isopropyl 2-amino-6-isopropyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻吩类
• 英文名称: isopropyl 2-amino-6-isopropyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate
• 英文别名: Propan-2-yl 2-amino-6-propan-2-yl-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate
• 化学式: C₁₅H₂₃NO₂S
• 分子量: 281.419
• InChiKey: ATARPKAXNPPVHM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  19
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  80.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  isopropyl 2-amino-6-isopropyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate 在 盐酸 、 caesium carbonate 作用下， 以 1,4-二氧六环 、 丙酮 为溶剂， 反应 12.0h， 生成 N-benzyl-2-(7-isopropyl-2-methyl-4-oxo-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-3(4H)-yl)acetamide
  参考文献：
  名称：

  Scaffold-based selective SHP2 inhibitors design using core hopping, molecular docking, biological evaluation and molecular simulation

  摘要：

  PTPN11 (coding the gene of SHP2), a classic non-receptor protein tyrosine phosphatase, is implicated in multiple cell signaling pathway. Abnormal activation of SHP2 has been shown to contribute to a variety of human diseases, including Juvenile myelomonocytic leukemia (JMML), Noonan syndrome and tumors. Thus, the SHP2 inhibitors have important therapeutic value. Here, based on the compound PubChem CID 8,478,960 (IC₅₀ = 45.01 μM), a series of thiophene [2,3-d] pyrimidine derivatives (IC₅₀ = 0.4-37.87 μM) were discovered as novel and efficient inhibitors of SHP2 through powerful "core hopping" and CDOCKER technology. Furthermore, the SHP2-PTP phosphatase activity assay indicated that Comp#5 (IC₅₀ = 0.4 μM) was the most active SHP2 inhibitor. Subsequently, the effects of Comp#5 on the structure and function of SHP2 were investigated through molecular dynamics (MD) simulation and post-kinetic analysis. The result indicated that Comp#5 enhanced the interaction of residues THR357, ARG362, LYS366, PRO424, CYS459, SER460, ALA461, ILE463, ARG465, THR507 and GLN510 with the surrounding residues, improving the stability of the catalytic active region and the entrance of catalytic active region. In particular, the Comp#5 conjugated with residue ARG362, elevating the efficient and selectivity of SHP2 protein. The study here may pave the way for discovering the novel SHP2 inhibitors for suffering cancer patients.

  DOI：

  10.1016/j.bioorg.2020.104391
• 作为产物：
  描述：

  4-异丙基环己酮 、 氰乙酸异丙酯 在 sulfur 、 吗啉 作用下， 以 乙醇 为溶剂， 反应 24.0h， 生成 isopropyl 2-amino-6-isopropyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate
  参考文献：
  名称：

  Scaffold-based selective SHP2 inhibitors design using core hopping, molecular docking, biological evaluation and molecular simulation

  摘要：

  PTPN11 (coding the gene of SHP2), a classic non-receptor protein tyrosine phosphatase, is implicated in multiple cell signaling pathway. Abnormal activation of SHP2 has been shown to contribute to a variety of human diseases, including Juvenile myelomonocytic leukemia (JMML), Noonan syndrome and tumors. Thus, the SHP2 inhibitors have important therapeutic value. Here, based on the compound PubChem CID 8,478,960 (IC₅₀ = 45.01 μM), a series of thiophene [2,3-d] pyrimidine derivatives (IC₅₀ = 0.4-37.87 μM) were discovered as novel and efficient inhibitors of SHP2 through powerful "core hopping" and CDOCKER technology. Furthermore, the SHP2-PTP phosphatase activity assay indicated that Comp#5 (IC₅₀ = 0.4 μM) was the most active SHP2 inhibitor. Subsequently, the effects of Comp#5 on the structure and function of SHP2 were investigated through molecular dynamics (MD) simulation and post-kinetic analysis. The result indicated that Comp#5 enhanced the interaction of residues THR357, ARG362, LYS366, PRO424, CYS459, SER460, ALA461, ILE463, ARG465, THR507 and GLN510 with the surrounding residues, improving the stability of the catalytic active region and the entrance of catalytic active region. In particular, the Comp#5 conjugated with residue ARG362, elevating the efficient and selectivity of SHP2 protein. The study here may pave the way for discovering the novel SHP2 inhibitors for suffering cancer patients.

  DOI：

  10.1016/j.bioorg.2020.104391