(Z)-ethyl 5-(4-chlorophenyl)-2-(3,4-dihydroxybenzylidene)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate

• 分子结构分类: 有机化合物 - 苯类化合物 - 酚类
• 英文名称: (Z)-ethyl 5-(4-chlorophenyl)-2-(3,4-dihydroxybenzylidene)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate
• 英文别名: ethyl (2Z)-5-(4-chlorophenyl)-2-[(3,4-dihydroxyphenyl)methylidene]-7-methyl-3-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-6-carboxylate
• 化学式: C₂₃H₁₉ClN₂O₅S
• 分子量: 470.933
• InChiKey: SCRLKHKDVUWPMH-WQRHYEAKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  32
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  125
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  乙酰乙酸乙酯 在 sodium acetate 、 溶剂黄146 、 氯乙酸 作用下， 反应 5.0h， 生成 (Z)-ethyl 5-(4-chlorophenyl)-2-(3,4-dihydroxybenzylidene)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate
  参考文献：
  名称：

  Ethyl 2-(benzylidene)-7-methyl-3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate analogues as a new scaffold for protein kinase casein kinase 2 inhibitor

  摘要：

  Protein kinase casein kinase 2 (PKCK2) is a constitutively active, growth factor-independent serine/threonine kinase, and changes in PKCK2 expression or its activity are reported in many cancer cells. To develop a novel PKCK2 inhibitor(s), we first performed cell-based phenotypic screening using 4000 chemicals purchased from ChemDiv chemical libraries (2000: randomly selected; 2000: kinase-biased) and performed in vitro kinase assay-based screening using hits found from the first screening. We identified compound 24 (C24)[(Z)-ethyl 5-(4-chlorophenyl)-2-(3,4-dihydroxybenzylidene)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo[3,2-a] pyrimidine-6-carboxylate] as a novel inhibitor of PKCK2 that is more potent and selective than 4,5,6,7-tetrabromobenzotriazole (TBB). In particular, compound 24 [half maximal inhibitory concentration (IC50)=0.56μM] inhibited PKCK2 2.2-fold more efficiently than did TBB (IC50=1.24μM), which is quite specific toward PKCK2 with respect to ATP binding, in a panel of 31 human protein kinases. The Ki values of compound 24 and TBB for PKCK2 were 0.78μM and 2.70μM, respectively. Treatment of cells with compound 24 inhibited endogenous PKCK2 activity and showed anti-proliferative and pro-apoptotic effects against stomach and hepatocellular cancer cell lines more efficiently than did TBB. As expected, compound 24 also enabled tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-resistant cancer cells to be sensitive toward TRAIL. In comparing the molecular docking of compound 24 bound to PKCK2α versus previously reported complexes of PKCK2 with other inhibitors, our findings suggest a new scaffold for specific PKCK2α inhibitors. Thus, compound 24 appears to be a selective, cell-permeable, potent, and novel PKCK2 inhibitor worthy of further characterization.

  DOI：

  10.1016/j.bmc.2014.07.037