5,7-dimethoxyflavonol | 15236-07-4

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 黄酮类化合物
• 英文名称: 5,7-dimethoxyflavonol
• 英文别名: 3-hydroxy-5,7-dimethoxy-2-phenyl-4H-1-benzopyran-4-one；3-hydroxy-5,7-dimethoxy-2-phenyl-4H-chromen-4-one；galangin 5,7-dimethylether；3-Hydroxy-5,7-dimethoxyflavone；3-hydroxy-5,7-dimethoxy-2-phenyl-chromen-4-one；3-Hydroxy-5,7-dimethoxy-2-phenyl-chromen-4-on；5,7-dimethoxy-3-hydroxyflavone；3-hydroxy-5,7-dimethoxy-2-phenylchromen-4-one
• CAS: 15236-07-4
• 化学式: C₁₇H₁₄O₅
• 分子量: 298.295
• InChiKey: CPYJUQBXJXCLAY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  22
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  65
• 氢给体数：
  1
• 氢受体数：
  5

ADMET

代谢

3-羟基-5,7-二甲氧基黄酮已知的人类代谢物包括(2S,3S,4S,5R)-6-(5,7-二甲氧基-4-氧代-2-苯基色烯-3-基)氧基-3,4,5-三羟基氧杂环己烷-2-羧酸。

3-Hydroxy-5,7-dimethoxyflavone has known human metabolites that include (2S,3S,4S,5R)-6-(5,7-dimethoxy-4-oxo-2-phenylchromen-3-yl)oxy-3,4,5-trihydroxyoxane-2-carboxylic acid.

来源:NORMAN Suspect List Exchange

反应信息

• 作为反应物：
  描述：

  5,7-dimethoxyflavonol 、 叔丁基二甲基氯硅烷 在 吡啶 、 4-二甲氨基吡啶 作用下， 反应 12.0h， 以63%的产率得到3-(tert-butyldimethylsilyloxy)-5,7-dimethoxy-2-phenyl-4H-chromen-4-one
  参考文献：
  名称：

  3-O-Arylmethylgalangin, a novel isostere for anti-HCV 1,3-diketoacids (DKAs)

  摘要：

  Through chelation of the metal ions at the enzyme active site, 1,3-diketoacids (DKAs) show potent inhibition of viral enzymes such as HIV integrase and HCV NS5B. In order to optimize the antiviral activity of the DKAs, structural modification of their metal-binding units, keto-enol acids or monoketo acids, have been actively performed. In this study, we proposed 3-O-arylmethylgalangin 3 as an alternative to ortho-substituted aromatic DKA, a potent inhibitor of HCV NS5B. As a proof-of-concept study, a series of 3-O-arylmethylgalangin derivatives (3a-3r) were prepared and their inhibitory activity against HCV NS5B was estimated. Structure-activity relationship of the 3-O-arylmethylgalangin derivatives was in good accordance with that of the ortho-substituted aromatic DKA series. In particular, two galangin ethers (3g and 3i) completely superimposable with the most potent ortho-substituted aromatic DKA analogue (2) in atom-by-atom fashion showed equipotent inhibitory activity to that of 2. Taken together, this result provides convincing evidence that the 3-O-arylmethylgalangin can successfully mimic the chelating function of the DKA pharmacophore to show potent inhibitory activity against the target enzyme, HCV NS5B. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2010.09.021
• 作为产物：
  描述：

  溴苯乙腈 在 sodium tetrahydroborate 、 正丁基锂 、 sodium hydride 、 二异丙胺 作用下， 以 四氢呋喃 、 乙醇 、 正己烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 5,7-dimethoxyflavonol
  参考文献：
  名称：

  通过碱介导的环化反应制备黄酮醇的新方法：3,5,6,7-四甲氧基黄酮的全合成

  摘要：

  描述了一种合成黄酮醇的新方法。关键步骤是碱介导的环化-异构化-消除反应，其导致黄酮醇的形成。使用这种策略，合成并表征了三种黄酮醇。 黄酮醇-碱介导的环化-3,5,6,7-四甲氧基黄酮-LDA

  DOI：

  10.1055/s-0031-1290207

文献信息

• Accurate Prediction of Glucuronidation of Structurally Diverse Phenolics by Human UGT1A9 Using Combined Experimental and In Silico Approaches
  作者：Baojian Wu、Xiaoqiang Wang、Shuxing Zhang、Ming Hu

  DOI：10.1007/s11095-012-0666-z

  日期：2012.6

  Catalytic selectivity of human UGT1A9, an important membrane-bound enzyme catalyzing glucuronidation of xenobiotics, was determined experimentally using 145 phenolics and analyzed by 3D-QSAR methods. Catalytic efficiency of UGT1A9 was determined by kinetic profiling. Quantitative structure activity relationships were analyzed using CoMFA and CoMSIA techniques. Molecular alignment of substrate structures was made by superimposing the glucuronidation site and its adjacent aromatic ring to achieve maximal steric overlap. For a substrate with multiple active glucuronidation sites, each site was considered a separate substrate. 3D-QSAR analyses produced statistically reliable models with good predictive power (CoMFA: q2 = 0.548, r2 = 0.949, r pred 2  = 0.775; CoMSIA: q2 = 0.579, r2 = 0.876, r pred 2  = 0.700). Contour coefficient maps were applied to elucidate structural features among substrates that are responsible for selectivity differences. Contour coefficient maps were overlaid in the catalytic pocket of a homology model of UGT1A9, enabling identification of the UGT1A9 catalytic pocket with a high degree of confidence. CoMFA/CoMSIA models can predict substrate selectivity and in vitro clearance of UGT1A9. Our findings also provide a possible molecular basis for understanding UGT1A9 functions and substrate selectivity.

  通过实验使用145种酚类化合物，并通过3D-QSAR方法分析，确定了人UGT1A9的催化选择性。UGT1A9是一种重要的膜结合酶，催化外源性物质的葡糖醛酸化反应。通过动力学分析确定了UGT1A9的催化效率。使用CoMFA和CoMSIA技术分析了定量结构活性关系。通过将葡糖醛酸化位点及其相邻的芳香环重叠，实现了底物结构的最大立体重叠。对于具有多个活性葡糖醛酸化位点的底物，每个位点被视为单独的底物。3D-QSAR分析产生了统计上可靠的模型，具有良好的预测能力（CoMFA：q2=0.548，r2=0.949，r pred 2=0.775；CoMSIA：q2=0.579，r2=0.876，r pred 2=0.700）。通过轮廓系数图阐明了底物中负责选择性差异的结构特征。将轮廓系数图叠加在UGT1A9的同源模型的催化口袋中，能够高度自信地识别UGT1A9的催化口袋。CoMFA/CoMSIA模型可以预测底物的选择性和UGT1A9的体外清除率。我们的发现还提供了理解UGT1A9功能和底物选择性的可能分子基础。
• Three-Dimensional Quantitative Structure-Activity Relationship Studies on UGT1A9-Mediated 3-O-Glucuronidation of Natural Flavonols Using a Pharmacophore-Based Comparative Molecular Field Analysis Model
  作者：Baojian Wu、John Kenneth Morrow、Rashim Singh、Shuxing Zhang、Ming Hu

  DOI：10.1124/jpet.110.175356

  日期：2011.2

  Glucuronidation is often recognized as one of the rate-determining factors that limit the bioavailability of flavonols. Hence, design and synthesis of more bioavailable flavonols would benefit from the establishment of predictive models of glucuronidation using kinetic parameters [e.g., K m, V max, intrinsic clearance (CLint) = V max/ K m] derived for flavonols. This article aims to construct position (3-OH)-specific comparative molecular field analysis (CoMFA) models to describe UDP-glucuronosyltransferase (UGT) 1A9-mediated glucuronidation of flavonols, which can be used to design poor UGT1A9 substrates. The kinetics of recombinant UGT1A9-mediated 3-O-glucuronidation of 30 flavonols was characterized, and kinetic parameters ( K m, V max, CLint) were obtained. The observed K m, V max, and CLint values of 3-O-glucuronidation ranged from 0.04 to 0.68 μM, 0.04 to 12.95 nmol/mg/min, and 0.06 to 109.60 ml/mg/min, respectively. To model UGT1A9-mediated glucuronidation, 30 flavonols were split into the training (23 compounds) and test (7 compounds) sets. These flavonols were then aligned by mapping the flavonols to specific common feature pharmacophores, which were used to construct CoMFA models of V max and CLint, respectively. The derived CoMFA models possessed good internal and external consistency and showed statistical significance and substantive predictive abilities ( V max model: q 2 = 0.738, r 2 = 0.976, r pred2 = 0.735; CLint model: q 2 = 0.561, r 2 = 0.938, rpred2 = 0.630). The contour maps derived from CoMFA modeling clearly indicate structural characteristics associated with rapid or slow 3-O-glucuronidation. In conclusion, the approach of coupling CoMFA analysis with a pharmacophore-based structural alignment is viable for constructing a predictive model for regiospecific glucuronidation rates of flavonols by UGT1A9.

  葡糖醛酸化通常被认为是限制类黄酮醇生物利用度的决定速率的因素之一。因此，利用类黄酮醇的动力学参数（如 Km、Vmax、内在清除率（CLint）= Vmax/ Km）建立葡糖醛酸化的预测模型，将有利于设计合成更多生物可利用的类黄酮醇。本文旨在构建针对3-OH位点的特定比较分子场分析（CoMFA）模型，描述UDP-葡糖醛酸基转移酶（UGT）1A9介导的类黄酮醇葡糖醛酸化过程，该模型可用于设计不佳的UGT1A9底物。我们对重组UGT1A9介导的30种类黄酮醇的3-O-葡糖醛酸化动力学进行了表征，并获得了动力学参数（Km、Vmax、CLint）。观察到的3-O-葡糖醛酸化Km、Vmax和CLint值分别在0.04至0.68 μM、0.04至12.95 nmol/mg/min和0.06至109.60 ml/mg/min之间。为了模拟UGT1A9介导的葡糖醛酸化，我们将30种类黄酮醇分为训练集（23个化合物）和测试集（7个化合物）。然后通过将类黄酮醇映射到特定的共同特征药效团来对齐，从而构建了Vmax和CLint的CoMFA模型。得到的CoMFA模型具有良好的内在和外在一致性，显示出统计学意义和实质性的预测能力（Vmax模型：q2 = 0.738，r2 = 0.976，rpred2 = 0.735；CLint模型：q2 = 0.561，r2 = 0.938，rpred2 = 0.630）。从CoMFA建模得到的轮廓图清晰地表明了与快速或慢速3-O-葡糖醛酸化相关的结构特征。总之，结合CoMFA分析和基于药效团的结构对齐方法是可行的，可以构建用于UGT1A9介导的类黄酮醇区域特异性葡糖醛酸化速率的预测模型。
• Galangin 3-benzyl-5-methylether derivatives function as an adiponectin synthesis-promoting peroxisome proliferator-activated receptor γ partial agonist
  作者：Hyejin Ko、Hongjun Jang、Seungchan An、In Guk Park、Sungjin Ahn、Junpyo Gong、Seok Young Hwang、Soyeon Oh、Soo Yeon Kwak、Won Jun Choi、Hyoungsu Kim、Minsoo Noh

  DOI：10.1016/j.bmc.2021.116564

  日期：2022.1

  Novel galangin derivatives were synthesized to improve adiponectin synthesis-promoting compounds by increasing the PPARγ activity of galangin and reducing its ERβ activity, because PPARγ functions can be inhibited by ERβ. Three galangin 3-benzyl-5-methylether derivatives significantly promoted adiponectin production by 2.88-, 4.47-, and 2.76-fold, respectively, compared to the effect of galangin. The

  已提出脂联素产生的上调作为治疗代谢疾病的新策略。高良姜素是一种天然类黄酮，在人骨髓间充质干细胞的脂肪形成过程中表现出促进脂联素合成的活性。在目标识别中，高良姜素结合过氧化物酶体增殖物激活受体 (PPAR) γ 和雌激素受体 (ER) β。合成了新的高良姜素衍生物，通过增加高良姜素的 PPARγ 活性和降低其 ERβ 活性来改善脂联素合成促进化合物，因为 PPARγ 功能可以被 ERβ 抑制。与高良姜素的作用相比，三种高良姜素 3-苄基-5-甲基醚衍生物分别显着促进脂联素的产生 2.88 倍、4.47 倍和 2.76 倍。最有效的化合物，高良姜素 3-benzyl-5,7-dimethylether，Ki , 1.7 μM)，而它不与 ERβ 结合。高良姜素 3-benzyl-5,7-dimethylether 在对接和药理竞争研究中被确定为 PPARγ 部分激动剂，表明它可能在多种代谢疾病中具有多种治疗潜力。
• Regioselective synthesis of 2-arylidene coumaran-3-ones by dye-sensitized photooxygenation of 2-hydroxyphenyl-styrylketones in the presence of sodium dodecyl sulphate
  作者：H. Mohindra Chawla、S. Kumar Sharma

  DOI：10.1016/s0040-4020(01)81970-0

  日期：1990.1

  2'-Hydroxyphenylstyrylketones when subjected to dye- sensitized photooxygenation in the presence of sodium dodecylsulphate (8× x 10-3M) in methanol, yielded the corresponding oxidatively cyclized products, i.e., 2-aryl idenecoumaran 3-ones and 2-phenyl-3-hydroxy-4H-benzopyran-4- ones. It has been observed that the nature of the substituents on the styryl moiety plays an important role in determining

  2'-羟基苯基苯乙烯基酮在甲醇中的十二烷基硫酸钠（8×x 10 -3 M）存在下进行染料敏化的光氧合时，会生成相应的氧化环化产物，即2-芳基亚烷基香豆素3-ones和2-phenyl- 3-羟基-4H-苯并吡喃-4-基。已经观察到，苯乙烯基部分上的取代基的性质在确定2-亚芳基香豆素-3-酮相对于2-芳基-3-羟基-4H-苯并吡喃-4-酮的优势中起重要作用。已经观察到该反应受阴离子胶束产生的疏水环境的影响。描述了反应的合理机制。
• Darzens reaction of 2-bromo-4,6-dimethoxy-3(2<i>H</i>)-benzofuranone with aromatic aldehydes to form flavonoids
  作者：Philipp A. Ottersbach、David Bolek、Eva Lepičová、Michael Gütschow、Martin Nieger

  DOI：10.1002/jhet.5570450432

  日期：2008.7

  The applicability of 2-bromo-4,6-dimethoxy-3(2H)-benzofuranone (1) to produce flavonoid-derived epoxides in the course of the Darzens reaction with aldehydes was investigated. However, instead of the epoxides, flavonols 3 and, in certain cases, benzofuranyl-substituted flavonols 4 were isolated. The generation of 3 is assumed due to a ring expansion of the initially formed epoxides. These flavonols

  研究了2-溴-4,6-二甲氧基-3（2 H）-苯并呋喃酮（1）在与醛类的Darzens反应过程中产生类黄酮衍生的环氧化物的适用性。然而，代替了环氧化物，分离了黄酮醇3，在某些情况下还分离了苯并呋喃基取代的黄酮醇4。假定生成3是由于最初形成的环氧化物的扩环。这些黄酮醇可与1反应生成次要产品，产生意想不到的1：2加合物4。六甲氧基衍生物4b（R 1 = H，R 2 = R 3 通过X射线晶体学分析确认＝（OMe）。