2-(N′,N′-dimethylformamidino)-9-[(2-hydroxyethoxy)methyl]-6-oxopurine | 100699-59-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: 2-(N′,N′-dimethylformamidino)-9-[(2-hydroxyethoxy)methyl]-6-oxopurine
• 英文别名: N(2)-DMF acyclovir；N'-(9-((2-hydroxyethoxy)-methyl)-6-oxo-6,9-dihydro-1H-purin-2-yl)-N,N-dimethylformimidamide；N'-[9-(2-hydroxyethoxymethyl)-6-oxo-1H-purin-2-yl]-N,N-dimethylmethanimidamide
• CAS: 100699-59-0
• 化学式: C₁₁H₁₆N₆O₃
• 分子量: 280.286
• InChiKey: CUYWXTJRHAMNBC-UHFFFAOYSA-N

物化性质

• 密度：
  1.45±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -1.3
• 重原子数：
  20
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  104
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  phenyl (benzyloxy-dimethylglycinyl)phosphorochloridate 、 2-(N′,N′-dimethylformamidino)-9-[(2-hydroxyethoxy)methyl]-6-oxopurine 在 叔丁基氯化镁 作用下， 以 四氢呋喃 为溶剂， 以93%的产率得到benzyl 2-[[2-[[2-(dimethylaminomethylideneamino)-6-oxo-1H-purin-9-yl]methoxy]ethoxy-phenoxyphosphoryl]amino]-2-methylpropanoate
  参考文献：
  名称：

  The Application of Phosphoramidate Protide Technology to Acyclovir Confers Anti-HIV Inhibition

  摘要：

  Recently, it has been reported that phosphorylated acyclovir (ACV) inhibits human immunodeficiency virus type 1 (HIV-1) reverse transcriptase in a cell-free system. To deliver phosphorylated ACV inside cells, we designed ACV monophosphorylated derivatives using ProTide technology. We found that the L-alanine derived ProTides show anti-HIV activity at noncytotoxic concentrations; ester and aryl variation was tolerated, ACV ProTides with other amino acids, other than L-phenylalanine, showed no detectable activity against HIV in cell culture. The inhibitory activity of the prodrugs against herpes simplex virus (HSV) types-1 and -2 and thymidine kinase-deficient HSV-1 revealed different structure-activity relationships but was again consistent with successful nucleoside kinase bypass. Enzymatic and molecular modeling studies have been performed in order to better understand the antiviral behavior of these compounds. ProTides showing diminished carboxypeptidase lability translated to poor anti-HIV agents and vice versa, so the assay became predictive.

  DOI：

  10.1021/jm9007856
• 作为产物：
  描述：

  阿昔洛韦 、 N,N-二甲基甲酰胺二甲基缩醛 以 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 以97%的产率得到2-(N′,N′-dimethylformamidino)-9-[(2-hydroxyethoxy)methyl]-6-oxopurine
  参考文献：
  名称：

  The Application of Phosphoramidate Protide Technology to Acyclovir Confers Anti-HIV Inhibition

  摘要：

  Recently, it has been reported that phosphorylated acyclovir (ACV) inhibits human immunodeficiency virus type 1 (HIV-1) reverse transcriptase in a cell-free system. To deliver phosphorylated ACV inside cells, we designed ACV monophosphorylated derivatives using ProTide technology. We found that the L-alanine derived ProTides show anti-HIV activity at noncytotoxic concentrations; ester and aryl variation was tolerated, ACV ProTides with other amino acids, other than L-phenylalanine, showed no detectable activity against HIV in cell culture. The inhibitory activity of the prodrugs against herpes simplex virus (HSV) types-1 and -2 and thymidine kinase-deficient HSV-1 revealed different structure-activity relationships but was again consistent with successful nucleoside kinase bypass. Enzymatic and molecular modeling studies have been performed in order to better understand the antiviral behavior of these compounds. ProTides showing diminished carboxypeptidase lability translated to poor anti-HIV agents and vice versa, so the assay became predictive.

  DOI：

  10.1021/jm9007856

文献信息

• Chemical Incorporation of Chain-Terminating Nucleoside Analogs as 3′-Blocking DNA Damage and Their Removal by Human ERCC1-XPF Endonuclease
  作者：Junpei Yamamoto、Chiaki Takahata、Isao Kuraoka、Kouji Hirota、Shigenori Iwai

  DOI：10.3390/molecules21060766

  日期：——

  Nucleoside/nucleotide analogs that lack the 3′-hydroxy group are widely utilized for HIV therapy. These chain-terminating nucleoside analogs (CTNAs) block DNA synthesis after their incorporation into growing DNA, leading to the antiviral effects. However, they are also considered to be DNA damaging agents, and tyrosyl-DNA phosphodiesterase 1, a DNA repair enzyme, is reportedly able to remove such CTNA-modifications

  缺乏 3'-羟基的核苷/核苷酸类似物被广泛用于 HIV 治疗。这些链终止核苷类似物 (CTNA) 在掺入生长的 DNA 后会阻止 DNA 合成，从而产生抗病毒作用。然而，它们也被认为是 DNA 损伤剂，据报道，酪氨酰 DNA 磷酸二酯酶 1（一种 DNA 修复酶）能够去除 DNA 的此类 CTNA 修饰。在这里，我们合成了代表性 CTNA 的亚磷酰胺构件，例如阿昔洛韦、阿巴卡韦、卡波韦和拉米夫定，并且在固体支持物上成功合成了具有 3'-CTNA 的寡核苷酸。使用化学合成的寡核苷酸，我们研究了人类切除修复交叉互补蛋白 1-色素干皮病 F 组（ERCC1-XPF）核酸内切酶对 DNA 中 3'-CTNA 的切除，该酶是核苷酸切除修复途径的主要成分之一。生化分析表明 ERCC1-XPF 核酸内切酶在 3'-阻断 CTNAs 上游 2-7 nt 处切割，并且在去除 CTNAs 后重新开始 Klenow
• Alkylation of 9-substituted guanine derivatives with α,ω-dihaloalkanes
  作者：Grzegorz Framski、Tomasz Goslinski、Piotr Januszczyk、Bozenna Golankiewicz、Tomasz Ostrowski

  DOI：10.1002/hc.21399

  日期：2017.9

  of 9-substituted guanine derivatives with NaH/1,2-dibromoethane, 1,3-dibromopropane, or 1,4-dibromobutane at room temperature resulted in the isolation of tricyclic 1,N2-(1,2-ethano)guanine, 1,N2-(1,3-propano)guanine, or 1,N2-(1,4-butano)guanine products, respectively. O6-Haloalkyl and N1-haloalkyl products were obtained following the use of NaH/1,4-dibromobutane, higher α,ω-dibromoalkanes, or α-b

  9-取代鸟嘌呤衍生物与 NaH/1,2-二溴乙烷、1,3-二溴丙烷或 1,4-二溴丁烷在室温下的反应导致三环 1,N2-(1,2-乙醇)鸟嘌呤的分离，分别为 1,N2-(1,3-丙烷)鸟嘌呤或 1,N2-(1,4-丁烷)鸟嘌呤产品。使用 NaH/1,4-二溴丁烷、高级 α,ω-二溴烷烃或 α-溴-ω-氟烷烃后，得到 O6-卤代烷基和 N1-卤代烷基产物。提高反应温度为 O6-鸟嘌呤-亚烷基-O6-鸟嘌呤和 N1-鸟嘌呤-亚烷基-O6-鸟嘌呤对称和不对称二聚体的合成开辟了道路。保护底物胺基以形成 N,N-二烷基甲脒提供了获得 N1-鸟嘌呤-亚烷基-N1-鸟嘌呤二聚体的途径。
• Successful kinase bypass with new acyclovir phosphoramidate prodrugs
  作者：Christopher McGuigan、Marco Derudas、Joachim J. Bugert、Graciela Andrei、Robert Snoeck、Jan Balzarini

  DOI：10.1016/j.bmcl.2008.06.069

  日期：2008.8

  Novel phosphoramidates of acyclovir have been prepared and evaluated in vitro against acyclovir-sensitive and -resistant herpes simplex virus (HSV) types 1 and 2 and varicella-zoster virus (VZV). Unlike the parent nucleoside these novel phosphate prodrugs retain antiviral potency versus the ACV-resistant virus strain, suggesting an efficient bypass of the viral thymidine kinase. Crown Copyright (c) 2008 Published by Elsevier Ltd. All rights reserved.