6-ethyl-3-methyl-3,4-dihydro-2H-benzo[e][1,3]oxazine | 819850-81-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并恶嗪类
• 英文名称: 6-ethyl-3-methyl-3,4-dihydro-2H-benzo[e][1,3]oxazine
• 英文别名: 6-Ethyl-3-methyl-2,4-dihydro-1,3-benzoxazine；6-ethyl-3-methyl-2,4-dihydro-1,3-benzoxazine
• CAS: 819850-81-2
• 化学式: C₁₁H₁₅NO
• 分子量: 177.246
• InChiKey: XEGFMWDLQLDBMN-UHFFFAOYSA-N

物化性质

• 沸点：
  253.4±19.0 °C(Predicted)
• 密度：
  1.035±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  13
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  12.5
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  4-乙基苯酚 、 6-ethyl-3-methyl-3,4-dihydro-2H-benzo[e][1,3]oxazine 以 neat (no solvent) 为溶剂， 反应 24.0h， 生成 N,N-bis(2-hydroxy-5-ethylbenzyl)methylamine
  参考文献：
  名称：

  6,6′-((Methylazanedyl)bis(methylene))bis(2,4-dimethylphenol) Induces Autophagic Associated Cell Death through mTOR-Mediated Autophagy in Lung Cancer

  摘要：

  自噬是消除受损细胞器和错误折叠蛋白质的多步骤机制。该机制具有先导性，可诱导细胞凋亡等其他程序的细胞死亡。本研究揭示了 24MD 在诱导肺癌细胞自噬方面的潜在药理作用。结果表明，24MD 可同时诱导自噬，自噬体染色和 ATG5、ATG7 的诱导以及泛素化蛋白 p62 的表达表明了这一点。处理 24 小时后，LC3-I 与 LC3-II 发生了强烈的对话，p62 则出现了下调。附件素 V-FITC/ 碘化丙啶染色和 caspase-3 激活表明，48 小时处理后发现了凋亡诱导活性。从机理角度来看，60 μM 的 24MD 处理 24 小时后会大幅下调 p-mTOR。同时，p-PI3K 和 p-Akt 也分别被浓度为 80 μM 和 100 μM 的 24MD 所抑制。我们通过 Western 印迹和免疫荧光检测，比较了 24MD 与雷帕霉素（一种强效的标准 mTOR1 抑制剂）的作用，进一步证实了 m-TOR 介导的自噬活性。虽然 24MD 对 p-mTOR 的抑制作用不如雷帕霉素，但雷帕霉素和 24MD 的联合使用可增强 mTOR 抑制活性和 LC3 活化。将 EMD 中的取代基（R 基）从二甲基苯酚改为乙基苯酚，或将 24CD 中的甲基氮杂环丁基改为环己基氮杂环丁基，只能诱导细胞凋亡活性，而不能诱导自噬活性。我们发现 24MD 是一种新型化合物，它通过影响 mTOR 介导的自噬作用来靶向自噬细胞死亡。

  DOI：

  10.3390/molecules27196230
• 作为产物：
  描述：

  聚合甲醛 、 4-乙基苯酚 、 甲胺 反应 6.0h， 生成 6-ethyl-3-methyl-3,4-dihydro-2H-benzo[e][1,3]oxazine
  参考文献：
  名称：

  对位取代酚基苯并恶嗪的开环反应自终止：通过分子内氢键的阻滞作用

  摘要：

  所述开环 聚合的p -取代酚系苯并恶嗪是自终止，一旦二聚体形成。该聚合的即使条件，温度，摩尔比，溶剂极性和反应物比率变化，苯并恶嗪单体也不会根据理论机理进行。推测的机理涉及具有分子间和分子内氢键的二聚体的独特结构，用于解释对开环聚合的阻碍作用。在本文中，我们阐明了化合物的立体结构控制反应并阻止理论机理所预期的聚合的重要情况。J.杂环化​​学，（2009）。

  DOI：

  10.1002/jhet.130

文献信息

• Self termination of ring opening reaction of<i>p</i>-substituted phenol-based benzoxazines: An obstructive effect<i>via</i>intramolecular hydrogen bond
  作者：Suwabun Chirachanchai、Apirat Laobuthee、Suttinun Phongtamrug

  DOI：10.1002/jhet.130

  日期：2009.7

  The ring opening polymerizations of p-substituted phenol-based benzoxazines are self-terminated as soon as dimers form. The polymerization of benzoxazine monomers does not proceed according to the theoretical mechanism even though the conditions, temperature, molar ratio, solvent polarity, and reactant ratio are varied. The speculated mechanism, involving the unique structure of a dimer with inter-

  所述开环 聚合的p -取代酚系苯并恶嗪是自终止，一旦二聚体形成。该聚合的即使条件，温度，摩尔比，溶剂极性和反应物比率变化，苯并恶嗪单体也不会根据理论机理进行。推测的机理涉及具有分子间和分子内氢键的二聚体的独特结构，用于解释对开环聚合的阻碍作用。在本文中，我们阐明了化合物的立体结构控制反应并阻止理论机理所预期的聚合的重要情况。J.杂环化​​学，（2009）。
• Crystallographic, spectroscopic (FT-IR/FT-Raman) and computational (DFT/B3LYP) studies on 4,4′-diethyl-2,2′-[methylazanediylbis(methylene)]diphenol
  作者：Worawat Wattanathana、Nollapan Nootsuwan、Chatchai Veranitisagul、Nattamon Koonsaeng、Songwut Suramitr、Apirat Laobuthee

  DOI：10.1016/j.molstruc.2015.12.069

  日期：2016.4

  temperatures studied. The geometrical parameters from theoretical calculation were in good agreement with the ones from X-ray analysis. Both the theoretical and experimental structures confirmed the presence of the remarkably asymmetric intramolecular hydrogen bonding within the molecule of the EMD compound. Conformational analysis was carried out to calculate energy barrier of breaking the intramolecular

  摘要 4,4'-diethyl-2,2'-[methylazanediylbis(methylene)]diphenol 的几何形状和振动波数的量子力学计算，表示为 EMD，通过密度泛函理论 (DFT/B3LYP) 方法与各种基组进行，即 6-311G(d)、6-311G(d,p) 和 6-311 + G(d,p)。在低温 (100 K) 和室温 (296 K) 下测量 EMD 化合物的 X 射线晶体结构。发现对于所研究的温度没有观察到结构变化。理论计算的几何参数与X射线分析的几何参数吻合良好。理论和实验结构都证实了 EMD 化合物分子内存在显着不对称的分子内氢键。进行构象分析以计算破坏分子内氢键的能垒。此外，还构建了理论红外光谱和拉曼光谱，与实验 FT-IR 和 FT-Raman 光谱进行了比较研究。结果表明，理论波数与实验值的偏差非常小。此外，还进行了详细的振动分配，并通过 VEDA4f
• Novel c-Myc–Targeting Compound <i>N</i>, <i>N</i>-Bis (5-Ethyl-2-Hydroxybenzyl) Methylamine for Mediated c-Myc Ubiquitin-Proteasomal Degradation in Lung Cancer Cells
  作者：Nicharat Sriratanasak、Korrakod Petsri、Apirat Laobuthee、Worawat Wattanathana、Chanida Vinayanuwattikun、Sudjit Luanpitpong、Pithi Chanvorachote

  DOI：10.1124/mol.120.119719

  日期：2020.8

  Aberrant cellular Myc (c-Myc) is a common feature in the majority of human cancers and has been linked to oncogenic malignancies. Here, we developed a novel c-Myc-targeting compound, N, N-bis (5-ethyl-2-hydroxybenzyl) methylamine (EMD), and present evidence demonstrating its effectiveness in targeting c-Myc for degradation in human lung carcinoma. EMD exhibited strong cytotoxicity toward various human lung cancer cell lines, as well as chemotherapeutic-resistant patient-derived lung cancer cells, through apoptosis induction in comparison with chemotherapeutic drugs. The IC50 of EMD against lung cancer cells was approximately 60 mu M. Mechanistically, EMD eliminated c-Myc in the cells and initiated caspase-dependent apoptosis cascade. Cycloheximide chase assay revealed that EMD tended to shorten the half-life of c-Myc by approximately half. The cotreatment of EMD with the proteasome inhibitor MG132 reversed its c-Myc-targeting effect, suggesting the involvement of u biquitin-mediated proteasomal degradation in the process. We further verified that EMD strongly induced the ubiquitination of c-Myc and promoted protein degradation. c-Myc inhibition and apoptosis induction were additionally shown in hematologic malignant K562 cells, indicating the generality of the observed EMD effects. Altogether, we identified EMD as a novel potent compound targeting oncogenic c-Myc that may offer new opportunities for lung cancer treatment.SIGNIFICANCE STATEMENTThe deregulation of c-Myc is frequently associated with cancer progression. This study examined the effect of a new compound, N, N-bis (5-ethyl-2-hydroxybenzyl) methylamine (EMD), in targeting c-Myc in several lung cancer cell lines and drug-resistant primary lung cancer cells. EMD induced dramatic c-Myc degradation through a ubiquitin-proteasomal mechanism. The promising anticancer and c-Myc-targeted activities of EMD support its use in potential new approaches to treat c-Myc-driven cancer.
• [EN] BENZOXAZINE POLYMERS AND METHODS OF MAKING AND USING THE SAME<br/>[FR] POLYMÈRES DE BENZOXAZINE ET LEURS PROCÉDÉS DE FABRICATION ET D'UTILISATION
  申请人：UNIV CALIFORNIA

  公开号：WO2019178547A1

  公开（公告）日：2019-09-19

  Disclosed herein, inter alia, are novel benzoxazine containing compounds and compositions, including polymers, and methods for making and using the same.
• 6,6′-((Methylazanedyl)bis(methylene))bis(2,4-dimethylphenol) Induces Autophagic Associated Cell Death through mTOR-Mediated Autophagy in Lung Cancer
  作者：Nicharat Sriratanasak、Worawat Wattanathana、Pithi Chanvorachote

  DOI：10.3390/molecules27196230

  日期：——

  Autophagy is the multistep mechanism for the elimination of damaged organelles and misfolded proteins. This mechanism is preceded and may induce other program cell deaths such as apoptosis. This study unraveled the potential pharmacological effect of 24MD in inducing the autophagy of lung cancer cells. Results showed that 24MD was concomitant with autophagy induction, indicating by autophagosome staining and the induction of ATG5, ATG7 and ubiquitinated protein, p62 expression after 12-h treatment. LC3-I was strongly conversed to LC3-II, and p62 was downregulated after 24-h treatment. The apoptosis-inducing activity was found after 48-h treatment as indicated by annexin V-FITC/propidium iodide staining and the activation of caspase-3. From a mechanistic perspective, 24-h treatment of 24MD at 60 μM substantially downregulated p-mTOR. Meanwhile, p-PI3K and p-Akt were also suppressed by 24MD at concentrations of 80 and 100 μM, respectively. We further confirmed m-TOR-mediated autophagic activity by comparing the effect of 24MD with rapamycin, a potent standard mTOR1 inhibitor through Western blot and immunofluorescence assays. Although 24MD could not suppress p-mTOR as much as rapamycin, the combination of rapamycin and 24MD could increase the mTOR suppressive activity and LC3 activation. Changing the substituent groups (R groups) from dimethylphenol to ethylphenol in EMD or changing methylazanedyl to cyclohexylazanedyl in 24CD could only induce apoptosis activity but not autophagic inducing activity. We identified 24MD as a novel compound targeting autophagic cell death by affecting mTOR-mediated autophagy.

  自噬是消除受损细胞器和错误折叠蛋白质的多步骤机制。该机制具有先导性，可诱导细胞凋亡等其他程序的细胞死亡。本研究揭示了 24MD 在诱导肺癌细胞自噬方面的潜在药理作用。结果表明，24MD 可同时诱导自噬，自噬体染色和 ATG5、ATG7 的诱导以及泛素化蛋白 p62 的表达表明了这一点。处理 24 小时后，LC3-I 与 LC3-II 发生了强烈的对话，p62 则出现了下调。附件素 V-FITC/ 碘化丙啶染色和 caspase-3 激活表明，48 小时处理后发现了凋亡诱导活性。从机理角度来看，60 μM 的 24MD 处理 24 小时后会大幅下调 p-mTOR。同时，p-PI3K 和 p-Akt 也分别被浓度为 80 μM 和 100 μM 的 24MD 所抑制。我们通过 Western 印迹和免疫荧光检测，比较了 24MD 与雷帕霉素（一种强效的标准 mTOR1 抑制剂）的作用，进一步证实了 m-TOR 介导的自噬活性。虽然 24MD 对 p-mTOR 的抑制作用不如雷帕霉素，但雷帕霉素和 24MD 的联合使用可增强 mTOR 抑制活性和 LC3 活化。将 EMD 中的取代基（R 基）从二甲基苯酚改为乙基苯酚，或将 24CD 中的甲基氮杂环丁基改为环己基氮杂环丁基，只能诱导细胞凋亡活性，而不能诱导自噬活性。我们发现 24MD 是一种新型化合物，它通过影响 mTOR 介导的自噬作用来靶向自噬细胞死亡。