N-(5-((2-amino-4-fluorophenyl)amino)-5-oxopentyl)-2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: N-(5-((2-amino-4-fluorophenyl)amino)-5-oxopentyl)-2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzamide
• 英文别名: N-[5-(2-amino-4-fluoroanilino)-5-oxopentyl]-2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzamide
• 化学式: C₂₇H₂₅F₂N₅O₃
• 分子量: 505.524
• InChiKey: ORVNABUSERWYLG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.91
• 重原子数：
  37.0
• 可旋转键数：
  9.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  129.97
• 氢给体数：
  4.0
• 氢受体数：
  5.0

反应信息

• 作为产物：
  描述：

  5-氨基颉草酸 在 氯化亚砜 、 lithium hydroxide monohydrate 、 1-羟基苯并三唑 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 28.5h， 生成 N-(5-((2-amino-4-fluorophenyl)amino)-5-oxopentyl)-2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzamide
  参考文献：
  名称：

  Design, synthesis and anticancer activities of novel dual poly(ADP-ribose) polymerase-1/histone deacetylase-1 inhibitors

  摘要：

  Currently, synergistic inhibition of poly(ADP-ribose) polymerase-1 (PARP-1) and histone deacetylases (HDACs) has been a potential effective strategy for cancer treatment. Herein, by combining critical pharmacophores in approved drugs olaparib and chidamide, a series of novel 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl) benzoic acid derivatives were designed and synthesized. All efforts led to a good dual PARP-1/HDAC-1 inhibitor, compound 4, with IC(50)values of 4.2 and 340 nM against PARP-1 and HDAC-1, which were as potent as olaparib and chidamide respectively. The MTT assay further demonstrated that compound 4 had potent inhibitory activities against BRCA1/2-proficient K562 and MDA-MB-231 cells with CI50 values of 5.6 and 4.3 mu M, respectively. Therefore, our results suggested that compound 4 could be a promising dual PARP-1/HDAC-1 inhibitor for further studies. In addition, a few excellent PARP-1 inhibitors such as 7-9 and HDAC-1 inhibitors such as 12 were serendipitously discovered, which also could be further studied in our next work.

  DOI：

  10.1016/j.bmcl.2020.127036

文献信息

• Design, synthesis and anticancer activities of novel dual poly(ADP-ribose) polymerase-1/histone deacetylase-1 inhibitors
  作者：Yongbin Tian、Zhouling Xie、Chenzhong Liao

  DOI：10.1016/j.bmcl.2020.127036

  日期：2020.4

  Currently, synergistic inhibition of poly(ADP-ribose) polymerase-1 (PARP-1) and histone deacetylases (HDACs) has been a potential effective strategy for cancer treatment. Herein, by combining critical pharmacophores in approved drugs olaparib and chidamide, a series of novel 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl) benzoic acid derivatives were designed and synthesized. All efforts led to a good dual PARP-1/HDAC-1 inhibitor, compound 4, with IC(50)values of 4.2 and 340 nM against PARP-1 and HDAC-1, which were as potent as olaparib and chidamide respectively. The MTT assay further demonstrated that compound 4 had potent inhibitory activities against BRCA1/2-proficient K562 and MDA-MB-231 cells with CI50 values of 5.6 and 4.3 mu M, respectively. Therefore, our results suggested that compound 4 could be a promising dual PARP-1/HDAC-1 inhibitor for further studies. In addition, a few excellent PARP-1 inhibitors such as 7-9 and HDAC-1 inhibitors such as 12 were serendipitously discovered, which also could be further studied in our next work.