2-hexylthio-8-azaadenosine | 1260177-40-9

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 2-hexylthio-8-azaadenosine
• 英文别名: (2R,3R,4S,5R)-2-(7-amino-5-(hexylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol；2-HexS-8-aza-adenosine；(2R,3R,4S,5R)-2-(7-amino-5-hexylsulfanyltriazolo[4,5-d]pyrimidin-3-yl)-5-(hydroxymethyl)oxolane-3,4-diol
• CAS: 1260177-40-9
• 化学式: C₁₅H₂₄N₆O₄S
• 分子量: 384.459
• InChiKey: NYFORUBUBBNVQJ-IDTAVKCVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  26
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.73
• 拓扑面积：
  178
• 氢给体数：
  4
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  2-hexylthio-8-azaadenosine 在 1,8-双二甲氨基萘 、 三氯氧磷 、 三正丁胺 、 bis(tributylammonium) methylenediphosphonate 作用下， 反应 2.85h， 以52%的产率得到8-aza-2-hexylthioadenosine-5'-triphosphate
  参考文献：
  名称：

  2-Hexylthio-β,γ-CH₂-ATP is an Effective and Selective NTPDase2 Inhibitor

  摘要：

  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.

  DOI：

  10.1021/jm401933c
• 作为产物：
  描述：

  2-(hexylthio)pyrimidine-4,6-diamine 在 盐酸 、 platinum(IV) oxide 、 H₄N⁽¹⁺⁾*O₄S^(2-) 、 氢气 、 溶剂黄146 、 六甲基二硅氮烷 、 sodium nitrite 作用下， 以 1,4-二氧六环 、 甲醇 、 乙醇 、 水 为溶剂， 140.0 ℃ 、101.33 kPa 条件下， 反应 24.5h， 生成 2-hexylthio-8-azaadenosine
  参考文献：
  名称：

  Investigations into the Origin of the Molecular Recognition of Several Adenosine Deaminase Inhibitors

  摘要：

  Inhibitors of adenosine deaminase (ADA, EC 3 5 4 4) are potential therapeutic agents for the treatment of various health disorders Several highly potent inhibitors were previously identified, yet they exhibit unacceptable toxicities We performed a SAR study involving a series of C2 or C8 substituted purine-riboside analogues with a view to discover less potent inhibitors with a lesser toxicity We found that any substitution at C8 position of nebularine resulted in total loss of activity toward calf intestinal ADA However several 2-substituted-adenosine, 8-aza-adenosine, and nebularine analogues exhibited inhibitory activity Specifically, 2-Cl-purine riboside, 8-aza-2-thiohexyl adenosine, 2-thiohexyl adenosine, and 2-MeS-purine riboside were found to be competitive inhibitors of ADA with K-i values of 25, 22, 6, and 3 mu M, respectively We concluded that electronic parameters are not major recognition determinants of ADA but rather steric parameters A C2 substituent which fits ADA hydrophobic pocket and improves H-bonding with the enzyme makes a good inhibitor In addition, a gg rotamer about C4'-C5' bond is apparently an important recognition determinant

  DOI：

  10.1021/jm101286g

文献信息

• Investigations into the Origin of the Molecular Recognition of Several Adenosine Deaminase Inhibitors
  作者：Irina Gillerman、Bilha Fischer

  DOI：10.1021/jm101286g

  日期：2011.1.13

  Inhibitors of adenosine deaminase (ADA, EC 3 5 4 4) are potential therapeutic agents for the treatment of various health disorders Several highly potent inhibitors were previously identified, yet they exhibit unacceptable toxicities We performed a SAR study involving a series of C2 or C8 substituted purine-riboside analogues with a view to discover less potent inhibitors with a lesser toxicity We found that any substitution at C8 position of nebularine resulted in total loss of activity toward calf intestinal ADA However several 2-substituted-adenosine, 8-aza-adenosine, and nebularine analogues exhibited inhibitory activity Specifically, 2-Cl-purine riboside, 8-aza-2-thiohexyl adenosine, 2-thiohexyl adenosine, and 2-MeS-purine riboside were found to be competitive inhibitors of ADA with K-i values of 25, 22, 6, and 3 mu M, respectively We concluded that electronic parameters are not major recognition determinants of ADA but rather steric parameters A C2 substituent which fits ADA hydrophobic pocket and improves H-bonding with the enzyme makes a good inhibitor In addition, a gg rotamer about C4'-C5' bond is apparently an important recognition determinant
• 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.