi: 10.1093/nar/gku1115. Epub 2014 Nov 14.
9
Indolicidin targets duplex DNA: structural and mechanistic insight through a combination of spectroscopy and microscopy.吲哚杀菌素作用于双链DNA：通过光谱学和显微镜技术相结合获得的结构与机制洞察
ChemMedChem. 2014 Sep;9(9):2052-8. doi: 10.1002/cmdc.201402215. Epub 2014 Jul 17.
10
Designing chemically modified oligonucleotides for targeted gene silencing.设计用于靶向基因沉默的化学修饰寡核苷酸。
Chem Biol. 2012 Aug 24;19(8):937-54. doi: 10.1016/j.chembiol.2012.07.011.