1-(2-hydroxyethyl)-3-(6-(2-methoxyphenyl)benzo[d]thiazol-2-yl)urea | 1430720-10-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噻唑类
• 英文名称: 1-(2-hydroxyethyl)-3-(6-(2-methoxyphenyl)benzo[d]thiazol-2-yl)urea
• 英文别名: 1-(2-Hydroxyethyl)-3-[6-(2-methoxyphenyl)-1,3-benzothiazol-2-yl]urea；1-(2-hydroxyethyl)-3-[6-(2-methoxyphenyl)-1,3-benzothiazol-2-yl]urea
• CAS: 1430720-10-7
• 化学式: C₁₇H₁₇N₃O₃S
• 分子量: 343.406
• InChiKey: LAAHHHDILCOULN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  24
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  112
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  2′-methoxybiphenyl-3,4-diamine 在 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 potassium carbonate 作用下， 以 1,4-二氧六环 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 生成 1-(2-hydroxyethyl)-3-(6-(2-methoxyphenyl)benzo[d]thiazol-2-yl)urea
  参考文献：
  名称：

  Discovery of New Benzothiazole-Based Inhibitors of Breakpoint Cluster Region-Abelson Kinase Including the T315I Mutant

  摘要：

  The existence of drug resistance caused by mutations in the break-point cluster region-Abelson tyrosine kinase (Bcr-Abl) kinase domain remains a clinical challenge due to limited effective treatment options for chronic myeloid leukemia (CML). Herein we report a novel series of benzothiazole-based inhibitors that are effective against wild-type and T315I mutant Bcr-Abl kinases. The original hit compound, nocodazole, was extensively modified through a structure-based drug design strategy, especially by varying the groups at the C2 and C6 positions of the scaffold. In addition, the introduction of water-solubilizing groups at the terminal ethyl group resulted in enhanced physicochemical properties and potency in cellular inhibition. Several compounds inhibited the kinase activity of both wild-type Bcr-Abl and the T315I mutant with IC50 values in the picomolar range and exhibited good antiproliferative effects on Ba/F3 cell lines transformed with either wild-type or T315I mutant Bcr-Abl.

  DOI：

  10.1021/jm301891t

文献信息

• 2-Ethynylbenzaldehyde-Based, Lysine-Targeting Irreversible Covalent Inhibitors for Protein Kinases and Nonkinases
  作者：Peng Chen、Guanghui Tang、Chengjun Zhu、Jie Sun、Xuan Wang、Menghua Xiang、Huisi Huang、Wei Wang、Lin Li、Zhi-Min Zhang、Liqian Gao、Shao Q. Yao

  DOI：10.1021/jacs.2c11595

  日期：——

  selective small-molecule inhibitors of ABL kinase by selectively targeting the conserved catalytic lysine in the enzyme. We showed the resulting compounds were cell-active, capable of covalently engaging endogenous ABL kinase in K562 cells with long-residence time and few off-targets. We further validated the generality of this strategy by developing EBA-based irreversible inhibitors against EGFR (a kinase)

  近年来，以赖氨酸为靶点的不可逆共价抑制剂引起了越来越多的兴趣，特别是在激酶研究领域。尽管取得了令人鼓舞的进展，但很少有化学方法可用于开发专门针对赖氨酸的、选择性的和细胞活性的抑制剂。我们在此报告了一种基于 2-乙炔基苯甲醛 (EBA) 的赖氨酸靶向策略，通过选择性靶向酶中保守的催化赖氨酸来生成 ABL 激酶的有效且选择性的小分子抑制剂。我们证明所得化合物具有细胞活性，能够与 K562 细胞中的内源 ABL 激酶共价结合，且停留时间长且脱靶很少。我们通过开发基于 EBA 的针对 EGFR（一种激酶）和 Mcl-1（一种非激酶）的不可逆抑制剂，进一步验证了该策略的普遍性，这些抑制剂与每个靶点内的催化和非催化赖氨酸发生共价反应。
• Discovery of New Benzothiazole-Based Inhibitors of Breakpoint Cluster Region-Abelson Kinase Including the T315I Mutant
  作者：Seunghee Hong、Jinhee Kim、Sun-Mi Yun、Hyunseung Lee、Yoonsu Park、Soon-Sun Hong、Sungwoo Hong

  DOI：10.1021/jm301891t

  日期：2013.5.9

  The existence of drug resistance caused by mutations in the break-point cluster region-Abelson tyrosine kinase (Bcr-Abl) kinase domain remains a clinical challenge due to limited effective treatment options for chronic myeloid leukemia (CML). Herein we report a novel series of benzothiazole-based inhibitors that are effective against wild-type and T315I mutant Bcr-Abl kinases. The original hit compound, nocodazole, was extensively modified through a structure-based drug design strategy, especially by varying the groups at the C2 and C6 positions of the scaffold. In addition, the introduction of water-solubilizing groups at the terminal ethyl group resulted in enhanced physicochemical properties and potency in cellular inhibition. Several compounds inhibited the kinase activity of both wild-type Bcr-Abl and the T315I mutant with IC50 values in the picomolar range and exhibited good antiproliferative effects on Ba/F3 cell lines transformed with either wild-type or T315I mutant Bcr-Abl.