(Z)-tert-butyl 4-({2-[(1H-indol-3-yl)methylene]-6-ethoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate | 1346151-63-0

• 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)-tert-butyl 4-({2-[(1H-indol-3-yl)methylene]-6-ethoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate
• 英文别名: tert-butyl (Z)-4-({2-[(1H-indol-3-yl)methylene]-6-ethoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate；tert-butyl 4-[[(2Z)-6-ethoxy-2-(1H-indol-3-ylmethylidene)-3-oxo-1-benzofuran-7-yl]methyl]piperazine-1-carboxylate
• CAS: 1346151-63-0
• 化学式: C₂₉H₃₃N₃O₅
• 分子量: 503.598
• InChiKey: LNVJUPJTRKHILM-XYGWBWBKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  37
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  84.1
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (Z)-tert-butyl 4-({2-[(1H-indol-3-yl)methylene]-6-ethoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate 在 盐酸 作用下， 以 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 2.0h， 以77%的产率得到(Z)-2-[(1H-indol-3-yl)methylene]-6-ethoxy-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
• 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 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 甲醇 、 甲苯 为溶剂， 反应 7.0h， 生成 (Z)-tert-butyl 4-({2-[(1H-indol-3-yl)methylene]-6-ethoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate
  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：Nagano Tetsuo

  公开号：US09156827B2

  公开（公告）日：2015-10-13

  An anticancer agent comprising a compound represented by the formula (I) [R1 represents hydrogen atom, hydroxyl group, a C1-6 alkoxy group and the like; R2 and R3 represents hydrogen atom, a halogen atom, a C1-6 alkyl group and the like; R4 represents hydrogen atom, a C1-6 alkyl group, a C1-6 alkylsulfonyl group and the like; R5 represents hydrogen atom or a substituent; represents a single bond or a double bond; R6 and R7 represents hydrogen atom, a C1-6 alkyl group and the like; R8 represents hydrogen atom, a C1-6 alkyl group and the like; A represents —O—, —S—, or —CH2—; D represents —C═ or —N═; X represents methylene group, —O—, or —CO—; Q represents —N═ or —C(R8)═; and Y represents a heterocyclic group or amino group], which shows a superior inhibitory activity against pim-1 kinase.

  一种抗癌剂，包括由公式（I）所代表的化合物 [ R1 代表氢原子、羟基、C1-6烷氧基等； R2 和 R3 代表氢原子、卤素原子、C1-6烷基等； R4 代表氢原子、C1-6烷基、C1-6烷基磺酰基等； R5 代表氢原子或取代基； 表示单键或双键； R6 和 R7 代表氢原子、C1-6烷基等； R8 代表氢原子、C1-6烷基等； A 代表-O-、-S-或-CH2-； D 代表-C═或-N═； X 代表亚甲基基、-O-或-CO-； Q 代表-N═或-C(R8)═； Y 代表杂环基或氨基]，该化合物对pim-1激酶具有卓越的抑制活性。
• 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.