N-benzyl-2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: N-benzyl-2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetamide
• 英文别名: N-benzyl-2-(3,7-dimethyl-2,6-dioxopurin-1-yl)acetamide
• 化学式: C₁₆H₁₇N₅O₃
• 分子量: 327.343
• InChiKey: DATUDOBMCUQTGH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  24
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  87.5
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  可可碱 在 苄基三乙基氯化铵 、 水 、 potassium carbonate 、 N,N'-羰基二咪唑 、 potassium hydroxide 作用下， 以 N,N-二甲基甲酰胺 、 丙酮 为溶剂， 反应 78.5h， 生成 N-benzyl-2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetamide
  参考文献：
  名称：

  Synthesis and Analgesic Activity of 3,7-dimethylpurine-2,6-dion-1-yl Derivatives of Acetic and Butanoic Acid

  摘要：

  肼基化合物是一类具有多样化生物活性、抗炎和镇痛活性的化合物。已知也存在具有这种活性的黄嘌呤衍生物。我们研究的目的是调查将肼基引入3,7-二甲基嘌呤-2,6-二酮-1-基醋酸和丁酸衍生物是否会增强其镇痛活性。设计的一系列化合物通过多步程序合成。它们的药理活性在扭体综合症测试中进行了研究。根据结果讨论了结构-活性关系。在合成的二十种化合物中，有十九种进行了体内测试。除了化合物4外，大多数化合物的镇痛活性在扭体综合症测试中均高于乙酰水杨酸。我们的研究表明，与具有自由羧基、酯、苄胺和肼基的衍生物相比，肼基的引入普遍增强了黄嘌呤衍生物的镇痛活性。氢氧基或高电子密度取代基的存在似乎对肼基衍生物的活性并不是必要条件。

  DOI：

  10.2174/1570180811666140718162449

文献信息

• New Anticancer Theobromine Derivative Targeting EGFRWT and EGFRT790M: Design, Semi-Synthesis, In Silico, and In Vitro Anticancer Studies
  作者：Eslam B. Elkaeed、Reda G. Yousef、Hazem Elkady、Aisha A. Alsfouk、Dalal Z. Husein、Ibrahim M. Ibrahim、Ahmed M. Metwaly、Ibrahim H. Eissa

  DOI：10.3390/molecules27185859

  日期：——

  Based on the pharmacophoric features of EGFR inhibitors, a new semisynthetic theobromine-derived compound was designed to interact with the catalytic pocket of EGFR. Molecular docking against wild (EGFRWT; PDB: 4HJO) and mutant (EGFRT790M; PDB: 3W2O) types of EGFR-TK indicated that the designed theobromine derivative had the potential to bind to that pocket as an antiangiogenic inhibitor. The MD and MM-GBSA experiments identified the exact binding with optimum energy and dynamics. Additionally, the DFT calculations studied electrostatic potential, stability, and total electron density of the designed theobromine derivative. Both in silico ADMET and toxicity analyses demonstrated its general likeness and safety. We synthesized the designed theobromine derivative (compound XI) which showed an IC50 value of 17.23 nM for EGFR inhibition besides IC50 values of 21.99 and 22.02 µM for its cytotoxicity against A549 and HCT-116 cell lines, respectively. Interestingly, compound XI expressed a weak cytotoxic potential against the healthy W138 cell line (IC50 = 49.44 µM, 1.6 times safer than erlotinib), exhibiting the high selectivity index of 2.2. Compound XI arrested the growth of A549 at the G2/M stage and increased the incidence of apoptosis.

  根据表皮生长因子受体抑制剂的药效学特征，我们设计了一种新的半合成可可碱衍生化合物与表皮生长因子受体的催化口袋相互作用。与野生型（EGFRWT；PDB：4HJO）和突变型（EGFRT790M；PDB：3W2O）EGFR-TK 的分子对接表明，所设计的可可碱衍生物具有作为抗血管生成抑制剂与该口袋结合的潜力。MD 和 MM-GBSA 实验确定了具有最佳能量和动力学的精确结合。此外，DFT 计算还研究了所设计的可可碱衍生物的静电势、稳定性和总电子密度。硅学 ADMET 和毒性分析表明了其总体相似性和安全性。我们合成了所设计的可可碱衍生物（化合物 XI），其抑制表皮生长因子受体的 IC50 值为 17.23 nM，对 A549 和 HCT-116 细胞株的细胞毒性 IC50 值分别为 21.99 和 22.02 µM。有趣的是，化合物 XI 对健康的 W138 细胞株具有微弱的细胞毒性潜力（IC50 = 49.44 µM，比厄洛替尼安全 1.6 倍），表现出 2.2 的高选择性指数。化合物 XI 在 G2/M 阶段阻止了 A549 的生长，并增加了细胞凋亡的发生率。
• Synthesis and Analgesic Activity of 3,7-dimethylpurine-2,6-dion-1-yl Derivatives of Acetic and Butanoic Acid
  作者：Mal.gorzata Zygmunt、Pawe.l Zmudzki、Graz.yna Chl.on.-Rzepa、Jacek Sapa、Maciej Pawl.owski

  DOI：10.2174/1570180811666140718162449

  日期：2014.10.1

  Hydrazones are a group of compounds possessing diversified biological activity, anti-inflammatory and analgesic activities. There are also known xanthine derivatives possessing such activity. The aim of our study was to investigate if introduction of hydrazone moiety to 3,7-dimethylpurine-2,6-dion-1-yl acetic and butanoic acid derivatives would enhance the analgesic activity. The designed series of compounds were synthesized in a multi-step procedure. Their pharmacological activity was investigated in the writhing syndrome test. Based on the results the structure-activity relationship was discussed. From the synthesized group of twenty compounds, nineteen were tested in vivo. The analgesic activity of most compounds, except for compound 4, was higher than for acetylsalicylic acid in the writhing syndrome test. Our study showed that the introduction of hydrazone moiety generally enhances analgesic activity of xanthine derivatives, compared to derivatives with free carboxylic group, ester, benzylamide and hydrazide moieties. The presence of hydroxyl moiety or substituent with high electron density does not seem to be necessary for the activity of hydrazone derivatives.

  肼基化合物是一类具有多样化生物活性、抗炎和镇痛活性的化合物。已知也存在具有这种活性的黄嘌呤衍生物。我们研究的目的是调查将肼基引入3,7-二甲基嘌呤-2,6-二酮-1-基醋酸和丁酸衍生物是否会增强其镇痛活性。设计的一系列化合物通过多步程序合成。它们的药理活性在扭体综合症测试中进行了研究。根据结果讨论了结构-活性关系。在合成的二十种化合物中，有十九种进行了体内测试。除了化合物4外，大多数化合物的镇痛活性在扭体综合症测试中均高于乙酰水杨酸。我们的研究表明，与具有自由羧基、酯、苄胺和肼基的衍生物相比，肼基的引入普遍增强了黄嘌呤衍生物的镇痛活性。氢氧基或高电子密度取代基的存在似乎对肼基衍生物的活性并不是必要条件。