N-(2-aminoethoxy)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide | 1596369-01-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-(2-aminoethoxy)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide
• 英文别名: N-(2-aminoethoxy)-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide
• CAS: 1596369-01-5
• 化学式: C₁₅H₁₃F₃IN₃O₂
• 分子量: 451.187
• InChiKey: WQJWGCAJXKXQQL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  24
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  76.4
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  N-(2-aminoethoxy)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide 在 吡啶 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 反应 1.5h， 生成
  参考文献：
  名称：

  Synthesis and Biological Evaluation of RGD-Conjugated MEK1/2 Kinase Inhibitors for Integrin-Targeted Cancer Therapy

  摘要：

  两种源于MEK1/2激酶抑制剂PD0325901的新型RGD-MEKI偶联物系列已被开发用于整合素受体介导的癌症治疗。第一系列，烷氧基胺类似物RGD-MEKI偶联物9a-g通过与PD0325901相同的机制在黑色素瘤A375细胞中显示出抗增殖活性。PEGylation使9f在A375测定中的IC50值增加了三倍，而多cRGD肽负载则显著提高了9g在整合素高表达的U87细胞中的受体特异性抗增殖活性。在第二系列中，RGD-PD0325901 13相比烷氧基胺类似物，通过抑制ERK通路活性和癌细胞的DNA复制，显示出显著增强的抗肿瘤特性。此外，13在U87测定中比PD0325901显示出更强的抗增殖活性，且呈剂量依赖性。所有这些数据表明，带有酯键连接的RGD-MEKI偶联物提高了对整合素高表达肿瘤细胞的靶向能力，从而增强了抗癌疗效。

  DOI：

  10.3390/molecules181113957
• 作为产物：
  描述：

  3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-N-{2-(tertbutoxycarbonylamino)ethoxy}benzamide 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 0.5h， 以90%的产率得到N-(2-aminoethoxy)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide
  参考文献：
  名称：

  具有肿瘤导向性治疗作用的多肽-药物缀合物 及其应用

  摘要：

  本发明涉及提供具有肿瘤导向性治疗作用的多肽‑药物缀合物，多肽‑药物缀合物的制备方法及其应用。本发明多肽‑药物缀合物可以特异性的将PD0325901类似物输送到整合素αvβ3过量表达的癌细胞内，进而起到对肿瘤导向性治疗的作用。

  公开号：

  CN104248770B

文献信息

• Inhibitors of MEK/PI3K, JAK/MEK, JAK/PI3K/mTOR and MEK/PI3K/mTOR biological pathways and methods for improving lymphatic uptake, bioavailability, and solubility of therapeutic compounds
  申请人：THE REGENTS OF THE UNIVERSITY OF MICHIGAN

  公开号：US11311624B2

  公开（公告）日：2022-04-26

  Inhibitors of mTOR, MEK, JAK and PI3K and compositions containing the same are disclosed. Methods of using the inhibitors in the treatment of a variety of diseases and conditions wherein inhibition of one or more of mTOR, MEK, JAK and PI3K provides a benefit also are disclosed. Methods of using chemical attachment moieties and linkers for the purposes of modifying compound solubility and/or lymphatic absorption are also disclosed.

  本研究公开了 mTOR、MEK、JAK 和 PI3K 的抑制剂以及含有这些抑制剂的组合物。还公开了使用这些抑制剂治疗各种疾病和病症的方法，其中抑制 mTOR、MEK、JAK 和 PI3K 中的一种或多种可带来益处。此外，还公开了使用化学附着分子和连接体来改变化合物溶解度和/或淋巴吸收的方法。
• Discovery of Bifunctional Oncogenic Target Inhibitors against Allosteric Mitogen-Activated Protein Kinase (MEK1) and Phosphatidylinositol 3-Kinase (PI3K)
  作者：Marcian E. Van Dort、Hao Hong、Hanxiao Wang、Charles A. Nino、Rachel L. Lombardi、Avery E. Blanks、Stefanie Galbán、Brian D. Ross

  DOI：10.1021/acs.jmedchem.5b01655

  日期：2016.3.24

  The synthesis of a series of single entity, bifunctional MEK1/PI3K inhibitors achieved by covalent linking of structural analogs of the ATP-competitive PI3K inhibitor ZSTK474 and the ATP-noncompetitive MEK inhibitor PD0325901 is described. Inhibitors displayed potent in vitro inhibition of MEK1 (0.015 < IC50 (nM) < 56.7) and PI3K (54 < IC50 (nM) < 341) in enzymatic inhibition assays. Concurrent MEK1 and PI3K inhibition was demonstrated with inhibitors 9 and 14 in two tumor cell lines (A549, D54). Inhibitors produced dose-dependent decreased cell viability similar to the combined administration of equivalent doses of ZSTK474 and PD0325901. In vivo efficacy of 14 following oral administration was demonstrated in D54 glioma and A549 lung tumor bearing mice. Compound 14 showed a 95% and 67% inhibition of tumor ERK1/2 and Akt phosphorylation, respectively, at 2 h postadministration by Western blot analysis, confirming the bioavailability and efficacy of this bifunctional inhibitor strategy toward combined MEK1/PI3K inhibition.
• INHIBITORS OF MEK/PI3K, JAK/MEK, JAK/PI3K/mTOR AND MEK/PI3K/mTOR BIOLOGICAL PATHWAYS AND METHODS FOR IMPROVING LYMPHATIC UPTAKE, BIOAVAILABILITY, AND SOLUBILITY OF THERAPEUTIC COMPOUNDS
  申请人：THE REGENTS OF THE UNIVERSITY OF MICHIGAN

  公开号：US20200164081A1

  公开（公告）日：2020-05-28

  Inhibitors of mTOR, MEK, JAK and PI3K and compositions containing the same are disclosed. Methods of using the inhibitors in the treatment of a variety of diseases and conditions wherein inhibition of one or more of mTOR, MEK, JAK and PI3K provides a benefit also are disclosed. Methods of using chemical attachment moieties and linkers for the purposes of modifying compound solubility and/or lymphatic absorption are also disclosed.
• Synthesis and Biological Evaluation of RGD-Conjugated MEK1/2 Kinase Inhibitors for Integrin-Targeted Cancer Therapy
  作者：Xiaoxiao Li、Jianjun Hou、Chao Wang、Xinjie Liu、Hongyan He、Ping Xu、Zhenjun Yang、Zili Chen、Yun Wu、Lihe Zhang

  DOI：10.3390/molecules181113957

  日期：——

  Two novel series of RGD-MEKI conjugates derived from a MEK1/2 kinase inhibitor—PD0325901—have been developed for integrin receptor mediated anticancer therapy. The first series, alkoxylamine analog RGD-MEKI conjugates 9a–g showed anti-proliferation activity in melanoma A375 cells by the same mechanism as that of PD0325901. PEGylation increased the IC50 value of 9f three-fold in the A375 assay, and the multi-cRGD peptide cargo significantly improved the receptor specific anti-proliferation activity of 9g in integrin-overexpressing U87 cells. In the second series, RGD-PD0325901 13 exhibited significantly increased antitumor properties compared to the alkoxylamine analogs by both inhibition of the ERK pathway activity and DNA replication of the cancer cells. Furthermore, 13 displayed more potent anti-proliferation activity in the U87 assay than PD0325901 in a dose-dependent manner. All these data demonstrate that RGD-MEKI conjugates with an ester bond linkage enhanced anticancer efficacy with improved targeting capability toward integrin-overexpressing tumor cells.

  两种源于MEK1/2激酶抑制剂PD0325901的新型RGD-MEKI偶联物系列已被开发用于整合素受体介导的癌症治疗。第一系列，烷氧基胺类似物RGD-MEKI偶联物9a-g通过与PD0325901相同的机制在黑色素瘤A375细胞中显示出抗增殖活性。PEGylation使9f在A375测定中的IC50值增加了三倍，而多cRGD肽负载则显著提高了9g在整合素高表达的U87细胞中的受体特异性抗增殖活性。在第二系列中，RGD-PD0325901 13相比烷氧基胺类似物，通过抑制ERK通路活性和癌细胞的DNA复制，显示出显著增强的抗肿瘤特性。此外，13在U87测定中比PD0325901显示出更强的抗增殖活性，且呈剂量依赖性。所有这些数据表明，带有酯键连接的RGD-MEKI偶联物提高了对整合素高表达肿瘤细胞的靶向能力，从而增强了抗癌疗效。
• 具有肿瘤导向性治疗作用的多肽-药物缀合物 及其应用
  申请人：北京大学

  公开号：CN104248770B

  公开（公告）日：2017-06-13

  本发明涉及提供具有肿瘤导向性治疗作用的多肽‑药物缀合物，多肽‑药物缀合物的制备方法及其应用。本发明多肽‑药物缀合物可以特异性的将PD0325901类似物输送到整合素αvβ3过量表达的癌细胞内，进而起到对肿瘤导向性治疗的作用。