1-(sec-butyl)-4-(4-(4-(4-(((2S,4R)-2-(2,4-dichlorophenyl)-2-((3,5-dimethyl-1H-1,2,4-triazol-1-yl)methyl)-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 1-(sec-butyl)-4-(4-(4-(4-(((2S,4R)-2-(2,4-dichlorophenyl)-2-((3,5-dimethyl-1H-1,2,4-triazol-1-yl)methyl)-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one
• 英文别名: 2-butan-2-yl-4-[4-[4-[4-[[(2S,4R)-2-(2,4-dichlorophenyl)-2-[(3,5-dimethyl-1,2,4-triazol-1-yl)methyl]-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one
• 化学式: C₃₇H₄₂Cl₂N₈O₄
• 分子量: 733.698
• InChiKey: LDZJZIYCUFWYOT-XUYWPELPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.5
• 重原子数：
  51
• 可旋转键数：
  11
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  101
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  1,3-二氯苯 在 aluminum (III) chloride 、 三氟甲磺酸 、 sodium hydride 、 potassium carbonate 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 、 甲苯 、 mineral oil 为溶剂， 反应 80.67h， 生成 1-(sec-butyl)-4-(4-(4-(4-(((2S,4R)-2-(2,4-dichlorophenyl)-2-((3,5-dimethyl-1H-1,2,4-triazol-1-yl)methyl)-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one
  参考文献：
  名称：

  Novel Tetrazole-Containing Analogues of Itraconazole as Potent Antiangiogenic Agents with Reduced Cytochrome P450 3A4 Inhibition

  摘要：

  Itraconazole has been found to possess potent antiangiogenic activity, exhibiting promising antitumor activity in several human clinical studies. The wider use of itraconazole in the treatment of cancer, however, has been limited by its potent inhibition of the drug metabolizing enzyme cytochrome P450 3A4 (CYP3A4). In an effort to eliminate the CYP3A4 inhibition while retaining its antiangiogenic activity, we designed and synthesized a series of derivatives in which the 1,2,4-triazole ring is replaced with various azoles and nonazoles. Among these analogues, 15n with tetrazole in place of 1,2,4-triazole exhibited optimal inhibition of human umbilical vein endothelial cell proliferation with an IC50 of 73 nM without a significant effect on CYP3A4 (EC50 > 20 mu M). Similar to itraconazole, 15n induced Niemann-Pick C phenotype (NPC phenotype) and blocked AMPK/mechanistic target of rapamycin signaling. These results suggest that 15n is a promising angiogenesis inhibitor that can be used in combination with most other known anticancer drugs.

  DOI：

  10.1021/acs.jmedchem.8b01252

文献信息

• Itraconazole analogs and use thereof
  申请人：The Johns Hopkins University

  公开号：US11028078B2

  公开（公告）日：2021-06-08

  Provided herein are Itraconazole analogs. Also provided herein are methods of inhibition of Hedgehog pathway, vascular endothelial growth factor receptor 2 (VEGFR2) glycosylation, angiogenesis and treatment of disease with Itraconazole analogs.

  本文提供的是伊曲康唑类似物。本文还提供了伊曲康唑类似物抑制刺猬通路、血管内皮生长因子受体 2（VEGFR2）糖基化、血管生成和治疗疾病的方法。
• ITRACONAZOLE ANALOGS AND USE THEREOF
  申请人：The Johns Hopkins University

  公开号：US20190040046A1

  公开（公告）日：2019-02-07

  Provided herein are Itraconazole analogs. Also provided herein are methods of inhibition of Hedgehog pathway, vascular endothelial growth factor receptor 2 (VEGFR2) glycosylation, angiogenesis and treatment of disease with Itraconazole analogs.
• [EN] ITRACONAZOLE ANALOGS AND USE THEREOF<br/>[FR] ANALOGUES D'ITRACONAZOLE ET UTILISATION ASSOCIÉE
  申请人：UNIV JOHNS HOPKINS

  公开号：WO2020072830A1

  公开（公告）日：2020-04-09

  Itraconazole, a widely used antifungal drug, has been found to possess potent anti-angiogenic and anti-hedgehog activities, exhibiting promising antitumor activity in several human clinical studies. The wider use of itraconazole in the treatment of cancer, however, has been limited by its potent inhibition of the drug metabolic enzyme CYP3A4 which causes drug-drug interactions. In an effort to eliminate the CYP3A4 inhibition of itraconazole while retaining its anti-angiogenic activity, we synthesized a series of itraconazole derivatives. The newly synthesized analogs of itraconazole were evaluated for their cytotoxicity against human umbilical vein endothelial cells (HUVEC) and their inhibitory activity against CYP3A4 enzyme.
• Novel Tetrazole-Containing Analogues of Itraconazole as Potent Antiangiogenic Agents with Reduced Cytochrome P450 3A4 Inhibition
  作者：Yingjun Li、Kalyan Kumar Pasunooti、Ruo-Jing Li、Wukun Liu、Sarah A. Head、Wei Q. Shi、Jun O. Liu

  DOI：10.1021/acs.jmedchem.8b01252

  日期：2018.12.27

  Itraconazole has been found to possess potent antiangiogenic activity, exhibiting promising antitumor activity in several human clinical studies. The wider use of itraconazole in the treatment of cancer, however, has been limited by its potent inhibition of the drug metabolizing enzyme cytochrome P450 3A4 (CYP3A4). In an effort to eliminate the CYP3A4 inhibition while retaining its antiangiogenic activity, we designed and synthesized a series of derivatives in which the 1,2,4-triazole ring is replaced with various azoles and nonazoles. Among these analogues, 15n with tetrazole in place of 1,2,4-triazole exhibited optimal inhibition of human umbilical vein endothelial cell proliferation with an IC50 of 73 nM without a significant effect on CYP3A4 (EC50 > 20 mu M). Similar to itraconazole, 15n induced Niemann-Pick C phenotype (NPC phenotype) and blocked AMPK/mechanistic target of rapamycin signaling. These results suggest that 15n is a promising angiogenesis inhibitor that can be used in combination with most other known anticancer drugs.