1-((9H-carbazol-4-yl)oxy)-3-(4-phenylpiperazin-1-yl)propan-2-ol | 1479050-61-7

• 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-(4-phenylpiperazin-1-yl)propan-2-ol
• 英文别名: 1-(9H-carbazol-4-yloxy)-3-(4-phenylpiperazin-1-yl)propan-2-ol
• CAS: 1479050-61-7
• 化学式: C₂₅H₂₇N₃O₂
• 分子量: 401.508
• InChiKey: UXUHQFVQJCNORL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.88
• 重原子数：
  30.0
• 可旋转键数：
  6.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  51.73
• 氢给体数：
  2.0
• 氢受体数：
  4.0

反应信息

• 作为产物：
  描述：

  4-羟基咔唑 在 sodium hydroxide 作用下， 以 乙醇 、 水 、 二甲基亚砜 为溶剂， 反应 32.0h， 生成 1-((9H-carbazol-4-yl)oxy)-3-(4-phenylpiperazin-1-yl)propan-2-ol
  参考文献：
  名称：

  新系列卡维地洛衍生物的设计、合成和生物学评估，通过阻断机械电传感器通道保护感觉毛细胞免受氨基糖苷类诱导的损伤。

  摘要：

  氨基糖苷类 (AG) 是用于治疗严重细菌感染的广谱抗生素，但具有限制使用的副作用，包括不可逆的听力损失。在这里，我们评估了卡维地洛在小鼠耳蜗培养和体内斑马鱼试验中的耳保护特性，并研究了它的保护机制，我们发现这可能是由毛细胞的机电传感器 (MET) 通道（主要进入途径）的阻断介导的对于 AG。为了了解卡维地洛的全部耳部保护潜力，制备了一系列 18 种类似物，并评估了它们对 AG 引起的损伤的作用以及它们对 MET 通道的亲和力。发现一种衍生物在耳蜗培养中比卡维地洛本身具有更大的保护作用，并且与 MET 通道的结合更紧密。

  DOI：

  10.1021/acs.jmedchem.8b01325

文献信息

• [EN] STORE OVERLOAD-INDUCED CALCIUM RELEASE INHIBITORS AND METHODS FOR PRODUCING AND USING THE SAME<br/>[FR] INHIBITEURS DE LIBÉRATION DU CALCIUM INDUITE PAR UNE SURCHARGE DU STOCK CALCIQUE ET LEURS MÉTHODES DE PRODUCTION ET D'UTILISATION
  申请人：UTI LIMITED PARTNERSHIP

  公开号：WO2015031914A1

  公开（公告）日：2015-03-05

  The present invention provides compounds having store overload-induced Ca2+ release (SOICR) inhibitory activity and methods for producing and using the same. In particular, compounds of the invention is of the formula: R1-X1-L-X2-R2, wherein R1, X1, L, X2, and R2 are those defined herein.

  本发明提供了具有存储过载诱导的Ca2+释放（SOICR）抑制活性的化合物以及生产和使用这些化合物的方法。特别是，本发明的化合物具有如下通式：R1-X1-L-X2-R2，其中R1、X1、L、X2和R2如本文所定义。
• Design, Synthesis, and Biological Evaluation of a New Series of Carvedilol Derivatives That Protect Sensory Hair Cells from Aminoglycoside-Induced Damage by Blocking the Mechanoelectrical Transducer Channel
  作者：Molly O’Reilly、Nerissa K. Kirkwood、Emma J. Kenyon、Rosemary Huckvale、Daire M. Cantillon、Simon J. Waddell、Simon E. Ward、Guy P. Richardson、Corné J. Kros、Marco Derudas

  DOI：10.1021/acs.jmedchem.8b01325

  日期：2019.6.13

  we found, may be mediated by a block of the hair cell's mechanoelectrical transducer (MET) channel, the major entry route for the AGs. To understand the full otoprotective potential of carvedilol, a series of 18 analogues were prepared and evaluated for their effect against AG-induced damage as well as their affinity for the MET channel. One derivative was found to confer greater protection than carvedilol

  氨基糖苷类 (AG) 是用于治疗严重细菌感染的广谱抗生素，但具有限制使用的副作用，包括不可逆的听力损失。在这里，我们评估了卡维地洛在小鼠耳蜗培养和体内斑马鱼试验中的耳保护特性，并研究了它的保护机制，我们发现这可能是由毛细胞的机电传感器 (MET) 通道（主要进入途径）的阻断介导的对于 AG。为了了解卡维地洛的全部耳部保护潜力，制备了一系列 18 种类似物，并评估了它们对 AG 引起的损伤的作用以及它们对 MET 通道的亲和力。发现一种衍生物在耳蜗培养中比卡维地洛本身具有更大的保护作用，并且与 MET 通道的结合更紧密。
• Novel Carvedilol Analogues That Suppress Store-Overload-Induced Ca²⁺ Release
  作者：Chris D. Smith、Aixia Wang、Kannan Vembaiyan、Jingqun Zhang、Cuihong Xie、Qiang Zhou、Guogen Wu、S. R. Wayne Chen、Thomas G. Back

  DOI：10.1021/jm401090a

  日期：2013.11.14

  Carvedilol is a uniquely effective drug for the treatment of cardiac arrhythmias in patients with heart failure. This activity is in part because of its ability to inhibit store-overload-induced calcium release (SOICR) through the RyR2 channel. We describe the synthesis, characterization, and bioassay of ca. 100 compounds based on the carvedilol motif to identify features that correlate with and optimize SOICR inhibition. A single-cell bioassay was employed on the basis of the RyR2-R4496C mutant HEK-293 cell line in which calcium release from the endoplasmic reticulum through the defective channel was measured. IC50 values for SOICR inhibition were thus obtained. The compounds investigated contained modifications to the three principal subunits of carvedilol, including the carbazole and catechol moieties, as well as the linker chain containing the beta-amino alcohol functionality. The SAR results indicate that significant alterations are tolerated in each of the three subunits.
• STORE OVERLOAD-INDUCED CALCIUM RELEASE INHIBITORS AND METHODS FOR PRODUCING AND USING THE SAME
  申请人：BACK Tom

  公开号：US20160214973A1

  公开（公告）日：2016-07-28

  The present invention provides compounds having store overload-induced Ca 2+ release (SOICR) inhibitory activity and methods for producing and using the same. In particular, compounds of the invention is of the formula: R 1 —X 1 -L-X 2 —R 2 , wherein R 1 , X 1 , L, X 2 , and R 2 are those defined herein.
• 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.