(1-methyl-5-nitro-1H-imidazol-2-yl)methyl 4-nitrophenyl carbonate | 263159-60-0

• 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: (1-methyl-5-nitro-1H-imidazol-2-yl)methyl 4-nitrophenyl carbonate
• 英文别名: (1-Methyl-5-nitroimidazol-2-yl)methyl (4-nitrophenyl) carbonate；(1-methyl-5-nitroimidazol-2-yl)methyl (4-nitrophenyl) carbonate
• CAS: 263159-60-0
• 化学式: C₁₂H₁₀N₄O₇
• 分子量: 322.234
• InChiKey: IESJSGAEAGSBME-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  23
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  145
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (1-methyl-5-nitro-1H-imidazol-2-yl)methyl 4-nitrophenyl carbonate 在 ammonium hydroxide 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 生成 洛硝哒唑
  参考文献：
  名称：

  Discovery of a Dual Tubulin Polymerization and Cell Division Cycle 20 Homologue Inhibitor via Structural Modification on Apcin

  摘要：

  Apcin is one of the few compounds that have been previously reported as a Cdc20 specific inhibitor, although Cdc20 is a very promising drug target. We reported here the design, synthesis, and biological evaluations of 2,2,2-trichloro-1-aryl carbamate derivatives as Cdc20 inhibitors. Among these derivatives, compound 9f was much more efficient than the positive compound apcin in inhibiting cancer cell growth, but it had approximately the same binding affinity with apcin in SPR assays. It is possible that another mechanism of action might exist. Further evidence demonstrated that compound 9f also inhibited tubulin polymerization, disorganized the microtubule network, and blocked the cell cycle at the M phase with changes in the expression of cyclins. Thus, it induced apoptosis through the activation of caspase-3 and PARP. In addition, compound 9f inhibited cell migration and invasion in a concentration-dependent manner. These results provide guidance for developing the current series as potential new anticancer therapeutics.

  DOI：

  10.1021/acs.jmedchem.9b02097
• 作为产物：
  描述：

  对硝基苯基氯甲酸酯 、 1-甲基-5-硝基-2-羟甲基咪唑 在 吡啶 作用下， 以 四氢呋喃 为溶剂， 生成 (1-methyl-5-nitro-1H-imidazol-2-yl)methyl 4-nitrophenyl carbonate
  参考文献：
  名称：

  用于硝基还原酶介导的基因指导的酶前药治疗的硝基杂环氨基甲酸酯前药的合成和评估。

  摘要：

  苯二胺芥末的1-甲基-2-硝基咪唑-5-氨基甲酸氨基甲酸酯被EMT6-NTR（neo）快速代谢，但未被EMT6细胞代谢，表明它是NTR的有效底物。尽管如此，苯二胺芥末的氨基甲酸酯在IC（50）分析中对NTR + ve细胞显示出相对较低的细胞毒性差异，显然是因为它们保留了足够的烷基化反应性，因此大多数前药在药物暴露期间会与亲核试剂反应。相反，相应的氨基-seco-CBI-TMI前药的NTR底物效率较低，但化学稳定性更高，效力更高，并且在细胞系面板中显示出相当大的NTR-ve / NTR + ve比，比例为15氨基-seco-CBI-TMI的1-甲基-2-硝基-1H-咪唑-5-基甲基和1-甲基-5-硝基-1H-咪唑-2-基甲基氨基甲酸酯的100倍。评估了这两种前药对表达NTR的EMT6肿瘤的活性，其中EMT6肿瘤约占10％。10％NTR + ve细胞。观察到对NTR + ve细胞的杀伤作用很小

  DOI：

  10.1021/jm030308b

文献信息

• Nitroarylmethylcarbamate prodrugs of doxorubicin for use with nitroreductase gene-directed enzyme prodrug therapy
  作者：Michael P. Hay、William R. Wilson、William A. Denny

  DOI：10.1016/j.bmc.2005.03.055

  日期：2005.6

  A series of nitrobenzyl- and nitroimidazolylmethyl carbamate prodrugs of doxorubicin were prepared and evaluated for their potential use in nitroreductase (NTR) mediated gene-directed enzyme prodrug therapy (GDEPT). The carbamate prodrugs and doxorubicin were tested in a cell line panel comprising parental and NTR transfected human (SKOV3/SKOV3-NTR(neo), WiDr/WiDr-NTR(neo)), Chinese hamster (V79/V79-NTR(puro))

  制备了阿霉素的一系列硝基苄基和硝基咪唑基甲基氨基甲酸酯前药，并评估了它们在硝基还原酶（NTR）介导的基因导向酶前药治疗（GDEPT）中的潜在用途。在包含亲本和NTR转染的人（SKOV3 / SKOV3-NTR（neo），WiDr / WiDr-NTR（neo）），中国仓鼠（V79 / V79-NTR（puro））的细胞系面板中测试了氨基甲酸酯前药和阿霉素的细胞系和鼠（EMT6 / EMT6-NTR（puro））细胞系对，并与已建立的NTR底物CB 1954（叠氮基二硝基苯甲酰胺）和类似的dibromomustard SN 29427比较。前药的低溶解度（3至39 microM ）排除了在某些情况下针对亲本细胞系确定IC（50）值的可能性。在24小时内，添加了5％胎牛血清的培养基中，所有前药均不稳定，尽管未观察到阿霉素的释放。在人细胞系SKOV3和WiDr中，前药的毒性比阿霉素低20-> 336倍，而在V79细胞系（11->
• Design, Synthesis and Evaluation of Imidazolylmethyl Carbamate Prodrugs of Alkylating Agents
  作者：Michael P. Hay、William R. Wilson、William A. Denny

  DOI：10.1016/s0040-4020(99)01031-5

  日期：2000.1

  Two approaches to prodrugs of alkylating agents based on an imidazolylmethyl carbamate nucleus were explored. A 2-azido analogue (3) of the bis-carbamate carmethizole (1) displayed similar aerobic cytotoxicity to 1 in a panel of human and murine cell lines. Approaches to the 2-amino and 2-carbamoyl analogues are described. In the second approach an imidazolylmethanol was used as a 'trigger' linked via a carbamate to the alkylating agent N,N-bis(2-chlorethyl)amine (BCEA). Nitroimidazole and methylsulphinylimidazole carbamate prodrugs 6-8 were 5-20-fold less toxic than BCEA. Despite this deactivation in the prodrug form, little increase in cytotoxicity was observed under hypoxia. The data suggest that BCEA released on bioreduction is not sufficiently potent to contribute significant additional cytotoxicity. (C) 2000 Elsevier Science Ltd. All rights reserved.
• N-PROTECTED AMINES AND THEIR USE AS PRODRUGS
  申请人：CANCER RESEARCH CAMPAIGN TECHNOLOGY LIMITED

  公开号：EP1173414A1

  公开（公告）日：2002-01-23
• [EN] N-PROTECTED AMINES AND THEIR USE AS PRODRUGS<br/>[FR] AMINES N-PROTEGE ET LEUR UTILISATION EN TANT QUE PROMEDICAMENTS
  申请人：CANCER RES CAMPAIGN TECH

  公开号：WO2000064864A1

  公开（公告）日：2000-11-02

  Compounds of formula (I) or (II), wherein X represents H, C1-6 alkyl or C1-6 alkoxy, said alkyl or alkoxy being optionally substituted with one or more groups; a is 0,1,2,3 or 4; Y represents H or C1-6 alkyl; 1, 2 or 3 of the members Z of the 5-membered aromatic ring are independently selected from -O-, -S-, -N= or -NR-, where R is H or C1-6 alkyl optionally substituted with one or more of groups; and E represents a moiety such that EH is an amine; provided that in formula (I) if a = 0 then Y≠H, are provided along with a method of selecting desired protecting groups by measuring the fragmentation rates of compounds of formula (I) or (II) when the nitro group is selected.
• Discovery of a Dual Tubulin Polymerization and Cell Division Cycle 20 Homologue Inhibitor via Structural Modification on Apcin
  作者：Pan Huang、Xiangyang Le、Fei Huang、Jie Yang、Haofeng Yang、Junlong Ma、Gaoyun Hu、Qianbin Li、Zhuo Chen

  DOI：10.1021/acs.jmedchem.9b02097

  日期：2020.5.14

  Apcin is one of the few compounds that have been previously reported as a Cdc20 specific inhibitor, although Cdc20 is a very promising drug target. We reported here the design, synthesis, and biological evaluations of 2,2,2-trichloro-1-aryl carbamate derivatives as Cdc20 inhibitors. Among these derivatives, compound 9f was much more efficient than the positive compound apcin in inhibiting cancer cell growth, but it had approximately the same binding affinity with apcin in SPR assays. It is possible that another mechanism of action might exist. Further evidence demonstrated that compound 9f also inhibited tubulin polymerization, disorganized the microtubule network, and blocked the cell cycle at the M phase with changes in the expression of cyclins. Thus, it induced apoptosis through the activation of caspase-3 and PARP. In addition, compound 9f inhibited cell migration and invasion in a concentration-dependent manner. These results provide guidance for developing the current series as potential new anticancer therapeutics.