4-(1-benzenesulfonyl-5-methoxy-1H-indol-2-yl)-4-hydroxy-cyclohexa-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-5-methoxy-1H-indol-2-yl)-4-hydroxy-cyclohexa-2,5-dienone
• 英文别名: 4-[1-(benzenesulfonyl)-5-methoxyindol-2-yl]-4-hydroxycyclohexa-2,5-dien-1-one
• 化学式: C₂₁H₁₇NO₅S
• 分子量: 395.436
• InChiKey: YXFKCAOTBBOXGT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  94
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  1-(苯磺酰基)-5-甲氧基吲哚 在 正丁基锂 、 溶剂黄146 作用下， 以 四氢呋喃 、 正己烷 、 丙酮 为溶剂， 反应 4.5h， 生成 4-(1-benzenesulfonyl-5-methoxy-1H-indol-2-yl)-4-hydroxy-cyclohexa-2,5-dienone
  参考文献：
  名称：

  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

  摘要：

  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.

  DOI：

  10.1021/jm040859h

文献信息

• [EN] 4-(1-(SULFONYL)-1H-INDOL-2-YL)-4-(HYDROXY)-CYCLOHEXA-2,5-DIENONE COMPOUNDS AND ANALOGS THEREOF AS THERAPEUTIC AGENTS<br/>[FR] COMPOSES DE 4-(1-(SULFONYL)-1H-INDOL-2-YL)-4-(HYDROXY)-CYCLOHEXA-2,5-DIENONE ET ANALOGUES DE CEUX-CI UTILISES COMME AGENTS THERAPEUTIQUES
  申请人：CANCER REC TECH LTD

  公开号：WO2004056361A1

  公开（公告）日：2004-07-08

  This invention pertains to certain 4-(1-(sulfonyl)-1H-indol-2-yl)-4-(hydroxy)-cyclohexa-2,5-dienone compounds, and analogs thereof, including compounds of the following formula, which are, inter alia, antiproliferative agents, anticancer agents, and/or thioredoxin/thioredoxin reductase inhibitors: formula (I) wherein: Ar is a 1-(sulfonyl)-1H-indol-2-yl group; the bond marked alpha is independently: (a) a single bond; or: (b) a double bond; the bond marked beta is independently: (a) a single bond; or: (b) a double bond; the group -OR is independently: (a) -OH; (b) an ether group (e.g., -OMe); or: (c) an acyloxy (i.e., reverse ester) group (e.g., -OC(=O)Me); each of R<2>, R<3>, R<5>, and R<6>, is independently a ring substituent and is: (a) H; (b) a monovalent monodentate substituent; or: (c) a ring substituent which, together with an adjacent ring substituent, and together with the ring atoms to which these ring substituents are attached, form a fused ring; and pharmaceutically acceptable salts, esters, amides, solvates, hydrates, and protected forms thereof. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, for example, in the treatment of proliferative conditions, (e.g., cancer), and/or conditions mediated by thioredoxin/thioredoxin reductase.

  本发明涉及某些4-(1-(磺酰基)-1H-吲哚-2-基)-4-(羟基)-环己-2,5-二酮化合物及其类似物，包括以下式的化合物，其中这些化合物是抗增殖剂、抗癌剂和/或硫代雷帕敏/硫代雷帕敏还原酶抑制剂：式(I)其中：Ar是1-(磺酰基)-1H-吲哚-2-基；标记为α的键独立地是：(a) 单键；或：(b) 双键；标记为β的键独立地是：(a) 单键；或：(b) 双键；-OR基独立地是：(a) -OH；(b) 一个醚基团（例如，-OMe）；或：(c) 一个酰氧基（即，反酯基）（例如，-OC(=O)Me）；R2、R3、R5和R6中的每一个独立地是一个环取代基，可以是：(a) H；(b) 一价单齿取代基；或：(c) 一个环取代基，与相邻的环取代基一起，以及与这些环取代基连接的环原子一起形成融合环；以及其药学上可接受的盐、酯、酰胺、溶剂合物、水合物和受保护形式。本发明还涉及含有这些化合物的药物组合物，以及这些化合物和组合物的用途，无论是在体外还是体内，例如，在治疗增殖性疾病（例如，癌症）和/或由硫代雷帕敏/硫代雷帕敏还原酶介导的疾病方面。
• 4-(1-(sulfonyl)-1h-indol-2-yl)-4-(hydroxy)-cyclohexa-2,5-dienone compounds and analogs thereof as therapeutic agents
  申请人：Stevens Francis Graham Malcolm

  公开号：US20060100265A1

  公开（公告）日：2006-05-11

  This invention pertains to certain 4-(1-(sulfonyl)-1H-indol-2-yl)-4-(hydroxy)-cyclohexa-2,5-dienone compounds, and analogs thereof, including compounds of the following formula, which are, inter alia, antiproliferative agents, anticancer agents, and/or thioredoxin/thioredoxin reductase inhibitors: formula (I) wherein: Ar is a 1-(sulfonyl)-1H-indol-2-yl group; the bond marked α is independently: (a) a single bond; or: (b) a double bond; the bond marked β is independently: (a) a single bond; or: (b) a double bond; the group —OR O is independently: (a) —OH; (b) an ether group (e.g., —OMe); or: (c) an acyloxy (i.e., reverse ester) group (e.g., —OC(═O)Me); each of R 2 , R 3 , R 5 , and R 6 , is independently a ring substituent and is: (a) H; (b) a monovalent monodentate substituent; or: (c) a ring substituent which, together with an adjacent ring substituent, and together with the ring atoms to which these ring substituents are attached, form a fused ring; and pharmaceutically acceptable salts, esters, amides, solvates, hydrates, and protected forms thereof. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, for example, in the treatment of proliferative conditions, (e.g., cancer), and/or conditions mediated by thioredoxin/thioredoxin reductase.

  本发明涉及某些4-(1-(磺酰基)-1H-吲哚-2-基)-4-(羟基)-环己-2,5-二酮化合物及其类似物，包括以下式的化合物，它们是抗增殖剂、抗癌剂和/或硫代还蛋白/硫代还蛋白还原酶抑制剂等：式(I)其中：Ar是1-(磺酰基)-1H-吲哚-2-基；标记为α的键独立地是：(a) 单键；或：(b) 双键；标记为β的键独立地是：(a) 单键；或：(b) 双键；—ORO基团独立地是：(a) -OH；(b) 醚基团（例如，-OMe）；或：(c) 酰氧基（即反酯基）基团（例如，-OC（═O）Me）；R2、R3、R5和R6中的每一个独立地是一个环取代基，并且是：(a) H；(b) 单价单齿取代基；或：(c) 与相邻的环取代基一起，并且与这些环取代基附着的环原子一起形成融合环的环取代基；以及其药学上可接受的盐、酯、酰胺、溶剂化物、水合物和保护形式。本发明还涉及包含这样的化合物的制药组合物，以及这样的化合物和组合物的使用，无论是体外还是体内，例如在治疗增殖性疾病（例如癌症）和/或由硫代还蛋白/硫代还蛋白还原酶介导的疾病中。
• 4- 1- (SULFONYL) -1H-INDOL-2-YL)-4- (HYDROXY) -CYCLOHEXA-2,5-DIENONE COMPOUNDS AND ANALOGS THEREOF AS THERAPEUTIC AGENTS
  申请人：Cancer Research Technology Limited

  公开号：EP1572197A1

  公开（公告）日：2005-09-14
• US7307099B2
  申请人：——

  公开号：US7307099B2

  公开（公告）日：2007-12-11
• 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.