[3-(4-{4-[bis(2-chloroethyl)amino]phenyl}butanamido)propyl]tricyclohexylphosphanium trifluoroacetate

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: [3-(4-{4-[bis(2-chloroethyl)amino]phenyl}butanamido)propyl]tricyclohexylphosphanium trifluoroacetate
• 英文别名: 3-[4-[4-[Bis(2-chloroethyl)amino]phenyl]butanoylamino]propyl-tricyclohexylphosphanium;2,2,2-trifluoroacetate；3-[4-[4-[bis(2-chloroethyl)amino]phenyl]butanoylamino]propyl-tricyclohexylphosphanium;2,2,2-trifluoroacetate
• 化学式: C₂F₃O₂*C₃₅H₅₈Cl₂N₂OP
• 分子量: 737.754
• InChiKey: NKVOSKBWJBOXMV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  9.11
• 重原子数：
  48.0
• 可旋转键数：
  16.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.78
• 拓扑面积：
  72.47
• 氢给体数：
  1.0
• 氢受体数：
  4.0

反应信息

• 作为产物：
  描述：

  (3-aminopropyl)tricyclohexylphosphonium bromide hydrobromide 、 三氟乙酸 、 苯丁酸氮芥 在 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 、 4-二甲氨基吡啶 作用下， 以 二氯甲烷 、 水 、 乙腈 为溶剂， 反应 16.08h， 以3.5%的产率得到[3-(4-{4-[bis(2-chloroethyl)amino]phenyl}butanamido)propyl]tricyclohexylphosphanium trifluoroacetate
  参考文献：
  名称：

  A Selective Mitochondrial-Targeted Chlorambucil with Remarkable Cytotoxicity in Breast and Pancreatic Cancers

  摘要：

  Nitrogen mustards, widely used as chemotherapeutics, have limited safety and efficacy. Mitochondria lack a functional nucleotide excision repair mechanism to repair DNA adducts and are sensitive to alkylating agents. Importantly, cancer cells have higher intrinsic mitochondrial membrane potential (Delta psi(mt),) than normal cells. Therefore, selectively targeting nitrogen mustards to cancer cell mitochondria based on Delta psi(mt), could overcome those limitations. Herein, we describe the design, synthesis, and evaluation of Mito-Chlor, a triphenylphosphonium derivative of the nitrogen mustard chlorambucil. We show that Mito-Chlor localizes to cancer cell mitochondria where it acts on mtDNA to arrest cell cycle and induce cell death, resulting in a 80-fold enhancement of cell kill in a panel of breast and pancreatic cancer cell lines that are insensitive to the parent drug. Significantly, Mito-Chlor delayed tumor progression in a mouse xenograft model of human pancreatic cancer. This is a first example of repurposing chlorambucil, a drug not used in breast and pancreatic cancer treatment, as a novel drug candidate for these diseases.

  DOI：

  10.1021/jm4012438

文献信息

• A Selective Mitochondrial-Targeted Chlorambucil with Remarkable Cytotoxicity in Breast and Pancreatic Cancers
  作者：Melissa Millard、John D. Gallagher、Bogdan Z. Olenyuk、Nouri Neamati

  DOI：10.1021/jm4012438

  日期：2013.11.27

  Nitrogen mustards, widely used as chemotherapeutics, have limited safety and efficacy. Mitochondria lack a functional nucleotide excision repair mechanism to repair DNA adducts and are sensitive to alkylating agents. Importantly, cancer cells have higher intrinsic mitochondrial membrane potential (Delta psi(mt),) than normal cells. Therefore, selectively targeting nitrogen mustards to cancer cell mitochondria based on Delta psi(mt), could overcome those limitations. Herein, we describe the design, synthesis, and evaluation of Mito-Chlor, a triphenylphosphonium derivative of the nitrogen mustard chlorambucil. We show that Mito-Chlor localizes to cancer cell mitochondria where it acts on mtDNA to arrest cell cycle and induce cell death, resulting in a 80-fold enhancement of cell kill in a panel of breast and pancreatic cancer cell lines that are insensitive to the parent drug. Significantly, Mito-Chlor delayed tumor progression in a mouse xenograft model of human pancreatic cancer. This is a first example of repurposing chlorambucil, a drug not used in breast and pancreatic cancer treatment, as a novel drug candidate for these diseases.