2-bromo-N-[(2-bromoethylamino)-[(1-methyl-5-nitroimidazol-2-yl)methoxy]phosphoryl]ethanamine | 918633-16-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 2-bromo-N-[(2-bromoethylamino)-[(1-methyl-5-nitroimidazol-2-yl)methoxy]phosphoryl]ethanamine
• CAS: 918633-16-6
• 化学式: C₉H₁₆Br₂N₅O₄P
• 分子量: 449.039
• InChiKey: HUBMMRPREFIQQL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.3
• 重原子数：
  21
• 可旋转键数：
  9
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  114
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  二(2-溴乙基氨基)次磷酸 、 1-甲基-5-硝基-2-羟甲基咪唑 在 偶氮二甲酸二异丙酯 、 三苯基膦 作用下， 以 四氢呋喃 为溶剂， 以51%的产率得到2-bromo-N-[(2-bromoethylamino)-[(1-methyl-5-nitroimidazol-2-yl)methoxy]phosphoryl]ethanamine
  参考文献：
  名称：

  Potent and Highly Selective Hypoxia-Activated Achiral Phosphoramidate Mustards as Anticancer Drugs

  摘要：

  A series of achiral hypoxia-activated prodrugs were synthesized on the basis of the DNA cross-linking toxin of the prodrug, ifosfamide. The hypoxia-selective cytotoxicity of several of the compounds was improved over previously reported racemic mixtures of chiral bioreductive phosphorami date prodrugs. Prodrugs activated by 2-nitroimidazole reduction demonstrated up to 400-fold enhanced cytotoxicity toward H460 cells in culture under hypoxia versus their potency under aerobic conditions. Compounds were further assessed for their stability to cytochrome P450 metabolism using a liver microsome assay. The 2-nitroimidazole containing lead compound 3b (TH-302) was selectively potent under hypoxia and stable to liver microsomes. It was active in an in vivo MIA PaCa-2 pancreatic cancer orthotopic xenograft model as a monotherapy and demonstrated dramatic efficacy when used in combination with gemcitabine, extending survival with one of eight animals tumor free at day-44. Compound 3b has emerged as a promising antitumor agent that shows excellent in vivo efficacy and is currently being evaluated in the clinic.

  DOI：

  10.1021/jm701028q

文献信息

• Phosphoramidate Alkylator Prodrugs
  申请人：Threshold Pharmaceuticals, Inc.

  公开号：US20140170240A1

  公开（公告）日：2014-06-19

  Phosphoramidate alkylator prodrugs can be used to treat cancer when administered alone or in combination with one or more anti-neoplastic agents.

  磷酰胺酸烷基化剂前药可单独或与一个或多个抗肿瘤药物联合使用治疗癌症。
• PHOSPHORAMIDATE ALKYLATOR PRODRUGS
  申请人：Threshold Pharmaceuticals, Inc.

  公开号：US20130303778A1

  公开（公告）日：2013-11-14

  Phosphoramidate alkylator prodrugs can be used to treat cancer when administered alone or in combination with one or more anti-neoplastic agents.

  磷酰胺烷基化剂前药可单独或与一个或多个抗肿瘤药物联合使用以治疗癌症。
• US8507464B2
  申请人：——

  公开号：US8507464B2

  公开（公告）日：2013-08-13
• US9226932B2
  申请人：——

  公开号：US9226932B2

  公开（公告）日：2016-01-05
• Potent and Highly Selective Hypoxia-Activated Achiral Phosphoramidate Mustards as Anticancer Drugs
  作者：Jian-Xin Duan、Hailong Jiao、Jacob Kaizerman、Timothy Stanton、James W. Evans、Leslie Lan、Gustavo Lorente、Monica Banica、Don Jung、Jinwei Wang、Huaiyu Ma、Xiaoming Li、Zhijian Yang、Robert M. Hoffman、W. Steve Ammons、Charles P. Hart、Mark Matteucci

  DOI：10.1021/jm701028q

  日期：2008.4.1

  A series of achiral hypoxia-activated prodrugs were synthesized on the basis of the DNA cross-linking toxin of the prodrug, ifosfamide. The hypoxia-selective cytotoxicity of several of the compounds was improved over previously reported racemic mixtures of chiral bioreductive phosphorami date prodrugs. Prodrugs activated by 2-nitroimidazole reduction demonstrated up to 400-fold enhanced cytotoxicity toward H460 cells in culture under hypoxia versus their potency under aerobic conditions. Compounds were further assessed for their stability to cytochrome P450 metabolism using a liver microsome assay. The 2-nitroimidazole containing lead compound 3b (TH-302) was selectively potent under hypoxia and stable to liver microsomes. It was active in an in vivo MIA PaCa-2 pancreatic cancer orthotopic xenograft model as a monotherapy and demonstrated dramatic efficacy when used in combination with gemcitabine, extending survival with one of eight animals tumor free at day-44. Compound 3b has emerged as a promising antitumor agent that shows excellent in vivo efficacy and is currently being evaluated in the clinic.