4-(4-biphenyl-2-ylmethyl-piperazin-1-yl)-benzoic acid ethyl ester | 926933-99-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 4-(4-biphenyl-2-ylmethyl-piperazin-1-yl)-benzoic acid ethyl ester
• 英文别名: Ethyl 4-[4-[(2-phenylphenyl)methyl]piperazin-1-yl]benzoate
• CAS: 926933-99-5
• 化学式: C₂₆H₂₈N₂O₂
• 分子量: 400.521
• InChiKey: UNAGMMVCAHUYLB-UHFFFAOYSA-N

物化性质

• 沸点：
  570.2±50.0 °C(Predicted)
• 密度：
  1.141±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  30
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  32.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-(4-biphenyl-2-ylmethyl-piperazin-1-yl)-benzoic acid ethyl ester 在 4-二甲氨基吡啶 、 lithium hydroxide 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 为溶剂， 反应 32.0h， 生成 4-(4-(biphenyl-2-ylmethyl)piperazin-1-yl)-N-(4-(2-methyl-1-(phenylthio)propan-2-ylamino)-3-nitrophenylsulfonyl)benzamide
  参考文献：
  名称：

  Studies Leading to Potent, Dual Inhibitors of Bcl-2 and Bcl-xL

  摘要：

  Overexpression of the antiapototic proteins Bcl-2 and Bcl-xL provides a common mechanism through which cancer cells gain a survival advantage and become resistant to conventional chemotherapy. Inhibition of these prosurvival proteins is an attractive strategy for cancer therapy. We recently described the discovery of a selective Bcl-xL antagonist that potentiates the antitumor activity of chemotherapy and radiation. Here we describe the use of structure-guided design to exploit a deep hydrophobic binding pocket on the surface of these proteins to develop the first dual, subnanomolar inhibitors of Bcl-xL and Bcl-2. This study culminated in the identification of 2, which exhibited EC50 values of 8 nM and 30 nM in Bcl-2 and Bcl-xL dependent cells, respectively. Compound 2 demonstrated single agent efficacy against human follicular lymphoma cell lines that overexpress Bcl-2, and efficacy in a murine xenograft model of lymphoma when given both as a single agent and in combination with etoposide.

  DOI：

  10.1021/jm061152t
• 作为产物：
  描述：

  2-苯基溴化甲基苯 、 4-(1-哌嗪基)苯甲酸乙酯 在 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 为溶剂， 反应 0.25h， 以100%的产率得到4-(4-biphenyl-2-ylmethyl-piperazin-1-yl)-benzoic acid ethyl ester
  参考文献：
  名称：

  Studies Leading to Potent, Dual Inhibitors of Bcl-2 and Bcl-xL

  摘要：

  Overexpression of the antiapototic proteins Bcl-2 and Bcl-xL provides a common mechanism through which cancer cells gain a survival advantage and become resistant to conventional chemotherapy. Inhibition of these prosurvival proteins is an attractive strategy for cancer therapy. We recently described the discovery of a selective Bcl-xL antagonist that potentiates the antitumor activity of chemotherapy and radiation. Here we describe the use of structure-guided design to exploit a deep hydrophobic binding pocket on the surface of these proteins to develop the first dual, subnanomolar inhibitors of Bcl-xL and Bcl-2. This study culminated in the identification of 2, which exhibited EC50 values of 8 nM and 30 nM in Bcl-2 and Bcl-xL dependent cells, respectively. Compound 2 demonstrated single agent efficacy against human follicular lymphoma cell lines that overexpress Bcl-2, and efficacy in a murine xenograft model of lymphoma when given both as a single agent and in combination with etoposide.

  DOI：

  10.1021/jm061152t

文献信息

• US8084607B2
  申请人：——

  公开号：US8084607B2

  公开（公告）日：2011-12-27
• Studies Leading to Potent, Dual Inhibitors of Bcl-2 and Bcl-xL
  作者：Milan Bruncko、Thorsten K. Oost、Barbara A. Belli、Hong Ding、Mary K. Joseph、Aaron Kunzer、Darlene Martineau、William J. McClellan、Michael Mitten、Shi-Chung Ng、Paul M. Nimmer、Tilman Oltersdorf、Cheol-Min Park、Andrew M. Petros、Alexander R. Shoemaker、Xiaohong Song、Xilu Wang、Michael D. Wendt、Haichao Zhang、Stephen W. Fesik、Saul H. Rosenberg、Steven W. Elmore

  DOI：10.1021/jm061152t

  日期：2007.2.1

  Overexpression of the antiapototic proteins Bcl-2 and Bcl-xL provides a common mechanism through which cancer cells gain a survival advantage and become resistant to conventional chemotherapy. Inhibition of these prosurvival proteins is an attractive strategy for cancer therapy. We recently described the discovery of a selective Bcl-xL antagonist that potentiates the antitumor activity of chemotherapy and radiation. Here we describe the use of structure-guided design to exploit a deep hydrophobic binding pocket on the surface of these proteins to develop the first dual, subnanomolar inhibitors of Bcl-xL and Bcl-2. This study culminated in the identification of 2, which exhibited EC50 values of 8 nM and 30 nM in Bcl-2 and Bcl-xL dependent cells, respectively. Compound 2 demonstrated single agent efficacy against human follicular lymphoma cell lines that overexpress Bcl-2, and efficacy in a murine xenograft model of lymphoma when given both as a single agent and in combination with etoposide.