2,2'-anhydro-1-(β-D-arabinofuranosyl)uracil | 847650-91-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 2,2'-anhydro-1-(β-D-arabinofuranosyl)uracil
• 英文别名: (2,2'-anhydrouridine)；2,2′-O-cyclouridine；2,2'-O-Cyclouridine；(2R,4R,5R,6R)-5-hydroxy-4-(hydroxymethyl)-3,7-dioxa-1,9-diazatricyclo[6.4.0.02,6]dodeca-8,11-dien-10-one
• CAS: 847650-91-3
• 化学式: C₉H₁₀N₂O₅
• 分子量: 226.189
• InChiKey: UUGITDASWNOAGG-XVFCMESISA-N

物化性质

• 熔点：
  238-239 °C(Solv: methanol (67-56-1))
• 沸点：
  456.3±55.0 °C(Predicted)
• 密度：
  2.01±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -2.5
• 重原子数：
  16
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  91.6
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2,2'-anhydro-1-(β-D-arabinofuranosyl)uracil 在 盐酸 、 水 、 sodium hydroxide 作用下， 反应 2.0h， 以68%的产率得到阿糖尿苷
  参考文献：
  名称：

  Phosphoramidates of 2′-β-d-arabinouridine (AraU) as phosphate prodrugs; design, synthesis, in vitro activity and metabolism

  摘要：

  2'-beta-D-Arabinouridine (AraU), the uridine analogue of the anticancer agent AraC, was synthesized and evaluated for antiviral activity and cytotoxicity. In addition, a series of AraU monophosphate prodrugs in the form of triester phosphoramidates (ProTides) were also synthesized and tested against a range of viruses, leukaemia and solid tumour cell lines. Unfortunately, neither the parent compound (AraU) nor any of its ProTides showed antiviral activity, nor potent inhibitory activity against any of the cancer cell lines. Therefore, the metabolism of AraU phosphoramidates to release AraU monophosphate was investigated. The results showed carboxypeptidase Y, hog liver esterase and crude CEM tumor cell extracts to hydrolyse the ester motif of phosphoramidates with subsequent loss of the aryl group, while molecular modelling studies suggested that the AraU L-alanine aminoacyl phosphate derivative might not be a good substrate for the phosphoramidase enzyme Hint-1. These findings are in agreement with the observed disappearance of intact prodrug and concomitant appearance of the corresponding phosphoramidate intermediate derivative in CEM cell extracts without measurable formation of araU monophosphate. These findings may explain the poor antiviral/cytostatic potential of the prodrugs. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2010.02.059
• 作为产物：
  描述：

  尿嘧啶核苷 在 碳酸二苯酯 、 碳酸氢钠 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以86 %的产率得到2,2'-anhydro-1-(β-D-arabinofuranosyl)uracil
  参考文献：
  名称：

  2'-O-二硫桥限制的RNA的合成和性质

  摘要：

  这项工作描述了两个相邻尿苷之间含有二乙烯（DEE）和二丙烯（DPE）二硫桥的寡核糖核苷酸的合成和性质。

  DOI：

  10.1002/open.202300232

文献信息

• [EN] ANTISENSE OLIGONUCLEOTIDES WITH IMPROVED PHARMACOKINETIC PROPERTIES<br/>[FR] OLIGONUCLÉOTIDES ANTISENS AYANT DES PROPRIÉTÉS PHARMACOCINÉTIQUES AMÉLIORÉES
  申请人：UNIV VIENNA

  公开号：WO2015032968A1

  公开（公告）日：2015-03-12

  The invention relates to an antisense or siRNA oligonucleotide or conjugate with improved pharmacokinetic properties, methods of producing the same as well as the use of such compounds and conjugates, e.g. as pharmaceutical composition, a pharmaceutical kit, a medicament or a tool in biomedical research. The conjugates of the invention have the formula I being P - (L - S - S - Y - X)n, wherein P represents a natural, artificial and/or modified oligonucleotide, L represents a linker group attached to one or more nucleosides at any position within the oligonucleotides sequence; S represents sulfur; X represents a ligand; Y represents a spacer and n is an integer ranging from 1 to the oligonucleotide length of P. The oligonucleotides of the invention have the formula II being P- (L - S - R)n, wherein P represents a natural, artificial and /or modified oligonucleotide, L represents a linker group attached to one or more nucleosides at any position within the oligonucleotides sequence, S represents sulfur, R represents either hydrogen or a thiol protecting group, preferably trityl or tertiary butyl, and n is an integer ranging from 1 to the oligonucleotide length of P. In addition, the pharmaceutical composition or pharmaceutical kit or conjugate can be used for the treatment of a disease or disorder that can be at least in part alleviated by therapy, wherein the disease or disorder is selected from the group consisting of bacterial infections, viral infections, cancer, metabolic diseases and immunological disorders and preferably cancer.

  该发明涉及具有改进的药代动力学性质的反义物或siRNA寡核苷酸或结合物，以及生产这些物质的方法，以及这些化合物和结合物的用途，例如作为药物组合物、药物工具包、药物或生物医学研究中的工具。该发明的结合物具有公式I，其中P代表天然、人工和/或修饰的寡核苷酸，L代表连接基团，连接到寡核苷酸序列中的一个或多个核苷酸的任何位置；S代表硫；X代表配体；Y代表间隔物，n是一个整数，范围从1到P的寡核苷酸长度。该发明的寡核苷酸具有公式II，其中P代表天然、人工和/或修饰的寡核苷酸，L代表连接基团，连接到寡核苷酸序列中的一个或多个核苷酸的任何位置，S代表硫，R代表氢或硫醇保护基团，优选三苯甲基或叔丁基，n是一个整数，范围从1到P的寡核苷酸长度。此外，药物组合物或药物工具包或结合物可用于治疗至少部分可通过治疗缓解的疾病或紊乱，其中所述疾病或紊乱选自细菌感染、病毒感染、癌症、代谢性疾病和免疫紊乱等组成的一组，优选癌症。
• Increased Affinity of 2′‐<i>O</i>‐(2‐Methoxyethyl)‐Modified Oligonucleotides to RNA through Conjugation of Spermine at Cytidines
  作者：Elodie Decuypere、Anastasia Lepikhina、François Halloy、Jonathan Hall

  DOI：10.1002/hlca.201900222

  日期：2019.12

  2′‐O‐position of riboses in oligonucleotide therapeutics is of critical importance for their use as drugs. To date, the methoxyethyl (MOE) substituent is the most important and features in dozens of antisense oligonucleotides that have been tested in clinical trials. Yet, the search for new improved modifications continues in a quest for increased oligonucleotide potency, improved transport in vivo and favorable

  寡核苷酸治疗剂中核糖2'- O-位的结构修饰对于将其用作药物至关重要。迄今为止，甲氧乙基（MOE）取代基是数十种已在临床试验中测试过的反义寡核苷酸中最重要的特征。然而，继续寻求新的改良修饰以寻求增加的寡核苷酸效价，改善的体内转运。和有利的新陈代谢。最近，我们描述了精胺基团与寡核苷酸中的嘧啶的缀合如何通过加速结合动力学极大地增加其对互补RNA的亲和力。在这里，我们描述了在固相合成过程中如何使用直接的“可转换核苷方法”将精胺与MOE-寡核苷酸中胞苷的环外氨基连接。单修饰或双修饰的寡核苷酸显示出对互补RNA的亲和力大大增强，具有新一代基于MOE的寡核苷酸药物的潜力。
• Scaling Catalytic Contributions of Small Self‐Cleaving Ribozymes
  作者：Michaela Egger、Raphael Bereiter、Stefan Mair、Ronald Micura

  DOI：10.1002/anie.202207590

  日期：2022.10.10

  General base knockout in nucleolytic ribozymes using deazaguanosine-modified mutants paves the way to scale the relative contributions of the four main strategies (α, β, γ, δ) applied in ribozyme general acid base catalysis.

  使用脱氮鸟苷修饰的突变体在溶核核酶中进行一般碱基敲除，为衡量核酶一般酸碱催化中应用的四种主要策略（α、β、γ、δ）的相对贡献铺平了道路。
• Recognition of mixed-sequence DNA using double-stranded probes with interstrand zipper arrangements of O2′-triphenylene- and coronene-functionalized RNA monomers
  作者：Saswata Karmakar、Dale C. Guenther、Bradley C. Gibbons、Patrick J. Hrdlicka

  DOI：10.1039/c7ob01920c

  日期：——

  Energetically activated double-stranded probes with interstrand arrangements of intercalator-functionalized nucleotides enable recognition of mixed-sequence DNA hairpins with excellent binding specificity.

  通过在链间排列插入功能化核苷酸的方式进行能量激活的双链探针，能够具有出色的结合特异性，以识别混合序列的DNA发夹。
• DELIVERY OF OLIGONUCLEOTIDES TO THE STRIATUM
  申请人：ALNYLAM PHARMACEUTICALS, INC.

  公开号：US20220307024A1

  公开（公告）日：2022-09-29

  One aspect of the present invention relates to a double stranded iRNA agent comprising an antisense strand which is complementary to a target gene; a sense strand which is complementary to said antisense strand; and one or more lipophilic moieties conjugated to one or more internal positions on at least one strand, optionally via a linker or carrier, which provides for targeting to, and uptake by, tissues and cells of the CNS, and in particular the striatum. Another aspect of the invention relates to a method of gene silencing in tissues and cells of the CNS, and in particular the striatum, that includes administering to a tissue/cell or a subject in need thereof a therapeutically effective amount of the lipophilic moieties-conjugated double-stranded iRNAs.

  本发明的一个方面涉及双链iRNA剂，包括一个与目标基因互补的反义链;一个与该反义链互补的正义链;以及一个或多个脂溶性基团，通过连接物或载体与至少一条链上的一个或多个内部位置结合，从而实现对中枢神经系统组织和细胞，特别是纹状体的靶向和摄取。本发明的另一个方面涉及一种在中枢神经系统组织和细胞，特别是纹状体中基因沉默的方法，包括向需要治疗的组织/细胞或受试者中注射足够疗效量的脂溶性基团结合的双链iRNA。