| 1473387-53-9

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• CAS: 1473387-53-9
• 化学式: C₅₀H₅₅Br₂F₂N₉O₆
• 分子量: 1075.85
• InChiKey: MTDZQTVIFGRPSQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  10.09
• 重原子数：
  69.0
• 可旋转键数：
  19.0
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  179.18
• 氢给体数：
  3.0
• 氢受体数：
  13.0

反应信息

• 作为反应物：
  描述：

  、 6-羧基荧光素琥珀酰亚胺醚 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 生成 4-[[1,8-Bis[4-[[4-(4-bromo-2-fluoroanilino)-6-methoxyquinazolin-7-yl]oxymethyl]piperidin-1-yl]-1,8-dioxooctan-2-yl]carbamoyl]-2-(3-hydroxy-6-oxoxanthen-9-yl)benzoic acid
  参考文献：
  名称：

  Specific Binding of Modified ZD6474 (Vandetanib) Monomer and Its Dimer with VEGF Receptor-2

  摘要：

  Tumor angiogenesis is an important component of cancer biology driven in part by the hypothesis that tumor vessel growth is a necessary requirement for tumor growth. Angiogenesis does not only depend on endothelial cell invasion and proliferation, it also requires pericyte coverage of vascular sprouts for vessel stabilization. These processes are coordinated by vascular endothelial growth factor (VEGF). Vandetanib, also known as ZD6474, is an orally bioavailable small molecule tyrosine kinase inhibitor of multiple growth factors that is an antagonist of the vascular endothelial growth factor receptor-2 (VEGFR-2). ZD6474 was purchased and modified to add a fluorescent dye (6-FAM). A linker was used to couple the ZD6474 monomer to create dimers, and similarly linked to FAM fluorescent dye. The two compounds were compared using human endothelial cell (HUVECs) and the cancer cell lines U-87-MG and MDA-MB-231. We compared cellular uptake and binding specificity, as well as effects on cellular viability and angiogenesis in a series of in vitro and in vivo studies. ZD6474 dimer demonstrated improved uptake in HUVECs and other VEGFR expressing cells over ZD6474 monomer in vitro. Therapeutic effects were mixed, with in vitro studies showing the dimer having the same or weaker effects compared to the monomer, while an in vivo study using pseudotumors (matrigel plug assay) seemed to indicate stronger effects could be obtained from the dimer. Finally, in biodistribution study in a xenograft tumor model, the dimer accumulated 20x greater concentration in the tumor than in the liver, spleen, or kidneys, and also 20X greater than the accumulation of the monomer or the dye alone, all at 24 h following compound injection. This study provides a rationale for the evaluation of dirneric ZD6474 as a potent imaging agent of angiogenic activity in vivo.

  DOI：

  10.1021/bc400374t
• 作为产物：
  描述：

  在 哌啶 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 生成
  参考文献：
  名称：

  Specific Binding of Modified ZD6474 (Vandetanib) Monomer and Its Dimer with VEGF Receptor-2

  摘要：

  Tumor angiogenesis is an important component of cancer biology driven in part by the hypothesis that tumor vessel growth is a necessary requirement for tumor growth. Angiogenesis does not only depend on endothelial cell invasion and proliferation, it also requires pericyte coverage of vascular sprouts for vessel stabilization. These processes are coordinated by vascular endothelial growth factor (VEGF). Vandetanib, also known as ZD6474, is an orally bioavailable small molecule tyrosine kinase inhibitor of multiple growth factors that is an antagonist of the vascular endothelial growth factor receptor-2 (VEGFR-2). ZD6474 was purchased and modified to add a fluorescent dye (6-FAM). A linker was used to couple the ZD6474 monomer to create dimers, and similarly linked to FAM fluorescent dye. The two compounds were compared using human endothelial cell (HUVECs) and the cancer cell lines U-87-MG and MDA-MB-231. We compared cellular uptake and binding specificity, as well as effects on cellular viability and angiogenesis in a series of in vitro and in vivo studies. ZD6474 dimer demonstrated improved uptake in HUVECs and other VEGFR expressing cells over ZD6474 monomer in vitro. Therapeutic effects were mixed, with in vitro studies showing the dimer having the same or weaker effects compared to the monomer, while an in vivo study using pseudotumors (matrigel plug assay) seemed to indicate stronger effects could be obtained from the dimer. Finally, in biodistribution study in a xenograft tumor model, the dimer accumulated 20x greater concentration in the tumor than in the liver, spleen, or kidneys, and also 20X greater than the accumulation of the monomer or the dye alone, all at 24 h following compound injection. This study provides a rationale for the evaluation of dirneric ZD6474 as a potent imaging agent of angiogenic activity in vivo.

  DOI：

  10.1021/bc400374t

文献信息

• Single‐Molecule Force Measurement Guides the Design of Multivalent Ligands with Picomolar Affinity
  作者：Zhen Yang、Sheng Jiang、Feng Li、Yatao Qiu、Jianhua Gu、Roderic I. Pettigrew、Mauro Ferrari、Dale J. Hamilton、Zheng Li

  DOI：10.1002/anie.201814347

  日期：2019.4.8

  this to assess the geometry of appropriate linkers for distinct multivalent binding modes. A tetravalent lead ZD‐4, which was developed from an antitumor drug ZD6474 (Vandetanib) with combined hybrid binding effects, yielded a 2000‐fold improvement in the binding affinity to VEGFR with IC50 value of 25 pm. We confirmed the improved affinity by the associated increase of tumor uptake in the VEGFR‐targeting

  多种实体和受体或多价的相互作用被广泛用于获得用于诊断和治疗目的的高亲和力配体。然而，缺乏关于活体受体分布的知识仍然是合理结构设计的挑战。在这里，我们开发了一个力测量平台来探测活细胞中细胞表面血管内皮生长因子受体 (VEGFR) 的分布和分离，并使用它来评估不同多价结合模式的适当接头的几何形状。由抗肿瘤药物 ZD6474 (Vandetanib) 开发的四价先导 ZD-4 具有组合的混合结合效应，与 VEGFR 的结合亲和力提高了 2000 倍，IC 50值为 25 p m. 我们通过使用 U87 肿瘤异种移植小鼠模型的 VEGFR 靶向正电子发射断层扫描 (PET) 成像中肿瘤摄取的相关增加证实了亲和力的提高。
• [EN] MULTIVALENT LIGANDS TARGETING VEGFR<br/>[FR] LIGANDS MULTIVALENTS CIBLANT VEGFR
  申请人：METHODIST HOSPITAL SYSTEM

  公开号：WO2015175750A1

  公开（公告）日：2015-11-19

  Compounds that target vascular endothelial growth factor receptors for therapy and imaging are disclosed. Methods for making the compounds and detecting or imaging cells expressing VEGFR using the compounds are also provided. In accordance with the purposes of the disclosed subject matter, as embodied and broadly described herein, disclosed are compounds, and methods of making and using the compounds. The disclosed compounds, in one aspect, are quinazoline compounds.

  揭示了针对血管内皮生长因子受体进行治疗和成像的化合物。还提供了制备这些化合物、以及使用这些化合物检测或成像表达VEGFR的细胞的方法。根据所披露主题的目的，如本文所体现和广泛描述的，披露了化合物及制备和使用这些化合物的方法。所披露的化合物在一个方面是喹唑啉化合物。
• [EN] MULTIVALENT LIGANDS TARGETING CELL SURFACE RECEPTORS AND FORCE MEASUREMENT PLATFORM FOR MAKING THE SAME<br/>[FR] LIGANDS MULTIVALENTS CIBLANT DES RÉCEPTEURS DE SURFACE CELLULAIRE ET PLATEFORME DE MESURE DE FORCE POUR LEUR FABRICATION
  申请人：THE METHODIST HOSPITAL SYSTEM

  公开号：WO2021155151A1

  公开（公告）日：2021-08-05

  Methods for probing the distribution and distance of the cell surface receptors and using the same to make multivalent ligands targeting said receptors are disclosed. Methods for making the multivalent ligands and detecting or imaging cells expressing receptors using the compounds are also provided.

  本发明揭示了探测细胞表面受体分布和距离的方法，并利用这些方法制备多价配体，以靶向所述受体。本发明还提供了制备多价配体以及使用该化合物检测或成像表达受体的细胞的方法。