N-(4-((7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯并嘧啶类
• 英文名称: N-(4-((7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
• 英文别名: N-(4-((7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-fluorophenyl)-N-(4-fluorophenyl)-1,1-dimethylamide；1-N'-[4-[[7-cyclopentyl-6-(dimethylcarbamoyl)pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-fluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
• 化学式: C₃₁H₃₁F₂N₇O₃
• 分子量: 587.629
• InChiKey: JMIVGNFJDFSSAK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  43
• 可旋转键数：
  8
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  121
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  1,1-环丙基二羧酸 在 氯化亚砜 、 palladium diacetate 、 caesium carbonate 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 醋酸异丙酯 为溶剂， 反应 30.0h， 生成 N-(4-((7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
  参考文献：
  名称：

  Discovery of a highly potent, selective and novel CDK9 inhibitor as an anticancer drug candidate

  摘要：

  A series of novel hybrid structure derivatives, containing both LEE011 and Cabozantinib pharmacophore, were designed, synthesized and evaluated. Surprisingly, a compound 4d was discovered that highly exhibited effective and selective activity of CDK9 inhibition with IC50 = 12 nM. It effectively induced apoptosis in breast and lung cancer cell lines at nanomolar level. Molecular docking of 4d to ATP binding site of CDK9 kinase demonstrated a new hydrogen bonding between F atom of 4-(3-fluorobenzyloxy) group and ASN116 residue, compared with the positive control, LEE011. The compound 4d could block the cell cycle both in G0/G1 and G2/M phase to prevent the proliferation and differentiation of cancer cells. Mice bared-breast cancer treated with compound 4d showed significant suppression of cancer with low toxicity. Taken together, this novel compound 4d could be a promising drug candidate for clinical application. (C) 2017 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2017.06.041

文献信息

• 新型1,1-环丙基二酰胺衍生物的制备与应用
  申请人：南开大学

  公开号：CN108929324A

  公开（公告）日：2018-12-04

  本发明新型1,1‑环丙基二酰胺衍生物的制备与应用，涉及新的具有式(I)的1,1‑环丙基二酰胺衍生物及其盐、包括可药用盐，其中R1、R2、R3、R4、R5和X、Z、L在本文被定义。包括可药用盐。本发明的化合物可用于治疗HIV及癌症类疾病，包括肺癌，肝癌，乳腺癌，淋巴癌，套细胞淋巴瘤、脂肉瘤、黑素瘤、鳞状细胞食管癌等。本发明的药物组合物能够制成有利于哺乳动物的组织、器官吸收利用的剂型，其在治疗癌症和HIV等疾病具有良好的应用前景。本发明还涉及包含本发明的化合物的药物组合物。
• Discovery of a highly potent, selective and novel CDK9 inhibitor as an anticancer drug candidate
  作者：Yongtao Li、Qingxiang Guo、Chao Zhang、Zhi Huang、Tianqi Wang、Xin Wang、Xiang Wang、Guangwei Xu、Yanhua Liu、Shengyong Yang、Yan Fan、Rong Xiang

  DOI：10.1016/j.bmcl.2017.06.041

  日期：2017.8

  A series of novel hybrid structure derivatives, containing both LEE011 and Cabozantinib pharmacophore, were designed, synthesized and evaluated. Surprisingly, a compound 4d was discovered that highly exhibited effective and selective activity of CDK9 inhibition with IC50 = 12 nM. It effectively induced apoptosis in breast and lung cancer cell lines at nanomolar level. Molecular docking of 4d to ATP binding site of CDK9 kinase demonstrated a new hydrogen bonding between F atom of 4-(3-fluorobenzyloxy) group and ASN116 residue, compared with the positive control, LEE011. The compound 4d could block the cell cycle both in G0/G1 and G2/M phase to prevent the proliferation and differentiation of cancer cells. Mice bared-breast cancer treated with compound 4d showed significant suppression of cancer with low toxicity. Taken together, this novel compound 4d could be a promising drug candidate for clinical application. (C) 2017 Elsevier Ltd. All rights reserved.