(Z)-2-[(1H-indol-3-yl)methylene]-6-methoxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one | 1346149-97-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: (Z)-2-[(1H-indol-3-yl)methylene]-6-methoxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one
• 英文别名: (2Z)-2-(1H-indol-3-ylmethylidene)-6-methoxy-7-(piperazin-1-ylmethyl)-1-benzofuran-3-one
• CAS: 1346149-97-0
• 化学式: C₂₃H₂₃N₃O₃
• 分子量: 389.454
• InChiKey: ZSHOEUJOJHPBFX-MTJSOVHGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  66.6
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  tert-butyl 4-((6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl)piperazine-1-carboxylate 在 哌啶 、 盐酸 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 甲苯 为溶剂， 反应 9.0h， 生成 (Z)-2-[(1H-indol-3-yl)methylene]-6-methoxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one
  参考文献：
  名称：

  Rational Evolution of a Novel Type of Potent and Selective Proviral Integration Site in Moloney Murine Leukemia Virus Kinase 1 (PIM1) Inhibitor from a Screening-Hit Compound

  摘要：

  Serine/threonine kinase PIM1 is an emerging therapeutic target for hematopoietic and prostate cancer therapy. To develop a novel PIM1 inhibitor, we focused on 1, a metabolically labile, nonselective kinase inhibitor discovered in our previous screening study. We adopted a rational optimization strategy based mainly on structural information for the PIM1-1 complex to improve the potency and selectivity. This approach afforded the potent and metabolically stable PIM1-selective inhibitor 14, which shows only a marginal increase in molecular weight compared with 1 but has a significantly decreased cLogP. The validity of our design concept was confirmed by X-ray structure analysis. In a cellular study, 14 potently inhibited the growth of human leukemia cell line MV4-11 but had a negligible effect on the growth of WI-38 (surrogate for general toxicity). These results demonstrate the effectiveness of our design strategy for evolving the screening-hit compound 1 into a novel type of PIM1 inhibitor, 14.

  DOI：

  10.1021/jm3001289

文献信息

• ANTICANCER AGENT
  申请人：The University of Tokyo

  公开号：EP2565192B9

  公开（公告）日：2015-11-25
• US9156827B2
  申请人：——

  公开号：US9156827B2

  公开（公告）日：2015-10-13
• Rational Evolution of a Novel Type of Potent and Selective Proviral Integration Site in Moloney Murine Leukemia Virus Kinase 1 (PIM1) Inhibitor from a Screening-Hit Compound
  作者：Hirofumi Nakano、Nae Saito、Lorien Parker、Yukio Tada、Masanao Abe、Keiko Tsuganezawa、Shigeyuki Yokoyama、Akiko Tanaka、Hirotatsu Kojima、Takayoshi Okabe、Tetsuo Nagano

  DOI：10.1021/jm3001289

  日期：2012.6.14

  Serine/threonine kinase PIM1 is an emerging therapeutic target for hematopoietic and prostate cancer therapy. To develop a novel PIM1 inhibitor, we focused on 1, a metabolically labile, nonselective kinase inhibitor discovered in our previous screening study. We adopted a rational optimization strategy based mainly on structural information for the PIM1-1 complex to improve the potency and selectivity. This approach afforded the potent and metabolically stable PIM1-selective inhibitor 14, which shows only a marginal increase in molecular weight compared with 1 but has a significantly decreased cLogP. The validity of our design concept was confirmed by X-ray structure analysis. In a cellular study, 14 potently inhibited the growth of human leukemia cell line MV4-11 but had a negligible effect on the growth of WI-38 (surrogate for general toxicity). These results demonstrate the effectiveness of our design strategy for evolving the screening-hit compound 1 into a novel type of PIM1 inhibitor, 14.