8,9-dihydro-3,11-diisopropoxy-2,12-dimethoxy-6H-[1]benzopyrano[4',3':4,5]pyrrolo[2,1-a]isoquinolin-6-one | 660397-47-7

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 香豆素及其衍生物
• 英文名称: 8,9-dihydro-3,11-diisopropoxy-2,12-dimethoxy-6H-[1]benzopyrano[4',3':4,5]pyrrolo[2,1-a]isoquinolin-6-one
• 英文别名: 8,16-Dimethoxy-7,17-di(propan-2-yloxy)-4-oxa-1-azapentacyclo[11.8.0.02,11.05,10.014,19]henicosa-2(11),5,7,9,12,14,16,18-octaen-3-one
• CAS: 660397-47-7
• 化学式: C₂₇H₂₉NO₆
• 分子量: 463.53
• InChiKey: FTQZXTUHATVOHX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  34
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  68.2
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  8,9-dihydro-3,11-diisopropoxy-2,12-dimethoxy-6H-[1]benzopyrano[4',3':4,5]pyrrolo[2,1-a]isoquinolin-6-one 在 N-溴代丁二酰亚胺(NBS) 、 四(三苯基膦)钯 、 cesium fluoride 、 2,3-二氯-5,6-二氰基-1,4-苯醌 、 silver(l) oxide 作用下， 以 乙二醇二甲醚 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 66.0h， 生成 3,11-diisopropoxy-14-(3-isopropoxy-4-methoxyphenyl)-2,12-dimethoxy-6H-[1]benzopyrano[4',3':4,5]pyrrolo[2,1-a]-isoquinolin-6-one
  参考文献：
  名称：

  Synthesis, Resolution, and Biological Evaluation of Atropisomeric (aR)- and (aS)-16-Methyllamellarins N: Unique Effects of the Axial Chirality on the Selectivity of Protein Kinases Inhibition

  摘要：

  The total synthesis of the optically active (aR)- and (aS)-16-methyllamellarins N (3a and 3b) was achieved via resolution on HPLC chiral stationary phase. The kinase inhibitory activities of both enantiomers were evaluated on eight protein Icinases relevant to cancer and neurodegenerative diseases (CDKI/cyclin B, CDK2/cyclin A, CDK5/p25, GSK-3 alpha/beta, PIM1, DYRK1A, CLIO, and CK1). Isomer (aR)-3b exhibited potent but nonselective inhibition on all protein kinases except CK1, while (aS)-3a selectively inhibited only GSK-3 alpha/beta, PIM1, and DYRKIA. The different inhibition profiles of (aS)-3a and (aR)-3b were elucidated by docking simulation studies. Although parental lamellarin N (2) inhibited the action of topoisomerase I, both (aS)-3a and (aR)-3b showed no inhibition of this enzyme. The phenotypic scytotoxic activities of 2, (aS)-3a, and (aR)-3b on three cancer cell lines (HeLa, SH-SYSY, and IMR32) changed according to their topoisomerase I and protein kinase inhibitory activities.

  DOI：

  10.1021/jm400719y
• 作为产物：
  描述：

  3-[2-(2-bromo-5-isopropoxy-4-methoxyphenyl)ethyl]-7-isopropoxy-8-methoxy[1]benzopyrano[3,4-b]pyrrol-4(3H)-one 在 四(三苯基膦)钯 、 potassium carbonate 作用下， 以 N,N-二甲基乙酰胺 为溶剂， 反应 20.0h， 以89%的产率得到8,9-dihydro-3,11-diisopropoxy-2,12-dimethoxy-6H-[1]benzopyrano[4',3':4,5]pyrrolo[2,1-a]isoquinolin-6-one
  参考文献：
  名称：

  靶向拓扑异构酶I的Lamellarin D类似物的设计与合成

  摘要：

  已经开发了一种一般的合成路线，以合理设计lamellarin D类似物，1-dearyllamellarin D（1）和1-取代的1-dearyllamellarin D（2）。关键的五环中间体22是通过钯催化的12的直接芳基化制备的，该芳基化反应又是通过15的C-2-选择性锂化反应，然后通过钯催化的交叉偶联作为关键反应而合成的。通过区域选择性亲电取代和钯催化的交叉偶联反应，将化合物22转化为多种C-1-取代的类似物2。

  DOI：

  10.1021/jo901589e

文献信息

• [EN] ANTITUMORAL ANALOGS OF LAMELLARINS<br/>[FR] ANALOGUES ANTITUMORAUX DE LAMELLARINES
  申请人：PHARMA MAR SAU

  公开号：WO2004014917A3

  公开（公告）日：2004-05-13
• Rotational Energy Barrier around the C1–C11 Single Bond in Lamellarins: A Study by Variable-Temperature NMR
  作者：Masatomo Iwao、Tsutomu Fukuda、Ryosuke Itoyama、Terufusa Minagawa

  DOI：10.3987/com-13-s(s)69

  日期：——

  In order to estimate the free energy barrier to rotation around the C1-C11 single bond in lamellarins, new lamellarin analogues (1a), (1b), (2a), and (2b) possessing diastereotopic protons or carbons at the C1 aryl moiety were synthesized. Variable-temperature H-1 and C-13 NMR measurements of these analogues revealed that the free energy barriers to rotation around the C1-C11 axis in 5,6-saturated and 5,6-unsaturated lamellarins were around 72-74 and 83-87 kJ/mol, respectively.
• Design and Synthesis of Lamellarin D Analogues Targeting Topoisomerase I
  作者：Takeshi Ohta、Tsutomu Fukuda、Fumito Ishibashi、Masatomo Iwao

  DOI：10.1021/jo901589e

  日期：2009.11.6

  synthetic route to rationally designed lamellarin D analogues, 1-dearyllamellarin D (1) and 1-substituted 1-dearyllamellarin D (2), has been developed. The key pentacyclic intermediate 22 was prepared by palladium-catalyzed direct arylation of 12, which in turn was synthesized via C-2-selective lithiation of 15 followed by palladium-catalyzed cross-coupling as the key reactions. Compound 22 was converted

  已经开发了一种一般的合成路线，以合理设计lamellarin D类似物，1-dearyllamellarin D（1）和1-取代的1-dearyllamellarin D（2）。关键的五环中间体22是通过钯催化的12的直接芳基化制备的，该芳基化反应又是通过15的C-2-选择性锂化反应，然后通过钯催化的交叉偶联作为关键反应而合成的。通过区域选择性亲电取代和钯催化的交叉偶联反应，将化合物22转化为多种C-1-取代的类似物2。
• Synthesis, Resolution, and Biological Evaluation of Atropisomeric (a<i>R</i>)- and (a<i>S</i>)-16-Methyllamellarins N: Unique Effects of the Axial Chirality on the Selectivity of Protein Kinases Inhibition
  作者：Kenyu Yoshida、Ryosuke Itoyama、Masashi Yamahira、Junji Tanaka、Nadège Loaëc、Olivier Lozach、Emilie Durieu、Tsutomu Fukuda、Fumito Ishibashi、Laurent Meijer、Masatomo Iwao

  DOI：10.1021/jm400719y

  日期：2013.9.26

  The total synthesis of the optically active (aR)- and (aS)-16-methyllamellarins N (3a and 3b) was achieved via resolution on HPLC chiral stationary phase. The kinase inhibitory activities of both enantiomers were evaluated on eight protein Icinases relevant to cancer and neurodegenerative diseases (CDKI/cyclin B, CDK2/cyclin A, CDK5/p25, GSK-3 alpha/beta, PIM1, DYRK1A, CLIO, and CK1). Isomer (aR)-3b exhibited potent but nonselective inhibition on all protein kinases except CK1, while (aS)-3a selectively inhibited only GSK-3 alpha/beta, PIM1, and DYRKIA. The different inhibition profiles of (aS)-3a and (aR)-3b were elucidated by docking simulation studies. Although parental lamellarin N (2) inhibited the action of topoisomerase I, both (aS)-3a and (aR)-3b showed no inhibition of this enzyme. The phenotypic scytotoxic activities of 2, (aS)-3a, and (aR)-3b on three cancer cell lines (HeLa, SH-SYSY, and IMR32) changed according to their topoisomerase I and protein kinase inhibitory activities.