N-[2-(2-硝基-1H-咪唑基)乙基]邻苯二甲酰亚胺 | 100579-78-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 中文名称: N-[2-(2-硝基-1H-咪唑基)乙基]邻苯二甲酰亚胺
• 英文名称: N-[2-(2-nitro-1H-imidazolyl)ethyl]phthalimide
• 英文别名: 1-(2-(N-phthalimido)ethyl)-2-nitroimidazole；2-(2-nitro-1H-imidazolyl)ethylphthalimide；1-(2-phthalimidoethyl)-2-nitroimidazole；2-[2-(2-nitro-1H-imidazol-1-yl)ethyl]-1H-isoindole-1,3(2H)-dione；2-[2-(2-nitroimidazol-1-yl)ethyl]isoindole-1,3-dione
• CAS: 100579-78-0
• 化学式: C₁₃H₁₀N₄O₄
• 分子量: 286.247
• InChiKey: OTGUNHRGVDGGRJ-UHFFFAOYSA-N

物化性质

• 熔点：
  210-212 °C(Solv: methanol (67-56-1))
• 沸点：
  534.7±52.0 °C(Predicted)
• 密度：
  1.56±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  101
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N-[2-(2-硝基-1H-咪唑基)乙基]邻苯二甲酰亚胺 在 一水合肼 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 反应 4.5h， 生成
  参考文献：
  名称：

  Synthesis of potential dual-acting radiation sensitizer antineoplastic agents: 2,2-dimethylphosphoraziridines containing 2-nitroimidazoles or other electron-affinic moieties

  摘要：

  In view of the in vivo demonstrated radiation-potentiating activities of several previously studied 2,2-dimethylphosphoraziridines, six new compounds incorporating the bis(2,2-dimethyl-1-aziridinyl)phosphinyl moiety, together with an electron-affinic group such as 2-nitroimidazole or nitrobenzyl, have been synthesized and tested (1) in vitro for ability to increase the effect of X-irradiation under hypoxic conditions on V-79 Chinese hamster lung fibroblast cells, (2) in vivo for antitumor activity in the absence of radiation against P388 leukemia in mice, and (3) in a preliminary experiment with compound 10 only, in combination with whole-body gamma-radiation, using the P388 leukemia mouse model for in vivo radiation-potentiating activity. The chemical-alkylating activities and hydrolytic behavior of these compounds, as well as their antitumor activities without radiation, were found to be comparable to those of other 2,2-dimethylphosphoraziridines, while their in vitro radiosensitizing activities were at low concentrations generally comparable to that of misonidazole, with compound 8 showing superior activity. At higher concentrations, only compound 10 was sufficiently soluble and nontoxic to the cells for evaluation in this assay. Thus, the bis(2,2-dimethyl-1-aziridinyl)phosphinyl moiety does not seem to have contributed to the hypoxic radiosensitizing activities (only to the cytotoxicities) of the electron-affinic moieties in this in vitro assay. In comparison, the prototype 2,2-dimethylphosphoraziridine, ethyl [bis(2,2-dimethyl-1-aziridinyl)phosphinyl]carbamate (AB-132), showed at nontoxic doses no radiosensitizing activity in this assay, and at cytotoxic doses increased the cell-killing effect of each given dose of X-radiation additively under both hypoxic and oxic conditions. Conversely, only the 2,2-dimethylphosphoraziridine moiety appeared to participate in the moderate "therapeutic radiation-potentiating" activity indicated by compound 10 in the in vivo experiment using the P388 leukemia model (on day 1), as the misonidazole standard was inactive in this nonhypoxic system. Clearly, the mechanism of the in vivo observed radiation-potentiating effect of AB-132 and other 2,2-dimethylphosphoraziridines is different from that of the hypoxic radiosensitizers, but the possible synergism between the two biologically active moieties of the new compounds could not be demonstrated with the experimental models so far employed.

  DOI：

  10.1021/jm00108a024
• 作为产物：
  描述：

  potassium phtalimide 在 potassium carbonate 作用下， 以 乙腈 为溶剂， 反应 24.0h， 生成 N-[2-(2-硝基-1H-咪唑基)乙基]邻苯二甲酰亚胺
  参考文献：
  名称：

  Synthesis and Bioevaluation of Novel [¹⁸F]FDG-Conjugated 2-Nitroimidazole Derivatives for Tumor Hypoxia Imaging

  摘要：

  Hypoxia imaging can guide tumor treatment and monitor changes in hypoxia during treatment. However, there is still no ideal hypoxia imaging agent for clinical applications. In this study, two novel 2-nitromidazole derivatives were synthesized and directly radiolabeled by [F-18]FDG in high radiochemical yield and excellent radiochemical purity. Cell experiments, biodistribution, and positron emission tomography (PET) imaging studies were also conducted in mice-bearing S180 or OS732 tumors. [F-18]FDG-2NNC2ON [(2R,3S,4R,E)-2-F-18-fluoro-3,4,5,6-tetrahydroxyhexanal O-3-(2-(2-nitro-1H-imidazole-1-yl)ethylamino)-2-oxopropyl oxime] and [F-18]FDG-2NNCSON [(2R,3S,4R,E)-2-F-18-fluoro-3,4,5,6-tetrahydroxyhexanal-O-3-(5-(2-nitro-1H-imidazole-1-yl)entylamino)-2-oxopropyl oxime] can be cleared from the blood quickly and specifically target hypoxic tumor cells. The uptake of the probes by hypoxic cells gradually increases with time. After 4 h, the uptake value of [F-18]FDG-2NNC2ON in hypoxic cells is 3.2 times higher than that in normoxia cells. In contrast, there is no difference in the uptake of [F-18]FDG between hypoxic cells and normoxia cells. Biodistribution resulting from two tumor models indicate that the uptake values of the two radiotracers in the tumor are higher at 1 h than those at 2 and 4 h. At 1 and 2 h, the tumors are clearly observed on the PET images and the imaging features of [F-18]FDG-2NNC5ON and [F-18]FDG-2NNC2ON are distinct from those of [F-18]FDG. Compared with [F-18]FDG-2NNC5ON, [F-18]FDG-2NNC2ON has a higher proportion of renal excretion, lower digestive tract uptake, and better imaging contrast because of its higher hydrophilicity. At 2 h, [F-18]FDG-2NNC2ON shows a good tumor-to-blood (T/B) ratio, tumor-to-muscle ratio based on biodistribution (Bio-T/M ratio), and tumor-to-muscle ratio based on regions of interest on the PET images [region of interest (ROI)-T/M ratio] in the two tumor models (T/B, Bio-T/M, and ROI-T/M ratios are 3.2, 2.6, and 3.9 in the S180 tumor model and are 3.4, 4.2, and 4.6 in the OS732 tumor model, respectively). The imaging features visualized with autoradiography mostly coincided with the positive areas of HIF1 alpha staining by immunofluorescence. Meanwhile, the biodistribution study and PET imaging revealed that the uptake of the radiotracers in the tumor cannot be competed by 5% glucose, confirming that [F-18]FDG-2NNC2ON targets the hypoxic regions of the tumors instead of targeting tumors through the glucose metabolism pathway. These results suggest that the new 2-nitroimidazole derivative conjugated with [F-18]FDG, [F-18]FDG-2NNC2ON, has potential as an imaging agent for hypoxia.

  DOI：

  10.1021/acs.molpharmaceut.9b00075

文献信息

• Synthesis and Stability Evaluation of New HYNIC Derivatives as Ligands for Technetium-99m
  作者：Yoann Joyard、Laurent Bischoff、Vincent Levacher、Cyril Papamicael、Pierre Vera、Pierre Bohn

  DOI：10.2174/15701786113106660087

  日期：2014.2

  An efficient synthetic route to prepare two new HYNIC derivatives with a 2-nitroimidazole moiety designed for tumor hypoxia imaging is described. During the course of the synthesis, the optimization of N-alkylation reaction of 2- nitroimidazole with propargyl bromide is reported to favor the formation of the terminal alkyne versus allene. Thereafter, the two ligands were used with tricine/EDDA to complex 99mTc. However, decomposition of these ligands was observed and we suggest a reasonable explanation based on LC-MS analysis.

  描述了一种高效的合成路线，用于制备两种新型HYNIC衍生物，它们含有2-硝基咪唑结构，设计用于肿瘤乏氧显像。在合成过程中，报道了对2-硝基咪唑与丙炔基溴的N-烷基化反应的优化，这有利于形成末端炔烃而非丙二烯。随后，这两种配体与tricine/EDDA一起用于络合99mTc。然而，观察到了这些配体的分解现象，我们基于LC-MS分析给出了一个合理的解释。
• Synthesis and Evaluation of Technetium-99m-Labeled Bioreductive Pharmacophores Conjugated with Amino Acids and Peptides for Tumor Imaging
  作者：Rinku Baishya、Dipak K. Nayak、Sanmoy Karmakar、Sankha Chattopadhyay、Satbir S. Sachdeva、Bharat R. Sarkar、Shantanu Ganguly、Mita C. Debnath

  DOI：10.1111/cbdd.12437

  日期：2015.4

  imaging agents to target tumor has become a major trend in nuclear medicine. With the aim to develop new potential 99mTc‐radiopharmaceuticals for targeting tumor, we have synthesized 5‐nitroimidazolyl amino acids and RGD‐coupled 2‐nitroimidazoles. Technetium‐99m radiolabeling with high radiochemical purity (>90%) was achieved for all the compounds. The radiolabeled complexes exhibited substantial in vitro

  靶向肿瘤的分子显像剂的开发已成为核医学的主要趋势。为了开发新的潜在99m Tc放射性药物靶向肿瘤，我们合成了5-硝基咪唑基氨基酸和RGD偶联的2-硝基咪唑。所有化合物均实现了具有高放射化学纯度（> 90％）的99m放射性标记。放射性标记的复合物在盐水，血清和组氨酸溶液（10 -2 m）中表现出显着的体外稳定性。EAC和B16F10细胞系中的细胞结合研究也显示出快速且相对较高的细胞内在化。在所有研究的化合物，的结合99米TC（CO）3 - 5 到B16F10细胞通过适度的竞争肽C [RGDfV]抑制，表明所述放射性配体的特异性朝向α v β 3受体。但是，当99m Tc标记的复合物与上述细胞的结合受到过量竞争肽的挑战时，未观察到结合放射性配体的显着位移。荧光显微镜研究提供的5（6）细胞内定位-羧基标记的2-硝基咪唑-RGD肽在的直接证据α v β 3阳性B16F10小鼠黑色素瘤细胞系。的配位
• Novel ^99mTc labelled complexes with 2-nitroimidazole isocyanide: design, synthesis and evaluation as potential tumor hypoxia imaging agents
  作者：Qing Ruan、Xuran Zhang、Xiao Lin、Xiaojiang Duan、Junbo Zhang

  DOI：10.1039/c8md00146d

  日期：——

  Radiolabelled 2-nitroimidazoles have been used for imaging hypoxia. With the aim of developing novel 99mTc radiotracers for imaging hypoxia, four novel 2-nitroimidazole isocyanide derivatives (2a, 2b, 2c, and 2d) were synthesized and radiolabelling was carried out for preparing their corresponding 99mTc complexes. These 99mTc complexes were stable in vitro and could exhibit good hypoxic selectivity

  放射性标记的 2-硝基咪唑已用于缺氧成像。为了开发用于缺氧成像的新型99m Tc放射性示踪剂，合成了四种新型2-硝基咪唑异氰化物衍生物（2a、2b、2c和2d ），并进行放射性标记以制备其相应的99m Tc配合物。这些99m Tc 配合物在体外稳定，并且具有良好的缺氧选择性。分配系数结果表明它们是亲水性的，并且对携带S180肿瘤的小鼠的生物分布评估表明所有复合物都可以在肿瘤中积聚。其中，99m Tc- 2c在注射后2小时表现出最高的肿瘤摄取以及肿瘤/血液和肿瘤/肌肉比率。此外，单光子发射计算机断层扫描 (SPECT) 成像研究表明肿瘤中存在明显的积累，表明99m Tc- 2c是缺氧成像的有希望的候选者。
• Real time detection of ESKAPE pathogens by a nitroreductase-triggered fluorescence turn-on probe
  作者：Shengnan Xu、Qinghua Wang、Qingyang Zhang、Leilei Zhang、Limin Zuo、Jian-Dong Jiang、Hai-Yu Hu

  DOI：10.1039/c7cc07050k

  日期：——

  Identification of bacterial pathogens is the critical first step in conquering infection diseases. A novel turn-on fluorescent probe for selective sensing nitroreductase (NTR) activity, and its initial applications in rapid, real time detection and identification of ESKAPE Pathogens have been reported.

  细菌病原体的鉴定是战胜感染性疾病的关键的第一步。据报道，一种新型的选择性检测硝基还原酶（NTR）活性的开启荧光探针及其在快速，实时检测和鉴定ESKAPE病原体中的初步应用。
• High selectivity imaging of nitroreductase using a near-infrared fluorescence probe in hypoxic tumor
  作者：Kehua Xu、Feng Wang、Xiaohong Pan、Renpu Liu、Jing Ma、Fanpeng Kong、Bo Tang

  DOI：10.1039/c3cc38980d

  日期：——

  A highly selective and sensitive near-infrared (NIR) fluorescence probe (Cy-NO2) for imaging nitroreductase was developed and was successfully applied to investigating the relationship between epithelial–mesenchymal transitions (EMTs) in tumour progression and intracellular hypoxic level.

  研究人员开发了一种高度选择性和灵敏的近红外（NIR）荧光探针（Cy-NO2），用于成像硝基还原酶，并成功应用于研究肿瘤进展中的上皮-间质转化（EMT）与细胞内低氧水平之间的关系。

表征谱图