1-[(2R,6S)-6-(羟基甲基)-4-(三苯基甲基)-2-吗啉基]-5-甲基-2,4(1H,3H)-嘧啶二酮 | 914361-76-5

• 物质功能分类: 医药中间体 - 嘧啶类化合物
• 分子结构分类: 有机化合物 - 苯类化合物 - 三苯基化合物
• 中文名称: 1-[(2R,6S)-6-(羟基甲基)-4-(三苯基甲基)-2-吗啉基]-5-甲基-2,4(1H,3H)-嘧啶二酮
• 英文名称: 1-((2R,6S)-6-(hydroxymethyl)-4-tritylmorpholin-2-yl)-5-methylpyrimidine-2,4(1H,3H)-dione
• 英文别名: 1-[(2R,6S)-6-(hydroxymethyl)-4-tritylmorpholin-2-yl]-5-methylpyrimidine-2,4-dione
• CAS: 914361-76-5
• 化学式: C₂₉H₂₉N₃O₄
• 分子量: 483.567
• InChiKey: SINOYLIIFJJPCM-IZZNHLLZSA-N

物化性质

• 密度：
  1.259±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  36
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  82.1
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1-[(2R,6S)-6-(羟基甲基)-4-(三苯基甲基)-2-吗啉基]-5-甲基-2,4(1H,3H)-嘧啶二酮 在 咪唑 、 N-氯代丁二酰亚胺 、 sodium azide 、 四丁基氟化铵 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 10.5h， 生成 ((2S,6R)-6-(3-(azidomethyl)-5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-tritylmorpholin-2-yl)methyl dimethylphosphoramidochloridate
  参考文献：
  名称：

  Direct Activation of Nucleobases with Small Molecules for the Conditional Control of Antisense Function

  摘要：

  Conditionally controlled antisense oligonucleotides provide precise interrogation of gene function at different developmental stages in animal models. Only one example of small molecule‐induced activation of antisense function exist. This has been restricted to cyclic caged morpholinos that, based on sequence, can have significant background activity in the absence of the trigger. Here, we provide a new approach using azido‐caged nucleobases that are site‐specifically introduced into antisense morpholinos. The caging group design is a simple azidomethylene (Azm) group that, despite its very small size, efficiently blocks Watson–Crick base pairing in a programmable fashion. Furthermore, it undergoes facile decaging via Staudinger reduction when exposed to a small molecule phosphine, generating the native antisense oligonucleotide under conditions compatible with biological environments. We demonstrated small molecule‐induced gene knockdown in mammalian cells, zebrafish embryos, and frog embryos. We validated the general applicability of this approach by targeting three different genes.

  DOI：

  10.1002/anie.202318773
• 作为产物：
  描述：

  5-甲基尿甙 在 sodium periodate 、 三乙胺 作用下， 以 乙醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 1-[(2R,6S)-6-(羟基甲基)-4-(三苯基甲基)-2-吗啉基]-5-甲基-2,4(1H,3H)-嘧啶二酮
  参考文献：
  名称：

  Solid-phase-supported synthesis of morpholinoglycine oligonucleotide mimics

  摘要：

  已开发出一种高效的固相支持肽合成（SPPS）方法，用于合成吗啡甘氨酸寡核苷酸（MorGly）模拟物。提出的策略包括一种新颖的特殊设计的易降解连接基团，其中包含草酰基残基和2-氨甲基吗啡核苷类似物作为第一个亚基。

  DOI：

  10.3762/bjoc.10.115

文献信息

• FUNCTIONALLY-MODIFIED OLIGONUCLEOTIDES AND SUBUNITS THEREOF
  申请人：Sarepta Therapeutics, Inc.

  公开号：US20140330006A1

  公开（公告）日：2014-11-06

  Functionally-modified oligonucleotide analogues comprising modified intersubunit linkages and/or modified 3′ and/or 5′-end groups are provided. The disclosed compounds are useful for the treatment of diseases where inhibition of protein expression or correction of aberrant mRNA splice products produces beneficial therapeutic effects.

  提供了包含修改的亚单位间连接和/或修改的3'和/或5'-末端基团的功能修饰寡核苷酸类似物。所公开的化合物对于治疗需要抑制蛋白质表达或纠正异常mRNA剪接产物以产生有益治疗效果的疾病是有用的。
• Improved Protocol for the Synthesis of Flexibly Protected Morpholino Monomers from Unprotected Ribonucleosides
  作者：Sankha Pattanayak、Sibasish Paul、Bappaditya Nandi、Surajit Sinha

  DOI：10.1080/15257770.2012.724491

  日期：2012.11

  protected morpholino monomers from unprotected ribonucleosides in high overall yield, using oxidative glycol cleavage and reductive amination strategy. Unlike the previous methods, the present strategy allows installing the exocyclic amine protections at a later stage, and thus avoids the use of expensive, or commercially unavailable, exocyclic amine-protected ribonucleosides as starting materials. To

  已经开发了一种廉价且大大改进的方案，使用氧化乙二醇裂解和还原胺化策略从未保护的核糖核苷以高总收率合成受保护的吗啉代单体。与先前的方法不同，本策略允许在稍后的阶段安装环外胺保护剂，从而避免使用昂贵的或市售的环外胺保护的核糖核苷作为起始原料。为了证明本发明方法在选择保护基上的灵活性，已在环外胺位置用几个具有不同解嵌段性质的此类基团保护了单体。
• MORPHOLINO-BASED ANTISENSE AGENT
  申请人：Sinha Surajit

  公开号：US20120296087A1

  公开（公告）日：2012-11-22

  Morpholino-based oligomers suitable as antisense agent comprising modifications of phosphorodiamidate backbone or modification with 5-substituted pyrimidines of morpholino compound that is soluble in culture medium and sufficient for cell penetration thereby eliminating the need for injecting into the cells. Monomers comprising the said oligomers and its method of manufacture, method of manufacture of the said oligomers and its dye, flurophore, drug, biomolecule conjugate wherein the said oligomers find different end use but not limited to regulation of gene expression, tissue culture with improved transfection efficiency and related studies on cellular transfection.

  基于Morpholino的寡聚体适用作为反义物质，包括对磷酸二胺酰基骨架的修饰或对Morpholino化合物进行5-取代嘧啶的修饰，该化合物在培养基中溶解并足以渗透细胞，从而消除了注射到细胞中的需要。包括上述寡聚体的单体及其制造方法，上述寡聚体及其染料、荧光素、药物、生物分子共轭物的制造方法，其中上述寡聚体具有不同的最终用途，但不限于调控基因表达，具有改善转染效率的组织培养以及有关细胞转染的相关研究。
• Design, Synthesis and Molecular Modeling Study of Conjugates of ADP and Morpholino Nucleosides as A Novel Class of Inhibitors of PARP-1, PARP-2 and PARP-3
  作者：Yuliya V. Sherstyuk、Nikita V. Ivanisenko、Alexandra L. Zakharenko、Maria V. Sukhanova、Roman Y. Peshkov、Ilia V. Eltsov、Mikhail M. Kutuzov、Tatiana A. Kurgina、Ekaterina A. Belousova、Vladimir A. Ivanisenko、Olga I. Lavrik、Vladimir N. Silnikov、Tatyana V. Abramova

  DOI：10.3390/ijms21010214

  日期：——

  as well as on the linkage between ADP and morpholino nucleoside. The 5-iodination of uracil and the introduction of the P–N bond in NAD+-mimetics have shown to increase inhibition properties. Structural modeling suggested that the P–N bond can stabilize the pyrophosphate group in active conformation due to the formation of an intramolecular hydrogen bond. The most active NAD+ analog against PARP-1 contained

  我们报告了腺苷二磷酸（ADP）和吗啉代核苷作为聚（ADP-核糖）聚合酶-1、2和3的潜在选择性抑制剂的共轭物的设计，合成和分子建模研究。16种含天然杂环碱基的二核苷焦磷酸盐烟酰胺腺嘌呤二核苷酸（NAD +）分子以5卤代嘧啶为主要成分，并模仿这些酶的主要底物，已高收率地合成。吗啉代核苷已通过磷酸酯或磷酰胺键连接到ADP的β-磷酸酯上。筛选这些衍生物对PARP-1和PARP-2的自聚聚（ADP-核糖基）的抑制特性表明，其作用取决于核碱基的类型以及ADP和吗啉代核苷之间的键合。已证明在NAD +模拟物中尿嘧啶的5碘化和P–N键的引入增加了抑制作用。结构模型表明，由于分子内氢键的形成，PN键可以使焦磷酸酯基团稳定在活性构象中。针对PARP-1的活性最高的NAD +类似物包含5-碘尿嘧啶2′-氨基甲基吗啉代核苷，IC50为126±6μM，而在PARP-2的情况下，它是腺嘌呤2′-氨基甲基吗啉代核苷（
• [EN] MYOSTATIN SIGNAL INHIBITOR<br/>[FR] INHIBITEUR DE SIGNAL MYOSTATINE
  申请人：NIPPON SHINYAKU CO LTD

  公开号：WO2020138509A1

  公开（公告）日：2020-07-02

  The present invention provides a new approach for inhibiting myostatin signaling by targeting ACVR2B at the mRNA level.

  本发明提供了一种通过针对ACVR2B在mRNA水平上的作用来抑制肌肉萎缩蛋白信号的新方法。