6-(azepane-1-carbonyl)-5H-thiazolo[3,2-a]pyrimidin-5-one

• 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: 6-(azepane-1-carbonyl)-5H-thiazolo[3,2-a]pyrimidin-5-one
• 英文别名: 6-(Azepane-1-carbonyl)-5H-[1,3]thiazolo[3,2-A]pyrimidin-5-one；6-(azepane-1-carbonyl)-[1,3]thiazolo[3,2-a]pyrimidin-5-one
• 化学式: C₁₃H₁₅N₃O₂S
• mdl: MFCD05021105
• 分子量: 277.347
• InChiKey: ZLOCQHCCUQMEIH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  19
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  78.3
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  环己亚胺 、 5-氧代-5H-噻唑并[3,2-a]嘧啶-6-甲酸 在 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 二氯甲烷 为溶剂， 反应 16.25h， 以9%的产率得到6-(azepane-1-carbonyl)-5H-thiazolo[3,2-a]pyrimidin-5-one
  参考文献：
  名称：

  Allosteric Inhibition of a Mammalian Lectin

  摘要：

  Glycan-binding proteins are key components of central physiological and cellular processes such as self-/non-self-recognition, cellular tissue homing, and protein homeostasis. Herein, C-type lectins are a diverse protein family that play important roles in the immune system, rendering them attractive drug targets. To evaluate C-type lectin receptors as target proteins for small-molecule effectors, chemical probes are required, which are, however, still lacking. To overcome the supposedly poor druggability of C-type lectin receptors and to identify starting points for chemical probe development, we screened murine langerin using H-1 and F-19 NMR against a library of 871 drug-like fragments. Subsequently, hits were validated by surface plasmon resonance and enzyme-linked lectin assay. Using structure activity relationship studies and chemical synthesis, we identified thiazolopyrimidine derivatives with double-digit micromolar activity that displayed langerin selectivity. Based on H-10-N-15 HSQC NMR and competitive binding and inhibition experiments, we demonstrate that thiazolopyrimidines allosterically inhibit langerin. To the best of our knowledge, this is the first report of drug-like allosteric inhibitors of a mammalian lectin.

  DOI：

  10.1021/jacs.8b08644

文献信息

• Allosteric Inhibition of a Mammalian Lectin
  作者：Jonas Aretz、Upendra R. Anumala、Felix F. Fuchsberger、Narges Molavi、Nandor Ziebart、Hengxi Zhang、Marc Nazaré、Christoph Rademacher

  DOI：10.1021/jacs.8b08644

  日期：2018.11.7

  Glycan-binding proteins are key components of central physiological and cellular processes such as self-/non-self-recognition, cellular tissue homing, and protein homeostasis. Herein, C-type lectins are a diverse protein family that play important roles in the immune system, rendering them attractive drug targets. To evaluate C-type lectin receptors as target proteins for small-molecule effectors, chemical probes are required, which are, however, still lacking. To overcome the supposedly poor druggability of C-type lectin receptors and to identify starting points for chemical probe development, we screened murine langerin using H-1 and F-19 NMR against a library of 871 drug-like fragments. Subsequently, hits were validated by surface plasmon resonance and enzyme-linked lectin assay. Using structure activity relationship studies and chemical synthesis, we identified thiazolopyrimidine derivatives with double-digit micromolar activity that displayed langerin selectivity. Based on H-10-N-15 HSQC NMR and competitive binding and inhibition experiments, we demonstrate that thiazolopyrimidines allosterically inhibit langerin. To the best of our knowledge, this is the first report of drug-like allosteric inhibitors of a mammalian lectin.