2-chloro-4-fluoro-N-(2-fluoro-5-nitrophenyl)-3-methylbenzamide | 1422389-81-8

• 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: 2-chloro-4-fluoro-N-(2-fluoro-5-nitrophenyl)-3-methylbenzamide
• CAS: 1422389-81-8
• 化学式: C₁₄H₉ClF₂N₂O₃
• 分子量: 326.687
• InChiKey: UGYXSBGZYJAIOV-UHFFFAOYSA-N

物化性质

• 沸点：
  375.8±42.0 °C(Predicted)
• 密度：
  1.506±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.09
• 重原子数：
  22.0
• 可旋转键数：
  3.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  72.24
• 氢给体数：
  1.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  2-chloro-4-fluoro-N-(2-fluoro-5-nitrophenyl)-3-methylbenzamide 、 1,2-diaminoethane dihydrochloride 在 potassium carbonate 作用下， 以 乙腈 为溶剂， 反应 6.0h， 以78.6%的产率得到N-(2-((2-aminoethyl)amino)-5-nitrophenyl)-2-chloro-4-fluoro-3-methylbenzamide
  参考文献：
  名称：

  High-affinity small molecular blockers of mixed lineage leukemia 1 (MLL1)-WDR5 interaction inhibit MLL1 complex H3K4 methyltransferase activity

  摘要：

  MLL1-WDR5 protein-protein interaction is essential for MLL1 H3K4 methyltransferase activity. Targeting MLL1 enzymatic activity to regulate expression level of MLL-dependent genes represents a therapeutic strategy for acute leukemia harboring MLL fusion proteins. Herein we reported a series of biphenyl compounds disturbed MLL1-WDR5 interaction. These compounds effectively inhibited MLL1 histone methyltransferase (HMT) activity in vitro and in MV4-11 cell line. The representative compound 30 (DDO-2084) inhibited proliferation and induced apoptosis of MV4-11 cells through deregulating expression level of Hoxa9 and Meis-1 genes, which emphasized our compounds were on-target. Optimization of compound 30 led to high-affinity inhibitors. Especially, compound 42 (DDO-2117, IC50 = 7.6 nM) bearing an amino and a 4-aminobutanamido group was the most potent inhibitor reported to-date, and showed the most potent inhibitory activity (IC50 = 0.19 mu M) in HMT assay. (C) 2016 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2016.08.036
• 作为产物：
  描述：

  2-氟-5-硝基苯胺 、 2-氯-4-氟-3-甲基苯甲酰氯 在 吡啶 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 以77.1%的产率得到2-chloro-4-fluoro-N-(2-fluoro-5-nitrophenyl)-3-methylbenzamide
  参考文献：
  名称：

  High-affinity small molecular blockers of mixed lineage leukemia 1 (MLL1)-WDR5 interaction inhibit MLL1 complex H3K4 methyltransferase activity

  摘要：

  MLL1-WDR5 protein-protein interaction is essential for MLL1 H3K4 methyltransferase activity. Targeting MLL1 enzymatic activity to regulate expression level of MLL-dependent genes represents a therapeutic strategy for acute leukemia harboring MLL fusion proteins. Herein we reported a series of biphenyl compounds disturbed MLL1-WDR5 interaction. These compounds effectively inhibited MLL1 histone methyltransferase (HMT) activity in vitro and in MV4-11 cell line. The representative compound 30 (DDO-2084) inhibited proliferation and induced apoptosis of MV4-11 cells through deregulating expression level of Hoxa9 and Meis-1 genes, which emphasized our compounds were on-target. Optimization of compound 30 led to high-affinity inhibitors. Especially, compound 42 (DDO-2117, IC50 = 7.6 nM) bearing an amino and a 4-aminobutanamido group was the most potent inhibitor reported to-date, and showed the most potent inhibitory activity (IC50 = 0.19 mu M) in HMT assay. (C) 2016 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2016.08.036

文献信息

• Synthesis, Optimization, and Evaluation of Novel Small Molecules as Antagonists of WDR5-MLL Interaction
  作者：Yuri Bolshan、Matthäus Getlik、Ekaterina Kuznetsova、Gregory A. Wasney、Taraneh Hajian、Gennadiy Poda、Kong T. Nguyen、Hong Wu、Ludmila Dombrovski、Aiping Dong、Guillermo Senisterra、Matthieu Schapira、Cheryl H. Arrowsmith、Peter J. Brown、Rima Al-awar、Masoud Vedadi、David Smil

  DOI：10.1021/ml300467n

  日期：2013.3.14

  The WD40-repeat protein WDRS plays a critical role in maintaining the integrity of MLL complexes and fully activating their methyltransferase function. MLL complexes, the trithorax-like family of SET1 methyltransferases, catalyze trimethylation of lysine 4 on histone 3, and they have been widely implicated in various cancers. Antagonism of WDR5 and MLL subunit interaction by small molecules has recently been presented as a practical way to inhibit activity of the MLL1 complex, and N-(2-(4-methylpiperazin-1-yl)-5-substituted-phenyl) benzamides were reported as potent and selective antagonists of such an interaction. Here, we describe the protein crystal structure guided optimization of prototypic compound 2 (K-dis = 7 mu M), leading to identification of more potent antagonist 47 (K-dis = 0.3 mu M).