2,3'-O-anhydro-1-(2-deoxy-2-fluoro-β-D-lyxofuranosyl)-5-ethyluracil | 1258272-77-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 2,3'-O-anhydro-1-(2-deoxy-2-fluoro-β-D-lyxofuranosyl)-5-ethyluracil
• 英文别名: 2,3'-Anhydro-1-(2-deoxy-2-fluoro-beta-D-lyxofuranosyl)-5-ethyluracil；(1R,9S,10R,12S)-4-ethyl-12-fluoro-10-(hydroxymethyl)-8,11-dioxa-2,6-diazatricyclo[7.2.1.02,7]dodeca-3,6-dien-5-one
• CAS: 1258272-77-3
• 化学式: C₁₁H₁₃FN₂O₄
• 分子量: 256.234
• InChiKey: AACCLVIODIYBLT-CHIQAWFVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.1
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  71.4
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2,3'-O-anhydro-1-(2-deoxy-2-fluoro-β-D-lyxofuranosyl)-5-ethyluracil 在 sodium azide 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 12.0h， 以16%的产率得到1-(3-azido-2,3-dideoxy-2-fluoro-β-D-arabinofuranosyl)-5-ethyluracil
  参考文献：
  名称：

  Discovery of novel 5-(ethyl or hydroxymethyl) analogs of 2′-‘up’ fluoro (or hydroxyl) pyrimidine nucleosides as a new class of Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium avium inhibitors

  摘要：

  Discovery of novel antimycobacterial compounds that work on distinctive targets and by diverse mechanisms of action is urgently required for the treatment of mycobacterial infections due to the emerging global health threat of tuberculosis. We have identified a new class of 5-ethyl or hydroxy (or methoxy) methyl-substituted pyrimidine nucleosides as potent inhibitors of Mycobacterium bovis, Mycobacterium tuberculosis (H37Ra, H37Rv) and Mycobacterium avium. A series of 2'-'up' fluoro (or hydroxy) nucleosides (1, 2,4-6, 9, 10, 13, 16, 18, 21, 24) was synthesized and evaluated for antimycobacterial activity. Among 20-fluorinated compounds, 1-(3-bromo-2,3-dideoxy-2-fluoro-beta-D-arabinofuranosyl)-5-ethyluracil (13) exhibited promising activity against M. bovis and Mtb alone, and showed synergism when combined with isoniazid. The most active compound emerging from these studies, 1-(beta-D-arabinofuranosyl)-4-thio-5hydroxymethyluracil (21) inhibited Mtb (H37Ra) (MIC50 = 0.5 mu g/mL) and M. bovis (MIC50 = 0.5 mu g/mL) at low concentrations, and was ten times more potent against Mtb (H37Ra) than cycloserine (MIC50 = 5.0 mu g/mL), a second line drug. It also showed an additive effect when combined with isoniazid. Compound 21 retained sensitivity against a rifampicin-resistant (H37Rv) strain of Mtb (MIC50 = 1 mu g/mL) at concentrations similar to that for a rifampicin-sensitive (H37Rv) strain, suggesting that it has no cross-resistance to a first-line anti-TB drug. In addition, the replication of M. avium was also inhibited by 21 (MIC50 = 10 mu g/mL). No cellular toxicity of 13 or 21 was observed up to the highest concentration tested (CC50 > 100 mu g/mL). These observations offer promise for a new drug treatment regimen to augment and complement the current chemotherapy of TB. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.05.004
• 作为产物：
  描述：

  1-(2-deoxy-2-fluoro-5-O-trityl-β-D-arabinofuranosyl)-5-ethyluracil 在 二乙胺基三氟化硫 、 水 、 溶剂黄146 作用下， 以 二氯甲烷 为溶剂， 反应 6.5h， 生成 2,3'-O-anhydro-1-(2-deoxy-2-fluoro-β-D-lyxofuranosyl)-5-ethyluracil
  参考文献：
  名称：

  Discovery of novel 5-(ethyl or hydroxymethyl) analogs of 2′-‘up’ fluoro (or hydroxyl) pyrimidine nucleosides as a new class of Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium avium inhibitors

  摘要：

  Discovery of novel antimycobacterial compounds that work on distinctive targets and by diverse mechanisms of action is urgently required for the treatment of mycobacterial infections due to the emerging global health threat of tuberculosis. We have identified a new class of 5-ethyl or hydroxy (or methoxy) methyl-substituted pyrimidine nucleosides as potent inhibitors of Mycobacterium bovis, Mycobacterium tuberculosis (H37Ra, H37Rv) and Mycobacterium avium. A series of 2'-'up' fluoro (or hydroxy) nucleosides (1, 2,4-6, 9, 10, 13, 16, 18, 21, 24) was synthesized and evaluated for antimycobacterial activity. Among 20-fluorinated compounds, 1-(3-bromo-2,3-dideoxy-2-fluoro-beta-D-arabinofuranosyl)-5-ethyluracil (13) exhibited promising activity against M. bovis and Mtb alone, and showed synergism when combined with isoniazid. The most active compound emerging from these studies, 1-(beta-D-arabinofuranosyl)-4-thio-5hydroxymethyluracil (21) inhibited Mtb (H37Ra) (MIC50 = 0.5 mu g/mL) and M. bovis (MIC50 = 0.5 mu g/mL) at low concentrations, and was ten times more potent against Mtb (H37Ra) than cycloserine (MIC50 = 5.0 mu g/mL), a second line drug. It also showed an additive effect when combined with isoniazid. Compound 21 retained sensitivity against a rifampicin-resistant (H37Rv) strain of Mtb (MIC50 = 1 mu g/mL) at concentrations similar to that for a rifampicin-sensitive (H37Rv) strain, suggesting that it has no cross-resistance to a first-line anti-TB drug. In addition, the replication of M. avium was also inhibited by 21 (MIC50 = 10 mu g/mL). No cellular toxicity of 13 or 21 was observed up to the highest concentration tested (CC50 > 100 mu g/mL). These observations offer promise for a new drug treatment regimen to augment and complement the current chemotherapy of TB. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.05.004

文献信息

• Antiviral activity of 2,3′-anhydro and related pyrimidine nucleosides against hepatitis B virus
  作者：Naveen C. Srivastav、Michelle Mak、Babita Agrawal、D. Lorne J. Tyrrell、Rakesh Kumar

  DOI：10.1016/j.bmcl.2010.08.120

  日期：2010.11

  Various 2,3′-anhydro analogs of 5-substituted 1-(2-deoxy-β-d-lyxofuranosyl)uracils (10–15) and a related 1-(3-O-mesyl-2-deoxy-β-d-lyxofuranosyl) pyrimidine nucleoside analog (18) have been synthesized for evaluation as a new class of potential anti-HBV agents. The compounds 10, 12, and 15 demonstrated most potent anti-HBV activities against duck HBV (DHBV) and human HBV with EC50 values in the range

  各种2,3'-脱水的5-取代的类似物的1-（2-脱氧β- d -lyxofuranosyl）尿嘧啶（10 - 15）和相关的1-（3- ö -mesyl -2-脱氧β- d -lyxofuranosyl）嘧啶核苷类似物（18）已被合成作为一种新型的潜在抗HBV药物进行评估。化合物10，12，和15显示出最有效的抗HBV活性抗鸭HBV（DHBV）和人HBV与EC 50个在2.5-10和5-10微克/毫升，分别范围内的值，在非毒性浓度（CC 50  => 200μg/ mL）。核苷18也显示了对DHBV的显着抗HBV活性，EC 50值为2.5μg/ mL，但是在2.2.15细胞中，其对HBV的活性较弱（EC 50  => 10μg/ mL）。
• Discovery of novel 5-(ethyl or hydroxymethyl) analogs of 2′-‘up’ fluoro (or hydroxyl) pyrimidine nucleosides as a new class of Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium avium inhibitors
  作者：Neeraj Shakya、Naveen C. Srivastav、Sudha Bhavanam、Chris Tse、Nancy Desroches、Babita Agrawal、Dennis Y. Kunimoto、Rakesh Kumar

  DOI：10.1016/j.bmc.2012.05.004

  日期：2012.7

  Discovery of novel antimycobacterial compounds that work on distinctive targets and by diverse mechanisms of action is urgently required for the treatment of mycobacterial infections due to the emerging global health threat of tuberculosis. We have identified a new class of 5-ethyl or hydroxy (or methoxy) methyl-substituted pyrimidine nucleosides as potent inhibitors of Mycobacterium bovis, Mycobacterium tuberculosis (H37Ra, H37Rv) and Mycobacterium avium. A series of 2'-'up' fluoro (or hydroxy) nucleosides (1, 2,4-6, 9, 10, 13, 16, 18, 21, 24) was synthesized and evaluated for antimycobacterial activity. Among 20-fluorinated compounds, 1-(3-bromo-2,3-dideoxy-2-fluoro-beta-D-arabinofuranosyl)-5-ethyluracil (13) exhibited promising activity against M. bovis and Mtb alone, and showed synergism when combined with isoniazid. The most active compound emerging from these studies, 1-(beta-D-arabinofuranosyl)-4-thio-5hydroxymethyluracil (21) inhibited Mtb (H37Ra) (MIC50 = 0.5 mu g/mL) and M. bovis (MIC50 = 0.5 mu g/mL) at low concentrations, and was ten times more potent against Mtb (H37Ra) than cycloserine (MIC50 = 5.0 mu g/mL), a second line drug. It also showed an additive effect when combined with isoniazid. Compound 21 retained sensitivity against a rifampicin-resistant (H37Rv) strain of Mtb (MIC50 = 1 mu g/mL) at concentrations similar to that for a rifampicin-sensitive (H37Rv) strain, suggesting that it has no cross-resistance to a first-line anti-TB drug. In addition, the replication of M. avium was also inhibited by 21 (MIC50 = 10 mu g/mL). No cellular toxicity of 13 or 21 was observed up to the highest concentration tested (CC50 > 100 mu g/mL). These observations offer promise for a new drug treatment regimen to augment and complement the current chemotherapy of TB. (C) 2012 Elsevier Ltd. All rights reserved.