4-(Piperidine-1-carboxamido)benzene-1-sulfonyl chloride

• 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: 4-(Piperidine-1-carboxamido)benzene-1-sulfonyl chloride
• 英文别名: 4-(piperidine-1-carbonylamino)benzenesulfonyl chloride
• 化学式: C₁₂H₁₅ClN₂O₃S
• 分子量: 302.782
• InChiKey: JQKMWXMBPALVCY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  19
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  74.9
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  4-(Piperidine-1-carboxamido)benzene-1-sulfonyl chloride 、 N-[4-[5-(3-aminophenyl)-1,2,4-oxadiazol-3-yl]-3-chlorophenyl]-3-pyridinecarboxamide 在 吡啶 作用下， 反应 24.0h， 以45%的产率得到N-[3-chloro-4-[5-[3-[[4-[(1-piperidinylcarbonyl)amino]phenylsulfonyl]amino]phenyl]-1,2,4-oxadiazol-3-yl]phenyl]-3-pyridinecarboxamide
  参考文献：
  名称：

  1,2,4-Oxadiazole derivatives targeting EGFR and c-Met degradation in TKI resistant NSCLC

  摘要：

  Development of small-molecule agents with the ability to facilitate oncoprotein degradation has emerged as a promising strategy for cancer therapy. Since EGFR and c-Met are both implicated in oncogenesis and tumor progression, we initiated a screening program by using an in-house library to identify agents capable of inducing the concomitant suppression of EGFR and c-Met expression, which led to the identification of compound 1, a 1,2,4-oxadiazole derivative. Based on the scaffold of 1, we developed a series of derivatives to assess their efficacies in facilitating the downregulation of EGFR and c-Met, among which compound 48 represented the optimal agent. 48 showed equipotent anti-proliferative activity against a panel of five NSCLC cell lines with different EGFR mutational status (IC50 = 0.2-0.6 mu M), while the same panel exhibited differential sensitivity to different EGFR kinase inhibitors tested. Cell cycle analysis indicated that the antiproliferative activity of 48 was associated with its ability to cause G2/M arrest and, to a lesser extent, apoptosis. Western blot and RT-PCR analyses revealed that 48 facilitated the downregulation of EGFR and c-Met at the protein level. In vivo data showed that oral administration of 48 was effective in suppressing gefitinib-resistant H1975 xenograft tumor growth in nude mice, and at a suboptimal dose, could sensitize H1975 tumors to gefitinib. Based on these findings, 48 represents a promising candidate for further development to target EGFR TKI-resistant NSCLC via dual inhibition of EGFR and c-Met oncoproteins. (C) 2019 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2019.111607

文献信息

• 1,2,4-Oxadiazole derivatives targeting EGFR and c-Met degradation in TKI resistant NSCLC
  作者：Eman M.E. Dokla、Chun-Sheng Fang、Khaled A.M. Abouzid、Ching S. Chen

  DOI：10.1016/j.ejmech.2019.111607

  日期：2019.11

  Development of small-molecule agents with the ability to facilitate oncoprotein degradation has emerged as a promising strategy for cancer therapy. Since EGFR and c-Met are both implicated in oncogenesis and tumor progression, we initiated a screening program by using an in-house library to identify agents capable of inducing the concomitant suppression of EGFR and c-Met expression, which led to the identification of compound 1, a 1,2,4-oxadiazole derivative. Based on the scaffold of 1, we developed a series of derivatives to assess their efficacies in facilitating the downregulation of EGFR and c-Met, among which compound 48 represented the optimal agent. 48 showed equipotent anti-proliferative activity against a panel of five NSCLC cell lines with different EGFR mutational status (IC50 = 0.2-0.6 mu M), while the same panel exhibited differential sensitivity to different EGFR kinase inhibitors tested. Cell cycle analysis indicated that the antiproliferative activity of 48 was associated with its ability to cause G2/M arrest and, to a lesser extent, apoptosis. Western blot and RT-PCR analyses revealed that 48 facilitated the downregulation of EGFR and c-Met at the protein level. In vivo data showed that oral administration of 48 was effective in suppressing gefitinib-resistant H1975 xenograft tumor growth in nude mice, and at a suboptimal dose, could sensitize H1975 tumors to gefitinib. Based on these findings, 48 represents a promising candidate for further development to target EGFR TKI-resistant NSCLC via dual inhibition of EGFR and c-Met oncoproteins. (C) 2019 Elsevier Masson SAS. All rights reserved.