8-(n-butylthioether)adenosine | 68807-84-1

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘌呤核苷
• 英文名称: 8-(n-butylthioether)adenosine
• 英文别名: 8-butylthioadenosine；(2R,3R,4S,5R)-2-(6-amino-8-(butylthio)-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol；(2R,3R,4S,5R)-2-(6-amino-8-butylsulfanylpurin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol
• CAS: 68807-84-1
• 化学式: C₁₄H₂₁N₅O₄S
• 分子量: 355.418
• InChiKey: AARKRUUVNCEOMU-QYVSTXNMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  24
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  165
• 氢给体数：
  4
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  8-(n-butylthioether)adenosine 在 磷酸三甲酯 、 对甲苯磺酸 、 三氯氧磷 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 26.85h， 生成 8-butylthio-2',3'-isopropylidene-adenosine β,γ-methylene 5'-triphosphate
  参考文献：
  名称：

  8-BuS-ATP derivatives as specific NTPDase1 inhibitors

  摘要：

  Background and PurposeEctonucleotidases control extracellular nucleotide levels and consequently, their (patho)physiological responses. Among these enzymes, nucleoside triphosphate diphosphohydrolase‐1 (NTPDase1), −2, −3 and −8 are the major ectonucleotidases responsible for nucleotide hydrolysis at the cell surface under physiological conditions, and NTPDase1 is predominantly located at the surface of vascular endothelial cells and leukocytes. Efficacious inhibitors of NTPDase1 are required to modulate responses induced by nucleotides in a number of pathological situations such as thrombosis, inflammation and cancer.Experimental ApproachHere, we present the synthesis and enzymatic characterization of five 8‐BuS‐adenine nucleotide derivatives as potent and selective inhibitors of NTPDase1.Key ResultsThe compounds 8‐BuS‐AMP, 8‐BuS‐ADP and 8‐BuS‐ATP inhibit recombinant human and mouse NTPDase1 by mixed type inhibition, predominantly competitive with Ki values <1 μM. In contrast to 8‐BuS‐ATP which could be hydrolyzed by other NTPDases, the other BuS derivatives were resistant to hydrolysis by either NTPDase1, −2, −3 or −8. 8‐BuS‐AMP and 8‐BuS‐ADP were the most potent and selective inhibitors of NTPDase1 expressed in human umbilical vein endothelial cells as well as in situ in human and mouse tissues. As expected, as a result of their inhibition of recombinant human NTPDase1, 8‐BuS‐AMP and 8‐BuS‐ADP impaired the ability of this enzyme to block platelet aggregation. Importantly, neither of these two inhibitors triggered platelet aggregation nor prevented ADP‐induced platelet aggregation, in support of their inactivity towards P2Y1 and P2Y12 receptors.Conclusions and ImplicationsThe 8‐BuS‐AMP and 8‐BuS‐ADP have therefore potential to serve as drugs for the treatment of pathologies regulated by NTPDase1.

  DOI：

  10.1111/bph.12135
• 作为产物：
  描述：

  8-溴膘苷 在 sodium hydroxide 、 sodium methylate 作用下， 以 甲醇 、 二甲基亚砜 为溶剂， 反应 5.0h， 生成 8-(n-butylthioether)adenosine
  参考文献：
  名称：

  P2Y（1）受体修饰的腺嘌呤核苷酸的分子识别。1.一种合成，生化和NMR方法。

  摘要：

  关于火鸡红细胞膜中P2Y（1）-受体（P2Y（1）-R）活化的2-硫醚-腺嘌呤核苷酸的显着高效能代表了某些替代天然物质所促进的最大效能提升受体配体。本文介绍了有关这些P2Y（1）-R配体比ATP高效力的起源的研究。在这项研究中，采用了一种综合方法，将新的ATP类似物的合成，其生化评估以及涉及NMR实验和理论计算的SAR分析相结合。进行这些实验和计算以阐明其构象并评估所研究的P2Y（1）-R配体的电子性质。合成的ATP类似物包括衍生物，其中C2或C8位置被供电子基团（例如醚，硫醚或胺）取代。测试了化合物在火鸡红细胞中诱导P2Y（1）-R介导的磷脂酶C活化和大鼠星形胶质细胞Ca（2+）反应的效力。8-取代的ATP和AMP衍生物对磷脂酶C或钙水平几乎没有或没有影响，而相应的2-取代的ATP类似物有效地增加了肌醇磷酸酯和Ca（2 +）（i）的水平。除2-丁基硫代-AMP引起小的Ca（2+）反应外，

  DOI：

  10.1021/jm990156d

文献信息

• Molecular Recognition of Modified Adenine Nucleotides by the P2Y₁-Receptor. 1. A Synthetic, Biochemical, and NMR Approach
  作者：Efrat Halbfinger、Dan T. Major、Marco Ritzmann、Joachim Ubl、Georg Reiser、Jose L. Boyer、Kendall T. Harden、Bilha Fischer

  DOI：10.1021/jm990156d

  日期：1999.12.1

  evaluation, and their SAR analysis involving NMR experiments and theoretical calculations. These experiments and calculations were performed to elucidate the conformation and to evaluate the electronic nature of the investigated P2Y(1)-R ligands. ATP analogues synthesized included derivatives where C2 or C8 positions were substituted with electron-donating groups such as ethers, thioethers, or amines

  关于火鸡红细胞膜中P2Y（1）-受体（P2Y（1）-R）活化的2-硫醚-腺嘌呤核苷酸的显着高效能代表了某些替代天然物质所促进的最大效能提升受体配体。本文介绍了有关这些P2Y（1）-R配体比ATP高效力的起源的研究。在这项研究中，采用了一种综合方法，将新的ATP类似物的合成，其生化评估以及涉及NMR实验和理论计算的SAR分析相结合。进行这些实验和计算以阐明其构象并评估所研究的P2Y（1）-R配体的电子性质。合成的ATP类似物包括衍生物，其中C2或C8位置被供电子基团（例如醚，硫醚或胺）取代。测试了化合物在火鸡红细胞中诱导P2Y（1）-R介导的磷脂酶C活化和大鼠星形胶质细胞Ca（2+）反应的效力。8-取代的ATP和AMP衍生物对磷脂酶C或钙水平几乎没有或没有影响，而相应的2-取代的ATP类似物有效地增加了肌醇磷酸酯和Ca（2 +）（i）的水平。除2-丁基硫代-AMP引起小的Ca（2+）反应外，
• Nucleotide Analog ARL67156 as a Lead Structure for the Development of CD39 and Dual CD39/CD73 Ectonucleotidase Inhibitors
  作者：Laura Schäkel、Constanze C. Schmies、Riham M. Idris、Xihuan Luo、Sang-Yong Lee、Vittoria Lopez、Salahuddin Mirza、The Hung Vu、Julie Pelletier、Jean Sévigny、Vigneshwaran Namasivayam、Christa E. Müller

  DOI：10.3389/fphar.2020.01294

  日期：——

  compounds’ potency. Selected inhibitors were additionally evaluated in an orthogonal, malachite green assay versus the natural substrate ATP. The most potent CD39 inhibitors of the present series were ARL67156 and its derivatives 31 and 33 with Ki values of around 1 µM. Selectivity studies showed that all three nucleotide analogs additionally blocked CD73 acting as dual-target inhibitors. Docking studies provided

  核苷三磷酸二磷酸水解酶1（NTPDase1，CD39）抑制剂具有作为癌症（免疫）治疗新药的潜力。它们增加了免疫刺激性ATP的细胞外浓度，并减少了AMP的形成，后者可以被ecto-5'-核苷酸酶（CD73）进一步水解为免疫抑制，促进癌症的腺苷。在本研究中，我们合成了标准CD39抑制剂ARL67156的类似物和衍生物，这是一种显示出竞争性抑制机制的核苷酸类似物。在人酶处分析了结构-活性之间的关系。ñ腺嘌呤核的6-和C8-位，以及三磷酸（on）酸酯链的修饰。使用荧光标记的ATP衍生物的毛细管电泳与激光诱导的荧光检测耦合，以确定化合物的效力。相对于天然底物ATP，还通过正交的孔雀石绿分析法评估了选定的抑制剂。本系列中最有效的CD39抑制剂是ARL67156及其衍生物31和33ķ我值约为1 µM。选择性研究表明，所有三个核苷酸类似物还阻断了CD73作为双重靶标抑制剂的作用。对接研究为两个靶标提供了可
• 8-BuS-ATP derivatives as specific NTPDase1 inhibitors
  作者：Joanna Lecka、Irina Gillerman、Michel Fausther、Mabrouka Salem、Mercedes N Munkonda、Jean-Philippe Brosseau、Christine Cadot、Mireia Martín-Satué、Pedro d'Orléans-Juste、Éric Rousseau、Donald Poirier、Beat Künzli、Bilha Fischer、Jean Sévigny

  DOI：10.1111/bph.12135

  日期：2013.5

  Background and PurposeEctonucleotidases control extracellular nucleotide levels and consequently, their (patho)physiological responses. Among these enzymes, nucleoside triphosphate diphosphohydrolase‐1 (NTPDase1), −2, −3 and −8 are the major ectonucleotidases responsible for nucleotide hydrolysis at the cell surface under physiological conditions, and NTPDase1 is predominantly located at the surface of vascular endothelial cells and leukocytes. Efficacious inhibitors of NTPDase1 are required to modulate responses induced by nucleotides in a number of pathological situations such as thrombosis, inflammation and cancer.Experimental ApproachHere, we present the synthesis and enzymatic characterization of five 8‐BuS‐adenine nucleotide derivatives as potent and selective inhibitors of NTPDase1.Key ResultsThe compounds 8‐BuS‐AMP, 8‐BuS‐ADP and 8‐BuS‐ATP inhibit recombinant human and mouse NTPDase1 by mixed type inhibition, predominantly competitive with Ki values <1 μM. In contrast to 8‐BuS‐ATP which could be hydrolyzed by other NTPDases, the other BuS derivatives were resistant to hydrolysis by either NTPDase1, −2, −3 or −8. 8‐BuS‐AMP and 8‐BuS‐ADP were the most potent and selective inhibitors of NTPDase1 expressed in human umbilical vein endothelial cells as well as in situ in human and mouse tissues. As expected, as a result of their inhibition of recombinant human NTPDase1, 8‐BuS‐AMP and 8‐BuS‐ADP impaired the ability of this enzyme to block platelet aggregation. Importantly, neither of these two inhibitors triggered platelet aggregation nor prevented ADP‐induced platelet aggregation, in support of their inactivity towards P2Y1 and P2Y12 receptors.Conclusions and ImplicationsThe 8‐BuS‐AMP and 8‐BuS‐ADP have therefore potential to serve as drugs for the treatment of pathologies regulated by NTPDase1.