6-(3-(1H-imidazol-1-yl)propyl)-2,3-dimethoxy-5H-[1,3]dioxolo[4′,5′:5,6]indeno[1,2-c]isoquinoline-5,12(6H)-dione | 915360-05-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异喹啉及其衍生物
• 英文名称: 6-(3-(1H-imidazol-1-yl)propyl)-2,3-dimethoxy-5H-[1,3]dioxolo[4′,5′:5,6]indeno[1,2-c]isoquinoline-5,12(6H)-dione
• 英文别名: 6-(3-(1H-imidazol-1-yl)propyl)-2,3-dimethoxy-5H-[1,3]dioxolo[4',5':5,6]indeno[1,2-c]isoquinoline-5,12(6H)-dione；6-(3-(1H-imodazol-1-yl)propyl)-2,3-dimethoxy-5H-[1,3]dioxolo[4',5':5,6]indeno[1,2-c]isoquinoline-5,12(6H)-dione；6-(3-(1H-imidazol-1-yl)propyl)-2,3-dimethoxy-5,6-dihydro-8,9-methylendioxy-5,12-dioxoindeno[1,2-c]isoquinoline；3-(imidazolyl-1-propyl)-5,6-dihydro-2,3-dimethoxy-8,9-methylenedioxy-5,11-dioxo-11H-indeno[1,2-c]isoquinoline；indimitecan；LMP776；20-(3-imidazol-1-ylpropyl)-15,16-dimethoxy-5,7-dioxa-20-azapentacyclo[10.8.0.02,10.04,8.013,18]icosa-1(12),2,4(8),9,13,15,17-heptaene-11,19-dione
• CAS: 915360-05-3
• 化学式: C₂₅H₂₁N₃O₆
• 分子量: 459.458
• InChiKey: GCILEJUNEYIABW-UHFFFAOYSA-N

物化性质

• 沸点：
  782.0±60.0 °C(Predicted)
• 密度：
  1.48±0.1 g/cm3(Predicted)
• 溶解度：
  DMSO：8.33 mg/mL（18.13 mM；超声波和加温，用 HCl 调节 pH 至 3，并加热至 60°C）

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  34
• 可旋转键数：
  6
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  92.1
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  6-(3-(1H-imidazol-1-yl)propyl)-2,3-dimethoxy-5H-[1,3]dioxolo[4′,5′:5,6]indeno[1,2-c]isoquinoline-5,12(6H)-dione 在 sodium tetrahydroborate 作用下， 以 甲醇 为溶剂， 反应 3.0h， 以64%的产率得到11-Hydroxy-20-(3-imidazol-1-ylpropyl)-15,16-dimethoxy-5,7-dioxa-20-azapentacyclo[10.8.0.02,10.04,8.013,18]icosa-1(12),2,4(8),9,13,15,17-heptaen-19-one
  参考文献：
  名称：

  Identification, Synthesis, and Biological Evaluation of Metabolites of the Experimental Cancer Treatment Drugs Indotecan (LMP400) and Indimitecan (LMP776) and Investigation of Isomerically Hydroxylated Indenoisoquinoline Analogues as Topoisomerase I Poisons

  摘要：

  Hydroxylated analogues of the anticancer topoisomerase I (Top1) inhibitors indotecan (LMP400) and indimitecan (LMP776) have been prepared because (1) a variety of potent Top1 poisons are known that contain strategically placed hydroxyl groups, which provides a clear rationale for incorporating them in the present case, and (2) the hydroxylated compounds could conceivably serve as synthetic standards for the identification of metabolites. Indeed, incubating LMP400 and LMP776 with human liver microsomes resulted in two major metabolites of each drug, which had HPLC retention times and mass fragmentation patterns identical to those of the synthetic standards. The hydroxylated indotecan and indimitecan metabolites and analogues were tested as Top1 poisons and for antiproliferative activity in a variety of human cancer cell cultures and in general were found to be very potent. Differences in activity resulting from the placement of the hydroxyl group are explained by molecular modeling analyses.

  DOI：

  10.1021/jm300519w
• 作为产物：
  描述：

  m-袂康宁 在 N-溴代丁二酰亚胺(NBS) 、 水 、 sodium methylate 、 乙酸酐 、 过氧化苯甲酰 作用下， 以 四氯化碳 、 氯仿 、 乙酸乙酯 为溶剂， 反应 141.0h， 生成 6-(3-(1H-imidazol-1-yl)propyl)-2,3-dimethoxy-5H-[1,3]dioxolo[4′,5′:5,6]indeno[1,2-c]isoquinoline-5,12(6H)-dione
  参考文献：
  名称：

  新型碳水化合物取代的茚并异喹啉拓扑异构酶 I 抑制剂的合成和生物学评价以及实验性抗癌剂 Indotecan (LMP400) 和 Indimitecan (LMP776) 的改进合成

  摘要：

  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。

  DOI：

  10.1021/jm401814y

文献信息

• 茚并异喹啉衍生物的制备方法
  申请人：姚清发

  公开号：CN109748870B

  公开（公告）日：2021-02-12

  一种如下式(I)所示的茚并异喹啉衍生物的制备方法，包括下列步骤：(A)提供一如下式(II)所示的第一反应物及一如下式(III)所示的第二反应物：其中，R1、R3、A、X、Y、Z、m及n如说明书中所定义；以及(B)将式(II)所示的第一反应物及式(III)所示的第二反应物置于一溶剂中进行反应，并选择性的添加R2NH2进行反应，以得到如式(I)所示的茚并异喹啉衍生物。
• Synthesis of Biologically Active Indenoisoquinoline Derivatives via a One-Pot Copper(II)-Catalyzed Tandem Reaction
  作者：Chia-Yu Huang、Veerababurao Kavala、Chun-Wei Kuo、Ashok Konala、Tang-Hao Yang、Ching-Fa Yao

  DOI：10.1021/acs.joc.6b02814

  日期：2017.2.17

  A concise route for the synthesis of indenoisoquinoline derivatives from 2-iodobenzamide and 1,3-indanedione derivatives in the presence of copper(II) chloride and cesium carbonate in acetonitrile solvent is reported. A wide variety of 2-iodobenzamide derivatives and indandiones could be used to synthesize indenoisoquinoline derivatives and other fused indenoisoquinoline in moderate to good yields

  据报道，在氯化铜（II）和碳酸铯存在下，在乙腈溶剂中，由2-碘联苯甲酰胺和1,3-茚满二酮衍生物合成茚并异喹啉衍生物的简便方法。各种各样的2-碘代苯甲酰胺衍生物和茚满二酮可用于以中等至良好的产率合成茚并异喹啉衍生物和其他稠合的茚并异喹啉。该方法适用于一步合成一系列临床活性拓扑异构酶I抑制剂，例如NSC 314622，LMP-400，LMP-776。
• SYNTHESIS AND USE OF DUAL TYROSYL-DNA PHOSPHODIESTERASE I (Tdp1) - TOPOISOMERASE I (Top1) INHIBITORS
  申请人：Purdue Research Foundation

  公开号：US20150133445A1

  公开（公告）日：2015-05-14

  The invention described herein pertains to the synthesis and use of certain N-substituted indenoisoquinoline compounds which inhibit the activity Tyrosyl-DNA Phosphodiesterase I (Tdp1) or Topoisomerase I (Top1) or both, or otherwise demonstrate anticancer activity. Also disclosed are novel N-substituted indenoisoquinoline compounds and pharmaceutical compositions comprising the novel N-substituted indenoisoquinoline compounds.

  本发明涉及合成和使用某些N-取代吲哚异喹啉化合物，其抑制酪氨酸-DNA磷酸二酯酶I（Tdp1）或拓扑异构酶I（Top1）或两者的活性，或表现出抗癌活性。还公开了新型N-取代吲哚异喹啉化合物和包含新型N-取代吲哚异喹啉化合物的制药组合物。
• INDENOQUINOLONE COMPOUND, PREPARATION METHOD AND USE THEREOF
  申请人：Song Yunlong

  公开号：US20130102598A1

  公开（公告）日：2013-04-25

  An indenoquinolone compounds of Formula (A) is disclosed, wherein the definition of each group is described in the description. These compounds may specifically inhibit topoisomerase I, and they have good activities against many kinds of human tumor cells, such as lung cancer, colon cancer, breast cancer, liver cancer and the like. They can be used in the manufacture of antitumor drugs. The method for preparing the compound of formula (A), and pharmaceutical compositions containing such compounds and the use in the manufacture of antitumor drugs are also disclosed.

  本发明公开了一种Formula (A)的吲哚喹啉类化合物，其中每个基团的定义在描述中说明。这些化合物可以特异性地抑制拓扑异构酶I，并且对许多种人类肿瘤细胞具有良好的活性，如肺癌、结肠癌、乳腺癌、肝癌等。它们可以用于制造抗肿瘤药物。本发明还公开了制备Formula (A)化合物的方法，以及含有这些化合物的制药组合物和用于制造抗肿瘤药物的用途。
• N-SUBSTITUTED INDENOISOQUINOLINES AND SYNTHESES THEREOF
  申请人：Purdue Research Foundation

  公开号：US20150218207A1

  公开（公告）日：2015-08-06

  N-Substituted indenoisoquinoline compounds, and pharmaceutical formulations of N-substituted indenoisoquinoline compounds are described. Also described are processes for preparing N-substituted indenoisoquinoline compounds. Also described are methods for treating cancer in mammals using the described N-substituted indenoisoquinoline compounds or pharmaceutical formulations thereof.

  本文描述了N-取代的吲哚异喹啉化合物及其药物制剂。还描述了制备N-取代的吲哚异喹啉化合物的方法。还描述了使用所述的N-取代的吲哚异喹啉化合物或其药物制剂治疗哺乳动物癌症的方法。