4-(1-benzenesulfonyl-6-fluoro-1H-indol-2-yl)-4-hydroxycyclohexa-2,5-dienone

• 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-(1-benzenesulfonyl-6-fluoro-1H-indol-2-yl)-4-hydroxycyclohexa-2,5-dienone
• 英文别名: 4-[1-(benzenesulfonyl)-6-fluoro-1H-indol-2-yl]-4-hydroxycyclohexa-2,5-dien-1-one；4-[1-(benzenesulfonyl)-6-fluoroindol-2-yl]-4-hydroxycyclohexa-2,5-dien-1-one
• 化学式: C₂₀H₁₄FNO₄S
• 分子量: 383.4
• InChiKey: NUKLBNRXGJLHIA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  27
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  84.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-(1-benzenesulfonyl-6-fluoro-1H-indol-2-yl)-4-hydroxycyclohexa-2,5-dienone 、 mesna 在 三乙胺 作用下， 以 水 、 丙酮 为溶剂， 生成 disodium 2,2'-(2-(6-fluoro-1-(phenylsulfonyl)-1H-indol-2-yl)-2-hydroxy-5-oxocyclohexane-1,3-diyl)bis(sulfanediyl)diethanesulfonate
  参考文献：
  名称：

  [EN] NOVEL PRODRUGS
  [FR] NOUVEAUX PROMÉDICAMENTS

  摘要：

  本发明涉及新型前药化合物或其药用可接受的盐，其在体内转化为活性物种4-(1-苯磺酰基-6-氟-1H-吲哚-2-基)-4-羟基-环己-2,5-二酮。本发明的前药化合物相对于4-(1-苯磺酰基-6-氟-1H-吲哚-2-基)-4-羟基-环己-2,5-二酮具有显著改善的溶解度，因此可以轻松制剂化用于给患者使用。因此，本发明的前药对于治疗细胞增殖障碍如癌症等疾病是有用的。

  公开号：

  WO2010109230A1
• 作为产物：
  描述：

  4,4-二甲氧基-2,5-环己二烯-1-酮 在 copper(l) iodide 、 四(三苯基膦)钯 二异丙胺 作用下， 以 四氢呋喃 、 N,N-二甲基乙酰胺 、 水 为溶剂， 反应 0.17h， 生成 4-(1-benzenesulfonyl-6-fluoro-1H-indol-2-yl)-4-hydroxycyclohexa-2,5-dienone
  参考文献：
  名称：

  喹诺醇类作为新型治疗剂。7.1通过Sonogashira反应合成抗肿瘤4- [1-（芳基磺酰基-1H-吲哚-2-基）]-4-羟基环己-2,5-二烯-1-酮。

  摘要：

  2-碘苯胺或5-氟-2-碘苯胺与一系列芳基磺酰氯的相互作用提供了磺酰胺，该磺酰胺在热或微波条件下与炔4-乙炔基-4-羟基环己-2,5-二烯-1-酮进行了Sonogashira偶联。然后环化成4- [1-（芳基磺酰基-1H-吲哚-2-基）]-4-羟基环-己基2，5-二烯-1-酮。该方法允许将一系列取代基并入芳基磺酰基部分中，并且化合物显示出对结肠和肾脏起源的癌细胞系的选择性体外抑制，这是带有喹诺酚药效团的化合物的特征。

  DOI：

  10.1021/jm061163m

文献信息

• Quinols as Novel Therapeutic Agents. 2. 4-(1-Arylsulfonylindol-2-yl)-4-hydroxycyclohexa-2,5-dien-1-ones and Related Agents as Potent and Selective Antitumor Agents
  作者：Jane M. Berry、Tracey D. Bradshaw、Iduna Fichtner、Ruobo Ren、Carl H. Schwalbe、Geoffrey Wells、Eng-Hui Chew、Malcolm F. G. Stevens、Andrew D. Westwell

  DOI：10.1021/jm040859h

  日期：2005.1.1

  A series of substituted 4-(1-arylsulfonylindol-2-yl)-4-hydroxycyclohexa-2, 5-dien-1-ones (indolylquinols) has been synthesized on the basis of the discovery of lead compound la and screened for antitumor activity. Synthesis of this novel series was accomplished via the one-pot" addition of lithiated (arylsulfonyl)indoles to 4,4-dimethoxycyclohexa-2,5-dienone followed by deprotection under acidic conditions. Similar methodology gave rise to the related naphtho-, 1H-indole-, and benzimidazole-substituted quinols. A number of compounds in this new series were found to possess in vitro human tumor cell line activity substantially more potent than the recently reported antitumor 4-substituted 4-hydroxycyclohexa-2,5-dien-1-ones(1) with similar patterns of selectivity against colon, renal, and breast cell lines. The most potent compound in the series in vitro, 4-(1-benzenesulfonyl-6-fluoro-1H-indol-2-yl)-4-hydroxycyclohexa-2,5-dienone (1h), exhibits a mean GI(50) value of 16 nM and a mean LC50 value of 2.24 muM in the NCl 60cell-line screen, with LC50 activity in the HCT 116 human colon cancer cell line below 10 nM. The crystal structure of the unsubstituted indolylquinol la exhibits two independent, molecules. both participating in intermolecular hydrogen bonds from quinol OH to carbonyl O-2 but one OH group also interacts intramolecularly with a sulfonyl O atom. This interaction, which strengthens upon ab initio optimization, may influence the chemical environment. of the bioactive quinol moiety. In vivo, significant antitumor activity was recorded (day 28) in mice bearing subcutaneously implanted MDA-MB-435 xenografts, following intraperitoneal treatment of mice with compound 1a at 50 mg/kg.
• Quinols As Novel Therapeutic Agents. 7. Synthesis of Antitumor 4-[1-(Arylsulfonyl-1<i>H</i>-indol-2-yl)]-4-hydroxycyclohexa-2,5-dien-1-ones by Sonogashira Reactions
  作者：Andrew J. McCarroll、Tracey D. Bradshaw、Andrew D. Westwell、Charles S. Matthews、Malcolm F. G. Stevens

  DOI：10.1021/jm061163m

  日期：2007.4.1

  arylsulfonyl chlorides affords sulfonamides that undergo Sonogashira couplings under thermal or microwave conditions with the alkyne 4-ethynyl-4-hydroxycyclohexa-2,5-dien-1-one followed by cyclization to 4-[1-(arylsulfonyl-1H-indol-2-yl)]-4-hydroxycyclo-hexa-2,5-dien-1-ones. This method allows for incorporation of a range of substituents into the arylsulfonyl moiety, and compounds showed selective in vitro

  2-碘苯胺或5-氟-2-碘苯胺与一系列芳基磺酰氯的相互作用提供了磺酰胺，该磺酰胺在热或微波条件下与炔4-乙炔基-4-羟基环己-2,5-二烯-1-酮进行了Sonogashira偶联。然后环化成4- [1-（芳基磺酰基-1H-吲哚-2-基）]-4-羟基环-己基2，5-二烯-1-酮。该方法允许将一系列取代基并入芳基磺酰基部分中，并且化合物显示出对结肠和肾脏起源的癌细胞系的选择性体外抑制，这是带有喹诺酚药效团的化合物的特征。
• [EN] NOVEL PRODRUGS<br/>[FR] NOUVEAUX PROMÉDICAMENTS
  申请人：PHARMINOX LTD

  公开号：WO2010109230A1

  公开（公告）日：2010-09-30

  The present invention relates to novel prodrug compounds, or pharmaceutically acceptable salts thereof, which convert in vivo to the active species 4-(1-benzenesulfonyl-6-fluoro-1H-indol-2-yl)-4-hydroxy-cyclohexa-2,5-dienone. The prodrug compounds of the invention have dramatically improved solubility relative to 4-(1-benzenesulfonyl-6-fluoro-1H- indol-2-yl)-4-hydroxy-cyclohexa-2,5-dienone and, accordingly, can be easily formulated for administration to a patient. The prodrugs of the invention are therefore useful for the treatment cellular proliferation disorders, such as cancer.

  本发明涉及新型前药化合物或其药用可接受的盐，其在体内转化为活性物种4-(1-苯磺酰基-6-氟-1H-吲哚-2-基)-4-羟基-环己-2,5-二酮。本发明的前药化合物相对于4-(1-苯磺酰基-6-氟-1H-吲哚-2-基)-4-羟基-环己-2,5-二酮具有显著改善的溶解度，因此可以轻松制剂化用于给患者使用。因此，本发明的前药对于治疗细胞增殖障碍如癌症等疾病是有用的。