methyl 3-((3-bromo-6-oxo-6H-anthra[1,9-cd]isoxazol-5-yl)amino)benzoate | 1396601-91-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 蒽
• 英文名称: methyl 3-((3-bromo-6-oxo-6H-anthra[1,9-cd]isoxazol-5-yl)amino)benzoate
• 英文别名: Methyl 3-[(12-bromo-8-oxo-15-oxa-14-azatetracyclo[7.6.1.02,7.013,16]hexadeca-1(16),2,4,6,9,11,13-heptaen-10-yl)amino]benzoate
• CAS: 1396601-91-4
• 化学式: C₂₂H₁₃BrN₂O₄
• 分子量: 449.26
• InChiKey: BLQDNJUTETXJLI-UHFFFAOYSA-N

物化性质

• 沸点：
  636.8±55.0 °C(Predicted)
• 密度：
  1.633±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  81.4
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  methyl 3-((3-bromo-6-oxo-6H-anthra[1,9-cd]isoxazol-5-yl)amino)benzoate 在 1-羟基苯并三唑 、 1,2-二氯乙烷 、 N,N-二异丙基乙胺 、 sodium hydroxide 作用下， 以 甲醇 、 二氯甲烷 、 水 、 乙腈 为溶剂， 反应 22.0h， 生成
  参考文献：
  名称：

  重新设计对转移性癌症的免疫反应：靶向尿激酶受体的抗体招募小分子

  摘要：

  制定治疗转移性癌症的选择性策略仍然是一项重大挑战。在此，我们报道了首个能够识别尿激酶型纤溶酶原激活物受体（uPAR）（一种独特的过表达的癌细胞表面标志物）并促进免疫介导的癌细胞破坏的抗体招募小分子（ARM）。获得了ARM-U2 / uPAR复合物的共晶体结构，代表了与非肽配体复合的uPAR的第一个晶体结构。最后，我们证明了ARM-U2与照护标准药物阿霉素不同，在没有体重减轻迹象的情况下可在体内显着抑制肿瘤生长。这项工作强调了抗体募集分子作为治疗癌症的免疫疗法的前景。

  DOI：

  10.1002/anie.201510866
• 作为产物：
  描述：

  5-羟基对萘醌 在 aluminum (III) chloride 、 硫酸 、 溴 、 potassium carbonate 、 potassium iodide 、 氯乙酰胺 、 sodium nitrite 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 76.0h， 生成 methyl 3-((3-bromo-6-oxo-6H-anthra[1,9-cd]isoxazol-5-yl)amino)benzoate
  参考文献：
  名称：

  重新设计对转移性癌症的免疫反应：靶向尿激酶受体的抗体招募小分子

  摘要：

  制定治疗转移性癌症的选择性策略仍然是一项重大挑战。在此，我们报道了首个能够识别尿激酶型纤溶酶原激活物受体（uPAR）（一种独特的过表达的癌细胞表面标志物）并促进免疫介导的癌细胞破坏的抗体招募小分子（ARM）。获得了ARM-U2 / uPAR复合物的共晶体结构，代表了与非肽配体复合的uPAR的第一个晶体结构。最后，我们证明了ARM-U2与照护标准药物阿霉素不同，在没有体重减轻迹象的情况下可在体内显着抑制肿瘤生长。这项工作强调了抗体募集分子作为治疗癌症的免疫疗法的前景。

  DOI：

  10.1002/anie.201510866

文献信息

• [EN] SMALL MOLECULE BASED ANTIBODY-RECRUITING COMPOUNDS FOR CANCER TREATMENT<br/>[FR] COMPOSÉS DE RECRUTEMENT D'ANTICORPS À BASE DE PETITES MOLÉCULES POUR LE TRAITEMENT DU CANCER
  申请人：UNIV YALE

  公开号：WO2017023994A1

  公开（公告）日：2017-02-09

  The present invention relates to chimeric (including bifunctional) compounds, compositions comprising those compounds and methods of treating cancer in a patient or subject, especially including metastatic cancer where cancer cells exhibit overexpression (heightened expression) of cell surface urokinase-type plasminogen activator receptor (urokinase receptor) compared to normal (non-cancerous) cells. The compounds bind to the urokinase-type plasminogen activator receptor (uPAR) on the surface of a cancer cell, including a metastatic cancer cell, and consequently recruit native antibodies of the patient or subject where the antibodies can selectively degrade and/or deactivate targeted cancer cells through antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity (ADCC) and/or complement dependent cytotoxicity (CDC) against a large number and variety of cancers, thus providing cancer cell death and an inhibition of growth, elaboration and/or metastasis of the cancer, including remission and cure of the patient's cancer.

  本发明涉及嵌合（包括双功能）化合物，包含这些化合物的组合物以及治疗患者或受试者癌症的方法，特别是包括转移性癌症，其中癌细胞相对于正常（非癌细胞）细胞表现出细胞表面尿激酶型纤溶酶原激活剂受体（尿激酶受体）的过表达（增强表达）。这些化合物与癌细胞表面的尿激酶型纤溶酶原激活剂受体（uPAR）结合，包括转移性癌细胞，从而招募患者或受试者的天然抗体，这些抗体可以通过抗体依赖性细胞吞噬和抗体依赖性细胞毒性（ADCC）和/或补体依赖性细胞毒性（CDC）选择性地降解和/或使靶向的癌细胞失活，针对大量和各种癌症，从而提供癌细胞死亡并抑制癌症的生长、扩散和/或转移，包括患者癌症的缓解和治愈。
• [EN] uPAR-uPA INTERACTION INHIBITORS AND METHODS FOR TREATING CANCER<br/>[FR] INHIBITEURS D'INTERACTION UPAR-UPA ET PROCÉDÉS POUR TRAITER LE CANCER
  申请人：UNIV INDIANA RES & TECH CORP

  公开号：WO2012119079A1

  公开（公告）日：2012-09-07

  The invention described herein pertains to compounds, compositions and formulations comprising the compounds, and methods for use of the compounds, compositions and/or formulations in the treatment of diseases responsive to the inhibition of uPAR-uPA interactions, such as cancer.

  本发明涉及化合物、组合物和制剂，其中包括这些化合物，以及使用这些化合物、组合物和/或制剂治疗对uPAR-uPA相互作用抑制有反应的疾病（如癌症）的方法。
• Small-molecule inhibition of the uPAR·uPA interaction: Synthesis, biochemical, cellular, in vivo pharmacokinetics and efficacy studies in breast cancer metastasis
  作者：Timmy Mani、Fang Wang、William Eric Knabe、Anthony L. Sinn、May Khanna、Inha Jo、George E. Sandusky、George W. Sledge、David R. Jones、Rajesh Khanna、Karen E. Pollok、Samy O. Meroueh

  DOI：10.1016/j.bmc.2012.12.047

  日期：2013.4

  The uPAR.uPA protein-protein interaction (PPI) is involved in signaling and proteolytic events that promote tumor invasion and metastasis. A previous study had identified 4 (IPR-803) from computational screening of a commercial chemical library and shown that the compound inhibited uPAR.uPA PPI in competition biochemical assays and invasion cellular studies. Here, we synthesize 4 to evaluate in vivo pharmacokinetic (PK) and efficacy studies in a murine breast cancer metastasis model. First, we show, using fluorescence polarization and saturation transfer difference (STD) NMR, that 4 binds directly to UPAR with sub-micromolar affinity of 0.2 mu M. We show that 4 blocks invasion of breast MDA-MB-231, and inhibits matrix metalloproteinase (MMP) breakdown of the extracellular matrix (ECM). Derivatives of 4 also inhibited MMP activity and blocked invasion in a concentration-dependent manner. Compound 4 also impaired MDA-MB-231 cell adhesion and migration. Extensive in vivo PK studies in NOD-SCID mice revealed a half-life of nearly 5 h and peak concentration of 5 mu M. Similar levels of the inhibitor were detected in tumor tissue up to 10 h. Female NSG mice inoculated with highly malignant TMD-MDA-MB-231 in their mammary fat pads showed that 4 impaired metastasis to the lungs with only four of the treated mice showing severe or marked metastasis compared to ten for the untreated mice. Compound 4 is a promising template for the development of compounds with enhanced PK parameters and greater efficacy. (C) 2013 Elsevier Ltd. All rights reserved.
• SMALL MOLECULE BASED ANTIBODY-RECRUITING COMPOUNDS FOR CANCER TREATMENT
  申请人：YALE UNIVERSITY

  公开号：US20180155332A1

  公开（公告）日：2018-06-07

  The present invention relates to chimeric (including bifunctional) compounds, compositions comprising those compounds and methods of treating cancer in a patient or subject, especially including metastatic cancer where cancer cells exhibit overexpression (heightened expression) of cell surface urokinase-type plasminogen activator receptor (urokinase receptor) compared to normal (non-cancerous) cells. The compounds bind to the urokinase-type plasminogen activator receptor (uPAR) on the surface of a cancer cell, including a metastatic cancer cell, and consequently recruit native antibodies of the patient or subject where the antibodies can selectively degrade and/or deactivate targeted cancer cells through antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity (ADCC) and/or complement dependent cytotoxicity (CDC) against a large number and variety of cancers, thus providing cancer cell death and an inhibition of growth, elaboration and/or metastasis of the cancer, including remission and cure of the patient's cancer.
• US9376406B2
  申请人：——

  公开号：US9376406B2

  公开（公告）日：2016-06-28