3-(3-aminopropoxy)-N-(4-chloro-2-hydroxyphenyl)-2-naphthamide hydrochloride | 1224567-46-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: 3-(3-aminopropoxy)-N-(4-chloro-2-hydroxyphenyl)-2-naphthamide hydrochloride
• 英文别名: 653-47 Hydrochloride；3-(3-aminopropoxy)-N-(4-chloro-2-hydroxyphenyl)naphthalene-2-carboxamide;hydrochloride
• CAS: 1224567-46-7
• 化学式: C₂₀H₁₉ClN₂O₃*ClH
• 分子量: 407.296
• InChiKey: HESNWSHDEFHION-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  27
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  84.6
• 氢给体数：
  4
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-(3-aminopropoxy)-N-(4-chloro-2-hydroxyphenyl)-2-naphthamide hydrochloride 、 2-(3-(tert-butoxycarbonylamino)propoxy)benzoic acid 在 甲基磺酰氯 、 三乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 0.5h， 以40%的产率得到tert-butyl (3-(2-((3-((3-((4-chloro-2-hydroxyphenyl)-carbamoyl)naphthalen-2-yl)oxy)propyl)carbamoyl)phenoxy)-propyl)carbamate
  参考文献：
  名称：

  Identification of a Potent Inhibitor of CREB-Mediated Gene Transcription with Efficacious in Vivo Anticancer Activity

  摘要：

  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.

  DOI：

  10.1021/acs.jmedchem.5b00468
• 作为产物：
  描述：

  tert-butyl (3-((3-((4-chloro-2-hydroxyphenyl)carbamoyl)naphthalen-2-yl)oxy)propyl)carbamate 在 盐酸 作用下， 以 甲醇 、 乙醚 、 氯仿 为溶剂， 以80%的产率得到3-(3-aminopropoxy)-N-(4-chloro-2-hydroxyphenyl)-2-naphthamide hydrochloride
  参考文献：
  名称：

  Novel Type of Prodrug Activation through a Long-Range O,N-Acyl Transfer: A Case of Water-Soluble CREB Inhibitor

  摘要：

  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.

  DOI：

  10.1021/ml500330n

文献信息

• 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.