2-(1-(3-((2-methoxy-5-(3,4,5-trimethoxystyryl)phenoxy)carbonyl)benzyl)-1H-1,2,3-triazol-4-yl)ethyl3-((4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d][1-3]triazol-1-yl)methyl)benzoate

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 缩酚酸和缩酚酸环醚类
• 英文名称: 2-(1-(3-((2-methoxy-5-(3,4,5-trimethoxystyryl)phenoxy)carbonyl)benzyl)-1H-1,2,3-triazol-4-yl)ethyl3-((4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d][1-3]triazol-1-yl)methyl)benzoate
• 英文别名: IDO/Tubulin-IN-2；[2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl] 3-[[4-[2-[3-[(4,9-dioxobenzo[f]benzotriazol-3-yl)methyl]benzoyl]oxyethyl]triazol-1-yl]methyl]benzoate
• 化学式: C₄₈H₄₀N₆O₁₀
• 分子量: 860.88
• InChiKey: BYONMJRCXBUVGH-NXVVXOECSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.57
• 重原子数：
  64.0
• 可旋转键数：
  16.0
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  185.08
• 氢给体数：
  0.0
• 氢受体数：
  16.0

反应信息

• 作为产物：
  描述：

  (Z)-3,4,5,4',-四甲氧基-3'-羟基二苯乙烯 在 4-二甲氨基吡啶 、 copper(ll) sulfate pentahydrate 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 维生素 C 作用下， 以 乙醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 28.0h， 生成 2-(1-(3-((2-methoxy-5-(3,4,5-trimethoxystyryl)phenoxy)carbonyl)benzyl)-1H-1,2,3-triazol-4-yl)ethyl3-((4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d][1-3]triazol-1-yl)methyl)benzoate
  参考文献：
  名称：

  Microtubule inhibitors containing immunostimulatory agents promote cancer immunochemotherapy by inhibiting tubulin polymerization and tryptophan-2,3-dioxygenase

  摘要：

  A combination therapeutic regimen via introducing tryptophan 2,3-dioxygenase inhibitors into microtubule inhibitors was performed and evaluated for their antitumor activity. Thereinto, HT2, composed of combretastatin A-4 (CA-4) and tryptophan-2,3-dioxygenase (TDO) inhibitor by a linker, displayed the most potent activity with 10-fold higher than its parent CA-4 against HepG2, A549 and HCT-116 cancer cell lines. Mechanism studies suggested that HT2 inhibited tubulin polymerization and cell migration, caused G2 phase arrest, induced apoptosis by mitochondrial mediated apoptotic pathway, concurrent depolarized the mitochondria membrane potentials and caused reactive oxygen species (ROS) production in HepG2 cells. Moreover, HT2 could enhance T-cell immune responses in vitro by releasing a TDO inhibitor to suppress TDO expression and blockade kynurenine production. As expected, HT2 could remarkably promote the antitumor activity of CA-4 in either immunocompetent H22 or immunodeficient A549 tumor xenograft models without observable toxic effects. More importantly, HT2 increased the level of splenic and tumor-infiltrated T cells and in turn effectively boosted the inhibition effect in H22 xenografted tumor growth. Collectively, this immunochemotherapeutic strategy can be applied to promote chemotherapeutic effect. (C) 2019 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2019.111949

文献信息

• Microtubule inhibitors containing immunostimulatory agents promote cancer immunochemotherapy by inhibiting tubulin polymerization and tryptophan-2,3-dioxygenase
  作者：Shixian Hua、Feihong Chen、Shaohua Gou

  DOI：10.1016/j.ejmech.2019.111949

  日期：2020.2

  A combination therapeutic regimen via introducing tryptophan 2,3-dioxygenase inhibitors into microtubule inhibitors was performed and evaluated for their antitumor activity. Thereinto, HT2, composed of combretastatin A-4 (CA-4) and tryptophan-2,3-dioxygenase (TDO) inhibitor by a linker, displayed the most potent activity with 10-fold higher than its parent CA-4 against HepG2, A549 and HCT-116 cancer cell lines. Mechanism studies suggested that HT2 inhibited tubulin polymerization and cell migration, caused G2 phase arrest, induced apoptosis by mitochondrial mediated apoptotic pathway, concurrent depolarized the mitochondria membrane potentials and caused reactive oxygen species (ROS) production in HepG2 cells. Moreover, HT2 could enhance T-cell immune responses in vitro by releasing a TDO inhibitor to suppress TDO expression and blockade kynurenine production. As expected, HT2 could remarkably promote the antitumor activity of CA-4 in either immunocompetent H22 or immunodeficient A549 tumor xenograft models without observable toxic effects. More importantly, HT2 increased the level of splenic and tumor-infiltrated T cells and in turn effectively boosted the inhibition effect in H22 xenografted tumor growth. Collectively, this immunochemotherapeutic strategy can be applied to promote chemotherapeutic effect. (C) 2019 Elsevier Masson SAS. All rights reserved.