16-Hydroxy-15-methoxy-20-(3-morpholin-4-ylpropyl)-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 | 1415806-84-6

• 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: 16-Hydroxy-15-methoxy-20-(3-morpholin-4-ylpropyl)-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
• 英文别名: 16-hydroxy-15-methoxy-20-(3-morpholin-4-ylpropyl)-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: 1415806-84-6
• 化学式: C₂₅H₂₄N₂O₇
• 分子量: 464.475
• InChiKey: WUQCLXHVNUJADE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  34
• 可旋转键数：
  5
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  97.8
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  16-Hydroxy-15-methoxy-20-(3-morpholin-4-ylpropyl)-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 在 三甲基铵三氧化硫共聚物 、 三乙胺 作用下， 以 乙腈 为溶剂， 反应 40.0h， 以52%的产率得到2-methoxy-6-(3-morpholinopropyl)-5,12-dioxo-6,12-dihydro-5H-[1,3]dioxolo[4',5':5,6]indeno[1,2-c]isoquinolin-3-yl hydrogen sulfate
  参考文献：
  名称：

  与实验性抗癌药Indotecan（LMP400）相关的潜在前药的设计，合成和生物学评估

  摘要：

  在临床试验中，茚并异喹啉拓扑异构酶I（Top1）抑制剂是一类具有两种化合物的新型抗癌药。Indotecan（LMP400）的最新代谢研究导致发现了具有生物活性的2-羟基化类似物和3-羟基化代谢物，从而为制备这两种化合物的各种潜在酯前药提供了战略上重要的位置。当前的研究详述了两个系列的茚并异喹啉前药的设计和合成，并且还揭示了A环O-2和O-3位置上与药物DNA-中裂解的DNA链相邻的取代基是如何产生的。 Top1三元裂解复合物，影响Top1的抑制活性和细胞毒性。许多茚并异喹啉前药是具有GI 50的强效抗增殖药 在各种人类癌细胞系中，该值低于10 nM。

  DOI：

  10.1021/acs.jmedchem.6b00220
• 作为产物：
  描述：

  高香草酸 在 盐酸 、 aluminum (III) chloride 、 potassium permanganate 、 氯化亚砜 、 水 、 potassium carbonate 、 溶剂黄146 、 乙酰氯 、 sodium iodide 、 potassium hydroxide 作用下， 以 氯仿 、 水 、 硝基苯 、 N,N-二甲基甲酰胺 、 丙酮 为溶剂， 反应 98.5h， 生成 16-Hydroxy-15-methoxy-20-(3-morpholin-4-ylpropyl)-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
  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

文献信息

• [EN] PRODRUGS OF ANTICANCER AGENTS INDOTECAN AND INDIMITECAN<br/>[FR] PROMÉDICAMENTS RÉUNISSANT LES AGENTS ANTICANCÉREUX INDOTÉCAN ET INDIMITÉCAN
  申请人：PURDUE RESEARCH FOUNDATION

  公开号：WO2017136616A1

  公开（公告）日：2017-08-10

  Indenoisoquinoline topoisomerase I (Topi) inhibitors are a novel class of anticancer agents. The present invention discloses series of prodrugs of two indenoisoquinoline compounds currently in clinical trials as a potential treatment for cancers.

  Indenoisoquinoline拓扑异构酶I（Topi）抑制剂是一类新型的抗癌药物。本发明揭示了两种Indenoisoquinoline化合物的一系列前药，目前正在临床试验中作为潜在的癌症治疗方法。
• PRODRUGS OF ANTICANCER AGENTS INDOTECAN AND INDIMITECAN
  申请人：Purdue Research Foundation

  公开号：US20190218226A1

  公开（公告）日：2019-07-18

  Indenoisoquinoline topoisomerase I (Top1) inhibitors are a novel class of anticancer agents. The present invention discloses series of prodrugs of two indenoisoquinoline compounds currently in clinical trials as a potential treatment for cancers.
• 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
  作者：Maris A. Cinelli、P. V. Narasimha Reddy、Peng-Cheng Lv、Jian-Hua Liang、Lian Chen、Keli Agama、Yves Pommier、Richard B. van Breemen、Mark Cushman

  DOI：10.1021/jm300519w

  日期：2012.12.27

  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.
• Design, Synthesis, and Biological Evaluation of Potential Prodrugs Related to the Experimental Anticancer Agent Indotecan (LMP400)
  作者：Peng-Cheng Lv、Mohamed S. A. Elsayed、Keli Agama、Christophe Marchand、Yves Pommier、Mark Cushman

  DOI：10.1021/acs.jmedchem.6b00220

  日期：2016.5.26

  two series of indenoisoquinoline prodrugs, and it also reveals how substituents on the O-2 and O-3 positions of the A ring, which are next to the cleaved DNA strand in the drug-DNA-Top1 ternary cleavage complex, affect Top1 inhibitory activity and cytotoxicity. Many of the indenoisoquinoline prodrugs were very potent antiproliferative agents with GI50 values below 10 nM in a variety of human cancer cell

  在临床试验中，茚并异喹啉拓扑异构酶I（Top1）抑制剂是一类具有两种化合物的新型抗癌药。Indotecan（LMP400）的最新代谢研究导致发现了具有生物活性的2-羟基化类似物和3-羟基化代谢物，从而为制备这两种化合物的各种潜在酯前药提供了战略上重要的位置。当前的研究详述了两个系列的茚并异喹啉前药的设计和合成，并且还揭示了A环O-2和O-3位置上与药物DNA-中裂解的DNA链相邻的取代基是如何产生的。 Top1三元裂解复合物，影响Top1的抑制活性和细胞毒性。许多茚并异喹啉前药是具有GI 50的强效抗增殖药 在各种人类癌细胞系中，该值低于10 nM。