N-(naphthalen-1-yl)-2-(3,4,5-trimethoxybenzoyl)hydrazinecarboxamide | 903847-70-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: N-(naphthalen-1-yl)-2-(3,4,5-trimethoxybenzoyl)hydrazinecarboxamide
• 英文别名: 1-naphthalen-1-yl-3-[(3,4,5-trimethoxybenzoyl)amino]urea
• CAS: 903847-70-1
• 化学式: C₂₁H₂₁N₃O₅
• 分子量: 395.415
• InChiKey: TWMUUGANVJSGAR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.33
• 重原子数：
  29.0
• 可旋转键数：
  5.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  97.92
• 氢给体数：
  3.0
• 氢受体数：
  5.0

反应信息

• 作为产物：
  描述：

  没食子酸 在 四丁基碘化铵 、 potassium carbonate 、 一水合肼 作用下， 以 甲醇 、 丙酮 为溶剂， 反应 15.0h， 生成 N-(naphthalen-1-yl)-2-(3,4,5-trimethoxybenzoyl)hydrazinecarboxamide
  参考文献：
  名称：

  N-(1′-naphthyl)-3,4,5-trimethoxybenzohydrazide as microtubule destabilizer: Synthesis, cytotoxicity, inhibition of cell migration and in vivo activity against acute lymphoblastic leukemia

  摘要：

  Tubulin-interacting agents, like vinca alkaloid and taxanes, play a fundamental role in cancer chemotherapy, making cellular microtubules (MT), one of the few validated anticancer targets. Cancer resistance to classical MT inhibitors has motivated the development of novel molecules with increased efficacy and lower toxicity. Aiming at designing structurally-simple inhibitors of MT assembly, we synthesized a series of thirty-one 3,4,5-trimethoxy-hydrazones and twenty-five derivatives or analogs. Docking simulations suggested that a representative N-acylhydrazone could adopt an appropriate stereochemistry inside the colchicine-binding domain of tubulin. Several of these compounds showed anti-leukemia effects in the nanomolar concentration range. Interference with MT polymerization was validated by the compounds' ability to inhibit MT assembly at the biochemical and cellular level. Selective toxicity investigations done with the most potent compound, a 3,4,5-trimethoxy-hydrazone with a 1-naphthyl group, showed remarkably selective toxicity against leukemia cells in comparison with stimulated normal lymphocytes, and no acute toxicity in vivo. Finally, this molecule was as active as vincristine in a murine model of human acute lymphoblastic leukemia at a weekly dose of 1 mg/kg. (C) 2015 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2015.02.041

文献信息

• Discovery and SAR of a Series of Agonists at Orphan G Protein-Coupled Receptor 139
  作者：Feng Shi、Jing Kang Shen、Danqi Chen、Karina Fog、Kenneth Thirstrup、Morten Hentzer、Jens-Jakob Karlsson、Veena Menon、Kenneth A. Jones、Kelli E. Smith、Garrick Smith

  DOI：10.1021/ml100293q

  日期：2011.4.14

  GPR139 is an orphan G-protein coupled receptor (GPCR) Which is primarily expressed in the central nervous system (CNS). In order to explore the biological function of this receptor, selective tool compounds are required. A screening campaign identified compound 1a as a high potency PR139 agonist with an EC(50) = 39 nM in a calcium mobilization assay in CHO-K1 cells stably expressing the GPR139 receptor. In the absence of a known endogenous ligand, the maximum effect was set as 100% for 1a. Screening against 90 diverse targets revealed no cross-reactivity issues. Assessment of the pharmacokinetic properties showed limited utility,as in vivo tool compound in rat with a poor whole brain exposure of 61 ng/g and a brain/plasma (b/p) ratio of 0.03. Attempts to identify a more suitable analogue identified the des-nitrogen analogue is with a reduced polar surface area of 76.7 angstrom(2) and an improved b/p ratio of 2.8. The whole brain exposure remained low at 95 ng/g due to a low plasma exposure.