15-(hydroxymethyl)-2-methoxy-11,14-dimethyl-14,14a-dihydro-6H-indolo[2',1':3,4]pyrazino[2,1-b]quinazolin-9(7H)-one

• 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: 15-(hydroxymethyl)-2-methoxy-11,14-dimethyl-14,14a-dihydro-6H-indolo[2',1':3,4]pyrazino[2,1-b]quinazolin-9(7H)-one
• 英文别名: 3-(Hydroxymethyl)-6-methoxy-17,21-dimethyl-10,13,21-triazapentacyclo[11.8.0.02,10.04,9.015,20]henicosa-2,4(9),5,7,15(20),16,18-heptaen-14-one；3-(hydroxymethyl)-6-methoxy-17,21-dimethyl-10,13,21-triazapentacyclo[11.8.0.02,10.04,9.015,20]henicosa-2,4(9),5,7,15(20),16,18-heptaen-14-one
• 化学式: C₂₂H₂₃N₃O₃
• 分子量: 377.443
• InChiKey: BBGLFXVJTSYIBY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  28
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  57.9
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  5-甲基-2-(甲基氨基)-苯甲酸甲酯 在 甲醇 、 sodium tetrahydroborate 、 三氯氧磷 作用下， 以 乙醇 、 甲苯 为溶剂， 反应 6.75h， 生成 15-(hydroxymethyl)-2-methoxy-11,14-dimethyl-14,14a-dihydro-6H-indolo[2',1':3,4]pyrazino[2,1-b]quinazolin-9(7H)-one
  参考文献：
  名称：

  Scaffold Hopping of Natural Product Evodiamine: Discovery of a Novel Antitumor Scaffold with Excellent Potency against Colon Cancer

  摘要：

  Inspired by the natural product evodiamine, a novel antitumor indolopyrazinoquinazolinone scaffold was designed by scaffold hopping. Structure-activity relationship studies led to the discovery of compound 15j, which shows low nanomolar inhibitory activity against the HCT116 cell line. Further antitumor mechanism studies indicated that compound 15j acted by the dual inhibition of topoisomerase 1 and tubulin and induced apoptosis with G2 cell-cycle arrest. The quaternary ammonium salt of compound 15j (compound 15js) exhibited excellent in vivo antitumor activity (TGI = 66.6%) in the HCT116 xenograft model with low toxicity. Indolopyrazinoquinazolinone derivatives represent promising multitargeting antitumor leads for the development of novel antitumor agents.

  DOI：

  10.1021/acs.jmedchem.9b01626

文献信息

• Scaffold Hopping of Natural Product Evodiamine: Discovery of a Novel Antitumor Scaffold with Excellent Potency against Colon Cancer
  作者：Lei Wang、Kun Fang、Junfei Cheng、Yu Li、Yahui Huang、Shuqiang Chen、Guoqiang Dong、Shanchao Wu、Chunquan Sheng

  DOI：10.1021/acs.jmedchem.9b01626

  日期：2020.1.23

  Inspired by the natural product evodiamine, a novel antitumor indolopyrazinoquinazolinone scaffold was designed by scaffold hopping. Structure-activity relationship studies led to the discovery of compound 15j, which shows low nanomolar inhibitory activity against the HCT116 cell line. Further antitumor mechanism studies indicated that compound 15j acted by the dual inhibition of topoisomerase 1 and tubulin and induced apoptosis with G2 cell-cycle arrest. The quaternary ammonium salt of compound 15j (compound 15js) exhibited excellent in vivo antitumor activity (TGI = 66.6%) in the HCT116 xenograft model with low toxicity. Indolopyrazinoquinazolinone derivatives represent promising multitargeting antitumor leads for the development of novel antitumor agents.