2-(2-甲基-5-硝基咪唑-1-基)乙基N-[2,2,2-三氯-1-(嘧啶-2-基氨基)乙基]氨基甲酸酯 | 300815-04-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 中文名称: 2-(2-甲基-5-硝基咪唑-1-基)乙基N-[2,2,2-三氯-1-(嘧啶-2-基氨基)乙基]氨基甲酸酯
• 中文别名: 3-(2-甲基-5-硝基咪唑-1-基)-N-(2,2,2-三氯-1-苯基氨基乙基)丙酰胺
• 英文名称: apcin
• 英文别名: 2-(2-methyl-5-nitroimidazol-1-yl)ethyl N-[2,2,2-trichloro-1-(pyrimidin-2-ylamino)ethyl]carbamate
• CAS: 300815-04-7
• 化学式: C₁₃H₁₄Cl₃N₇O₄
• 分子量: 438.658
• InChiKey: ZEXHXVOGJFGTRX-UHFFFAOYSA-N

物化性质

• 密度：
  1.68±0.1 g/cm3(Predicted)
• 溶解度：
  DMF：25mg/mL； DMSO：25mg/mL； DMSO:PBS (pH 7.2) (1:1)：0.5 mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  27
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  140
• 氢给体数：
  2
• 氢受体数：
  8

安全信息

• 危险性防范说明：
  P302+P352,P305+P351+P338
• 危险性描述：
  H315,H319,H335
• 储存条件：
  室温

制备方法与用途

生物活性 Apcin (APC inhibitor) 是一种有丝分裂的 anaphase-promoting complex/cyclosome (APC/C) 的E3连接酶活性抑制剂，能够与Cdc20结合并竞争性地抑制含D-box底物的泛素化。

靶点

Target	Value
APC/C
CDC20

体外研究

Apcin (25-50 μM; 48小时) 显著增加MM细胞凋亡，结合proTAME (6, 12 μM) 后效果更佳。 Apcin (25 μM; 2-14小时) 引起的滑移过程较为缓慢。 Apcin (50-200 μM) 最有效地稳定了cycB1-NT和securin，对全长cyclin B1的影响较弱。 Apcin (1.5-200 μM; 18小时) 与proTAME (细胞可渗透的TAME前药) 协同作用，延长RPE1细胞有丝分裂时间。

凋亡分析

细胞系	HMCLs LP-1和RPMI-8226细胞
浓度	25, 50 μM
孵育时间	48小时
结果	单独作用对多发性骨髓瘤（MM）细胞影响较小，结合proTAME (6, 12 μM) 后显著增加MM细胞凋亡。

Western blot分析

细胞系	Nocodazole (100 nM)处理的HeLa细胞
浓度	25 μM
孵育时间	2-14小时
结果	引起Cdc27去磷酸化，并在有丝分裂开始后4-6小时，观察到cyclin B1、securin和磷酸化组蛋白H3水平降低，导致滑移过程缓慢。

反应信息

• 作为产物：
  描述：

  甲硝唑 在 ammonium hydroxide 、 氯化亚砜 、 三乙胺 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 21.0h， 生成 2-(2-甲基-5-硝基咪唑-1-基)乙基N-[2,2,2-三氯-1-(嘧啶-2-基氨基)乙基]氨基甲酸酯
  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

文献信息

• CELL PERMEABLE INHIBITORS OF ANAPHASE PROMOTING COMPLEX
  申请人：President and Fellows of Harvard College

  公开号：US20150328214A1

  公开（公告）日：2015-11-19

  The disclosure provides compositions and methods for treating cell cycle disorders. Compositions of the disclosure include proTAME, a prodrug analog of TAME and apcin, the combination of which inhibits an activity or function of the anaphase promoting complex (APC) by a synergistic mechanism.

  本公开提供了用于治疗细胞周期紊乱的组合物和方法。本公开的组合物包括proTAME和apcin，它们的组合通过协同作用机制抑制负责有丝分裂后期促进复合物（APC）的活性或功能。其中，proTAME是TAME的前药类似物。
• US9572788B2
  申请人：——

  公开号：US9572788B2

  公开（公告）日：2017-02-21
• 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.