1-[4-butanoyl-(p-bis(2-chloroethyl)amino)-L-phenylalanine ethyl ester]-7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: 1-[4-butanoyl-(p-bis(2-chloroethyl)amino)-L-phenylalanine ethyl ester]-7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one
• 英文别名: (R)-3-{4-[Bis-(2-chloro-ethyl)-amino]-phenyl}-2-[4-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-benzo[e][1,4]diazepin-1-yl)-butyrylamino]-propionic acid ethyl ester；ethyl (2R)-3-[4-[bis(2-chloroethyl)amino]phenyl]-2-[4-(7-chloro-2-oxo-5-phenyl-3H-1,4-benzodiazepin-1-yl)butanoylamino]propanoate
• 化学式: C₃₄H₃₇Cl₃N₄O₄
• 分子量: 672.051
• InChiKey: IDHGEFGDZPCYJX-GDLZYMKVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6
• 重原子数：
  45
• 可旋转键数：
  16
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  91.3
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  去甲西泮 在 氢氧化钾 、 sodium hydride 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 甲醇 为溶剂， 反应 3.0h， 生成 1-[4-butanoyl-(p-bis(2-chloroethyl)amino)-L-phenylalanine ethyl ester]-7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one
  参考文献：
  名称：

  Modulation of Melphalan Resistance in Glioma Cells with a Peripheral Benzodiazepine Receptor Ligand−Melphalan Conjugate

  摘要：

  Peripheral benzodiazepine receptors (PBRs) are located on the outer membrane of mitochondria, and their density is increased in brain tumors. Thus, they may serve as a unique intracellular and selective target for antineoplastic agents. A PBR ligand-melphalan conjugate (PBR-MEL) was synthesized and evaluated for cytotoxicity and affinity for PBRs. PBR-MEL (9) (i.e., 670 amu) was synthesized by coupling of two key intermediates: 4-[bis(2-chloroethyl)amino]-L-phenylalanine ethyl ester trifluoroacetate (6) and 1-(3'-carboxylpropyl)-7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (8). On the basis of receptor-binding displacement assays in rat brain and glioma cells, 9 had appreciable binding affinity and displaced a prototypical PBR ligand, Ro 5-4864, with IC50 values between 289 and 390 nM. 9 displayed differential cytotoxicity to a variety of rat and human brain tumor cell lines. In some of the cell lines tested including rat and human melphalan-resistant cell lines, 9 demonstrated appreciable cytotoxicity with IC50 values in the micromolar range, lower than that of melphalan alone. The enhanced activity of 9 may reflect increased membrane permeability, increased intracellular retention, or modulation of melphalan's mechanisms of resistance. The combined data support additional studies to determine how 9 may modulate melphalan resistance, its mechanisms of action, and if target selectivity can be achieved in in vivo glioma models.

  DOI：

  10.1021/jm960592p

文献信息

• Modulation of Melphalan Resistance in Glioma Cells with a Peripheral Benzodiazepine Receptor Ligand−Melphalan Conjugate
  作者：Lidia Kupczyk-Subotkowska、Teruna J. Siahaan、Anthony S. Basile、Henry S. Friedman、Patricia E. Higgins、Di Song、James M. Gallo

  DOI：10.1021/jm960592p

  日期：1997.5.1

  Peripheral benzodiazepine receptors (PBRs) are located on the outer membrane of mitochondria, and their density is increased in brain tumors. Thus, they may serve as a unique intracellular and selective target for antineoplastic agents. A PBR ligand-melphalan conjugate (PBR-MEL) was synthesized and evaluated for cytotoxicity and affinity for PBRs. PBR-MEL (9) (i.e., 670 amu) was synthesized by coupling of two key intermediates: 4-[bis(2-chloroethyl)amino]-L-phenylalanine ethyl ester trifluoroacetate (6) and 1-(3'-carboxylpropyl)-7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (8). On the basis of receptor-binding displacement assays in rat brain and glioma cells, 9 had appreciable binding affinity and displaced a prototypical PBR ligand, Ro 5-4864, with IC50 values between 289 and 390 nM. 9 displayed differential cytotoxicity to a variety of rat and human brain tumor cell lines. In some of the cell lines tested including rat and human melphalan-resistant cell lines, 9 demonstrated appreciable cytotoxicity with IC50 values in the micromolar range, lower than that of melphalan alone. The enhanced activity of 9 may reflect increased membrane permeability, increased intracellular retention, or modulation of melphalan's mechanisms of resistance. The combined data support additional studies to determine how 9 may modulate melphalan resistance, its mechanisms of action, and if target selectivity can be achieved in in vivo glioma models.