3-(3-tert-butoxycarbonylaminopropoxy)-2-naphthoic acid

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: 3-(3-tert-butoxycarbonylaminopropoxy)-2-naphthoic acid
• 英文别名: 3-[3-[(2-Methylpropan-2-yl)oxycarbonylamino]propoxy]naphthalene-2-carboxylic acid
• 化学式: C₁₉H₂₃NO₅
• 分子量: 345.395
• InChiKey: SZSKVDFNMCZWGU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  25
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  84.9
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3-(3-tert-butoxycarbonylaminopropoxy)-2-naphthoic acid 在 4-二甲氨基吡啶 、 palladium on activated charcoal 、 氢气 、 三乙胺 、 三氟乙酸 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.5h， 生成
  参考文献：
  名称：

  笼养的内源转录因子抑制剂的光解释放能够实现对CREB介导的基因表达的光化学控制。

  摘要：

  已经开发了一种直接的光化学方法，用于调节基因功能，该方法是通过对无活性的笼状前体进行解囊来开发的，该前体的片段化后会产生CREB（cAMP-反应元件结合蛋白）抑制剂，该抑制剂与负责调节CREB介导的基因表达水平的内源性转录因子结合。

  DOI：

  10.1021/acs.orglett.9b03568
• 作为产物：
  描述：

  3-羟基-2-萘甲酸甲酯 在 偶氮二甲酸二异丙酯 、 水 、 三苯基膦 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 生成 3-(3-tert-butoxycarbonylaminopropoxy)-2-naphthoic acid
  参考文献：
  名称：

  笼养的内源转录因子抑制剂的光解释放能够实现对CREB介导的基因表达的光化学控制。

  摘要：

  已经开发了一种直接的光化学方法，用于调节基因功能，该方法是通过对无活性的笼状前体进行解囊来开发的，该前体的片段化后会产生CREB（cAMP-反应元件结合蛋白）抑制剂，该抑制剂与负责调节CREB介导的基因表达水平的内源性转录因子结合。

  DOI：

  10.1021/acs.orglett.9b03568

文献信息

• [EN] PHARMACEUTICAL COMPOSITIONS COMPRISING NAPTHAMIDES<br/>[FR] COMPOSITIONS PHARMACEUTIQUES COMPRENANT DES NAPTHAMIDES
  申请人：UNIV OREGON HEALTH & SCIENCE

  公开号：WO2013067379A1

  公开（公告）日：2013-05-10

  Disclosed herein are napthamide and quinoline carboxamide compounds containing two bicyclic moieties, pharmaceutical compositions comprising those compounds and methods of using the compositions in the treatment of cancers mediated by cyclic-AMP (cAMP) response element binding protein (CREB). The disclosed compositions have utility in the treatment of lung, prostate and breast cancers in a human subject.

  本文披露了含有两个双环基团的萘酰胺和喹啉羧酰胺化合物，包括这些化合物的药物组合物以及使用这些组合物治疗由环磷酸腺苷（cAMP）响应元件结合蛋白（CREB）介导的癌症的方法。所披露的组合物在治疗人体主体的肺癌、前列腺癌和乳腺癌方面具有实用性。
• Mechanistic insights into the activation of ester prodrugs of 666-15
  作者：Fuchun Xie、Pedro Martín-Acosta、Bingbing X. Li、Xiangshu Xiao

  DOI：10.1016/j.bmcl.2020.127455

  日期：2020.10

  solubility of 666-15, amino ester prodrugs 1 and 4 were designed and synthesized. Detailed chemical and biological studies of 1 and 4 revealed that a small portion of the prodrugs were converted into 666-15 through intermediate 3 instead of a long-range O,N-acyl transfer reaction that was initially proposed. These results provide unique insights into the activation of these ester prodrugs.

  cAMP 反应元件结合蛋白 (CREB) 是一种致癌转录因子，与许多不同类型的癌症有关。我们以前报道的发现666 - 15为CREB介导的基因转录的有效抑制剂。在以提高的水溶解度的努力666 - 15，氨基酯前药1和4，设计并合成。详细的化学和生物学研究1和4显示，该前药的一小部分被转换成666 - 15通过中间3代替远程ø，最初提出的N-酰基转移反应。这些结果为这些酯前药的活化提供了独特的见解。
• [EN] SYNERGISTIC INHIBITORS OF CREB-MEDIATED GENE TRANSCRIPTION<br/>[FR] INHIBITEURS SYNERGIQUES DE LA TRANSCRIPTION GÉNIQUE MÉDIÉE PAR CREB
  申请人：UNIV OREGON HEALTH & SCIENCE

  公开号：WO2021081448A1

  公开（公告）日：2021-04-29

  Disclosed herein are uses for a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from the group of 0, 1, 2, 3, and 4, or a pharmaceutically acceptable salt thereof, for enhancing the effect of an ant-cancer agent, such as an inhibitor of CREB-mediated gene transcription.

  本文披露了一种化合物(I)或其药学上可接受的盐的用途，其中n是从0、1、2、3和4组成的整数之一，或其药学上可接受的盐，用于增强抗癌药物的效果，例如CREB介导的基因转录抑制剂。
• Identification of a Potent Inhibitor of CREB-Mediated Gene Transcription with Efficacious in Vivo Anticancer Activity
  作者：Fuchun Xie、Bingbing X. Li、Alina Kassenbrock、Changhui Xue、Xiaoyan Wang、David Z. Qian、Rosalie C. Sears、Xiangshu Xiao

  DOI：10.1021/acs.jmedchem.5b00468

  日期：2015.6.25

  Recent studies have shown that nuclear transcription factor cyclic adenosine monophosphate response element binding protein (CREB) is overexpressed in many different types of cancers. Therefore, CREB has been pursued as a novel cancer therapeutic target. Naphthol AS-E and its closely related derivatives have been shown to inhibit CREB-mediated gene transcription and cancer cell growth. Previously, we identified naphthamide 3a as a different chemotype to inhibit CREB's transcription activity. In a continuing effort to discover more potent CREB inhibitors, a series of structural congeners of 3a was designed and synthesized. Biological evaluations of these compounds uncovered compound 3i (666-15) as a potent and selective inhibitor of CREB-mediated gene transcription (IC50 = 0.081 +/- 0.04 mu M). 666-15 also potently inhibited cancer cell growth without harming normal cells. In an in vivo MDA-MB-468 xenograft model, 666-15 completely suppressed the tumor growth without overt toxicity. These results further support the potential of CREB as a valuable cancer drug target.
• Novel Type of Prodrug Activation through a Long-Range <i>O</i>,<i>N</i>-Acyl Transfer: A Case of Water-Soluble CREB Inhibitor
  作者：Bingbing X. Li、Fuchun Xie、Qiuhua Fan、Kerry M. Barnhart、Curtis E. Moore、Arnold L. Rheingold、Xiangshu Xiao

  DOI：10.1021/ml500330n

  日期：2014.10.9

  CREB (cANIP response element binding protein) has been shown to play an important role in tumor initiation, progression, and metastasis. We discovered that naphthol AS-E, a cell-permeable CREB inhibitor, presented antiproliferative activity in a broad panel of cancer cell lines in vitro. However, it has limited aqueous solubility. In this report, we described a water-soluble inhibitor (compound 6) of CREB-mediated gene transcription with in vivo anticancer activity. Unexpectedly, compound 6 was found to be a prodrug of compound 12 necessitating an unprecedented long-range O,Nacyl transfer. The rate of this transfer was pH- and temperature-dependent. To the best of our knowledge, this is the first time to show that a long-range O,N-acyl transfer could be exploited as a prodrug activation strategy to improve aqueous solubility. This type of prodrug may be applicable to other structures with spatially arranged hydroxyl amide to improve their aqueous solubility.