3-chloro-N-(2-cyanophenyl)propanamide | 401641-37-0

• 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: 3-chloro-N-(2-cyanophenyl)propanamide
• CAS: 401641-37-0
• 化学式: C₁₀H₉ClN₂O
• mdl: MFCD03014496
• 分子量: 208.647
• InChiKey: POIJQLFEUWZNHB-UHFFFAOYSA-N

物化性质

• 沸点：
  436.3±30.0 °C(Predicted)
• 密度：
  1.25±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  14
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  52.9
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  四氢异喹啉 、 3-chloro-N-(2-cyanophenyl)propanamide 在 三乙胺 作用下， 以 乙腈 为溶剂， 反应 0.17h， 以70%的产率得到N-(2-cyanophenyl)-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
• 作为产物：
  描述：

  3-氯丙酰氯 、 2-氨基苯甲腈 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 以66%的产率得到3-chloro-N-(2-cyanophenyl)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.