2-chloro-2'-deoxyadenosine-5'-trisphosphate | 106867-30-5

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘌呤核苷酸
• 英文名称: 2-chloro-2'-deoxyadenosine-5'-trisphosphate
• 英文别名: PF5；2-chlorodeoxyadenosine triphosphate；2-Chloro-2'-deoxyadenosine-5'-triphosphate；[[(2R,3S,5R)-5-(6-amino-2-chloropurin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate
• CAS: 106867-30-5
• 化学式: C₁₀H₁₅ClN₅O₁₂P₃
• 分子量: 525.63
• InChiKey: PZCJNHCKXRBBNN-KVQBGUIXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -3
• 重原子数：
  31
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  259
• 氢给体数：
  6
• 氢受体数：
  16

反应信息

• 作为反应物：
  描述：

  Guanosine 5'-triphosphate 、 2-chloro-2'-deoxyadenosine-5'-trisphosphate 在 mouse cyclic GMP−AMP synthase 、 magnesium chloride 作用下， 以 aq. buffer 为溶剂， 反应 16.0h， 生成 2-amino-9-[(1R,6R,8R,10S,15R,17R,18R)-8-(6-amino-2-chloropurin-9-yl)-3,12,18-trihydroxy-3,12-dioxo-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one
  参考文献：
  名称：

  2'-5'，3'-5'-环二核苷酸的酶法制备，它们与干扰素基因衔接子蛋白刺激物的结合特性以及结构/活性相关性。

  摘要：

  环状二核苷酸是环状GMP-AMP合酶（cGAS）-干扰素基因刺激（STING）途径的第二信使，在识别肿瘤细胞和病毒或细菌感染中起着重要作用。它们与STING衔接蛋白结合并通过TANK结合激酶1（TBK1）/干扰素调节因子3（IRF3）和核因子-κB（IκB）激酶（IKK）/核因子-κB（NFκB）抑制剂触发细胞因子的表达信号级联。在这项工作中，我们描述了使用人，小鼠和鸡的环状GMP-AMP合成酶（cGAS）酶法制备2'-5'，3'-5'-环二核苷酸（2'3'CDNs）的方法。我们通过使用一个小的核苷酸5'-三磷酸（NTP）类似物文库来分析这些酶的底物特异性，并使用它们来制备33个2'3'CDN。我们还确定了这些CDN对基于细胞和生化分析的五种不同STING单倍型的亲和力，并描述了它们对所有STING单倍型的最佳活性所需的特性。接下来，我们研究它们对人外周血单核细胞（PBMC）诱导的细胞因子

  DOI：

  10.1021/acs.jmedchem.9b01062
• 作为产物：
  描述：

  克拉屈滨 在 磷酸三甲酯 、 三正丁胺 、 N,N'-羰基二咪唑 、 三氯氧磷 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 14.75h， 生成 2-chloro-2'-deoxyadenosine-5'-trisphosphate
  参考文献：
  名称：

  2-ClATP exerts anti-tumoural actions not mediated by P2 receptors in neuronal and glial cell lines

  摘要：

  We investigated the effects of the ATP analogue and P2 receptor agonist 2-ClATP on growth and survival of different neuronal (PC12, PC12nnr5 and SH-SY5Y) and glial (U87 and U373) cell lines, by the use of direct count of intact nuclei, fluorescence microscopy, fluorescence-activated cell sorter analysis (FACS) and high pressure liquid chromatography (HPLC). 2-ClATP lowered the number of cultured PC12nnr5, SH-SY5Y, U87 and U373 cells to almost 5%, and of PC12 cells to about 35% after 3-4 days of treatment. EC50 was in the 5-25 muM range, with 2-ClATP behaving as a cytotoxic or cytostatic agent. Analysis of the biological mechanisms demonstrated that pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (P2 receptor antagonist and nucleotidases inhibitor), but not Caffeine or CGS-15493 (PI receptor antagonists) effectively prevented 2-ClATP-induced toxicity. 2-ClATP metabolic products (2-ClADP, 2-ClAMP, 2-Cladenosine) and new synthesis derivatives (2-CldAMP, 2-Cldadenosine-3',5'-bisphosphate and 2-CldATP) exerted similar cytotoxic actions. Inhibition of both serum nucleotidases and purine nucleoside transporters strongly reduced 2-ClATP-induced cell death, which was conversely increased by the nucleotide hydrolyzing enzyme apyrase. The adenosine kinase inhibitor 5-iodotubericidin totally prevented 2-ClATP or 2-Cladenosine-induced toxicity.In summary, our findings indicate that 2-ClATP exerts either cell cycle arrest or cell death, acting neither on P2 nor on P1 receptors, but being extracellularly metabolized into 2-Cladenosine, intracellularly transported and re-phosphorylated. (C) 2003 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.bcp.2003.09.015

文献信息

• 2'3' CYCLIC DINUCLEOTIDES WITH PHOSPHONATE BOND ACTIVATING THE STING ADAPTOR PROTEIN
  申请人：INSTITUTE OF ORGANIC CHEMISTRY AND BIOCHEMISTRY ASCR,V.V.I.

  公开号：US20190185510A1

  公开（公告）日：2019-06-20

  The present disclosure relates to 2′3′ cyclic phosphonate dinucleotides of general formula (J), their pharmaceutically acceptable salts, their pharmaceutical composition and combinations of said substances and other medicaments or pharmaceuticals. The disclosure also relates to the use of said compounds for the treatment or prevention of diseases or conditions modifiable by STING protein modulation, such as cancer or viral, allergic and inflammatory diseases. In addition, these substances can be used as adjuvants in vaccines.

  本公开涉及一般式（J）的2′3′环磷酸二核苷酸，其药用可接受盐，其药物组合物以及所述物质与其他药物或药品的组合物。该公开还涉及使用所述化合物治疗或预防可通过STING蛋白调节改变的疾病或状况，如癌症或病毒性、过敏性和炎症性疾病。此外，这些物质可用作疫苗的辅助剂。
• Facile Small Scale Synthesis of Nucleoside 5′-Phosphate Mixtures
  作者：Robert S. Jansen、Hilde Rosing、Jan HM Schellens、Jos H. Beijnen

  DOI：10.1080/15257770903451546

  日期：2010.1

  phosphorylate small amounts of nucleosides (0.05 μmol) into mixtures of their 5′-mono-, di-, and triphosphates in a one-pot reaction. The nucleosides were first converted into their dichlorophosphates using a large excess (15–18 equivalents) of phosphorous oxychloride in trimethylphosphate. The large excess resulted in good dichlorophosphate yields (46–76%) for the four nucleosides tested. Upon the addition

  我们提出了一种简便的方法，可以在一锅反应中将少量的核苷（0.05μmol）磷酸化为5'-单-，二-和三磷酸的混合物。首先使用磷酸三甲酯中大量过量的氯氧化磷（15-18当量）将核苷转化为其二氯磷酸酯。大量过量导致所测试的四种核苷的二氯磷酸酯收率良好（46–76％）。在将磷酸三丁铵与另外的三丁胺（均20当量）一起加入后，将二氯磷酸酯转化为含有等量的单磷酸酯，二磷酸酯和三磷酸酯的混合物。所提出的方法已成功地应用于合成稳定同位素标记的核苷酸的混合物，该混合物可用作定量质谱分析中的内标。
• 3'3' CYCLIC DINUCLEOTIDES WITH PHOSPHONATE BOND ACTIVATING THE STING ADAPTOR PROTEIN
  申请人：INSTITUTE OF ORGANIC CHEMISTRY AND BIOCHEMISTRY ASCR, V.V.I.

  公开号：US20190183917A1

  公开（公告）日：2019-06-20

  Provided herein are the 3′3′ cyclic phosphonate dinucleotides of general formula J, their pharmaceutically acceptable salts, a pharmaceutical composition containing them and combinations of said substances and other medicaments or pharmaceuticals. The disclosure also relates to the use of said compounds for the treatment or prevention of diseases or conditions modifiable by STING protein modulation, such as cancer or viral, allergic and inflammatory diseases. In addition, these substances can be used as adjuvants in vaccines.

  本文提供了一般式J的3′3′环磷酸二核苷酸及其药学上可接受的盐、包含它们的制药组合物以及与其他药物或制药品的混合物。本文还涉及使用这些化合物治疗或预防可通过STING蛋白调节改变的疾病或病症，例如癌症或病毒性、过敏性和炎症性疾病。此外，这些物质可以用作疫苗佐剂。
• CDDO-compounds and combination therapies thereof
  申请人：Board of

  公开号：US20030119732A1

  公开（公告）日：2003-06-26

  CDDO-compounds in combination with other chemotherapeutic agents induce and potentiate cytotoxicity and apoptosis in cancer cell. One class of chemotherapeutic agents include retinoids. Cancer therapies based on these combination therapies are provided. Also provided are methods to treat graft versus host diseases using the CDDO compounds.

  CDDO化合物与其他化疗药物结合使用，可诱导和增强癌细胞的细胞毒性和凋亡。其中一类化疗药物包括视黄醇类。提供了基于这些联合治疗的癌症治疗方法。还提供了使用CDDO化合物治疗移植物抗宿主病的方法。
• CDDO-COMPOUNDS AND COMBINATION THERAPIES THEREOF
  申请人：Konopleva Marina

  公开号：US20090093447A1

  公开（公告）日：2009-04-09

  CDDO-compounds in combination with other chemotherapeutic agents induce and potentiate cytotoxicity and apoptosis in cancer cell. One class of chemotherapeutic agents include retinoids. Cancer therapies based on these combination therapies are provided. Also provided are methods to treat graft versus host diseases using the CDDO compounds.

  CDDO化合物与其他化疗药物结合使用可诱导和增强癌细胞的细胞毒性和凋亡。一类化疗药物包括视黄醇。提供基于这些联合疗法的癌症治疗。还提供使用CDDO化合物治疗移植物抗宿主病的方法。