2-(5-bromo-2-methoxyphenyl)-4-hydroxyquinazoline | 1262849-75-1

• 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: 2-(5-bromo-2-methoxyphenyl)-4-hydroxyquinazoline
• 英文别名: 2-(5-bromo-2-methoxyphenyl)quinazolin-4-ol；2-(5-bromo-2-methoxy-phenyl)-3H-quinazolin-4-one；2-(5-bromo-2-methoxyphenyl)-3H-quinazolin-4-one
• CAS: 1262849-75-1
• 化学式: C₁₅H₁₁BrN₂O₂
• 分子量: 331.169
• InChiKey: WOHDPRWTCOWUBC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  20
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  50.7
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-(5-bromo-2-methoxyphenyl)-4-hydroxyquinazoline 在 三氯氧磷 作用下， 反应 2.0h， 以91.7%的产率得到2-(5-bromo-2-methoxyphenyl)-4-chloroquinazoline
  参考文献：
  名称：

  喹唑啉衍生物作为L858R / T790M / C797S三突变表皮生长因子受体酪氨酸激酶抑制剂的设计，合成和生物学评价

  摘要：

  事实证明，抑制表皮生长因子受体（EGFR）是治疗非小细胞肺癌的最有希望的策略之一。设计并合成了一系列2-芳基-4-氨基取代的喹唑啉衍生物，旨在克服L858R / T790M / C797S（CTL）三突变体耐药性以及抑制CTL激酶和EGFR野生型（WT）的生物学活性。被评估。三种化合物（20，24和27）表现出优异的抑制活性针对EGFR激酶三重突变体CTL（IC 50  <1μM）和高选择性（IC 50：WT / CTL> 10000）。细胞株评估表明，最有效的化合物27对H1975-EGFR L858R / T790M（IC 50  = 3.3 µM）和H1975-EGFR L858R / T790M / C797S（IC 50  = 1.2 µM）具有显着的抗性。化合物27在人，大鼠和小鼠肝脏中也表现出良好的微粒体稳定性，但生物利用度较低。这项工作对于发现新的喹唑啉衍生物作为靶向三重突变体L858R

  DOI：

  10.1248/cpb.c20-00411
• 作为产物：
  描述：

  5-bromo-2-methoxybenzoyl chloride 在 双氧水 、 N,N-二异丙基乙胺 、 sodium hydroxide 作用下， 以 1,4-二氧六环 、 氯仿 、 水 为溶剂， 反应 44.0h， 生成 2-(5-bromo-2-methoxyphenyl)-4-hydroxyquinazoline
  参考文献：
  名称：

  Structure-Based Design of Potent and Selective 2-(Quinazolin-2-yl)phenol Inhibitors of Checkpoint Kinase 2

  摘要：

  Structure-based design was applied to the optimization of a series of 2-(quinazolin-2-yl)phenols to generate potent and selective ATP-competitive inhibitors of the DNA damage response signaling enzyme checkpoint kinase 2 (CHK2). Structure-activity relationships for multiple substituent positions were optimized separately and in combination leading to the 2-(quinazolin-2-yl)phenol 46 (IC(50) 3 nM) with good selectivity for CHK2 against CHK1 and a wider panel of kinases and with promising in vitro ADMET properties. Off-target activity at hERG ion channels shown by the core scaffold was successfully reduced by the addition of peripheral polar substitution. In addition to showing mechanistic inhibition of CHK2 in HT29 human colon cancer cells, a concentration dependent radioprotective effect in mouse thymocytes was demonstrated for the potent inhibitor 46 (CCT241533).

  DOI：

  10.1021/jm101150b

文献信息

• Computer-Aided Design, Synthesis and Validation of 2-Phenylquinazolinone Fragments as CDK9 Inhibitors with Anti-HIV-1 Tat-Mediated Transcription Activity
  作者：Luca Sancineto、Nunzio Iraci、Serena Massari、Vanessa Attanasio、Gianmarco Corazza、Maria Letizia Barreca、Stefano Sabatini、Giuseppe Manfroni、Nilla Roberta Avanzi、Violetta Cecchetti、Christophe Pannecouque、Alessandro Marcello、Oriana Tabarrini

  DOI：10.1002/cmdc.201300287

  日期：2013.12

  The activity of the cyclin‐dependent kinase 9 (CDK9) is critical for HIV‐1 Tat‐mediated transcription and represents a promising target for antiviral therapy. Here we present computational studies that, along with preliminary synthetic efforts, allowed us to identify and characterize a new class of nontoxic anti‐CDK9 chemotypes based on the 2‐phenylquinazolinone scaffold. Inhibition of CDK9 translated

  细胞周期蛋白依赖性激酶9（CDK9）的活性对于HIV-1 Tat介导的转录至关重要，是抗病毒治疗的有希望的靶标。在这里，我们介绍了计算研究，以及初步的合成努力，使我们能够鉴定和表征基于2-苯基喹唑啉酮骨架的新型无毒抗CDK9化学型。对CDK9的抑制转化为选择性干扰Tat介导的病毒启动子反式激活的能力以及对潜伏感染细胞中HIV-1激活的抑制的能力，其中最有效的衍生物37（2-（4-氨基苯基）-7-氯喹唑啉-4（3 H ^） -酮）示出IC 50为4.0μ值中号。由于本文报道的2-苯基喹唑啉酮仅仅是片段，因此它们在很大程度上是可优化的，从而为开发具有更高效能的衍生物铺平了道路。
• Design, Synthesis and Biological Evaluation of the Quinazoline Derivatives as L858R/T790M/C797S Triple Mutant Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors
  作者：Mingguang Zhang、Yunyun Wang、Jia Wang、Zhaogang Liu、Jingmiao Shi、Mingxin Li、Yongqiang Zhu、Shifa Wang

  DOI：10.1248/cpb.c20-00411

  日期：2020.10.1

  Inhibition of the epidermal growth factor receptor (EGFR) has been proved to be one of the most promising strategies for the treatment of non-small cell lung cancers. A series of 2-aryl-4-amino substituted quinazoline derivatives were designed and synthesized with the purpose to overcome L858R/T790M/C797S (CTL) triple mutant drug resistance and the biological activity for inhibition of CTL kinases and EGFR

  事实证明，抑制表皮生长因子受体（EGFR）是治疗非小细胞肺癌的最有希望的策略之一。设计并合成了一系列2-芳基-4-氨基取代的喹唑啉衍生物，旨在克服L858R / T790M / C797S（CTL）三突变体耐药性以及抑制CTL激酶和EGFR野生型（WT）的生物学活性。被评估。三种化合物（20，24和27）表现出优异的抑制活性针对EGFR激酶三重突变体CTL（IC 50  <1μM）和高选择性（IC 50：WT / CTL> 10000）。细胞株评估表明，最有效的化合物27对H1975-EGFR L858R / T790M（IC 50  = 3.3 µM）和H1975-EGFR L858R / T790M / C797S（IC 50  = 1.2 µM）具有显着的抗性。化合物27在人，大鼠和小鼠肝脏中也表现出良好的微粒体稳定性，但生物利用度较低。这项工作对于发现新的喹唑啉衍生物作为靶向三重突变体L858R
• Structure-Based Design of Potent and Selective 2-(Quinazolin-2-yl)phenol Inhibitors of Checkpoint Kinase 2
  作者：John J. Caldwell、Emma J. Welsh、Cornelis Matijssen、Victoria E. Anderson、Laurent Antoni、Kathy Boxall、Frederique Urban、Angela Hayes、Florence I. Raynaud、Laurent J. M. Rigoreau、Tony Raynham、G. Wynne Aherne、Laurence H. Pearl、Antony W. Oliver、Michelle D. Garrett、Ian Collins

  DOI：10.1021/jm101150b

  日期：2011.1.27

  Structure-based design was applied to the optimization of a series of 2-(quinazolin-2-yl)phenols to generate potent and selective ATP-competitive inhibitors of the DNA damage response signaling enzyme checkpoint kinase 2 (CHK2). Structure-activity relationships for multiple substituent positions were optimized separately and in combination leading to the 2-(quinazolin-2-yl)phenol 46 (IC(50) 3 nM) with good selectivity for CHK2 against CHK1 and a wider panel of kinases and with promising in vitro ADMET properties. Off-target activity at hERG ion channels shown by the core scaffold was successfully reduced by the addition of peripheral polar substitution. In addition to showing mechanistic inhibition of CHK2 in HT29 human colon cancer cells, a concentration dependent radioprotective effect in mouse thymocytes was demonstrated for the potent inhibitor 46 (CCT241533).