1-((9H-carbazol-4-yl)oxy)-3-([1,1'-biphenyl]-4-ylamino)propan-2-ol

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 1-((9H-carbazol-4-yl)oxy)-3-([1,1'-biphenyl]-4-ylamino)propan-2-ol
• 英文别名: 1-(9H-carbazol-4-yloxy)-3-(4-phenylanilino)propan-2-ol
• 化学式: C₂₇H₂₄N₂O₂
• 分子量: 408.5
• InChiKey: KULGSXAPQGZJEO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.5
• 重原子数：
  31
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  57.3
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  4-羟基咔唑 在 sodium hydroxide 作用下， 以 水 、 二甲基亚砜 、 异丙醇 为溶剂， 反应 7.33h， 生成 1-((9H-carbazol-4-yl)oxy)-3-([1,1'-biphenyl]-4-ylamino)propan-2-ol
  参考文献：
  名称：

  Drug repurposing and rediscovery: Design, synthesis and preliminary biological evaluation of 1-arylamino-3-aryloxypropan-2-ols as anti-melanoma agents

  摘要：

  Malignant melanoma (MM) presents as the highest morbidity and mortality type in skin cancer. Herein, inspired by the previously reported anti-melanoma effect of propranolol, a widely applied beta adrenergic receptor antagonist as cardiovascular drug, we set out to exploit its potential as anti-melanoma therapy based on the drug repurposing strategy. Structural optimization of propranolol yielded 5m, which exhibits dramatically improved potency on human melanoma cell growth (1.98-3.70 mu M), compared to propranolol (59.5-75.8 mu M). Further investigation demonstrated that 5m could inhibit colony formation of melanoma cell line (completely abolished at 2 mu M for 5m, partially inhibited at 50 mu M for propranolol), induce cell apoptosis and cell cycle arrest in the G(2)/M phase (both observed at 1 mu M). Preliminary mechanism study indicated that 5m could disrupt the cellular microtubule network, which suggested tubulin as a potential target. Docking study provided a structural insight into the interaction between 5m and tubulin. In summary, our study presents a drug repurposing case that redirects a cardiovascular agent to an anti-melanoma agent.

  DOI：

  10.1016/j.bmc.2020.115404

文献信息

• Discovery of novel small molecule TLR4 inhibitors as potent anti-inflammatory agents
  作者：Yao Xu、Shujun Chen、Ying Cao、Pingzheng Zhou、Zhipeng Chen、Kui Cheng

  DOI：10.1016/j.ejmech.2018.05.033

  日期：2018.6

  Toll-like receptor 4 (TLR4) initiates innate immune response to release inflammatory cytokines and has been pathologically linked to variety of inflammatory diseases. Recently, we found that Carvedilol, as the classic anti-heart failure and anti-inflammatory clinic drug, could inhibit the TLR4 signaling in the TLR4 overexpressed cells. Herein, we have designed and synthesized a small library of novel Carvedilol derivatives and investigated their potential inhibitory activity. The results indicate that the most potent compound 8a (SMU-XY3) could effectively inhibited TLR4 protein and the LPS triggered alkaline phosphatase signaling in HEK-Blue hTLR4 cells. It down regulated the nitric oxide (NO) in both RAW264.7 cells and BV-2 microglial cells, in addition to blocking the TNF-alpha signaling in ex-vivo human peripheral blood mononuclear cells (PBMC). More interestingly, 8a shows higher affinity to hyperpolarization-activated cyclic nucleotide-gated 4 (HCN4) over HCN2, which probably indicates the new application of TLR4 inhibitor 8a in heart failure, coronary heart disease, and other inflammatory diseases. (C) 2018 Elsevier Masson SAS. All rights reserved.
• Drug repurposing and rediscovery: Design, synthesis and preliminary biological evaluation of 1-arylamino-3-aryloxypropan-2-ols as anti-melanoma agents
  作者：Qi Chang、Jing Long、Liqing Hu、Zhuo Chen、Qianbin Li、Gaoyun Hu

  DOI：10.1016/j.bmc.2020.115404

  日期：2020.5

  Malignant melanoma (MM) presents as the highest morbidity and mortality type in skin cancer. Herein, inspired by the previously reported anti-melanoma effect of propranolol, a widely applied beta adrenergic receptor antagonist as cardiovascular drug, we set out to exploit its potential as anti-melanoma therapy based on the drug repurposing strategy. Structural optimization of propranolol yielded 5m, which exhibits dramatically improved potency on human melanoma cell growth (1.98-3.70 mu M), compared to propranolol (59.5-75.8 mu M). Further investigation demonstrated that 5m could inhibit colony formation of melanoma cell line (completely abolished at 2 mu M for 5m, partially inhibited at 50 mu M for propranolol), induce cell apoptosis and cell cycle arrest in the G(2)/M phase (both observed at 1 mu M). Preliminary mechanism study indicated that 5m could disrupt the cellular microtubule network, which suggested tubulin as a potential target. Docking study provided a structural insight into the interaction between 5m and tubulin. In summary, our study presents a drug repurposing case that redirects a cardiovascular agent to an anti-melanoma agent.