5-(aziridin-1-yl)-2-hydroxylamino-4-nitrobenzamide | 119643-83-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 5-(aziridin-1-yl)-2-hydroxylamino-4-nitrobenzamide
• 英文别名: 5-(aziridin-1-yl)-2-hydroxyamino-4-nitrobenzamide；2-hydroxylamino metabolite；Benzamide, 5-(1-aziridinyl)-2-(hydroxyamino)-4-nitro-；5-(aziridin-1-yl)-2-(hydroxyamino)-4-nitrobenzamide
• CAS: 119643-83-3
• 化学式: C₉H₁₀N₄O₄
• 分子量: 238.203
• InChiKey: LQYDLQVLLUVETH-UHFFFAOYSA-N

物化性质

• 沸点：
  452.7±55.0 °C(Predicted)
• 密度：
  1.707±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.2
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  124
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  5-(1-氮杂环丙基)-2,4-二硝基苯甲酰胺 在 1,4-dihydronicotinamide adenine dinucleotide 、 Escherichia coli K₁₂ nitroreductase 作用下， 以 二甲基亚砜 为溶剂， 反应 0.08h， 生成 5-(aziridin-1-yl)-2-hydroxylamino-4-nitrobenzamide
  参考文献：
  名称：

  Improving Nature's Enzyme Active Site with Genetically Encoded Unnatural Amino Acids

  摘要：

  The ability to site-specifically incorporate a diverse set of unnatural amino acids (> 30) into proteins and quickly add new structures of interest has recently changed our approach to protein use and study. One important question yet unaddressed with unnatural amino acids ( UAAs) is whether they can improve the activity of an enzyme beyond that available from the natural 20 amino acids. Herein, we report the > 30- fold improvement of prodrug activator nitroreductase activity with an UAA over that of the native active site and a > 2.3- fold improvement over the best possible natural amino acid. Because immense structural and electrostatic diversity at a single location can be sampled very quickly, UAAs can be implemented to improve enzyme active sites and tune a site to multiple substrates.

  DOI：

  10.1021/ja061099y

文献信息

• Time dependent HPLC analysis of the product ratio of enzymatically reduced prodrug CB1954 by a modified and immobilised nitroreductase
  作者：Patrick Ball、Emma Thompson、Simon Anderson、Vanessa Gwenin、Chris Gwenin

  DOI：10.1016/j.ejps.2018.11.001

  日期：2019.1

  to determine the hydroxylamine product ratios formed when reacted with CB1954. Time-dependent HPLC studies were carried out to assess how this ratio changes over time. It was shown that the hydroxylamine ratio formed by the reduction of CB1954 by a nitroreductase changes over time and that this change in ratio relates directly to the kinetics of the reaction. Thus, the hydroxylamine ratio measured using

  定向酶前药疗法是一种化学疗法策略，利用前药激活酶在肿瘤部位激活前药，从而降低脱靶效应。与CB1954前药一起使用的最常研究的酶是来自大肠杆菌的NfnB硝基还原酶。文献指出，CB1954在2或4位上以1：1的比例被NfnB还原；在文献中已经观察到与该比率的偏差，但是没有进一步研究。基因修饰酶的动力学参数；评估了NfnB-his，NfnB-cys和AuNP-NfnB-cys，并使用HPLC分析来确定与CB1954反应时形成的羟胺产物比率。进行了与时间有关的HPLC研究，以评估该比率如何随时间变化。结果表明，由硝基还原酶还原CB1954形成的羟胺比率随时间变化，该比率的变化直接与反应动力学有关。因此，在给定的时间点使用HPLC测量的羟胺比率并不是真实地表明催化过程中硝基还原酶的偏好。这些结果质疑如何根据羟胺比率评估硝基还原酶，并且怀疑该现象也可能适用于其他酶/前药组合。
• Improvements relating to the control of neoplastic tissue growth
  申请人：Roberts, John J.

  公开号：EP0330432A1

  公开（公告）日：1989-08-30

  Compounds of the general formula: wherein R is H, an acyl group or a hydrocarbyl group containing up to 6 carbon atoms, have cytotoxic activity against several tumours. The 4-hydroxylamino compound can be obtained directly from the corresponding 2,4-dinitro compound by selective chemical reduction or by the action of a nitroreductase obtainable from Walker tumour cells. The 2,4-dinitro compound is substantially devoid of cytotoxic activity except in relation to Walker tumour cells and hence can act as a prodrug in regimes where a prodrug is localised in vivo in the regions of a tumour to be treated and is then activated to the cytotoxic 4-hydroxylamino compound under the influence of the enzyme.

  通式如下的化合物 其中 R 是 H、酰基或含有多达 6 个碳原子的烃基，对多种肿瘤具有细胞毒活性。4- 羟基氨基化合物可通过选择性化学还原法或可从沃克肿瘤细胞中获得的硝基还原酶的作用，直接从相应的 2,4-二硝基化合物中获得。2,4-二硝基化合物除对沃克肿瘤细胞外基本上没有细胞毒性活性，因此可以作为一种原药，在治疗肿瘤的过程中，原药在体内定位，然后在酶的作用下活化成具有细胞毒性的 4-羟基氨基化合物。
• Bacterial nitroreductase for the reduction of CB 1954 and analogues thereof to a cytotoxic form
  申请人：CANCER RESEARCH CAMPAIGN TECHNOLOGY LIMITED

  公开号：EP0540263A1

  公开（公告）日：1993-05-05

  The invention provides a nitroreductase, obtainable from a bacterium having the following characteristics as exemplified by examples isolated from Escherichia coli B and Bacillus amyloliquifaciens: 1. It is a flavoprotein having a molecular weight in the range 20-60 Kilodaltons; 2. It requires either NADH or NAD(P)H or analogues thereof as a cofactor; 3. It has a Km for NADH or NAD(P)H in the range 1-100µM; and 4. It is capable of reducing either or both nitro groups of CB 1954 and analogues thereof to a cytotoxic form e.g. the hydroxylamine. The sequence of one such nitroreductase is shown in Seq. ID No.1. The nitroreductase may be conjugated to a tumor targeting agent such as a monoclonal antibody and used to convert prodrugs into active antitumour agents. Such prodrugs and drugs are also provided.

  本发明提供了一种硝基还原酶，可从具有以下特征的细菌中获得，例如从大肠杆菌 B 和淀粉芽孢杆菌中分离的实例： 1.它是一种黄素蛋白，分子量在 20-60 千道尔顿之间； 2.2. 它需要 NADH 或 NAD(P)H 或其类似物作为辅助因子； 3.它对 NADH 或 NAD(P)H 的 Km 值在 1-100µM 之间；以及 4.4. 它能够将 CB 1954 及其类似物的一个或两个硝基还原成具有细胞毒性的形式，如羟胺。 其中一种硝基还原酶的序列如 Seq.ID No.1。硝基还原酶可与单克隆抗体等肿瘤靶向药结合，用于将原药转化为活性抗肿瘤药。还提供了此类原药和药物。
• Treatment for cancer
  申请人：The University of Nottingham

  公开号：US10183062B2

  公开（公告）日：2019-01-22

  The present invention provides a method of treatment for cancer in a subject comprising the administration of a prodrug, wherein the subject is colonised with an obligate anaerobic microorganism capable of expressing a polypeptide having nitroreductase activity, wherein the polypeptide exhibits preferential reduction of CB1954 to a 4-hydroxylamine (4HX) derivative instead of a 2-hydroxylamine derivative; and is capable of reducing CB1954 to the 4HX derivative with a Km of less than 30 micromolar. The present invention further provides an isolated polypeptide, nucleic acids encoding said polypeptide, vectors and host cells comprising said nucleic acids and vectors and uses of the above in treating solid tumours.

  本发明提供了一种治疗受试者癌症的方法，包括给药原药，其中受试者体内定植有一种能表达具有硝基还原酶活性的多肽的厌氧微生物，该多肽能优先将CB1954还原成4-羟胺(4HX)衍生物，而不是2-羟胺衍生物；并能将CB1954还原成4HX衍生物，其Km小于30微摩尔。本发明进一步提供了一种分离的多肽、编码所述多肽的核酸、包含所述核酸和载体的载体和宿主细胞，以及上述物质在治疗实体瘤中的用途。
• Use of alpha-hydroxy carbonyl compounds as reducing agents
  申请人：Morvus Technology Ltd

  公开号：US10398676B2

  公开（公告）日：2019-09-03

  There is provided the use as reducing agents of alpha-hydroxycarbonyl compounds capable of forming cyclic dimers. There is also provided corresponding methods of reducing reducible compounds, particularly reduction-activated prodrugs. Examples of the alpha-hydroxycarbonyl compounds used are dihydroxyacetone, glycolaldehyde, glyceraldehyde, erythrose, xylulose, erythrulose or 3-hydroxy-2-butanone.

  提供了能够形成环状二聚体的α-羟基羰基化合物作为还原剂的用途。还提供了相应的还原可还原化合物，特别是还原活化原药的方法。所使用的α-羟基羰基化合物的例子有二羟基丙酮、乙醛、甘油醛、赤藓糖醇、木糖、赤藓糖醇或 3-羟基-2-丁酮。