(+/-)-3'-O,4'-O-bis(3,4-dimethoxybenzoyl)-trans-khellactone

• 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: (+/-)-3'-O,4'-O-bis(3,4-dimethoxybenzoyl)-trans-khellactone
• 英文别名: [(9R,10S)-9-(3,4-dimethoxybenzoyl)oxy-8,8-dimethyl-2-oxo-9,10-dihydropyrano[2,3-f]chromen-10-yl] 3,4-dimethoxybenzoate
• 化学式: C₃₂H₃₀O₁₁
• 分子量: 590.584
• InChiKey: LLRRVYIWUFNDGZ-URLMMPGGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  43
• 可旋转键数：
  10
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  125
• 氢给体数：
  0
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  藜芦酸 、 反式-(-)-凯林内酯 在 4-二甲氨基吡啶 、 N,N'-二环己基碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 生成 (+/-)-3'-O,4'-O-bis(3,4-dimethoxybenzoyl)-trans-khellactone
  参考文献：
  名称：

  Angular Pyranocoumarins, Process for Preparation and Uses Thereof

  摘要：

  本发明涉及用于逆转癌细胞中多药耐药的化合物、组合物，以及其制备过程和在治疗癌症中的用途。更具体地，本发明涉及用于逆转P-糖蛋白过表达介导的癌细胞多药耐药的3′,4′-芳香酰氧基取代的7,8-吡喃香豆素化合物，含有吡喃香豆素的组合物，其制备过程以及在治疗癌症中的用途。

  公开号：

  US20090111836A1

文献信息

• 3′-O, 4′-O-aromatic acyl substituted 7,8-pyranocoumarins: a new class of P-glycoprotein modulators
  作者：Xiaoling Shen、Guangying Chen、Guoyuan Zhu、Jiazhong Cai、Lu Wang、Yingjie Hu、Wang-Fun Fong

  DOI：10.1111/j.2042-7158.2011.01378.x

  日期：2011.12.8

  P-glycoprotein (Pgp) overexpression in tumour cells leads to multidrug resistance (MDR) and causes failure in cancer chemotherapy. We have previously identified (±)-praeruptorin A (PA) as a potential lead compound for Pgp modulators. In this study we investigated the MDR-reversing activities of PA derivatives.

  Series 7,8-pyranocoumarins with various C-3′ and C-4′ side chains had been semi-synthesized and their MDR-reversing activity was investigated in Pgp-overexpressing MDR tumour cell line HepG2/Dox and in a KB V1 xenograft animal model.

  All 7,8-pyranocoumarins exhibited equal or higher activity in modulating Pgp. DCK (12), DMDCK (15), 16, 21, 23 and 24 at 4 µm achieved 91%∼99% decrease in IC50 value (concentration inhibiting cell growth by 50%) of anticancer agents vinblastine, doxorubicin, puromycin and paclitaxel, and were more active than others. DMDCK also remarkably enhanced the growth inhibitory effect of paclitaxel on KB V1 xenografts (P < 0.05), showing a potency required for clinical usage. Mechanistic studies suggested that these 7,8-pyranocoumarins might reverse Pgp-MDR through directly binding to substrate binding site(s) or allosteric site(s) on Pgp therefore impairing Pgp-mediated drug transport.

  Results from the study suggested that 3′-O, 4′-O-aromatic acyl substituted 7,8-pyranocoumarins could serve as a new class of Pgp modulator. Acyls play an important role in maintaining and enhancing the Pgp-modulating ability of pyranocoumarins. 3,4-Dimethoxyl substituted aromatic acyls, bearing a methoxy that might interact with Pgp as hydrogen bond accepter, were shown to be the most potent for reversing MDR.

  摘要：本研究旨在探讨(±)-praeruptorin A (PA)衍生物的多药耐药（MDR）逆转活性。我们发现，所有7,8-吡喃香豆素在调节Pgp方面表现出相等或更高的活性。其中DCK（12）、DMDCK（15）、16、21、23和24在4微米时，可以使抗癌药物长春新碱、阿霉素、普鲁霉素和紫杉醇的IC50值（抑制细胞生长50%的浓度）降低91%∼99%，比其他衍生物更活跃。DMDCK还显著增强了对KB V1异种移植动物模型中紫杉醇的生长抑制作用（P < 0.05），表现出临床应用所需的效力。机制研究表明，这些7,8-吡喃香豆素可能通过直接结合Pgp的底物结合位点或变构位点，从而损害Pgp介导的药物转运，逆转Pgp-MDR。研究结果表明，3′-O、4′-O-芳基酰基取代的7,8-吡喃香豆素可以作为一类新型Pgp调节剂。酰基在维持和增强吡喃香豆素的Pgp调节能力中起着重要作用。3,4-二甲氧基取代的芳基酰基，具有一个可能与Pgp作为氢键受体相互作用的甲氧基，被证明是最有效的逆转MDR。
• Angular Pyranocoumarins, Process for Preparation and Uses Thereof
  申请人：Fong Wangfun

  公开号：US20090111836A1

  公开（公告）日：2009-04-30

  The present invention relates to compounds, compositions for use in reversing multidrug resistance in cancer cells, process for the preparation thereof and their uses in treating cancers. More particularly, the present invention relates to 3′,4′-aromatic acyloxy substituted 7,8-pyranocoumarins compounds for use in reversing P-glycoprotein overexpression mediated multidrug resistance in cancer cells, pyranocoumarins containing compositions, process for the preparation thereof and their uses in treating cancers.

  本发明涉及用于逆转癌细胞中多药耐药的化合物、组合物，以及其制备过程和在治疗癌症中的用途。更具体地，本发明涉及用于逆转P-糖蛋白过表达介导的癌细胞多药耐药的3′,4′-芳香酰氧基取代的7,8-吡喃香豆素化合物，含有吡喃香豆素的组合物，其制备过程以及在治疗癌症中的用途。