2′-amino-5′-[N-(D-biotinoyl)sulfamoyl]amino-3′,5′-dideoxyadenosine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 生物素及其衍生物
• 英文名称: 2′-amino-5′-[N-(D-biotinoyl)sulfamoyl]amino-3′,5′-dideoxyadenosine
• 英文别名: 5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]-N-[[(2R,3S,4R,5R)-4-amino-5-(6-aminopurin-9-yl)-3-hydroxyoxolan-2-yl]methylsulfamoyl]pentanamide;N,N-diethylethanamine
• 化学式: C₆H₁₅N*C₂₀H₃₀N₁₀O₆S₂
• 分子量: 671.845
• InChiKey: NVCFATWBAAQDQA-XCWKCCEMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -2.76
• 重原子数：
  45
• 可旋转键数：
  13
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.73
• 拓扑面积：
  286
• 氢给体数：
  7
• 氢受体数：
  14

反应信息

• 作为产物：
  描述：

  阿糖腺苷 在 吡啶 、 咪唑 、 4-二甲氨基吡啶 、 sodium azide 、 偶氮二甲酸二异丙酯 、 水 、 caesium carbonate 、 溶剂黄146 、 三乙胺 、 三苯基膦 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 209.0h， 生成 2′-amino-5′-[N-(D-biotinoyl)sulfamoyl]amino-3′,5′-dideoxyadenosine
  参考文献：
  名称：

  Targeting Mycobacterium tuberculosis Biotin Protein Ligase (MtBPL) with Nucleoside-Based Bisubstrate Adenylation Inhibitors

  摘要：

  Mycobacterium tuberculosis (Mtb), responsible for second leading cause of mortality among infectious diseases worldwide. Mycobacterial biotin protein ligase (MtBPL) is an both latent and symptomatic tuberculosis (TB), remains the essential enzyme in Mtb and regulates lipid metabolism through the post-translational biotinylation of acyl coenzyme A carboxylases. We report the synthesis and evaluation of a systematic series of potent nucleoside-based inhibitors of MtBPL that contain modifications to the ribofuranosyl ring of the nucleoside. All compounds were characterized by isothermal titration calorimetry (ITC) and shown to bind potently with K(D)s <= 2 nM. Additionally, we obtained high-resolution cocrystal structures for a majority of the compounds. Despite fairly uniform biochemical potency, the whole-cell Mtb activity varied greatly with minimum inhibitory concentrations (MIC) ranging from 0.78 to >100 mu M. Cellular accumulation studies showed a nearly 10-fold enhancement in accumulation of a C-2'-alpha analogue over the corresponding C-2'-beta analogue, consistent with their differential whole-cell activity.

  DOI：

  10.1021/acs.jmedchem.5b00719

文献信息

• Targeting <i>Mycobacterium tuberculosis</i> Biotin Protein Ligase (MtBPL) with Nucleoside-Based Bisubstrate Adenylation Inhibitors
  作者：Matthew R. Bockman、Alvin S. Kalinda、Riccardo Petrelli、Teresa De la Mora-Rey、Divya Tiwari、Feng Liu、Surendra Dawadi、Madhumitha Nandakumar、Kyu Y. Rhee、Dirk Schnappinger、Barry C. Finzel、Courtney C. Aldrich

  DOI：10.1021/acs.jmedchem.5b00719

  日期：2015.9.24

  Mycobacterium tuberculosis (Mtb), responsible for second leading cause of mortality among infectious diseases worldwide. Mycobacterial biotin protein ligase (MtBPL) is an both latent and symptomatic tuberculosis (TB), remains the essential enzyme in Mtb and regulates lipid metabolism through the post-translational biotinylation of acyl coenzyme A carboxylases. We report the synthesis and evaluation of a systematic series of potent nucleoside-based inhibitors of MtBPL that contain modifications to the ribofuranosyl ring of the nucleoside. All compounds were characterized by isothermal titration calorimetry (ITC) and shown to bind potently with K(D)s <= 2 nM. Additionally, we obtained high-resolution cocrystal structures for a majority of the compounds. Despite fairly uniform biochemical potency, the whole-cell Mtb activity varied greatly with minimum inhibitory concentrations (MIC) ranging from 0.78 to >100 mu M. Cellular accumulation studies showed a nearly 10-fold enhancement in accumulation of a C-2'-alpha analogue over the corresponding C-2'-beta analogue, consistent with their differential whole-cell activity.