3-nitroindeno[1,2-c]isochromene-5,11-dione | 884902-28-7

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 异香豆素及其衍生物
• 英文名称: 3-nitroindeno[1,2-c]isochromene-5,11-dione
• 英文别名: 3-nitrobenz[d]indeno[1,2-b]pyran-5,11-dione
• CAS: 884902-28-7
• 化学式: C₁₆H₇NO₅
• 分子量: 293.235
• InChiKey: GJUWJQPGHZKUFS-UHFFFAOYSA-N

物化性质

• 熔点：
  271-272 °C(Solv: chloroform (67-66-3))
• 沸点：
  539.9±50.0 °C(Predicted)
• 密度：
  1.60±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  22
• 可旋转键数：
  0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  89.2
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3-nitroindeno[1,2-c]isochromene-5,11-dione 在 palladium 10% on activated carbon 、 氢气 作用下， 以 四氢呋喃 、 甲醇 、 氯仿 为溶剂， 反应 15.0h， 以44%的产率得到3-amino-11-hydroxyindeno[1,2-c]isochromen-5(11H)-one
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of Indenoisoquinoline Rexinoids with Chemopreventive Potential

  摘要：

  Nuclear receptors, such as the retinoid X receptor (RXR), are proteins that regulate a myriad of cellular processes. Molecules that function as RXR agonists are of special interest for the prevention and control of carcinogenesis. The majority of these ligands possess an acidic moiety that is believed to be key for RXR activation. This communication presents the design, synthesis, and biological evaluation of both acidic and nonacidic indenoisoquinolines as new RXR ligands. In addition, a comprehensive structure-activity relationship study is presented that identifies the important features of the indenoisoquinoline rexinoids. The ease of modification of the indenoisoquinoline core and the lack of the necessity of a carboxyl group for activity make them an attractive and unusual family of RXR agonists. This work establishes a structural foundation for the design of new and novel rexinoid cancer chemopreventive agents.

  DOI：

  10.1021/jm400026k
• 作为产物：
  描述：

  2-甲酰基-5-硝基-苯甲酸 在 sodium methylate 、 对甲苯磺酸 作用下， 以 甲醇 、 乙酸乙酯 、 苯 为溶剂， 反应 18.0h， 生成 3-nitroindeno[1,2-c]isochromene-5,11-dione
  参考文献：
  名称：

  Synthesis of benz[d]indeno[1,2-b]pyran-5,11-diones: Versatile intermediates for the design and synthesis of topoisomerase I inhibitors

  摘要：

  A method has been developed that relies on a two-step, one-pot condensation between phthalide and 2-carboxybenzaldehydes to provide benz[a]indeno[ 1,2-h]pyran-5,11-diones in a multi-gram fashion. Treatment of these compounds with a primary amine allows rapid access to various N-substituted indenoisoquinolines, whose in vitro anticancer activity and topoisomerase I inhibition have been evaluated. (C) 2006 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2006.01.008

文献信息

• Alcohol-, Diol-, and Carbohydrate-Substituted Indenoisoquinolines as Topoisomerase I Inhibitors: Investigating the Relationships Involving Stereochemistry, Hydrogen Bonding, and Biological Activity
  作者：Katherine E. Peterson、Maris A. Cinelli、Andrew E. Morrell、Akhil Mehta、Thomas S. Dexheimer、Keli Agama、Smitha Antony、Yves Pommier、Mark Cushman

  DOI：10.1021/jm101338z

  日期：2011.7.28

  topoisomerase I (Top1) can be inhibited by heterocyclic compounds such as indolocarbazoles and indenoisoquinolines. Carbohydrate and hydroxyl-containing side chains are essential for the biological activity of indolocarbazoles. The current study investigated how similar functionalities could be “translated” to the indenoisoquinoline system and how stereochemistry and hydrogen bonding affect biological

  DNA松弛酶拓扑异构酶I（Top1）可以被杂环化合物如吲哚并咔唑和茚并异喹啉抑制。碳水化合物和含羟基的侧链对于吲哚并咔唑的生物活性是必不可少的。目前的研究调查了如何将相似的功能“转化”到茚并异喹啉系统，以及立体化学和氢键如何影响生物活性。本文描述了用短链醇、二醇和碳水化合物取代的茚并异喹啉的制备和测定。几种化合物（包括那些来自糖的化合物）显示出有效的 Top1 中毒和抗增殖活性。二醇取代的茚并异喹啉的 Top1 中毒活性取决于立体化学。虽然效果惊人，由于配体和 Top1-DNA 复合物之间类似的计算相互作用以及结合模式的模糊性，分子建模和对接研究没有表明活性差异的任何原因。还观察到碳水化合物衍生的茚并异喹啉具有立体化学依赖性。尽管在其他类别的 Top1 抑制剂中观察到了类似的趋势，但这种效应的确切性质尚未阐明。
• Synthesis and Biological Evaluation of New Carbohydrate-Substituted Indenoisoquinoline Topoisomerase I Inhibitors and Improved Syntheses of the Experimental Anticancer Agents Indotecan (LMP400) and Indimitecan (LMP776)
  作者：Daniel E. Beck、Keli Agama、Christophe Marchand、Adel Chergui、Yves Pommier、Mark Cushman

  DOI：10.1021/jm401814y

  日期：2014.2.27

  Carbohydrate moieties were strategically transported from the indolocarbazole topoisomerase I (Top1) inhibitor class to the indenoisoquinoline system in search of structurally novel and potent Top1 inhibitors. The syntheses and biological evaluation of 20 new indenoisoquinolines glycosylated with linear and cyclic sugar moieties are reported. Aromatic ring substitution with 2,3-dimethoxy-8,9-methylenedioxy

  碳水化合物部分被策略性地从吲哚并咔唑拓扑异构酶 I (Top1) 抑制剂类转移到茚并异喹啉系统，以寻找结构新颖且有效的 Top1 抑制剂。报告了 20 种新型茚并异喹啉糖基化的线性和环状糖基的合成和生物学评价。2,3-二甲氧基-8,9-亚甲二氧基或3-硝基的芳环取代对抗增殖和Top1抑制活性有很强的影响。虽然碳水化合物侧链的长度与抗增殖活性明显相关，但立体化学和生物活性之间的关系不太清楚。12 种新茚并异喹啉表现出等于或优于喜树碱的 Top1 抑制活性。
• WO2007/59008
  申请人：——

  公开号：——

  公开（公告）日：——
• Identification, Synthesis, and Biological Evaluation of the Metabolites of 3-Amino-6-(3′-aminopropyl)-5<i>H</i>-indeno[1,2-<i>c</i>]isoquinoline-5,11-(6<i>H</i>)dione (AM6–36), a Promising Rexinoid Lead Compound for the Development of Cancer Chemotherapeutic and Chemopreventive Agents
  作者：Lian Chen、Martin Conda-Sheridan、P. V. Narasimha Reddy、Andrew Morrell、Eun-Jung Park、Tamara P. Kondratyuk、John M. Pezzuto、Richard B. van Breemen、Mark Cushman

  DOI：10.1021/jm3006806

  日期：2012.6.28

  Activation of the retinoid X receptor (RXR), which is involved in cell proliferation, differentiation, and apoptosis, is a strategy for cancer chemotherapy and chemoprevention, and 3-amino-6-(3'-aminopropyl)-5H-indeno[1,2-c]isoquinoline-5,11-(6H)dione (AM6-36) (3) is among the few RXR ligands known. The presently reported studies of 3 include its binding to human plasma proteins, metabolic stability using human liver microsomes, metabolism by human liver microsomes and hepatocytes, and in vivo disposition in rat serum, liver, and mammary tissue. Compound 3 was 75% bound to human plasma proteins, and its metabolic stability was much greater than propranolol. One phase I metabolite was formed by human liver microsomes, seven phase I and II metabolites were formed by human hepatoc-ytes, and five metabolites were detected in rat serum and liver after oral administration. The putative metabolites predicted using LC-MS-MS were synthesized to confirm their structures and to provide sufficient material for investigation of induction of RXRE transcriptional activity and inhibition of NF kappa B.
• Synthesis and Biological Evaluation of Bisindenoisoquinolines as Topoisomerase I Inhibitors
  作者：Muthukaman Nagarajan、Andrew Morrell、Smitha Antony、Glenda Kohlhagen、Keli Agama、Yves Pommier、Patricia A. Ragazzon、Nichola C. Garbett、Jonathan B. Chaires、Melinda Hollingshead、Mark Cushman

  DOI：10.1021/jm060046o

  日期：2006.8.1

  The indenoisoquinolines represent a class of non-camptothecin topoisomerase I (Top1) inhibitors that exert cytotoxicity by trapping the covalent complex formed between DNA and Top1 during relaxation of DNA supercoils. As an ongoing evaluation of Top1 inhibition and anticancer activity, indenoisoquinolines were linked via their lactam side chains to provide polyamines end-capped with intercalating motifs. The resulting bisindenoisoquinolines were evaluated for cytotoxicity in the National Cancer Institute's human cancer cell screen and for Top1 inhibition. Preliminary findings suggested that the 2-3-2and 3-3-3 linkers, referring to the number of carbons between nitrogen atoms, were optimal for both potent Top1 inhibition and cytotoxicity. Using optimized linkers, bisindenoisoquinolines were synthesized with nitro and methoxy substituents on the aromatic rings. The biological results for substituted compounds revealed a disagreement between the structure-activity relationships of monomeric indenoisoquinolines and bisindenoisoquinolines as Top1 inhibitors, but cytotoxicity was maintained for both series of compounds.