(E)-3-(4-chlorophenyl)-1-(2,4,6-trimethoxyphenyl)prop-2-en-1-one | 1017898-78-0

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 直链 1,3-二芳基丙烷
• 英文名称: (E)-3-(4-chlorophenyl)-1-(2,4,6-trimethoxyphenyl)prop-2-en-1-one
• 英文别名: (2E)-1-(2,4,6-trimethoxyphenyl)-3-(4-chlorophenyl)-2-propen-1-one；(2E)-3-(4-chlorophenyl)-1-(2,4,6-trimethoxyphenyl)prop-2-en-1-one
• CAS: 1017898-78-0
• 化学式: C₁₈H₁₇ClO₄
• 分子量: 332.784
• InChiKey: KLMMUYXZWHIJCG-RMKNXTFCSA-N

物化性质

• 沸点：
  504.4±50.0 °C(Predicted)
• 密度：
  1?+-.0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  23
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  44.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (E)-3-(4-chlorophenyl)-1-(2,4,6-trimethoxyphenyl)prop-2-en-1-one 在 N-羟基-4-甲基苯磺酰胺 、 potassium carbonate 作用下， 以 甲醇 、 水 为溶剂， 反应 69.0h， 以78%的产率得到5-(4-chlorophenyl)-3-(2,4,6-trimethoxyphenyl)isoxazole
  参考文献：
  名称：

  3,5-二芳基异恶唑衍生物作为潜在抗癌药的设计，合成和生物学评估。

  摘要：

  本研究是在试图合成一类新的包括11种化合物（潜在的抗癌剂的情况下进行24 - 34共享3,5- diarylisoxazole作为芯）。通过IR，1 H NMR，13 C NMR和元素分析确定了新合成化合物的化学结构。通过使用癌症PC3细胞和非致瘤性PNT1a细胞评估了它们对前列腺癌的生物学潜力。有趣的是，化合物26与其他化合物的区别在于它具有相当高的选择性值，可与5-FU相比。装订方式26 通过基于GLIDE标准精度以及MM-GBSA计算的对接模拟，详细研究了针对核糖体蛋白S6激酶beta-1（S6K1）的核糖体蛋白。

  DOI：

  10.1016/j.bmcl.2020.127427
• 作为产物：
  描述：

  间苯三酚 在 盐酸 、 potassium carbonate 、 potassium hydroxide 、 sodium hydroxide 、 zinc(II) chloride 作用下， 以 甲醇 、 乙醚 、 丙酮 为溶剂， 反应 48.0h， 生成 (E)-3-(4-chlorophenyl)-1-(2,4,6-trimethoxyphenyl)prop-2-en-1-one
  参考文献：
  名称：

  三甲氧基查尔酮衍生物抑制巴西利什曼原虫的生长：合成，生物学评估，分子建模和结构-活性关系（SAR）

  摘要：

  在这项工作中，我们描述了一系列查尔酮衍生物的合成，抗菌活性以及分子建模和结构-活性关系（SAR）评估。在这些化合物中，甲氧基查耳酮2h，2i，2j，2k和2l表现出显着的抗菌活性（IC 50  <10μM）。有趣的是2i（IC 50  = 2.7μM），2j（IC 50  =  3.9μM ）和2k（IC 50 = 4.6μM）衍生物表现出比对照药物喷他idine（IC 50 = 6.0μM）。我们的SAR研究表明，在苯环A上进行甲氧基二邻取代的重要性以及这些分子的前沿轨道HOMO系数分布与其活性之间的关系。活性最高的化合物2h，2i，2j，2k和2l符合Lipinski的5法则，这在理论上对于良好的药物吸收和通过生物膜的渗透非常重要。2j的电位分布（IC 50  = 3.9μM，CC 50  = 216μM）表明，这种查耳酮衍生物是一种命中化合物，需要在抗衰老药物设计中进一步探索。

  DOI：

  10.1016/j.bmc.2011.06.023

文献信息

• Trimethoxylated Halogenated Chalcones as Dual Inhibitors of MAO-B and BACE-1 for the Treatment of Neurodegenerative Disorders
  作者：Vishal Payyalot Vishal、Jong Min Oh、Ahmed Khames、Mohamed A. Abdelgawad、Aathira Sujathan Nair、Lekshmi R. Nath、Nicola Gambacorta、Fulvio Ciriaco、Orazio Nicolotti、Hoon Kim、Bijo Mathew

  DOI：10.3390/pharmaceutics13060850

  日期：——

  Six halogenated trimethoxy chalcone derivatives (CH1–CH6) were synthesized and spectrally characterized. The compounds were further evaluated for their inhibitory potential against monoamine oxidases (MAOs) and β-secretase (BACE-1). Six compounds inhibited MAO-B more effectively than MAO-A, and the 2′,3′,4′-methoxy moiety in CH4–CH6 was more effective for MAO-B inhibition than the 2′,4′,6′-methoxy moiety in CH1–CH3. Compound CH5 most potently inhibited MAO-B, with an IC50 value of 0.46 µM, followed by CH4 (IC50 = 0.84 µM). In 2′,3′,4′-methoxy derivatives (CH4-CH6), the order of inhibition was –Br in CH5 > -Cl in CH4 > -F in CH6 at the para-position in ring B of chalcone. CH4 and CH5 were selective for MAO-B, with selectivity index (SI) values of 15.1 and 31.3, respectively, over MAO-A. CH4 and CH5 moderately inhibited BACE-1 with IC50 values of 13.6 and 19.8 µM, respectively. When CH4 and CH5 were assessed for their cell viability studies on the normal African Green Monkey kidney cell line (VERO) using MTT assays, it was noted that both compounds were found to be safe, and only a slightly toxic effect was observed in concentrations above 200 µg/mL. CH4 and CH5 decreased reactive oxygen species (ROS) levels of VERO cells treated with H2O2, indicating both compounds retained protective effects on the cells by antioxidant activities. All compounds showed high blood brain barrier permeabilities analyzed by a parallel artificial membrane permeability assay (PAMPA). Molecular docking and ADME prediction of the lead compounds provided more insights into the rationale behind the binding and the CNS drug likeness. From non-test mutagenicity and cardiotoxicity studies, CH4 and CH5 were non-mutagenic and non-/weak-cardiotoxic. These results suggest that CH4 and CH5 could be considered candidates for the cure of neurological dysfunctions.

  六种卤代三甲氧基查尔酮衍生物（CH1–CH6）被合成并进行了光谱表征。进一步评估这些化合物对单胺氧化酶（MAOs）和β-分泌酶（BACE-1）的抑制潜力。六种化合物对MAO-B的抑制作用比对MAO-A更有效，而在CH4–CH6中的2′,3′,4′-甲氧基对于MAO-B的抑制作用比CH1–CH3中的2′,4′,6′-甲氧基更有效。化合物CH5对MAO-B的抑制最为有效，IC50值为0.46 µM，其次是CH4（IC50 = 0.84 µM）。在2′,3′,4′-甲氧基衍生物（CH4-CH6）中，抑制顺序为B环对位的–Br在CH5 > –Cl在CH4 > –F在CH6。CH4和CH5对MAO-B具有选择性，其选择性指数（SI）值分别为15.1和31.3，超过MAO-A。CH4和CH5对BACE-1有中等抑制作用，IC50值分别为13.6和19.8 µM。在正常非洲绿猴肾细胞系（VERO）上使用MTT实验评估CH4和CH5的细胞活力研究时，发现两种化合物是安全的，只有在浓度超过200 µg/mL时才观察到轻微毒性作用。CH4和CH5降低了用H2O2处理的VERO细胞的活性氧（ROS）水平，表明两种化合物通过抗氧化活性对细胞具有保护作用。所有化合物通过平行人工膜渗透实验（PAMPA）显示出高血脑屏障透过性。主要化合物的分子对接和ADME预测提供了更多关于结合和中枢神经系统药物相似性背后的理解。从非试验性突变原性和心毒性研究结果来看，CH4和CH5是非突变原性的，且心脏毒性为非/弱。这些结果表明，CH4和CH5可能被考虑作为治疗神经功能障碍的候选药物。
• Synthesis and pharmacological activity of chalcones derived from 2,4,6-trimethoxyacetophenone in RAW 264.7 cells stimulated by LPS: Quantitative structure–activity relationships
  作者：Louise Domeneghini Chiaradia、Rodrigo dos Santos、Carlos Eduardo Vitor、André Alexandre Vieira、Paulo César Leal、Ricardo José Nunes、João Batista Calixto、Rosendo Augusto Yunes

  DOI：10.1016/j.bmc.2007.10.039

  日期：2008.1

  induced enzymes involved is potentially an important strategy for obtaining antiinflammatory agents. In the search for hits to obtain lead compounds for new drugs of this class, 14 synthetic chalcones derived from 2,4,6-trimethoxyacetophenone were evaluated in terms of their inhibitory action, in vitro, in relation to NO production in murine macrophages of the line RAW 264.7 induced by bacterial lipopolysaccharides

  通过改变所涉及的诱导酶的表达来抑制一氧化氮（NO）的产生可能是获得抗炎药的重要策略。为了寻找此类新药的先导化合物，在寻找成功的途径中，评估了14种衍生自2,4,6-三甲氧基苯乙酮的合成查耳酮在体外对小鼠巨噬细胞NO生成的抑制作用。细菌脂多糖（LPS）诱导的RAW 264.7品系。所有化合物都是在碱性条件下通过苯乙酮与相应的醛之间的醛缩合获得的。在四个独立的实验中，通过剂量与抑制作用曲线计算出的平均IC（50）值在1.34至27.60microM之间变化，并与阳性对照化合物1400W（IC（50）= 3）进行了比较。78microM），一种高度选择性的iNOS抑制剂（诱导型一氧化氮合酶）。八个查耳酮的平均IC（50）值小于或等于1400W的平均IC（50）值，这表明这些分子可能充当炎症过程的抑制剂。QSAR研究表明，B环中的吸电子基团似乎增加了亚硝酸盐生成的抑制，主要是在2位时。A环的邻位取代似乎是活性所必需的。
• Conformational Mobility of Substituted 2-Methoxychalcones under the Action of Lanthanide Shift Reagents
  作者：A. V. Turov、S. P. Bondarenko、A. A. Tkachuk、V. P. Khilya

  DOI：10.1007/s11178-005-0118-x

  日期：2005.1

  Various lanthanide shift reagents Ln(fod)3 were found to affect the conformational composition of 2-methoxychalcones. Coordination of Yb(fod)3 occurs mainly at the carbonyl oxygen atom of the substrate, while Eu(fod)3 and shift reagents derived from other lanthanides coordinate substituted chalcones as bidentate ligands, giving rise to a secondary tetrachelate with the corresponding change of conformation of the substrate molecule. The possibility for chelation is determined by steric hindrances in the vicinity of the substrate coordination centers and concurrent coordination of other electron-donor groups present in the substrate molecule.

  各种镧系位移试剂Ln(fod)3被发现会影响2-甲氧基查耳酮的构象组成。镱(fod)3主要在底物的羰基氧原子上发生配位，而铕(fod)3及其他镧系衍生的位移试剂则以双齿配体形式配位取代的查耳酮，导致形成次级四齿螯合物，伴随底物分子构象的相应变化。是否能形成螯合取决于底物配位中心附近的位阻以及底物分子中存在的其他电子供体基团的协同配位。
• Novel Neohesperidin Dihydrochalcone Analogue Inhibits Adipogenic Differentiation of Human Adipose-Derived Stem Cells through the Nrf2 Pathway
  作者：Ga Han、Hee-Taik Kang、Sungkyun Chung、Changjin Lim、John Linton、Jin-Hee Lee、Wooki Kim、Seok-Ho Kim、Jong Lee

  DOI：10.3390/ijms19082215

  日期：——

  Obesity, characterized by excess lipid accumulation, has emerged as a leading public health problem. Excessive, adipocyte-induced lipid accumulation raises the risk of metabolic disorders. Adipose-derived stem cells (ASCs) are mesenchymal stem cells (MSCs) that can be obtained from abundant adipose tissue. High fat mass could be caused by an increase in the size (hypertrophy) and number (hyperplasia) of adipocytes. Reactive oxygen species (ROS) are involved in the adipogenic differentiation of human adipose-derived stem cells (hASCs). Lowering the level of ROS is important to blocking or retarding the adipogenic differentiation of hASCs. Nuclear factor erythroid 2-related factor-2 (Nrf2) is a transcription factor that mediates various antioxidant enzymes and regulates cellular ROS levels. Neohesperidin dihydrochalcone (NHDC), widely used as artificial sweetener, has been shown to have significant free radical scavenging activity. In the present study, (E)-3-(4-chlorophenyl)-1-(2,4,6-trimethoxyphenyl)prop-2-en-1-one (CTP), a novel NHDC analogue, was synthesized and examined to determine whether it could inhibit adipogenic differentiation. The inhibition of adipogenic differentiation in hASCs was tested using NHDC and CTP. In the CTP group, reduced Oil Red O staining was observed compared with the differentiation group. CTP treatment also downregulated the expression of PPAR-γ and C/EBP-α, adipogenic differentiation markers in hASCs, compared to the adipogenic differentiation group. The expression of FAS and SREBP-1 decreased in the CTP group, along with the fluorescent intensity (amount) of ROS. Expression of the Nrf2 protein was slightly decreased in the differentiation group. Meanwhile, in both the NHDC and CTP groups, Nrf2 expression was restored to the level of the control group. Moreover, the expression of HO-1 and NQO-1 increased significantly in the CTP group. Taken together, these results suggest that CTP treatment suppresses the adipogenic differentiation of hASCs by decreasing intracellular ROS, possibly through activation of the Nrf2 cytoprotective pathway. Thus, the use of bioactive substances such as CTP, which activates Nrf2 to reduce the cellular level of ROS and inhibit the adipogenic differentiation of hASCs, could be a new strategy for overcoming obesity.

  肥胖症，以过多脂质积累为特征，已成为主要的公共健康问题。过度的脂肪细胞诱导的脂质积累增加了代谢紊乱的风险。脂肪来源的干细胞（ASCs）是可以从丰富的脂肪组织中获得的间充质干细胞（MSCs）。高脂肪量可能是由于脂肪细胞大小（肥大）和数量（增生）的增加引起的。活性氧（ROS）参与了人类脂肪来源干细胞（hASCs）的脂肪生成分化。降低ROS水平对于阻止或减缓hASCs的脂肪生成分化至关重要。核因子红细胞2相关因子-2（Nrf2）是介导各种抗氧化酶并调节细胞ROS水平的转录因子。柚皮苷二氢黄酮（NHDC），作为人工甜味剂广泛使用，已被证明具有显著的自由基清除活性。在本研究中，合成并检测了一种新型NHDC类似物(E)-3-(4-氯苯基)-1-(2,4,6-三甲氧基苯基)丙-2-烯-1-酮（CTP），以确定它是否能抑制脂肪生成分化。使用NHDC和CTP测试了hASCs中脂肪生成分化的抑制。在CTP组中，与分化组相比观察到减少的Oil Red O染色。CTP处理还下调了PPAR-γ和C/EBP-α的表达，这是hASCs中的脂肪生成分化标记，与脂肪生成分化组相比。在CTP组中，FAS和SREBP-1的表达减少，以及ROS的荧光强度（数量）。Nrf2蛋白的表达在分化组中略有下降。同时，在NHDC和CTP组中，Nrf2表达恢复到对照组水平。此外，在CTP组中，HO-1和NQO-1的表达显著增加。总的来说，这些结果表明CTP处理通过降低细胞内ROS，可能通过激活Nrf2细胞保护途径，抑制了hASCs的脂肪生成分化。因此，利用激活Nrf2以减少细胞ROS水平并抑制hASCs的脂肪生成分化的生物活性物质，如CTP，可能是克服肥胖的新策略。
• Mechanisms of action and structure-activity relationships of cytotoxic flavokawain derivatives
  作者：Charlotte Thieury、Nicolas Lebouvier、Rémy Le Guével、Yann Barguil、Gaëtan Herbette、Cyril Antheaume、Edouard Hnawia、Yoshinori Asakawa、Mohammed Nour、Thierry Guillaudeux

  DOI：10.1016/j.bmc.2017.01.049

  日期：2017.3

  22 Flavokawain derivatives (FKd) were obtained by one step syntheses in order to conduct a SAR study to understand the structural requirements for optimum and selective cytotoxicity. FKd and natural flavokawains A and B found into kava, a South Pacific traditional beverage, were evaluated against nine cancer and one healthy cell lines. The targeted cell cycle phases as well as the effects on the induction of apoptosis and cell cycle protein levels were investigated. Therapeutic improvements (more activity and selectivity) were achieved with FKd compared to natural flavokawains and notably with the 2',3,4',6'-tetramethoxychalcone (FKd 19). FKd induced a Gl/S arrest on p53 wild-type cells and an M arrest on p53 mutant-type, via the up-regulation of p21 and cyclin B1 proteins, followed by apoptosis. Moreover, FKd exhibited a 24 h-effect on Akt/mTor normal cells versus a 48 h-effect on Akt/mTor up-regulated cells. The SAR study resulted in the conclusion that trimethoxy A-ring allowed the best compromise between cytotoxicity and selectivity, as well as the substitution of the meta position on the B-ring and the use of halogens substituents. (C) 2017 Elsevier Ltd. All rights reserved.