N-(3-氨基丙基)-2-(6-氨基嘌呤-9-基)乙酰胺 | 918529-79-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 中文名称: N-(3-氨基丙基)-2-(6-氨基嘌呤-9-基)乙酰胺
• 英文名称: 9-aminopropylaminoacetyladenine
• 英文别名: N-(3-Aminopropyl)-2-(6-amino-9H-purin-9-yl)acetamide；N-(3-aminopropyl)-2-(6-aminopurin-9-yl)acetamide
• CAS: 918529-79-0
• 化学式: C₁₀H₁₅N₇O
• 分子量: 249.275
• InChiKey: YWKPUKZXAAGFSH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.2
• 重原子数：
  18
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  125
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  N-(3-氨基丙基)-2-(6-氨基嘌呤-9-基)乙酰胺 在 potassium carbonate 、 1-羟基苯并三唑 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 5.0h， 生成 N'-[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-N-[3-[[2-(6-aminopurin-9-yl)acetyl]amino]propyl]butanediamide
  参考文献：
  名称：

  Conjugation of Adenosine and Hexa-(d-arginine) Leads to a Nanomolar Bisubstrate-Analog Inhibitor of Basophilic Protein Kinases

  摘要：

  Conjugates of oligoarginine peptides with adenine, adenosine, adenosine-5'-carboxylic acid, and 5-isoquino-linesulfonic acid were synthesized and characterized as bisubstrate-analog inhibitors of cAMP-dependent protein kinase. Adenosine and adenine derivatives were connected to the N- or C-terminus of peptides containing four to six L- or D-arginine residues via a linker with a length that had been optimized in structure-activity studies. The orientation of the peptide chain strongly affected the activity of compounds incorporating D-arginines. The biligand inhibitor containing Hidaka's H9 isoquinolinesulfonamide connected to the L- peptide had 65 times higher potency than the corresponding adenosine-containing conjugate, while both types of the conjugate comprising D-peptides had similar low nanomolar activity. Two of the most active adenosine-and H9-peptide conjugates were tested in the panel of 52 different kinases. At 1 mu M concentration, both compounds showed strong (more than 95%) inhibition of several basophilic AGC kinases, including pharmaceutically important kinases ROCK II and PKB/Akt.

  DOI：

  10.1021/jm0605942
• 作为产物：
  描述：

  6-乙基水杨酸甲酯 、 1,3-丙二胺 以78 %的产率得到N-(3-氨基丙基)-2-(6-氨基嘌呤-9-基)乙酰胺
  参考文献：
  名称：

  A Chemical Proteomic Strategy Reveals Inhibitors of Lipoate Salvage in Bacteria and Parasites

  摘要：

  摘要新型抗感染药物的开发需要采用前所未有的策略，以病原体中存在而人类中不存在的途径为目标。根据这一原则，我们开发了硫辛酸（LA）挽救抑制剂，这是硫辛酸辅助细菌和寄生虫生存的关键途径，但在人体细胞中却不是必需的。在完整细胞中，一种基于 LA 的探针通过硫辛酸蛋白连接酶（LPL）选择性地转移到底物蛋白上，并通过质谱测定其结合位点。探针标记可作为 LPL 活性的替代物，从而实现原位筛选细胞渗透性 LPL 抑制剂。通过对重点化合物库的分析，发现了两种底物类似物（LAMe 和 C3）作为抑制剂，并通过结合研究和共晶体学进一步验证了这两种类似物。重要的是，LAMe 在人体细胞中表现出低毒性，对红细胞中的恶性疟原虫有杀伤作用，EC50 值为 15 μM，是迄今为止报道的最有效的 LPL 抑制剂。

  DOI：

  10.1002/anie.202304533

文献信息

• Conjugation of Adenosine and Hexa-(<scp>d</scp>-arginine) Leads to a Nanomolar Bisubstrate-Analog Inhibitor of Basophilic Protein Kinases
  作者：Erki Enkvist、Darja Lavogina、Gerda Raidaru、Angela Vaasa、Indrek Viil、Marje Lust、Kaido Viht、Asko Uri

  DOI：10.1021/jm0605942

  日期：2006.11.30

  Conjugates of oligoarginine peptides with adenine, adenosine, adenosine-5'-carboxylic acid, and 5-isoquino-linesulfonic acid were synthesized and characterized as bisubstrate-analog inhibitors of cAMP-dependent protein kinase. Adenosine and adenine derivatives were connected to the N- or C-terminus of peptides containing four to six L- or D-arginine residues via a linker with a length that had been optimized in structure-activity studies. The orientation of the peptide chain strongly affected the activity of compounds incorporating D-arginines. The biligand inhibitor containing Hidaka's H9 isoquinolinesulfonamide connected to the L- peptide had 65 times higher potency than the corresponding adenosine-containing conjugate, while both types of the conjugate comprising D-peptides had similar low nanomolar activity. Two of the most active adenosine-and H9-peptide conjugates were tested in the panel of 52 different kinases. At 1 mu M concentration, both compounds showed strong (more than 95%) inhibition of several basophilic AGC kinases, including pharmaceutically important kinases ROCK II and PKB/Akt.
• A Chemical Proteomic Strategy Reveals Inhibitors of Lipoate Salvage in Bacteria and Parasites
  作者：Jan‐Niklas Dienemann、Shu‐Yu Chen、Manuel Hitzenberger、Montana L. Sievert、Stephan M. Hacker、Sean T. Prigge、Martin Zacharias、Michael Groll、Stephan A. Sieber

  DOI：10.1002/anie.202304533

  日期：2023.8

  The development of novel anti‐infectives requires unprecedented strategies targeting pathways which are solely present in pathogens but absent in humans. Following this principle, we developed inhibitors of lipoic acid (LA) salvage, a crucial pathway for the survival of LA auxotrophic bacteria and parasites but non‐essential in human cells. An LA‐based probe was selectively transferred onto substrate proteins via lipoate protein ligase (LPL) in intact cells, and their binding sites were determined by mass spectrometry. Probe labeling served as a proxy of LPL activity, enabling in situ screenings for cell‐permeable LPL inhibitors. Profiling a focused compound library revealed two substrate analogs (LAMe and C3) as inhibitors, which were further validated by binding studies and co‐crystallography. Importantly, LAMe exhibited low toxicity in human cells and achieved killing of Plasmodium falciparum in erythrocytes with an EC₅₀ value of 15 μM, making it the most effective LPL inhibitor reported to date.

  摘要新型抗感染药物的开发需要采用前所未有的策略，以病原体中存在而人类中不存在的途径为目标。根据这一原则，我们开发了硫辛酸（LA）挽救抑制剂，这是硫辛酸辅助细菌和寄生虫生存的关键途径，但在人体细胞中却不是必需的。在完整细胞中，一种基于 LA 的探针通过硫辛酸蛋白连接酶（LPL）选择性地转移到底物蛋白上，并通过质谱测定其结合位点。探针标记可作为 LPL 活性的替代物，从而实现原位筛选细胞渗透性 LPL 抑制剂。通过对重点化合物库的分析，发现了两种底物类似物（LAMe 和 C3）作为抑制剂，并通过结合研究和共晶体学进一步验证了这两种类似物。重要的是，LAMe 在人体细胞中表现出低毒性，对红细胞中的恶性疟原虫有杀伤作用，EC50 值为 15 μM，是迄今为止报道的最有效的 LPL 抑制剂。