2-(Hexylthio)adenosine | 50823-26-2

• 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: 2-(Hexylthio)adenosine
• 英文别名: 2-(6-amino-2-hexylsulfanyl-7H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol；8-azaadenosine-5′-triphosphate；2-HexS-adenosine；S-hexyl-2-thio-isoguanosine；2-(n-Hexylthio)adenosin；(2R,3R,4S,5R)-2-(6-amino-2-(hexylthio)-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol；(2R,3R,4S,5R)-2-(6-amino-2-hexylsulfanylpurin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol
• CAS: 50823-26-2
• 化学式: C₁₆H₂₅N₅O₄S
• 分子量: 383.472
• InChiKey: NVINXDUHMZXGJN-SDBHATRESA-N

物化性质

• 沸点：
  719.9±70.0 °C(Predicted)
• 密度：
  1.60±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  26
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.69
• 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：

  2-(Hexylthio)adenosine 在 吡啶 、 Proton Sponge 、 三正丁胺 、 三丁基焦磷酸铵 、 三氯氧磷 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 8.03h， 生成 2-(6-amino-2-hexylsulfanyl-7H-purin-9-yl)-5-O-(1-thiotriphosphate-methyl)tetrahydrofuran-3,4-diol triethylammonium salt
  参考文献：
  名称：

  2-硫醚5'-O-（1-硫代三磷酸）腺苷衍生物作为通过P2Y受体发挥作用的新型胰岛素促分泌剂。

  摘要：

  P2-受体（P2-Rs）代表了新药开发的重要目标。在胰腺B细胞上也鉴定出P2-R，并且它们参与胰岛素分泌。因此，合成了新型的P2Y-R配体2-硫醚5'-O-硫代磷酸腺苷腺苷衍生物（2-RS-ATP-α-S）作为潜在的胰岛素促分泌剂。描述了这些核苷酸的有效合成和分离手性产物的简便方法。评估了化合物对猪胰腺I型ATPDase的酶稳定性。ATPDase水解2-己基硫基5'-O-（1-硫代三磷酸）腺苷（2-己基硫基-ATP-α-S）异构体的速率为ATP的28％。一些2-硫醚5'-（单硫代磷酸酯）腺苷衍生物（2-RS-AMP-S）对ATPDase产生抑制作用。化合物对P2Y（1）-R的表观亲和力是通过测量土耳其红细胞膜中P2Y-R促进的磷脂酶C活性来确定的。2-RS-ATP-α-S衍生物是激动剂，可刺激K（0.5）值在纳摩尔范围内的肌醇磷酸酯的产生。2-RS-AMP-S衍生物是完全的激动剂，尽管效力

  DOI：

  10.1021/jm990158y
• 作为产物：
  描述：

  (2R,3R,4S,5R)-2-(6-氨基-7-氧代嘌呤-7-鎓-9-基)-5-(羟基甲基)四氢呋喃-3,4-二醇 在 sodium hydroxide 、 三乙胺 作用下， 反应 8.0h， 生成 2-(Hexylthio)adenosine
  参考文献：
  名称：

  Identification of potent, selective P2Y-purinoceptor agonists: structure-activity relationships for 2-thioether derivatives of adenosine 5'-triphosphate

  摘要：

  Study of P-2-purinoceptor subtypes has been difficult due to the lack of potent and selective ligands. With the goal of developing high affinity P-2-purinoceptor-selective agonists, we have synthesized a series of analogues of adenine nucleotides modified on the purine ring as chain-extended 2-thioethers or as N-6-methyl-substituted compounds. Chemical functionality incorporated in the thioether moiety included cyanoalkyl, nitroaromatic, amino, thiol, cycloalkyl, n-alkyl, and olefinic groups. Apparent affinity of the compounds for P-2Y-purinoceptors was established by measurement of P-2Y-purinoceptor-promoted phospholipase C activity in turkey erythrocyte membranes and relaxation of carbachol-contracted smooth muscle in three different preparations (guinea pig taenia coli, rabbit aorta, and rabbit mesenteric artery). Activity at P-2X-purinoceptors was established by measurement of contraction of rabbit saphenous artery and of the guinea pig vas deferens and urinary bladder. All 11 of the 2-thioethers of ATP stimulated the production of inositol phosphates with K-0.5 values of 1.5-770 nM, with an (aminophenyl)ethyl derivative being most potent. Two adenosine diphosphate analogues were equipotent to the corresponding ATP analogues. Adenosine monophosphate analogues were full agonists, although generally 4 orders of magnitude less potent. ATP 2-thioethers displayed pD(2) values in the range of 6-8 in smooth muscle assay systems for activity at P-2Y-receptors. There was a significant correlation for the 2-thioether compounds between the pK(0.5) values for inositol phosphate production and the pD(2) values for relaxation mediated via the P-2Y-purinoceptors in the guinea pig taenia coli, but not for the vascular P-2Y-receptors or for the P-2X-receptors. At P-2X-receptors, no activity was observed in the rabbit saphenous artery, but variable degrees of activity were observed in the guinea pig vas deferens and bladder depending on distal substituents of the thioether moiety. N-6-Methyl-ATP was inactive at P-2X-receptors, and approximately equipotent to ATP at taenia coli P-2Y-receptors. This suggested that hybrid N-6-methyl and 2-thioether ATP derivatives might be potent and selective for certain P-2Y-receptors, as was shown for one such derivative, N-6-methyl-2-(5-hexenylthio)-ATP.

  DOI：

  10.1021/jm00076a023

文献信息

• Nucleoside-5′-monophosphates as Prodrugs of Adenosine A_2A Receptor Agonists Activated by ecto-5′-Nucleotidase†Contribution to celebrate the 100th anniversary of the Division of Medicinal Chemistry of the American Chemical Society.
  作者：Ali El-Tayeb、Jamshed Iqbal、Andrea Behrenswerth、Michael Romio、Marion Schneider、Herbert Zimmermann、Jürgen Schrader、Christa E. Müller

  DOI：10.1021/jm900538v

  日期：2009.12.10

  Prodrugs of adenosine A2A receptor agonists were developed that are activated by ecto-5′-nucleotidase (ecto-5′-NT, CD73). Because ecto-5′-NT is upregulated in inflamed tissue, the A2A agonists are expected to be released from their prodrug form at the sites of inflammation. 2-(Ar)alkyl-substituted AMP derivatives were synthesized and investigated. Certain 2-substituted AMP derivatives, including 2-hexylthio-AMP

  开发了腺苷A 2A受体激动剂的前药，它们被ecto-5'-核苷酸酶（ecto-5'-NT，CD73）激活。由于ecto-5'-NT在发炎的组织中上调，因此A 2A激动剂有望在炎症部位从其前药形式释放出来。合成并研究了2-（Ar）烷基取代的AMP衍生物。某些2-取代的AMP衍生物，包括2-己基硫基-AMP，2-环戊基硫基-AMP，2-环己基甲硫基-AMP和2-环己基乙硫基-AMP被ecto-5'-NT接受为底物，并易于转化为相应的2取代的腺苷衍生物。2-环己基乙硫基取代是ecto-5'-NT和腺苷A 2A的良好折衷方案受体。相应的AMP衍生物（12g）是与AMP本身相似的良好底物，而所得的腺苷衍生物（11g）是相对有效的A 2A激动剂（放射配体与大鼠脑纹状体膜的结合力：K i = 372 nM；抑制抗-在小鼠CD4 +细胞中CD3 /抗CD28诱导的IFN-γ释放：EC 50 = 50 nM
• 2-Hexylthio-β,γ-CH₂-ATP is an Effective and Selective NTPDase2 Inhibitor
  作者：Irina Gillerman、Joanna Lecka、Luba Simhaev、Mercedes N. Munkonda、Michel Fausther、Mireia Martín-Satué、Hanoch Senderowitz、Jean Sévigny、Bilha Fischer

  DOI：10.1021/jm401933c

  日期：2014.7.24

  NTPDase2 catabolizes nucleoside triphosphates and consequently, through the interaction of nucleotides with P2 receptors, controls multiple biological responses. NTPDase2 inhibitors could modulate responses induced by nucleotides in thrombosis, inflammation, cancer, etc. Here we developed a set of ATP analogues as potential NTPDase inhibitors and identified a subtype-selective and potent NTPDase2 inhibitor, 2-hexylthio-beta,gamma-methylene-ATP, 2. Analogue 2 was stable to hydrolysis by NTPDase1, -2, -3, and -8. It inhibited hNTPDase2 with K-i 20 mu M, while only marginally (5-15%) inhibiting NTPDase1, -3, and -8. Homology models of hNTPDase1 and -2 were constructed. Docking and subsequent linear interaction energy (LIE) simulations provided a correlation with r(2) = 0.94 between calculated and experimental inhibition data for the triphosphate analogues considered in this work. The origin of selectivity of 2 for NTPDase2 over NTPDase1 is the thiohexyl moiety of 2 which is favorably located within a hydrophobic pocket, whereas in NTPDase1 it is exposed to the solvent.
• 2-Thioether 5‘-<i>O</i>-(1-Thiotriphosphate)adenosine Derivatives as New Insulin Secretagogues Acting through P2Y-Receptors
  作者：Bilha Fischer、Ana Chulkin、Jose L. Boyer、Kendall T. Harden、Fernand-Pierre Gendron、Adrien R. Beaudoin、Jeannie Chapal、Dominique Hillaire-Buys、Pierre Petit

  DOI：10.1021/jm990158y

  日期：1999.9.1

  (2-RS-ATP-alpha-S), were synthesized as potential insulin secretagogues. An efficient synthesis of these nucleotides and a facile method for separation of the chiral products are described. The enzymatic stability of the compounds toward pig pancreas type I ATPDase was evaluated. The rate of hydrolysis of 2-hexylthio-5'-O-(1-thiotriphosphate)adenosine (2-hexylthio-ATP-alpha-S) isomers by ATPDase was 28% of that of

  P2-受体（P2-Rs）代表了新药开发的重要目标。在胰腺B细胞上也鉴定出P2-R，并且它们参与胰岛素分泌。因此，合成了新型的P2Y-R配体2-硫醚5'-O-硫代磷酸腺苷腺苷衍生物（2-RS-ATP-α-S）作为潜在的胰岛素促分泌剂。描述了这些核苷酸的有效合成和分离手性产物的简便方法。评估了化合物对猪胰腺I型ATPDase的酶稳定性。ATPDase水解2-己基硫基5'-O-（1-硫代三磷酸）腺苷（2-己基硫基-ATP-α-S）异构体的速率为ATP的28％。一些2-硫醚5'-（单硫代磷酸酯）腺苷衍生物（2-RS-AMP-S）对ATPDase产生抑制作用。化合物对P2Y（1）-R的表观亲和力是通过测量土耳其红细胞膜中P2Y-R促进的磷脂酶C活性来确定的。2-RS-ATP-α-S衍生物是激动剂，可刺激K（0.5）值在纳摩尔范围内的肌醇磷酸酯的产生。2-RS-AMP-S衍生物是完全的激动剂，尽管效力
• Identification of potent, selective P2Y-purinoceptor agonists: structure-activity relationships for 2-thioether derivatives of adenosine 5'-triphosphate
  作者：Bilha Fischer、Jose L. Boyer、Charles H. V. Hoyle、Airat U. Ziganshin、Antonia L. Brizzolara、Gillian E. Knight、Jeffrey Zimmet、Geoffrey Burnstock、T. Kendall Harden、Kenneth A. Jacobson

  DOI：10.1021/jm00076a023

  日期：1993.11

  Study of P-2-purinoceptor subtypes has been difficult due to the lack of potent and selective ligands. With the goal of developing high affinity P-2-purinoceptor-selective agonists, we have synthesized a series of analogues of adenine nucleotides modified on the purine ring as chain-extended 2-thioethers or as N-6-methyl-substituted compounds. Chemical functionality incorporated in the thioether moiety included cyanoalkyl, nitroaromatic, amino, thiol, cycloalkyl, n-alkyl, and olefinic groups. Apparent affinity of the compounds for P-2Y-purinoceptors was established by measurement of P-2Y-purinoceptor-promoted phospholipase C activity in turkey erythrocyte membranes and relaxation of carbachol-contracted smooth muscle in three different preparations (guinea pig taenia coli, rabbit aorta, and rabbit mesenteric artery). Activity at P-2X-purinoceptors was established by measurement of contraction of rabbit saphenous artery and of the guinea pig vas deferens and urinary bladder. All 11 of the 2-thioethers of ATP stimulated the production of inositol phosphates with K-0.5 values of 1.5-770 nM, with an (aminophenyl)ethyl derivative being most potent. Two adenosine diphosphate analogues were equipotent to the corresponding ATP analogues. Adenosine monophosphate analogues were full agonists, although generally 4 orders of magnitude less potent. ATP 2-thioethers displayed pD(2) values in the range of 6-8 in smooth muscle assay systems for activity at P-2Y-receptors. There was a significant correlation for the 2-thioether compounds between the pK(0.5) values for inositol phosphate production and the pD(2) values for relaxation mediated via the P-2Y-purinoceptors in the guinea pig taenia coli, but not for the vascular P-2Y-receptors or for the P-2X-receptors. At P-2X-receptors, no activity was observed in the rabbit saphenous artery, but variable degrees of activity were observed in the guinea pig vas deferens and bladder depending on distal substituents of the thioether moiety. N-6-Methyl-ATP was inactive at P-2X-receptors, and approximately equipotent to ATP at taenia coli P-2Y-receptors. This suggested that hybrid N-6-methyl and 2-thioether ATP derivatives might be potent and selective for certain P-2Y-receptors, as was shown for one such derivative, N-6-methyl-2-(5-hexenylthio)-ATP.