三氮唑核苷-5'-磷酸酯 | 40925-28-8

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 三唑核糖核苷和核糖核苷酸
• 中文名称: 三氮唑核苷-5'-磷酸酯
• 中文别名: ((2R,3S,4R,5R)-5-(3-氨基甲酰基-1H-1,2,4-三唑-1-基)-3,4-二羟基四氢呋喃-2-基)甲基二氢磷酸盐
• 英文名称: ribavirin monophosphate
• 英文别名: ribavirin 5'-monophosphate；ribavirin；[(2R,3S,4R,5R)-5-(3-carbamoyl-1,2,4-triazol-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl dihydrogen phosphate
• CAS: 40925-28-8
• 化学式: C₈H₁₃N₄O₈P
• 分子量: 324.187
• InChiKey: SDWIOXKHTFOULX-AFCXAGJDSA-N

物化性质

• 沸点：
  767.3±70.0 °C(Predicted)
• 密度：
  2.33±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -3.5
• 重原子数：
  21
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  190
• 氢给体数：
  5
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  三氮唑核苷-5'-磷酸酯 在 三正丁胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 51.0h， 生成 1H-1,2,4-三唑-3-甲酰胺腺嘌呤二核苷酸
  参考文献：
  名称：

  Ribavirin, tiazofurin, and selenazofurin: mononucleotides and nicotinamide adenine dinucleotide analogs. Synthesis, structure, and interactions with IMP dehydrogenase

  摘要：

  A series of dinucleotides, analogous to nicotinamide adenine dinucleotide but containing the five-membered base nucleosides tiazofurin (1a), selenazofurin (1b), ribavirin (2), and AICAR (3) in place of nicotinamide ribonucleoside, were prepared in greater than 50% yield by reacting the corresponding nucleotide imidazolidates (6a-d) with adenosine 5'-monophosphate (AMP). The symmetric dinucleotides of tiazofurin (TTD, 8e) and selenazofurin (SSD, 8f) were also prepared by a similar methodology. These dinucleotides were characterized by 1H NMR and fast atom bombardment MS and were evaluated for their inhibitory potency against a partially purified preparation of tumoral inosine monophosphate dehydrogenase (IMPD) from P388 cells. The order of potency found was SAD (8b) greater than TAD (8a) much greater than SSD (8f) congruent to TTD (8e) congruent to RAD (8c) much much greater than ZAD (8d). On kinetic analysis none of the dinucleotides produced competitive inhibition of IMPD with NAD as a variable substrate. In addition to their superior IMPD inhibitory activity, SAD and TAD appear to be the only dinucleotides, besides NAD, that are formed naturally by the NAD pyrophosphorylase from P388 lymphoblasts.

  DOI：

  10.1021/jm00379a018
• 作为产物：
  描述：

  利巴韦林 在 Chinese hamster ovary cell-derived adenosine kinase 、 5’-三磷酸腺苷 、 magnesium chloride 作用下， 以 phosphate buffer 为溶剂， 生成 三氮唑核苷-5'-磷酸酯
  参考文献：
  名称：

  Phosphorylation of Ribavirin and Viramidine by Adenosine Kinase and Cytosolic 5′-Nucleotidase II: Implications for Ribavirin Metabolism in Erythrocytes

  摘要：

  摘要许多核苷类似物药物，如利巴韦林和紫杉烷，在体内通过 5′-磷酸化作用被激活或代谢。在本报告中，我们测定了腺苷激酶对利巴韦林和维拉嘧啶进行 5′-单磷酸化的稳态动力学参数。利巴韦林的表观 Km 为 540 μM，kcat 为 1.8 min-1。其催化效率为 3.3 × 10-3min-1- μM-1，比腺苷低 1200 倍。与人们普遍认为利巴韦林只能被腺苷激酶磷酸化不同，研究发现细胞质 5′-核苷酸酶 II 在体外也能催化利巴韦林的磷酸化。该反应在生理浓度的 ATP 或 2,3-二磷酸甘油酯的刺激下达到最佳状态。在磷酸盐缓冲盐水加 ATP 和 2,3-二磷酸甘油酯中，利巴韦林的表观 Km 为 88 μM，kcat 为 4.0 min-1。这些发现表明，细胞质 5′-核苷酸酶 II 可能参与了体内利巴韦林的磷酸化过程。与利巴韦林一样，维拉米定也被腺苷激酶或细胞质 5′-核苷酸酶 II 磷酸化，尽管其活性要低得多。紫氨嘧啶磷酸化的催化效率比利巴韦林低 10 到 330 倍，这表明其他核苷激酶可能参与了体内紫氨嘧啶的磷酸化。利巴韦林和维拉嘧啶都不会被脱氧胞苷激酶和尿苷-胞苷激酶磷酸化。红细胞中存在高浓度的 2,3-二磷酸甘油酯这一巧合表明，细胞膜 5′-核苷酸酶 II 可能在利巴韦林磷酸化过程中发挥重要作用，并有助于利巴韦林三磷酸在红细胞中的合成代谢。阐明利巴韦林和维拉嘧啶的磷酸化机制将有助于了解它们的体内代谢，尤其是利巴韦林诱导的红细胞溶血性贫血。

  DOI：

  10.1128/aac.49.6.2164-2171.2005

文献信息

• Polymeric carriers linked to nucleotide analogues via a phosphoramide
  申请人：Advanced Magnetics, Inc.

  公开号：US05981507A1

  公开（公告）日：1999-11-09

  Novel compositions of nucleotide analog prodrugs for the treatment of viral infections and cancer are herein disclosed. The prodrugs have a biocompatible polymeric carrier conjugated to the nucleotide analog via an amino-phosphate linkage. The amino group is provided by the carrier, which either inherently possesses a primary amine, or is modified with reactive groups that incorporate the primary amine onto the carrier. The carrier can be a polyamino acid, a polyvinylic polymer, a polysaccharide or combinations thereof, such as polylysine, HPMA, dextran, hydroxyethyl starch, or polyethylene glycol; the nucleotide analog can be ribavirin araA, AZT, acyclovir, 5-FUDR, araC or ddI. Methods of treating a viral infection of cancer using these prodrugs are also disclosed. The prodrugs endow the nucleotide analogs with substantially enhanced therapeutic efficacy and reduces toxicity in comparison to the nucleotide analog alone.

  本文披露了用于治疗病毒感染和癌症的新型核苷酸类似物前药的组合物。这些前药具有生物相容性聚合物载体，通过氨基磷酸酯键与核苷酸类似物结合。氨基基团由载体提供，它可以天然具有一次胺基，或者被修饰以将一次胺基合并到载体上。载体可以是多聚氨基酸、多乙烯基聚合物、多糖或其组合物，例如聚赖氨酸、HPMA、右旋糖、羟乙基淀粉或聚乙二醇；核苷酸类似物可以是利巴韦林、阿拉A、AZT、阿昔洛韦、5-FUDR、阿拉C或ddI。本文还披露了使用这些前药治疗病毒感染或癌症的方法。这些前药使核苷酸类似物具有显著增强的治疗效果，并减少与核苷酸类似物单独使用时的毒性。
• Methods for modulating taste receptors
  申请人：MARS, INCORPORATED

  公开号：US11185100B2

  公开（公告）日：2021-11-30

  Amino acids present in domains of an umami taste receptor are described herein, wherein the amino acids interact with at least one nucleotide derivative and/or at least one transmembrane compound that potentiates, modulates, increases, and/or enhances the activity of the umami receptor. Such compounds can be used in flavor compositions to enhance the umami taste and/or palatability of food products.

  本文描述了存在于鲜味受体结构域中的氨基酸，其中氨基酸与至少一种核苷酸衍生物和/或至少一种跨膜化合物相互作用，从而增强、调节、增加和/或提高鲜味受体的活性。此类化合物可用于调味组合物，以增强食品的鲜味和/或适口性。
• Synthesis of Azole Nucleoside 5′‐Monophosphate Mimics (P1Ms) and Their Inhibitory Properties of IMP Dehydrogenases
  作者：Guangyi Wang、Kandasamy Sakthivel、Vasanthakumar Rajappan、Thomas W. Bruice、Kathleen Tucker、Patrick Fagan、Jennifer L. Brooks、Tiffany Hurd、Janet M. Leeds、P. Dan Cook

  DOI：10.1081/ncn-120027838

  日期：2004.1.1

  IMPDH inhibitors have potential antimicrobial, anticancer and immunomodulatory effects. Nucleoside inhibitors of IMPDH exert their inhibitory effects via nucleoside 5'-MPs. Conversion of nucleoside analogs to NMPs by cellular nucleoside kinases is not assured, and usually is inefficient. In order to bypass cellular phosphorylation, a series of azole nucleoside 5'-MP mimics (P1Ms) based on ribavirin, EICAR and bredinin were synthesized and screened against human and C. albicans IMP dehydrogenises. P1Ms 8, 16, 25, 28 and 29 demonstrated substantial IMPDH inhibition with K-i values in low micromolar range.
• Synthesis and antiviral activity of some phosphates of the broad-spectrum antiviral nucleoside, 1-.beta.-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (ribavirin)
  作者：Lois B. Allen、K. H. Boswell、Tasneem A. Khwaja、Rich B. Meyer、Robert W. Sidwell、J. T. Witkowski、Leon F. Christensen、Roland K. Robins

  DOI：10.1021/jm00206a005

  日期：1978.8

  1-beta-D-Ribofuranosyl-1,2,4-triazole-3-carboxamide 5'-phosphate (2) was prepared and converted into the following derivatives: the 5'-phosphoramidate 3, the 5'-diphosphate 4, the 5'-triphosphate 5, and the cyclic 3',5'-phosphate 6. The cyclic 2',3'-phosphate 7 was prepared from the parent nucleoside, 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (1), and was opened to the 2'(3')-phosphate 8. These compounds were found to exhibit significant antiviral activity against several viruses in cell culture. Ribavirin 5'-phosphate (2) was shown to be effective when tested against lethal infections in mice caused by influenza A2, influenza B, and murine hepatitis viruses.
• DUDCHIK, N. V.;ZINCHENKO, A. I.;BARAJ, V. N.;MAURINSH, YU. A.;SENTYUREVA,+, VESIT AN BSSR. CEP. XIM. N.,(1990) N, S. 90-94
  作者：DUDCHIK, N. V.、ZINCHENKO, A. I.、BARAJ, V. N.、MAURINSH, YU. A.、SENTYUREVA,+

  DOI：——

  日期：——