bis(2,5-dioxopyrrolidin-1-yl) 2-(9H-fluoren-9-ylmethoxycarbonylamino)octanedioate | 1208999-97-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 芴
• 英文名称: bis(2,5-dioxopyrrolidin-1-yl) 2-(9H-fluoren-9-ylmethoxycarbonylamino)octanedioate
• CAS: 1208999-97-6
• 化学式: C₃₁H₃₁N₃O₁₀
• 分子量: 605.601
• InChiKey: IXFVSIFGVHHQSB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  44
• 可旋转键数：
  15
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  166
• 氢给体数：
  1
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  bis(2,5-dioxopyrrolidin-1-yl) 2-(9H-fluoren-9-ylmethoxycarbonylamino)octanedioate 、 N-(4-溴-2-氟苯基)-6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉-4-胺 在 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 24.0h， 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
• 作为产物：
  描述：

  N-羟基丁二酰亚胺 、 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)octanedioic acid 在 N,N'-二环己基碳二亚胺 作用下， 以 乙酸乙酯 为溶剂， 反应 8.0h， 生成 bis(2,5-dioxopyrrolidin-1-yl) 2-(9H-fluoren-9-ylmethoxycarbonylamino)octanedioate
  参考文献：
  名称：

  [EN] MULTIVALENT LIGANDS TARGETING VEGFR
  [FR] LIGANDS MULTIVALENTS CIBLANT VEGFR

  摘要：

  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。

  公开号：

  WO2015175750A1

文献信息

• Labeled, non-peptidic, multivalent integrin antagonist compounds; methods for synthesis and uses thereof
  申请人：The Methodist Hospital Research Institute

  公开号：US09833520B2

  公开（公告）日：2017-12-05

  Disclosed are multivalent, integrin-receptor antagonists that are useful in a variety of therapeutic, prophylactic, and/or diagnostic imaging modalities. In illustrative embodiments, such compounds have been prepared and utilized in the imaging, detection, localization, and/or quantitation of one or more samples of biological interest. Similarly, these compounds, as well as formulations comprising them, find utility in the prevention, treatment, and/or amelioration of one or more symptoms of a disease, abnormal condition, dysfunction, etc., including, for example proliferative diseases such as cancer in affected animals. In certain embodiments, fluorescently- or radio-labeled-non-peptidic, multivalent integrin αvβ3 compounds are provided. Compositions including such compounds have been shown to have utility in detecting, localizing, quantitating, and/or imaging integrin αvβ3 receptor-expressing cells, including, for example, cancer cells in vitro, in vivo, and/or in situ.

  揭示了多价整合素受体拮抗剂，可用于各种治疗、预防和/或诊断成像模式。在说明性实施例中，这些化合物已经制备并用于生物样本的成像、检测、定位和/或定量。同样，这些化合物以及包含它们的配方在预防、治疗和/或改善疾病、异常状况、功能障碍等的一个或多个症状方面具有用途，包括例如受影响动物体内的增殖性疾病如癌症。在某些实施例中，提供了荧光或放射性标记的非肽、多价整合素αvβ3化合物。包括这些化合物的组合物已被证明在检测、定位、定量和/或成像整合素αvβ3受体表达的细胞方面具有用途，包括例如癌细胞在体外、体内和/或原位。
• [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。
• Synthesis and Evaluation of a Near-Infrared Fluorescent Non-Peptidic Bivalent Integrin α_vβ₃ Antagonist for Cancer Imaging
  作者：Feng Li、Jiacheng Liu、Gouri S. Jas、Jiawei Zhang、Guoting Qin、Jiong Xing、Claudia Cotes、Hong Zhao、Xukui Wang、Laura A. Diaz、Zheng-Zheng Shi、Daniel Y. Lee、King C. P. Li、Zheng Li

  DOI：10.1021/bc900313d

  日期：2010.2.17

  Computer modeling approaches to identify new inhibitors are essentially a very sophisticated and efficient way to design drugs. In this study, a bivalent nonpeptide intergrin alpha(v)beta(3) antagonist (bivalent IA) has been synthesized on the basis of an in silico rational design approach. A near-infrared (NIR) fluorescent imaging probe has been developed from this bivalent compound. In vitro binding assays have shown that the bivalent IA (IC50 = 0.40 +/- 0.11 nM) exhibited improved integrin alpha(v)beta(3) affinity in comparison with the monovalent IA (IC50 = 22.33 +/- 4.51 nM), resulting in an over 50-fold improvement in receptor affinity. NIR imaging probe, bivalent-IA-Cy5.5 conjugate, also demonstrated significantly increased binding affinity (IC50 = 0.13 +/- 0.02 nM). Fluorescence microscopy studies showed integrin-mediated endocytosis of bivalent-IA-Cy5.5 in U87 cells which was effectively blocked by nonfluorescent bivalent IA. We also demonstrated tumor accumulation of this NIR imaging probe in U87 mouse xenografts.
• US9833520B2
  申请人：——

  公开号：US9833520B2

  公开（公告）日：2017-12-05