N-(2-((2-(bis(4-methoxybenzyl)amino)-4,6-dimethoxypyrimidin-5-yl)thio)pyrimidin-4-yl)acetamide | 1568905-44-1

• 分子结构分类: 有机化合物 - 有机硫化合物 - 硫醚类
• 英文名称: N-(2-((2-(bis(4-methoxybenzyl)amino)-4,6-dimethoxypyrimidin-5-yl)thio)pyrimidin-4-yl)acetamide
• CAS: 1568905-44-1
• 化学式: C₂₈H₃₀N₆O₅S
• 分子量: 562.649
• InChiKey: SWHWAJKAJWTAHK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.62
• 重原子数：
  40.0
• 可旋转键数：
  12.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  120.82
• 氢给体数：
  1.0
• 氢受体数：
  11.0

反应信息

• 作为反应物：
  描述：

  N-(2-((2-(bis(4-methoxybenzyl)amino)-4,6-dimethoxypyrimidin-5-yl)thio)pyrimidin-4-yl)acetamide 在 碳酸氢钠 、 氟化氢吡啶 、 三乙胺 、 间氯过氧苯甲酸 、 三氟乙酸 、 sodium hydroxide 、 sodium nitrite 作用下， 以 甲醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 35.63h， 生成 4-(5-((4-acrylamidopyrimidin-2-yl)thio)-4,6-dimethoxypyrimidin-2-yl)-1-methylpiperazine 1-oxide
  参考文献：
  名称：

  Heat Shock Protein 70 Inhibitors. 1. 2,5′-Thiodipyrimidine and 5-(Phenylthio)pyrimidine Acrylamides as Irreversible Binders to an Allosteric Site on Heat Shock Protein 70

  摘要：

  Heat shock protein 70 (Hsp70) is an important emerging. cancer. target whose inhibition may affect multiple cancer-associated signaling pathways and, moreover, result in significant cancer cell apoptosis. Despite considerable interest from both academia and pharmaceutical companies in the discovery and development of druglike Hsp70 inhibitors, little success has been reported so far. Here we describe structure activity relationship studies in the first rationally designed Hsp70 inhibitor class that binds to a novel allosteric pocket located in the N-terminal domain of the protein. These 2,5'-thiodipyrimidine and 5-(phenylthio)-pyrimidine acrylamides take advantage of an active cysteine embedded in the allosteric pocket to act as covalent protein modifiers upon binding. The study identifies derivatives 17a and 20a, which selectively bind to Hsp70 in cancer cells. Addition of high nanomolar to low micromolar concentrations of these inhibitors to cancer cells leads to a reduction in the steady-state levels of Hsp70-sheltered oncoproteins, an effect associated with inhibition of cancer cell growth and apoptosis. In summary, the described scaffolds represent a viable starting point for the development of druglike Hsp70 inhibitors as novel anticancer therapeutics.

  DOI：

  10.1021/jm401551n
• 作为产物：
  描述：

  4-甲氧基氯苄 在 N-碘代丁二酰亚胺 、 copper(l) iodide 、 新铜试剂 、 sodium hydride 、 potassium carbonate 作用下， 以 二甲基亚砜 、 N,N-二甲基甲酰胺 、 乙腈 、 mineral oil 为溶剂， 反应 18.17h， 生成 N-(2-((2-(bis(4-methoxybenzyl)amino)-4,6-dimethoxypyrimidin-5-yl)thio)pyrimidin-4-yl)acetamide
  参考文献：
  名称：

  Heat Shock Protein 70 Inhibitors. 1. 2,5′-Thiodipyrimidine and 5-(Phenylthio)pyrimidine Acrylamides as Irreversible Binders to an Allosteric Site on Heat Shock Protein 70

  摘要：

  Heat shock protein 70 (Hsp70) is an important emerging. cancer. target whose inhibition may affect multiple cancer-associated signaling pathways and, moreover, result in significant cancer cell apoptosis. Despite considerable interest from both academia and pharmaceutical companies in the discovery and development of druglike Hsp70 inhibitors, little success has been reported so far. Here we describe structure activity relationship studies in the first rationally designed Hsp70 inhibitor class that binds to a novel allosteric pocket located in the N-terminal domain of the protein. These 2,5'-thiodipyrimidine and 5-(phenylthio)-pyrimidine acrylamides take advantage of an active cysteine embedded in the allosteric pocket to act as covalent protein modifiers upon binding. The study identifies derivatives 17a and 20a, which selectively bind to Hsp70 in cancer cells. Addition of high nanomolar to low micromolar concentrations of these inhibitors to cancer cells leads to a reduction in the steady-state levels of Hsp70-sheltered oncoproteins, an effect associated with inhibition of cancer cell growth and apoptosis. In summary, the described scaffolds represent a viable starting point for the development of druglike Hsp70 inhibitors as novel anticancer therapeutics.

  DOI：

  10.1021/jm401551n