2-chloro-4-fluoro-3-methyl-5-nitro-N-(2-(4-methylpiperazin-1-yl)-5-(pyridin-4-yl)phenyl)benzamide

• 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-3-methyl-5-nitro-N-(2-(4-methylpiperazin-1-yl)-5-(pyridin-4-yl)phenyl)benzamide
• 英文别名: 2-chloro-4-fluoro-3-methyl-N-[2-(4-methylpiperazin-1-yl)-5-pyridin-4-ylphenyl]-5-nitrobenzamide
• 化学式: C₂₄H₂₃ClFN₅O₃
• 分子量: 483.93
• InChiKey: ACUIMZWGYBOVKD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  34
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  94.3
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  2-chloro-4-fluoro-3-methyl-5-nitro-N-(2-(4-methylpiperazin-1-yl)-5-(pyridin-4-yl)phenyl)benzamide 在 tin(II) chloride dihdyrate 作用下， 以 乙酸乙酯 为溶剂， 反应 5.0h， 以35.3%的产率得到5-amino-2-chloro-4-fluoro-3-methyl-N-(2-(4-methylpiperazin-1-yl)-5-(pyridin-4-yl)phenyl)benzamide
  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-chloro-4-fluoro-3-methyl-5-nitrobenzoic acid 在 吡啶 、 氯化亚砜 作用下， 以 二氯甲烷 为溶剂， 反应 10.0h， 生成 2-chloro-4-fluoro-3-methyl-5-nitro-N-(2-(4-methylpiperazin-1-yl)-5-(pyridin-4-yl)phenyl)benzamide
  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

• High-affinity small molecular blockers of mixed lineage leukemia 1 (MLL1)-WDR5 interaction inhibit MLL1 complex H3K4 methyltransferase activity
  作者：Dong-Dong Li、Wei-Lin Chen、Zhi-Hui Wang、Yi-Yue Xie、Xiao-Li Xu、Zheng-Yu Jiang、Xiao-Jin Zhang、Qi-Dong You、Xiao-Ke Guo

  DOI：10.1016/j.ejmech.2016.08.036

  日期：2016.11

  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.