N-(3-acetylphenyl)-3-(3,4-dihydroisoquinolin-2(1H)-yl)propanamide

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: N-(3-acetylphenyl)-3-(3,4-dihydroisoquinolin-2(1H)-yl)propanamide
• 英文别名: N-(3-acetylphenyl)-3-(3,4-dihydroisoquinolin-2-yl)propanamide；N-(3-acetylphenyl)-3-(3,4-dihydro-1H-isoquinolin-2-yl)propanamide
• 化学式: C₂₀H₂₂N₂O₂
• 分子量: 322.407
• InChiKey: AHVDWGYMSVZTEB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  24
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  49.4
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  间氨基苯乙酮 在 三乙胺 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 0.17h， 生成 N-(3-acetylphenyl)-3-(3,4-dihydroisoquinolin-2(1H)-yl)propanamide
  参考文献：
  名称：

  Discovery of new potent protein arginine methyltransferase 5 (PRMT5) inhibitors by assembly of key pharmacophores from known inhibitors

  摘要：

  Protein arginine methyltransferase 5 (PRMT5) is an epigenetics related enzyme that has been validated as a promising therapeutic target for human cancer. Up to now, two small molecule PRMT5 inhibitors has been put into phase I clinical trial. In the present study, a series of candidate molecules were designed by combining key pharmacophores of formerly reported PRMT5 inhibitors. The in vitro PRMT5 inhibitory testing of compound 4b14 revealed an IC50 of 2.71 mu M, exhibiting high selectivity over PRMT1 and PRMT4 (> 70-fold selective). As expected, 4b14 exhibited potent anti-proliferative activity against a panel of leukemia and lymphoma cells, including MV4-11, Pfeiffer, SU-DHL-4 and KARPAS-422. Besides, 4b14 showed significant cell cycle arrest and apoptosis-inducing effects, as well as reduced the cellular symmetric arginine dimethylation level of SmD3 protein. Finally, affinity profiling analysis indicated that hydrophobic interactions, pi-pi stacking and cation-pi actions made the major contributions to the overall binding affinity. This scaffold provides a new chemical template for further development of better lead compounds targeting PRMT5.

  DOI：

  10.1016/j.bmcl.2018.10.026

文献信息

• Discovery of new potent protein arginine methyltransferase 5 (PRMT5) inhibitors by assembly of key pharmacophores from known inhibitors
  作者：Kongkai Zhu、Jia-Li Song、Hong-Rui Tao、Zhi-Qiang Cheng、Cheng-Shi Jiang、Hua Zhang

  DOI：10.1016/j.bmcl.2018.10.026

  日期：2018.12

  Protein arginine methyltransferase 5 (PRMT5) is an epigenetics related enzyme that has been validated as a promising therapeutic target for human cancer. Up to now, two small molecule PRMT5 inhibitors has been put into phase I clinical trial. In the present study, a series of candidate molecules were designed by combining key pharmacophores of formerly reported PRMT5 inhibitors. The in vitro PRMT5 inhibitory testing of compound 4b14 revealed an IC50 of 2.71 mu M, exhibiting high selectivity over PRMT1 and PRMT4 (> 70-fold selective). As expected, 4b14 exhibited potent anti-proliferative activity against a panel of leukemia and lymphoma cells, including MV4-11, Pfeiffer, SU-DHL-4 and KARPAS-422. Besides, 4b14 showed significant cell cycle arrest and apoptosis-inducing effects, as well as reduced the cellular symmetric arginine dimethylation level of SmD3 protein. Finally, affinity profiling analysis indicated that hydrophobic interactions, pi-pi stacking and cation-pi actions made the major contributions to the overall binding affinity. This scaffold provides a new chemical template for further development of better lead compounds targeting PRMT5.