10-(4-hydroxy-3,5-dimethoxyphenyl)-4-(2-hydroxyethyl)-3,4,6,7.8,10-hexahydro-2-oxa-4-aza-dicyclopenta[b,g]naphthalen-1-one | 1334323-86-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 10-(4-hydroxy-3,5-dimethoxyphenyl)-4-(2-hydroxyethyl)-3,4,6,7.8,10-hexahydro-2-oxa-4-aza-dicyclopenta[b,g]naphthalen-1-one
• 英文别名: 8-(4-Hydroxy-3,5-dimethoxyphenyl)-2-(2-hydroxyethyl)-5-oxa-2-azatetracyclo[7.7.0.03,7.011,15]hexadeca-1(9),3(7),10,15-tetraen-6-one
• CAS: 1334323-86-2
• 化学式: C₂₄H₂₅NO₆
• 分子量: 423.466
• InChiKey: KLVSBBRWPFKCDD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  31
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  88.5
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  5-氨基茚旦 在 吡啶 、 乙醇 、 potassium hydroxide 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 生成 10-(4-hydroxy-3,5-dimethoxyphenyl)-4-(2-hydroxyethyl)-3,4,6,7.8,10-hexahydro-2-oxa-4-aza-dicyclopenta[b,g]naphthalen-1-one
  参考文献：
  名称：

  Identification of the First Inhibitor of the GBP1:PIM1 Interaction. Implications for the Development of a New Class of Anticancer Agents against Paclitaxel Resistant Cancer Cells

  摘要：

  Class III beta-tubulin plays a prominent role in the development of drug resistance to paclitaxel by allowing the incorporation of the GBP1 GTPase into microtubules. Once in the cytoskeleton. GBP1 binds to prosurvival kinases such as PIM1 and initiates a signaling pathway that induces resistance to paclitaxel. Therefore, the inhibition of the GBP1:PIM1 interaction could potentially revert resistance to paclitaxel. A panel of 44 4-azapodophyllotoxin. derivatives was screened in the NCI-60 cell panel. The result is that 31 are active and the comparative analysis demonstrated specific activity in paclitax el-resistant cells, Using surface plasmon resonance, we were able to prove that NSC756093 is a potent in vitro inhibitor of the GBP1:PIM1 interaction and that this property is maintained in vivo in ovarian cancer cells resistant to paclitaxel. Through bioinformatics, molecular modeling and mutagenesis studies, we identified the putative NSC756093 binding site at the interface between the helical and the LG domain of GBP1. According to our results by binding to this site the NSC756093 compound is able to stabilize a conformation of GBP1 not suitable for binding to PIM1.

  DOI：

  10.1021/jm5009902

文献信息

• Method for Immunomodulation of using Aza-podophyllotoxin derivatives
  申请人：Kumar Ajay

  公开号：US20160250305A1

  公开（公告）日：2016-09-01

  Disclosed is the novel use of some Aza-podophyllotoxin derivatives (AZPs) for modulation of the immune system (immunomodulation), including a method for modulating an immune response comprising administering to a subject an effective amount of at least one Aza-podophyllotoxin derivative of general formula wherein A-ring is selected from the group consisting of 1,3-dioxolane, cyclopentane, 1,4-dioxane, one methoxy, two methoxys, and ethyl; and wherein E-ring is selected from the group consisting of dimethoxyanisole, veratrol, anisole, benzene, syringol, bromobenzene, chlorobenzene, 1,2-dichlorobenzene, 2,3-dimethoxybenzene, 3,4,5-trimethoxybenzene.
• Identification of the First Inhibitor of the GBP1:PIM1 Interaction. Implications for the Development of a New Class of Anticancer Agents against Paclitaxel Resistant Cancer Cells
  作者：Mirko Andreoli、Marco Persico、Ajay Kumar、Nausicaa Orteca、Vineet Kumar、Antonella Pepe、Sakkarapalayam Mahalingam、Antonio E. Alegria、Lella Petrella、Laima Sevciunaite、Alessia Camperchioli、Marisa Mariani、Antonio Di Dato、Ettore Novellino、Giovanni Scambia、Sanjay V. Malhotra、Cristiano Ferlini、Caterina Fattorusso

  DOI：10.1021/jm5009902

  日期：2014.10.9

  Class III beta-tubulin plays a prominent role in the development of drug resistance to paclitaxel by allowing the incorporation of the GBP1 GTPase into microtubules. Once in the cytoskeleton. GBP1 binds to prosurvival kinases such as PIM1 and initiates a signaling pathway that induces resistance to paclitaxel. Therefore, the inhibition of the GBP1:PIM1 interaction could potentially revert resistance to paclitaxel. A panel of 44 4-azapodophyllotoxin. derivatives was screened in the NCI-60 cell panel. The result is that 31 are active and the comparative analysis demonstrated specific activity in paclitax el-resistant cells, Using surface plasmon resonance, we were able to prove that NSC756093 is a potent in vitro inhibitor of the GBP1:PIM1 interaction and that this property is maintained in vivo in ovarian cancer cells resistant to paclitaxel. Through bioinformatics, molecular modeling and mutagenesis studies, we identified the putative NSC756093 binding site at the interface between the helical and the LG domain of GBP1. According to our results by binding to this site the NSC756093 compound is able to stabilize a conformation of GBP1 not suitable for binding to PIM1.