1,5-二甲基-2-硝基-1H-咪唑 | 5213-48-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 中文名称: 1,5-二甲基-2-硝基-1H-咪唑
• 英文名称: 1,5-Dimethyl-2-nitroimidazole
• CAS: 5213-48-9
• 化学式: C₅H₇N₃O₂
• 分子量: 141.129
• InChiKey: BILWDWLNZFTXAN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.2
• 重原子数：
  10
• 可旋转键数：
  0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  63.6
• 氢给体数：
  0
• 氢受体数：
  3

安全信息

• 海关编码：
  2933290090

反应信息

• 作为反应物：
  描述：

  1,5-二甲基-2-硝基-1H-咪唑 在 氘氧化钠 、 甲醇-d3 、 重水 作用下， 生成
  参考文献：
  名称：

  Carbanion stabilization in C,N-dimethylnitroimidazoles

  摘要：

  DOI：

  10.1021/jo00336a018
• 作为产物：
  描述：

  2-硝基-5-甲基-1H-咪唑 、 对甲苯磺酸甲酯 在 potassium carbonate 作用下， 以 丙酮 为溶剂， 反应 2.0h， 以25%的产率得到1,5-二甲基-2-硝基-1H-咪唑
  参考文献：
  名称：

  Cellular pharmacology of evofosfamide (TH-302): A critical re-evaluation of its bystander effects

  摘要：

  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.

  DOI：

  10.1016/j.bcp.2018.08.027

文献信息

• 2-Nitroimidazole derivatives
  申请人：Gruppo Lepetit S.p.A.

  公开号：US03954789A1

  公开（公告）日：1976-05-04

  2-Nitroimidazole derivatives of the general formula ##SPC1## Wherein R is a lower alkyl group and Y is a member of the group consisting of --CH.sub.2 OH, --CHO, CH.sub.3 CO--, vinyl, formylvinyl, styryl, substituted iminomethyl, 2-benzimidazolyl and 5-amino-1,3,4-thiadiazol-2-yl. The term "lower alkyl" designates aliphatic groups of from 1 to 4 carbon atoms; the term "substituted iminomethyl" designates nitrogen-containing functional derivatives of the aldehydic group. The compounds have antimicrobial activity.

  通式为##SPC1##的2-硝基咪唑衍生物，其中R为较低的烷基团，Y为以下组成的一员：--CH.sub.2 OH、--CHO、CH.sub.3 CO--、乙烯基、甲酰乙烯基、苯乙烯基、取代亚胺基甲基、2-苯并咪唑基和5-氨基-1,3,4-噻二唑-2-基。术语“较低的烷基”指碳原子数为1至4的脂肪族基；术语“取代亚胺基甲基”指醛基的含氮功能衍生物。这些化合物具有抗微生物活性。
• 2-Nitroimidazol derivatives
  申请人：Gruppo Lepetit S.p.A.

  公开号：US03987053A1

  公开（公告）日：1976-10-19

  2-Nitroimidazole derivatives of the general formula ##SPC1## Wherein R is a lower alkyl group and Y is a member of the group consisting of --CH.sub.2 OH, --CHO, CH.sub.3 CO--, vinyl, formylvinyl, styryl, substituted iminomethyl, 2-benzimidazolyl and 5-amino-1,3,4-thiadiazol-2-yl. The term "lower alkyl" designates aliphatic groups of from 1 to 4 carbon atoms; the term "substituted iminomethyl" designates nitrogen-containing functional derivatives of the aldehydic group. The compounds have antimicrobial activity.

  2-硝基咪唑衍生物的一般式为##SPC1## 其中R是低碳基，Y是由以下组成的一种：--CH.sub.2 OH, --CHO, CH.sub.3 CO--, 乙烯基，甲酰乙烯基，苯乙烯基，取代亚胺甲基，2-苯并咪唑基和5-氨基-1,3,4-噻二唑-2-基。术语“低碳基”指碳原子数为1至4的脂肪族基；术语“取代亚胺甲基”指醛基的含氮功能衍生物。这些化合物具有抗微生物活性。
• Carbanion stabilization in C,N-dimethylnitroimidazoles
  作者：C. Rav-Acha、Louis A. Cohen

  DOI：10.1021/jo00336a018

  日期：1981.11
• 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.