UPR 1157 | 1233953-79-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: UPR 1157
• 英文别名: N-(4-(3-bromoanilino)quinazolin-6-yl)-3-(dimethylamino)propanamide；N-[4-(3-bromoanilino)quinazolin-6-yl]-3-(dimethylamino)propanamide
• CAS: 1233953-79-1
• 化学式: C₁₉H₂₀BrN₅O
• 分子量: 414.305
• InChiKey: FGNHHQRGJTYKKZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  26
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  70.2
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  2-氰基-4-硝基苯胺 在 氯化亚砜 、 硫酸 、 铁粉 、 溶剂黄146 、 potassium iodide 作用下， 以 1,4-二氧六环 、 乙醇 、 水 为溶剂， 反应 14.25h， 生成 UPR 1157
  参考文献：
  名称：

  Irreversible Inhibition of Epidermal Growth Factor Receptor Activity by 3-Aminopropanamides

  摘要：

  Irreversible epidermal growth factor receptor (EGFR) inhibitors contain a reactive warhead which covalently interacts with a conserved cysteine residue in the kinase domain. The acrylamide fragment, a commonly employed warhead, effectively alkylates Cys797 of EGFR, but its reactivity can cause rapid metabolic deactivation or nonspecific reactions with off-targets. We describe here a new series of irreversible inhibitors containing a 3-aminopropanamide linked in position 6 to 4-anilinoquinazoline or 4-anilinoquinoline-3-carbonitrile driving portions. Some of these compounds proved to be as efficient as their acrylamide analogues in inhibiting EGFR-TK (TK = tyrosine kinase) autophosphorylation in A549 lung cancer cells. Moreover, several 3-aminopropanamides suppressed proliferation of gefitinib-resistant H1975 cells, harboring the T790M mutation in EGFR, at significantly lower concentrations than did gefitinib. A prototypical compound, N-(4-(3-bromoanilino)quinazolin-6-yl)-3-(dimethylamino)propanamide (5), did not show covalent binding to cell-free EGFR-TK in a fluorescence assay, while it underwent selective activation in the intracellular environment, releasing an acrylamide derivative which can react with thiol groups.

  DOI：

  10.1021/jm201507x

文献信息

• [EN] IRREVERSIBLE EGFR INHIBITOR COMPOUNDS WITH ANTIPROLIFERATIVE ACTIVITY<br/>[FR] COMPOSÉS INHIBITEURS IRRÉVERSIBLES DE L'EGFR DOTÉS D'UNE ACTIVITÉ ANTIPROLIFÉRATIVE
  申请人：UNIV PARMA

  公开号：WO2010076764A1

  公开（公告）日：2010-07-08

  The invention concerns a derivative of Formule (VII) wherein R27, R28 are, independently of each other, hydrogen, (C1-C6)alkyl, (CH2)n- COOR33, (CH2)n-CONR33R34, (CH2)n-NR33R34 or (CH2)n-morpholine; or NR27R28 is — N N-R27 selected from morpholine, piperidine and Formula (VIII), where R33, R34 are, independently, hydrogen or (C1-C6)alkyl; R29 is hydrogen or (C1-C6)alkyl; R30 is hydrogen or -OR35, where R35 is (C1-C6)alkyl, (CH2)n-NR33R34 or (CH2)n-piperidine or (CH2)n-morpholine, where R33, R34 are, independently, hydrogen or (C1-C6)alkyl; Y is a nitrogen atom or a carbon atom substituted by a cyano group; R31 and R32 are, independently of each other, hydrogen, bromine, chlorine, fluorine, ethinyl or methyl; X is hydrogen, bromine, chlorine, fluorine or -O(CH2)n-Q; Q is an aryl or heteroaryl group, optionally substituted by one or more substituents selected, independently of each other, from hydrogen, chlorine, fluorine, the CF3 radical or - NO2; n is a whole number selected from 0, 1, 2, 3, 4, 5, or 6. The derivatives of the invention are used as irreversible EGFR inhibitors with antiproliferative activity.

  本发明涉及Formule（VII）的衍生物，其中R27，R28分别独立地是氢，（C1-C6）烷基，（CH2）n- COOR33，（ ）n-CONR33R34，（ ）n-NR33R34或（ ）n-吗啉；或NR27R28是所选自吗啉，哌啶和Formula（VIII）的— N N-R27，其中R33，R34独立地是氢或（C1-C6）烷基；R29是氢或（C1-C6）烷基；R30是氢或-OR35，其中R35是（C1-C6）烷基，（ ）n-NR33R34或（ ）n-哌啶或（ ）n-吗啉，其中R33，R34独立地是氢或（C1-C6）烷基；Y是氮原子或被氰基取代的碳原子；R31和R32独立地是氢，溴，氯，氟，乙炔或甲基；X是氢，溴，氯，氟或-O（ ）n-Q；Q是芳基或杂环芳基，可选地由一个或多个取代基取代，所选自氢，氯，氟，三氟甲基基团或-NO2；n是选自0，1，2，3，4，5或6的整数。本发明的衍生物被用作具有抗增殖活性的不可逆EGFR抑制剂。
• Long-lasting inhibition of EGFR autophosphorylation in A549 tumor cells by intracellular accumulation of non-covalent inhibitors
  作者：Federica Vacondio、Caterina Carmi、Elena Galvani、Michele Bassi、Claudia Silva、Alessio Lodola、Silvia Rivara、Andrea Cavazzoni、Roberta R. Alfieri、Pier Giorgio Petronini、Marco Mor

  DOI：10.1016/j.bmcl.2013.08.008

  日期：2013.10

  In the present study, a small set of reversible or irreversible 4-anilinoquinazoline EGFR inhibitors was tested in A549 cells at early (1 h) and late (8 h) time points after inhibitor removal from culture medium. A combination of assays was employed to explain the observed long-lasting inhibition of EGFR autophosphorylation. We found that EGFR inhibition at 8 h can be due, besides to the covalent interaction of the inhibitor with Cys797, as for PD168393 (2) and its prodrug 4, to the intracellular accumulation of non-covalent inhibitors by means of an active cell uptake, as for 5 and 6. Compounds 5-6 showed similar potency and duration of inhibition of EGFR autophosphorylation as the covalent inhibitor 2, while being devoid of reactive groups forming covalent bonds with protein thiols. (C) 2013 Elsevier Ltd. All rights reserved.