N-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazolin-4-amine | 202475-65-8

• 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: N-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazolin-4-amine
• CAS: 202475-65-8
• 化学式: C₁₈H₁₉N₃O₄
• 分子量: 341.367
• InChiKey: CCHZXKUIBPNVKD-UHFFFAOYSA-N

物化性质

• 沸点：
  482.7±45.0 °C(Predicted)
• 密度：
  1.254±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  25
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  74.7
• 氢给体数：
  1
• 氢受体数：
  7

安全信息

• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

反应信息

• 作为产物：
  描述：

  2-氨基-4,5-二甲氧基苯甲酸 在 三氯氧磷 作用下， 以 异丙醇 为溶剂， 反应 9.0h， 生成 N-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazolin-4-amine
  参考文献：
  名称：

  Investigation of quinazolines as inhibitors of breast cancer resistance protein (ABCG2)

  摘要：

  Chemotherapy is one of the major forms of cancer treatment. Unfortunately, tumors are prone to multidrug resistance leading to failure of treatment. Breast cancer resistance protein (BCRP), the second member of ABC transporter subfamily G, has been found to play a major role in drug efflux and hence multidrug resistance. Until now, very few potent and selective BCRP inhibitors like Ko143 have been identified. In the search for more potent and selective BCRP inhibitors, we synthesized and investigated a series of differently substituted quinazoline compounds. Several variations at positions 2, 4, 6 and 7 of the quinazoline scaffold were carried out to develop a structure-activity-relationship analysis for these compounds. It was found that compounds bearing a phenyl substituent at position 2 of the 4-anilinoquinazoline scaffold were most potent. On the aniline ring at position 4 of the quinazoline moiety substituents like NO2, CN, CF3 led to very high BCRP inhibition potencies. The most potent compounds were further investigated for their intrinsic cytotoxicity and their ability to reverse the multidrug resistance. Compound 20, an anilinoquinazoline bearing a phenyl ring at position 2 and meta-nitro substitution on the 4-anilino ring, was found to have the highest therapeutic ratio. The most active compounds from each variation were also investigated for their effect on BCRP expression. It was found that compound 20 has no significant effect on BCRP expression, while compound 31 decreased the surface BCRP expression. The only difference in the two compounds was the presence of a 3,4-dimethoxyphenyl ring in compound 31 instead of phenyl substitution at position 2 of the quinazoline moiety. From the study of all target compounds, compound 20 was the most prominent compound having inhibitory potency even higher than Ko143, the most potent BCRP inhibitor known. Compound 20 was also found to be selective towards BCRP with a very high therapeutic ratio. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.10.007

文献信息

• Antiproliferative Efficacy of N-(3-chloro-4-fluorophenyl)-6,7-dimethoxyquinazolin-4-amine, DW-8, in Colon Cancer Cells Is Mediated by Intrinsic Apoptosis
  作者：Rabin Neupane、Saloni Malla、Mariam Sami Abou-Dahech、Swapnaa Balaji、Shikha Kumari、Digambar Kumar Waiker、N. S. Hari Narayana Moorthy、Piyush Trivedi、Charles R. Ashby、Chandrabose Karthikeyan、Amit K. Tiwari

  DOI：10.3390/molecules26154417

  日期：——

  A novel series of 4-anilinoquinazoline analogues, DW (1–10), were evaluated for anticancer efficacy in human breast cancer (BT-20) and human colorectal cancer (CRC) cell lines (HCT116, HT29, and SW620). The compound, DW-8, had the highest anticancer efficacy and selectivity in the colorectal cancer cell lines, HCT116, HT29, and SW620, with IC50 values of 8.50 ± 2.53 µM, 5.80 ± 0.92 µM, and 6.15 ± 0.37 µM, respectively, compared to the non-cancerous colon cell line, CRL1459, with an IC50 of 14.05 ± 0.37 µM. The selectivity index of DW-8 was >2-fold in colon cancer cells incubated with vehicle. We further determined the mechanisms of cell death induced by DW-8 in SW620 CRC cancer cells. DW-8 (10 and 30 µM) induced apoptosis by (1) producing cell cycle arrest at the G2 phase; (2) activating the intrinsic apoptotic pathway, as indicated by the activation of caspase-9 and the executioner caspases-3 and 7; (3) nuclear fragmentation and (4) increasing the levels of reactive oxygen species (ROS). Overall, our results suggest that DW-8 may represent a suitable lead for developing novel compounds to treat CRC.

  一系列新型的4-苯胺基喹唑啉类似物DW（1-10）在人类乳腺癌（BT-20）和人类结肠癌（CRC）细胞系（HCT116、HT29和SW620）中进行了抗癌功效评估。化合物DW-8在结肠癌细胞系HCT116、HT29和SW620中表现出最高的抗癌功效和选择性，其IC50值分别为8.50±2.53 µM、5.80±0.92 µM和6.15±0.37 µM，而非癌性结肠细胞系CRL1459的IC50为14.05±0.37 µM。DW-8在与载体培养的结肠癌细胞中的选择性指数大于2倍。我们进一步确定了DW-8在SW620结肠癌细胞中诱导细胞死亡的机制。DW-8（10和30 µM）通过（1）在G2期引起细胞周期停滞；（2）激活内源性凋亡途径，表现为caspase-9和执行者caspase-3和7的激活；（3）核碎裂和（4）增加活性氧化物种（ROS）水平来诱导凋亡。总的来说，我们的结果表明DW-8可能是开发治疗CRC的新型化合物的合适先导。
• 一类喹唑啉类化合物及其制备方法与应用
  申请人：中山大学

  公开号：CN106632089B

  公开（公告）日：2019-06-18

  本发明公开了一类喹唑啉类化合物及其制备方法与应用，所述喹唑啉类化合物具有式（I）所示结构，其中，R为环状或非环状的脂肪胺、芳香或杂环胺、含酰基基团、含羟基基团、含巯基基团；R1为氢或甲氧基、甲基、乙基、卤素、三氟甲基、乙氧基、乙酰基、氰基、硝基、N,N‑二甲基、氯甲基、苄氧基、非取代或取代氨基、取代胍基、取代或非取代磷酸基、取代或非取代磺酸基、末端芳或杂环取代的长链脂肪烷基团。本发明提供的喹唑啉类化合物是一类结构新颖的化合物，而且该类化合物对磷酸二酯酶10型具有良好的抑制作用，同时对磷酸二酯酶3型的选择性良好，可作为磷酸二酯酶10型的选择性抑制剂使用。另外，本发明所述的喹唑啉类化合物的制备方法具有快速、简单、成本低等优点。
• Synthesis, biological evaluation and molecular modelling studies of 4-anilinoquinazoline derivatives as protein kinase inhibitors
  作者：Digambar Kumar Waiker、Chandrabose Karthikeyan、Vasanthanathan Poongavanam、Jacob Kongsted、Olivier Lozach、Laurent Meijer、Piyush Trivedi

  DOI：10.1016/j.bmc.2014.01.044

  日期：2014.3

  A series of novel 4-anilinoquinazoline derivatives (3a-3j) has been synthesized and evaluated as potential inhibitors for protein kinases implicated in Alzheimer's disease. Among all the synthesized compounds, compound 3e (N-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazolin-4-amine) exhibited the most potent inhibitory activity against CLK1 and GSK-3 alpha/beta kinase with IC50 values of 1.5 mu M and 3 mu M, respectively. Docking studies were performed to elucidate the binding mode of the compounds to the active site of CLK1 and GSK-3 beta. The results of our study suggest that compound 3e may serve as a valuable template for the design and development of dual inhibitors of CLK1 and GSK-3 alpha/beta enzymes with potential therapeutic application in Alzheimer's disease. (C) 2014 Elsevier Ltd. All rights reserved.
• A novel series of 4-phenoxyquinolines: potent and highly selective inhibitors of PDGF receptor autophosphorylation
  作者：Kazuo Kubo、Toshiyuki Shimizu、Shin-ichi Ohyama、Hideko Murooka、Tsuyoshi Nishitoba、Shinichiro Kato、Yoshiko Kobayashi、Mikio Yagi、Toshiyuki Isoe、Kazuhide Nakamura、Tatsushi Osawa、Toshio Izawa

  DOI：10.1016/s0960-894x(97)10117-2

  日期：1997.12

  A novel series of 4-phenoxyquinolines, some of which showed potent and highly selective inhibitory activities for PDGF receptor autophosphorylation, was discovered. Interestingly, their structures were very similar to those of the selective inhibitors for EGF receptor autophosphorylation. (C) 1997 Elsevier Science Ltd.
• QUINAZOLINE DERIVATIVES FOR THE TREATMENT OF HERPESVIRAL INFECTIONS
  申请人：GPC Biotech AG

  公开号：EP1673346A1

  公开（公告）日：2006-06-28