4'-fluoro-N-(2-methyl-5-(3-(3,4,5-trimethoxybenzoyl)thioureido)phenyl)-[1,1'-biphenyl]-4-carboxamide | 1359944-50-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 4'-fluoro-N-(2-methyl-5-(3-(3,4,5-trimethoxybenzoyl)thioureido)phenyl)-[1,1'-biphenyl]-4-carboxamide
• 英文别名: 4'-fluoro-N-(2-methyl-5-(3-(3,4,5-trimethoxybenzoyl)thioureido)phenyl)biphenyl-4-carboxamide；N-[[3-[[4-(4-fluorophenyl)benzoyl]amino]-4-methylphenyl]carbamothioyl]-3,4,5-trimethoxybenzamide
• CAS: 1359944-50-5
• 化学式: C₃₁H₂₈FN₃O₅S
• 分子量: 573.645
• InChiKey: UYGWJHNCQVCGDK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.4
• 重原子数：
  41
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  130
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  4'-fluoro-N-(2-methyl-5-(3-(3,4,5-trimethoxybenzoyl)thioureido)phenyl)-[1,1'-biphenyl]-4-carboxamide 在 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 六甲基二硅氮烷 作用下， 以 乙腈 为溶剂， 反应 5.0h， 以63%的产率得到4'-fluoro-N-(2-methyl-5-(3-(3,4,5-trimethoxybenzoyl)guanidino)phenyl)biphenyl-4-carboxamide
  参考文献：
  名称：

  Acylthiourea, Acylurea, and Acylguanidine Derivatives with Potent Hedgehog Inhibiting Activity

  摘要：

  The Smoothened (Smo) receptor is the major transducer of the Hedgehog (Hh) signaling pathway. On the basis of the structure of the acylthiourea Smo antagonist (MRT-10), a number of different series of analogous compounds were prepared by ligand-based structural optimization. The acylthioureas, originally identified as actives, were converted into the corresponding acylureas or acylguanidines. In each series, similar structural trends delivered potent compounds with IC50 values in the nanomolar range with respect to the inhibition of the Hh signaling pathway in various cell-based assays and of BODIPY-cyclopamine binding to human Smo. The similarity of their biological activities, in spite of discrete structural differences, may reveal the existence of hydrogen-bonding interactions between the ligands and the receptor pocket. Biological potency of compounds 61, 72, and 86 (MRT-83) were comparable to those of the clinical candidate GDC-0449. These findings suggest that these original molecules will help delineate Smo and Hh functions and can be developed as potential anticancer agents.

  DOI：

  10.1021/jm2013369
• 作为产物：
  描述：

  2-氨基-4-硝基甲苯 在 吡啶 、 5%-palladium/activated carbon 、 氢气 作用下， 以 甲醇 、 二氯甲烷 、 丙酮 为溶剂， 反应 5.0h， 生成 4'-fluoro-N-(2-methyl-5-(3-(3,4,5-trimethoxybenzoyl)thioureido)phenyl)-[1,1'-biphenyl]-4-carboxamide
  参考文献：
  名称：

  酰基硫脲和酰基胍类的刺猬通路抑制剂在体外和体内均对结肠癌具有抗肿瘤活性

  摘要：

  以克级合成小系列的酰基胍和酰基硫脲衍生物，并分析其调节Hh信号通路的能力。体外研究表明，其对肿瘤细胞系的微摩尔抑制活性较低，而口服给药则显示出优异的体内ADME特性。在体外和异种移植小鼠模型中，化合物5均成为结肠癌细胞最有效和最安全的抑制剂。基于这些数据，可以从临床研究的角度优先考虑5进一步开发。

  DOI：

  10.1016/j.ejmech.2018.07.053

文献信息

• Acylthiourea, Acylurea, and Acylguanidine Derivatives with Potent Hedgehog Inhibiting Activity
  作者：Antonio Solinas、Hélène Faure、Hermine Roudaut、Elisabeth Traiffort、Angèle Schoenfelder、André Mann、Fabrizio Manetti、Maurizio Taddei、Martial Ruat

  DOI：10.1021/jm2013369

  日期：2012.2.23

  The Smoothened (Smo) receptor is the major transducer of the Hedgehog (Hh) signaling pathway. On the basis of the structure of the acylthiourea Smo antagonist (MRT-10), a number of different series of analogous compounds were prepared by ligand-based structural optimization. The acylthioureas, originally identified as actives, were converted into the corresponding acylureas or acylguanidines. In each series, similar structural trends delivered potent compounds with IC50 values in the nanomolar range with respect to the inhibition of the Hh signaling pathway in various cell-based assays and of BODIPY-cyclopamine binding to human Smo. The similarity of their biological activities, in spite of discrete structural differences, may reveal the existence of hydrogen-bonding interactions between the ligands and the receptor pocket. Biological potency of compounds 61, 72, and 86 (MRT-83) were comparable to those of the clinical candidate GDC-0449. These findings suggest that these original molecules will help delineate Smo and Hh functions and can be developed as potential anticancer agents.
• Hedgehog pathway inhibitors of the acylthiourea and acylguanidine class show antitumor activity on colon cancer in vitro and in vivo
  作者：Loredana Vesci、Ferdinando Maria Milazzo、Maria Antonietta Stasi、Silvia Pace、Francesco Manera、Carlo Tallarico、Elena Cini、Elena Petricci、Fabrizio Manetti、Rita De Santis、Giuseppe Giannini

  DOI：10.1016/j.ejmech.2018.07.053

  日期：2018.9

  gram-scale and assayed for their ability to modulate the Hh signalling pathway. In vitro studies showed a low micromolar inhibitory activity toward tumor cell lines, while the oral administration revealed an excellent ADME profile in vivo. Compound 5 emerged as the most active and safe inhibitor of colon cancer cells both in vitro and in a xenograft mouse model. Based on these data, 5 could be prioritized

  以克级合成小系列的酰基胍和酰基硫脲衍生物，并分析其调节Hh信号通路的能力。体外研究表明，其对肿瘤细胞系的微摩尔抑制活性较低，而口服给药则显示出优异的体内ADME特性。在体外和异种移植小鼠模型中，化合物5均成为结肠癌细胞最有效和最安全的抑制剂。基于这些数据，可以从临床研究的角度优先考虑5进一步开发。