N,N'-bis(2-bromoethyl-1,1,2,2-d₄)phosphorodiamidic acid | 918633-72-4

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 有机磷酸及其衍生物
• 英文名称: N,N'-bis(2-bromoethyl-1,1,2,2-d₄)phosphorodiamidic acid
• 英文别名: Bis[(2-bromo-1,1,2,2-tetradeuterioethyl)amino]phosphinic acid
• CAS: 918633-72-4
• 化学式: C₄H₁₁Br₂N₂O₂P
• 分子量: 317.862
• InChiKey: FUNYDODCWWGJJA-SVYQBANQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.1
• 重原子数：
  11
• 可旋转键数：
  6
• 环数：
  0.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  61.4
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

   N,N'-bis(2-bromoethyl-1,1,2,2-d₄)phosphorodiamidic acid 、 (3-甲基-2-硝基-3H-咪唑-4-基)-甲醇 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， 反应 2.0h， 生成 2-bromo-N-[[(2-bromo-1,1,2,2-tetradeuterioethyl)amino]-[(3-methyl-2-nitroimidazol-4-yl)methoxy]phosphoryl]-1,1,2,2-tetradeuterioethanamine
  参考文献：
  名称：

  WO2007/2931

  摘要：

  公开号：
• 作为产物：
  描述：

  2-bromo-N-[[(2-bromo-1,1,2,2-tetradeuterioethyl)amino]-phenoxyphosphoryl]-1,1,2,2-tetradeuterioethanamine 在 platinum(IV) oxide 氢气 作用下， 以 甲醇 为溶剂， 反应 3.0h， 生成  N,N'-bis(2-bromoethyl-1,1,2,2-d₄)phosphorodiamidic acid
  参考文献：
  名称：

  WO2007/2931

  摘要：

  公开号：

文献信息

• Cellular pharmacology of evofosfamide (TH-302): A critical re-evaluation of its bystander effects
  作者：Cho Rong Hong、Benjamin D. Dickson、Jagdish K. Jaiswal、Frederik B. Pruijn、Francis W. Hunter、Michael P. Hay、Kevin O. Hicks、William R. Wilson

  DOI：10.1016/j.bcp.2018.08.027

  日期：2018.10

  Evofosfamide (TH-302) is a clinical-stage hypoxia-activated prodrug with proven efficacy against hypoxic cells in preclinical tumour models. TH-302 is designed to release the DNA crosslinking agent bromo-isophosphoramide mustard (Br-IPM) when reduced in hypoxic tissue. Br-IPM is considered to diffuse locally from hypoxic regions, eliciting additional tumour cell killing, but the latter 'bystander effect' has not been demonstrated directly. Previous studies with multicellular co-cultures that included cells expressing the E. coli nitroreductase NfsA as a model TH-302 reductase have provided clear evidence of a bystander effect (which we confirm in the present study). However, NfsA is an oxygen-insensitive two-electron reductase that is not expected to generate the nitro radical intermediate that has been demonstrated to fragment to release Br-IPM. Here, we use mass spectrometry methods to characterise TH-302 metabolites generated by one-electron reduction (steady-state radiolysis by ionising radiation and cellular metabolism under hypoxia, including HCT116 cells that overexpress P450 oxidoreductase, POR) or by NfsA expressed in HCT116 cells under oxic conditions, and investigate the stability and cytotoxicity of these products. Br-IPM is shown to have very low cytotoxic potency when added to extracellular culture medium and to be rapidly converted to other hydrophilic products including dichloro-isophosphoramide mustard (IPM). Only traces of Br-IPM or IPM were detected in the extracellular medium when generated by cellular metabolism of TH-302. We identify, in NfsA-expressing cells, the hydroxylamine metabolite of TH-302, and downstream products resulting from rearrangement or hydration of the imidazole ring, and demonstrate that formation of these candidate bystander effect mediators is suppressed by hypoxia. This characterisation of the cellular pharmacology of TH-302 implies that bystander effects from hypoxic activation of TH-302 are unlikely to contribute to its anticancer activity.
• WO2007/2931
  申请人：——

  公开号：——

  公开（公告）日：——