TH-308

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 呋喃
• 英文名称: TH-308
• 英文别名: 2-bromo-N-[(2-bromoethylamino)-[(5-nitrofuran-2-yl)methoxy]phosphoryl]ethanamine
• 化学式: C₉H₁₄Br₂N₃O₅P
• 分子量: 435.009
• InChiKey: AVOXVOMQQZNGRK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  20
• 可旋转键数：
  9
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  109
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  5-硝基糠醇 、 二(2-溴乙基氨基)次磷酸 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50%的产率得到TH-308
  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：Matteucci Mark

  公开号：US20100137254A1

  公开（公告）日：2010-06-03

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

  磷酰胺酰化烷基化剂前药可以在单独或与一个或多个抗肿瘤剂联合使用时用于治疗癌症。
• Phosphoramidate Alkylator Prodrugs
  申请人：Matteucci Mark

  公开号：US20110251159A1

  公开（公告）日：2011-10-13

  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，用于治疗癌症。
• Phosphoramidate alkylator prodrugs
  申请人：Threshold Pharmaceuticals, Inc.

  公开号：EP2336141A2

  公开（公告）日：2011-06-22

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

  磷酰胺烷化剂原药可单独或与一种或多种其他抗肿瘤药物联合用于治疗癌症。
• ADMINISTRATION OF HYPOXIA ACTIVATED PRODRUGS AND ANTIANGIOGENIC AGENTS FOR THE TREATMENT OF CANCER
  申请人：Threshold Pharmaceuticals, Inc.

  公开号：EP2593139B1

  公开（公告）日：2017-08-23
• TREATMENT OF BLOOD CANCER
  申请人：Curd Karen

  公开号：US20130296273A1

  公开（公告）日：2013-11-07

  Hypoxia activated prodrugs, such as, e.g., TH-281, TH-302, and TH-308, are useful for the treatment of various blood cancers, such as acute leukemias, chronic leukemias, MDS, MF, and multiple myeloma.