9-(4-chlorobenzoyl)-6-methoxy-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid | 36405-72-8

• 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: 9-(4-chlorobenzoyl)-6-methoxy-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid
• 英文别名: 9-(4-Chlor-benzoyl)-6-methoxy-1,2,3,4-tetrahydro-carbazol-3-carbonsaeure；9-(4-Chlorobenzoyl)-6-methoxy-1,2,3,4-tetrahydrocarbazole-3carboxylic acid；9-(4-Chlorobenzoyl)-6-methoxy-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid
• CAS: 36405-72-8
• 化学式: C₂₁H₁₈ClNO₄
• 分子量: 383.831
• InChiKey: QVDWMUNEMKEXNZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  27
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  68.5
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  甲基磺酰胺 、 9-(4-chlorobenzoyl)-6-methoxy-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid 在 N,N'-羰基二咪唑 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 二氯甲烷 为溶剂， 反应 22.0h， 以79%的产率得到9-(4-chlorobenzoyl)-6-methoxy-N-methylsulfonyl-1,2,3,4-tetrahydrocarbazole-3-carboxamide
  参考文献：
  名称：

  Development of Potent and Selective Indomethacin Analogues for the Inhibition of AKR1C3 (Type 5 17β-Hydroxysteroid Dehydrogenase/Prostaglandin F Synthase) in Castrate-Resistant Prostate Cancer

  摘要：

  Castrate-resistant prostate cancer (CRPC) is a fatal, metastatic form of prostate cancer. CRPC is characterized by reactivation of the androgen axis due to changes in androgen receptor signaling and/or adaptive intratumoral androgen biosynthesis. AKR1C3 is upregulated in CRPC where it catalyzes the formation of potent androgens. This makes AKR1C3 a target for the treatment of CRPC. AKR1C3 inhibitors should not inhibit AKR1C1/AKR1C2, which inactivate 5 alpha-dihydrotestosterone. Indomethacin, used to inhibit cyclooxygenase, also inhibits AKR1C3 and displays selectivity over AKR1C1/AKR1C2. Parallel synthetic strategies were used to generate libraries of indomethacin analogues, which exhibit reduced cyclooxygenase inhibitory activity but retain AKR1C3 inhibitory potency and selectivity. The lead compounds inhibited AKR1C3 with nanomolar potency, displayed >100-fold selectivity over AKR1C1/AKR1C2, and blocked testosterone formation in LNCaP-AKR1C3 cells. The AKR1C3.NADP(+).2'-des-methyl-indomethacin crystal structure was determined, and it revealed a unique inhibitor binding mode. The compounds reported are promising agents for the development of therapeutics for CRPC.

  DOI：

  10.1021/jm3017656
• 作为产物：
  描述：

  Acetaldehyd-N₁-(p-chlorbenzoyl)-p-methoxy-phenylhydrazon 在 盐酸 、 溶剂黄146 作用下， 以 二氯甲烷 、 水 为溶剂， 反应 4.5h， 生成 9-(4-chlorobenzoyl)-6-methoxy-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid
  参考文献：
  名称：

  Development of Potent and Selective Indomethacin Analogues for the Inhibition of AKR1C3 (Type 5 17β-Hydroxysteroid Dehydrogenase/Prostaglandin F Synthase) in Castrate-Resistant Prostate Cancer

  摘要：

  Castrate-resistant prostate cancer (CRPC) is a fatal, metastatic form of prostate cancer. CRPC is characterized by reactivation of the androgen axis due to changes in androgen receptor signaling and/or adaptive intratumoral androgen biosynthesis. AKR1C3 is upregulated in CRPC where it catalyzes the formation of potent androgens. This makes AKR1C3 a target for the treatment of CRPC. AKR1C3 inhibitors should not inhibit AKR1C1/AKR1C2, which inactivate 5 alpha-dihydrotestosterone. Indomethacin, used to inhibit cyclooxygenase, also inhibits AKR1C3 and displays selectivity over AKR1C1/AKR1C2. Parallel synthetic strategies were used to generate libraries of indomethacin analogues, which exhibit reduced cyclooxygenase inhibitory activity but retain AKR1C3 inhibitory potency and selectivity. The lead compounds inhibited AKR1C3 with nanomolar potency, displayed >100-fold selectivity over AKR1C1/AKR1C2, and blocked testosterone formation in LNCaP-AKR1C3 cells. The AKR1C3.NADP(+).2'-des-methyl-indomethacin crystal structure was determined, and it revealed a unique inhibitor binding mode. The compounds reported are promising agents for the development of therapeutics for CRPC.

  DOI：

  10.1021/jm3017656

文献信息

• [EN] INDOMETHACIN ANALOGS FOR THE TREATMENT OF CASTRATE-RESISTANT PROSTATE CANCER<br/>[FR] ANALOGUES DE L'INDOMÉTACINE DESTINÉS AU TRAITEMENT DU CANCER DE LA PROSTATE RÉSISTANT À LA CASTRATION
  申请人：UNIV VANDERBILT

  公开号：WO2013059245A1

  公开（公告）日：2013-04-25

  Provided are compositions for inhibiting a biological activity of an aldoketo reductase family 1, member C3 (AKR1 C3) polypeptide. In some embodiments, the compositions are indomethacin derivatives that are AKR1 C3-specific inhibitors. Also provided are methods for producing disclosed indomethacin derivatives that substantially lack cyclooxygenase inhibitory activity but that have AKR1C3 inhibitory activity, methods for inhibiting AKR1C3 polypeptide biological activities, and methods for treating prostate tumors in subjects.

  提供了用于抑制醛酮还原酶家族1成员C3（AKR1 C3）多肽的生物活性的组合物。在某些实施例中，这些组合物是吲哚美酸衍生物，是AKR1 C3特异性抑制剂。还提供了生产所述吲哚美酸衍生物的方法，这些衍生物基本缺乏环氧合酶抑制活性，但具有AKR1C3抑制活性，以及抑制AKR1C3多肽生物活性的方法，以及治疗受试者前列腺肿瘤的方法。
• 9-Acyl-1,2,3,4-tetrahydrocarbazole-3 and 4-carboxylic acids
  申请人：Sterling Drug Inc.

  公开号：US03948939A1

  公开（公告）日：1976-04-06

  Novel 9-aroyl-1,2,3,4-tetrahydrocarbazoles bearing a carboxy substituent at position 3 or 4 and corresponding esters having antiinflammatory activity, the preparation thereof and novel intermediates therefor are described.

  描述了具有3或4位上的羧基取代基的新型9-芳酰基-1,2,3,4-四氢吲哚衍生物及具有抗炎活性的相应酯类化合物，以及它们的制备方法和新型中间体。
• Discovery of tetrahydrocarbazoles with potent hypoglycemic and hypolipemic activities
  作者：Ji-Quan Zhang、Shu-Min Li、Xiao Ma、Gang Zhong、Rui Chen、Xiao-Shuang Li、Gao-Feng Zhu、Bo Zhou、Bing Guo、Hao-Shu Wu、Lei Tang

  DOI：10.1016/j.ejmech.2018.02.069

  日期：2018.4

  A series of tetrahydrocarbazole derivatives was designed and synthesized on the basis of the AMP-activated protein kinase activator GY3. All the synthesized compounds were screened in HepG2 cell lines for glucose consumption activity and several of them showed potent glucose decreasing activity. In vivo evaluation of the hypoglycemic and hypolipemic effects indicated that 7a exhibited comparable activity

  在AMP活化的蛋白激酶活化剂GY3的基础上，设计合成了一系列四氢咔唑衍生物。在HepG2细胞系中筛选所有合成的化合物的葡萄糖消耗活性，其中一些显示出有效的葡萄糖降低活性。体内降血糖和降血脂作用的评估表明7a表现出与吡格列酮相当的活性，但体重增加作用较弱。还研究了7a的药代动力学特征。
• INDOMETHACIN ANALOGS FOR THE TREATMENT OF CASTRATE-RESISTANT PROSTATE CANCER
  申请人：Vanderbilt University

  公开号：US20140371261A1

  公开（公告）日：2014-12-18

  Provided are compositions for inhibiting a biological activity of an aldoketo reductase family 1, member C3 (AKR1 C3) polypeptide. In some embodiments, the compositions are indomethacin derivatives that are AKR1 C3-specific inhibitors. Also provided are methods for producing disclosed indomethacin derivatives that substantially lack cyclooxygenase inhibitory activity but that have AKR1C3 inhibitory activity, methods for inhibiting AKR1C3 polypeptide biological activities, and methods for treating prostate tumors in subjects.

  提供了一些用于抑制醛酮还原酶家族1成员C3（AKR1 C3）多肽生物活性的组合物。在某些实施例中，这些组合物是AKR1 C3特异性抑制剂的吲哚美辛衍生物。还提供了制备所述吲哚美辛衍生物的方法，这些方法基本上缺乏环氧合酶抑制活性，但具有AKR1C3抑制活性，以及抑制AKR1C3多肽生物活性的方法和治疗受试者的前列腺肿瘤的方法。
• Indomethacin analogs for the treatment of castrate-resistant prostate cancer
  申请人：Vanderbilt University

  公开号：US10398678B2

  公开（公告）日：2019-09-03

  Provided are compositions for inhibiting a biological activity of an aldo-keto reductase family 1, member C3 (AKR1C3) polypeptide. In some embodiments, the compositions are indomethacin derivatives that are AKR1C3-specific inhibitors. Also provided are methods for producing disclosed indomethacin derivatives that substantially lack cyclooxygenase inhibitory activity but that have AKR1C3 inhibitory activity, methods for inhibiting AKR1C3 polypeptide biological activities, and methods for treating prostate tumors in subjects.

  本文提供了用于抑制醛酮还原酶家族 1 成员 C3（AKR1C3）多肽生物活性的组合物。在某些实施方案中，这些组合物是 AKR1C3 特异性抑制剂的吲哚美辛衍生物。还提供了生产所公开的基本上缺乏环氧化酶抑制活性但具有AKR1C3抑制活性的吲哚美辛衍生物的方法、抑制AKR1C3多肽生物活性的方法以及治疗受试者前列腺肿瘤的方法。