3-[5-{4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl}furan-2-yl]-N-hydroxyacrylamide hydrochloride | 1152131-95-7

• 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: 3-[5-{4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl}furan-2-yl]-N-hydroxyacrylamide hydrochloride
• 英文别名: (E)-3-(5-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]quinazolin-6-yl}furan-2-yl)-N-hydroxy-acrylamide hydrochloride
• CAS: 1152131-95-7
• 化学式: C₂₈H₂₀ClFN₄O₄*ClH
• 分子量: 567.404
• InChiKey: ICPUFDONZGBGAI-RVDQCCQOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.95
• 重原子数：
  39.0
• 可旋转键数：
  8.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.04
• 拓扑面积：
  109.51
• 氢给体数：
  3.0
• 氢受体数：
  7.0

反应信息

• 作为产物：
  描述：

  6-碘-4(H)-喹唑啉酮 在 盐酸 、 bis(triphenylphosphine)palladium(II) dichloride 、 水 、 sodium carbonate 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 三乙胺 、 三氟乙酸 、 sodium hydroxide 、 三氯氧磷 作用下， 以 甲醇 、 乙二醇二甲醚 、 乙醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 63.5h， 生成 3-[5-{4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl}furan-2-yl]-N-hydroxyacrylamide hydrochloride
  参考文献：
  名称：

  Novel Chimeric Histone Deacetylase Inhibitors: A Series of Lapatinib Hybrides as Potent Inhibitors of Epidermal Growth Factor Receptor (EGFR), Human Epidermal Growth Factor Receptor 2 (HER2), and Histone Deacetylase Activity

  摘要：

  Reversible lysine-specific acetylation has been described as an important posttranslational modification, regulating chromatin structure and transcriptional activity in the case of core histone proteins. Histone deacetylases (HDAC) are considered as a promising target for anticancer drug development, with 2a as pan-HDAC inhibitor approved for cutanous T-cell lymphoma therapy and several other HDAC inhibitors currently in preclinical and clinical development. Protein kinases are a well-established target for cancer therapy with the EGFR/HER2 inhibitor 5 approved for treatment of advanced, HER2 positive breast cancer as a prominent example. In the present report, we present a novel strategy for cancer drug development by combination of EGFR/HER2 kinase and HDAC inhibitory activity in one molecule. By combining the structural features of 5 with an (E)-3-(aryl)-N-hydroxyacrylamide motif known from HDAC inhibitors like 1 or 3, we obtained selective inhibitors for both targets with potent cellular activity (target inhibition and cytotoxicity) of selected compounds 6a and 6c. By combining two distinct pharmacologically properties in one molecule, we postulate a broader activity spectrum and less likelihood of drug resistance in cancer patients.

  DOI：

  10.1021/jm100665z

文献信息

• [EN] NOVEL BIFUNCTIONAL COMPOUNDS WHICH INHIBIT PROTEIN KINASES AND HISTONE DEACETYLASES<br/>[FR] NOUVEAUX COMPOSÉS BIFONCTIONNELS QUI INHIBENT LES PROTÉINES KINASES ET LES HISTONES DÉSACÉTYLASES
  申请人：4SC AG

  公开号：WO2009063054A1

  公开（公告）日：2009-05-22

  The present invention relates to a bifunctional compound of formula I or its pharmaceutically acceptable salts or solvates A-L-B (I) wherein A is a histone deacetylase (HDAC) inhibitory moiety, L is a single bond or a linker group and B is a protein kinase inhibitory moiety. The bifunctional compound according to formula (I) is useful for the treatment of malignant and non-malignant neoplasia and diseases related to abnormal cell growth.

  本发明涉及公式I的双功能化合物或其药用可接受的盐或溶剂A-L-B（I），其中A是组蛋白去乙酰化酶（HDAC）抑制基团，L是单键或连接基团，B是蛋白激酶抑制基团。根据公式（I）的双功能化合物可用于治疗恶性和非恶性肿瘤以及与异常细胞生长相关的疾病。