(Z)-2-(4-chlorobenzylidene)-6-hydroxybenzofuran-3(2H)-one | 139276-14-5

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 橙酮类黄酮
• 英文名称: (Z)-2-(4-chlorobenzylidene)-6-hydroxybenzofuran-3(2H)-one
• 英文别名: (Z)-6-hydroxy-2-(4-chlorobenzylidene)benzofuran-3(2H)-one；2-(4'-chlorobenzylidene)-6-hydroxybenzofuran-3(2H)-one；2-(p-chlorobenzylidene)-6-hydroxy-3(2H)-benzofuranone；(2Z)-2-(4-chlorobenzylidene)-6-hydroxy-1-benzofuran-3(2H)-one；(2Z)-2-[(4-chlorophenyl)methylidene]-6-hydroxy-1-benzofuran-3-one
• CAS: 139276-14-5
• 化学式: C₁₅H₉ClO₃
• 分子量: 272.688
• InChiKey: BDTDMWIIDULIHT-AUWJEWJLSA-N

物化性质

• 沸点：
  502.4±50.0 °C(Predicted)
• 密度：
  1.480±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  19
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  46.5
• 氢给体数：
  1
• 氢受体数：
  3

安全信息

• 危险等级：
  IRRITANT

反应信息

• 作为反应物：
  描述：

  (Z)-2-(4-chlorobenzylidene)-6-hydroxybenzofuran-3(2H)-one 在 palladium on activated charcoal 盐酸 、 氢气 、 potassium carbonate 、 magnesium 、 1,2-二溴乙烷 作用下， 以 乙醇 、 乙酸乙酯 、 丙酮 为溶剂， 25.0 ℃ 、101.33 kPa 条件下， 反应 24.0h， 生成 2-(p-chlorobenzyl)-3--6-methoxybenzofuran
  参考文献：
  名称：

  Synthesis of 2-(p-chlorobenzyl)-3-aryl-6-methoxybenzofurans as selective ligands for antiestrogen-binding sites. Effects on cell proliferation and cholesterol synthesis

  摘要：

  A series of nonsteroidal compounds, 2-(p-chlorobenzyl)-3-aryl-6-methoxybenzofurans derived from the 2-(p-chlorobenzyl)-6-methoxy-3(2H)-benzofuranones has been synthesized. The key steps in the synthesis were reactions of 2-(p-chlorobenzyl)-6-methoxy-3(2H)-benzofuranones with the arylorganometallic reagents followed by dehydration of the resulting carbinols. The benzofurans are ligands for antiestrogen-binding sites (AEBS) and display no significant interaction with the estrogen receptor (ER). All bind to AEBS with equivalent or greater affinity than tamoxifen. These compounds decrease [H-3]thymidine incorporation in AEBS-containing EL4 lymphoid cells and MCF7 breast cancer cells in a concentration-dependent manner between 10(-8) and 10(-6) M and are generally more inhibitory than tamoxifen. In contrast, they have no effect on [H-3]thymidine incorporation by an AEBS-deficient variant of the MCF7 cell line, RTx6. The present findings of (1) selective and high affinity binding of the benzofurans to AEBS, (2) their concentration-dependent inhibition of [H-3]thymidine incorporation in AEBS-containing cells, and (3) their lack of antiproliferative effect in an AEBS-deficient cell line suggest a functional role for AEBS in mediating the antigrowth effect of these compounds. Two of the more active benzofuran compounds also significantly inhibited de novo cholesterol biosynthesis in EL4 cells which lack ER. This effect could be obtained after 5 h of treatment and preceded significant loss of cell viability. This is the first demonstration that selective ligands of AEBS (other than the known nonsteroidal antiestrogens) interfere with cholesterol biosynthesis-an action that may contribute to their antigrowth effect.

  DOI：

  10.1021/jm00086a002
• 作为产物：
  描述：

  2-氯-1-(2,4-二羟基苯基)乙酮 在 sodium hydroxide 作用下， 以 甲醇 、 水 为溶剂， 生成 (Z)-2-(4-chlorobenzylidene)-6-hydroxybenzofuran-3(2H)-one
  参考文献：
  名称：

  Drug Design, Synthesis and In Vitro Evaluation of Substituted Benzofurans as Hsp90 Inhibitors

  摘要：

  背景：热休克蛋白90是一种分子伴侣，参与多种促进癌细胞生长和/或存活的目标蛋白的稳定性和功能。Hsp90抑制剂的发现已成为癌症治疗研究中的一个有吸引力的目标。天然产物如胶丹霉素和雷地西酮已被确立为Hsp90抑制剂，但在体内研究中面临着毒性和无活性等限制。然而，它们为设计新型合成或半合成的相关化合物作为Hsp90抑制剂奠定了逻辑起点。 目标：本文聚焦于取代的2-芳基/杂芳基-6-羟基苯并呋喃-3(2H)-酮类似物的结构基础药物设计，以优化和模拟有效Hsp90抑制剂雷地西酮的药效团相互作用。 方法：通过Surflex dock-Geom (SYBYL-X 1.2药物发现套件)进行虚拟对接研究，设计的配体通过传统方法合成，使用对苯二酚和氯对苯二酚作为起始材料。进行二维化学相似性搜索，以识别与已报道Hsp90抑制剂相比的'SY'系列化学空间。采用体外细胞增殖测定（重氮还原法）和蛋白质组学研究（DARTS）对全细胞裂解液进行评估，以评估抗癌活性。 结果：所有合成化合物的化学结构通过红外光谱、1H-NMR和质谱分析得到确认。化学相似性搜索的结果表明，SY系列符合现有Hsp90抑制剂所定义的化学空间。在针对人黑色素瘤和乳腺癌细胞系的体外细胞增殖测定中，'SY3'被识别为该系列中有前景的抗癌剂。 结论：对接研究、二维化学相似性搜索、重氮还原测定和定性蛋白组学分析都确认了'SY3'作为该系列中有前景的Hsp90抑制剂。

  DOI：

  10.2174/1573406413666170623085534

文献信息

• Design, synthesis, and biological evaluation of a novel dual peroxisome proliferator-activated receptor alpha/delta agonist for the treatment of diabetic kidney disease through anti-inflammatory mechanisms
  作者：Kai Liu、Xing Zhao、Xue Qi、Dong-Liang Hou、Hao-Bin Li、Yu-Hao Gu、Qing-Long Xu

  DOI：10.1016/j.ejmech.2021.113388

  日期：2021.6

  a dual PPAR-α/δ agonist, and the selectivity against PPAR-γ is still to be improved. Sulfuretin has been shown to suppress the expression of PPAR-γ and improve the pathogenesis of diabetic complications. In this study, by hybridizing the carboxylic acid of GFT505 and the parent nucleus of sulfuretin, we pioneeringly designed and synthetized a series of novel dual PPAR-α/δ agonists, expecting to provide

  糖尿病肾病 (DKD) 是几乎所有病因类型糖尿病 (DM) 最后阶段的主要特征。迄今为止，很少有安全有效的药物可用于治疗。过氧化物酶体增殖物激活受体 (PPARs) 由三个成员组成：PPAR-α、PPAR-δ 和 PPAR-γ，通过血糖控制和脂质代谢在 DKD 中发挥保护作用，而 PPAR-γ 的全身激活会导致严重的副作用- 在临床试验中的作用。GFT505是双PPAR-α/δ激动剂，对PPAR-γ的选择性仍有待提高。Sulfuretin 已被证明可抑制 PPAR-γ 的表达并改善糖尿病并发症的发病机制。在本研究中，通过杂化GFT505的羧酸和硫磺素的母核，我们开创性地设计合成了一系列新型双 PPAR-α/δ 激动剂，期望为 PPARs 提供更好的收益/风险比。在所有合成的化合物中，化合物12被鉴定为对 PPAR-α/δ 具有高活性和对 PPAR-γ 的选择性高于GFT505（EC 50 :
• Drug Design, Synthesis and In Vitro Evaluation of Substituted Benzofurans as Hsp90 Inhibitors
  作者：Sundeep Kadasi、Thadeu E.M.M. Costa、Neha Arukala、Mallika Toshakani、Chaitanya Duggineti、Sreekanth Thota、Sayan D. Gupta、Shiva Raj、Carmen Penido、Maria G. Henriques、Nulgumnalli M. Raghavendra

  DOI：10.2174/1573406413666170623085534

  日期：2018.1.11

  Background: Heat shock protein 90 is a molecular chaperone required for the stability and function of several client proteins that promote cancer cell growth and/or survival. Discovery of Hsp90 inhibitors has emerged as an attractive target of research in cancer therapeutics. Natural products like geldanamycin and radicicol are established Hsp90 inhibitors, but face limitations with toxicity and inactivity, by in vivo studies respectively. However, they lay the logical starting point for the design of novel synthetic or semi-synthetic congeners as Hsp90 inhibitors. Objective: In this article, the structure based drug design of substituted 2-aryl/heteroarylidene-6- hydroxybenzofuran-3(2H)-one analogues to optimize and mimic the pharmacophoric interactions of the valid Hsp90 inhibitor radicicolis focused. Method: In silico docking study was performed by Surflex dock-Geom (SYBYL- X 1.2 drug discovery suite) and the designed ligands were chemically synthesized by conventional method using resorcinol and chlororesorcinol as starting materials. Two dimensional chemical similarity search was carried out to identify the chemical space of ‘SY' series in comparison with reported Hsp90 inhibitors. The in vitro cell proliferation assay (resazurin reduction method) and proteomic investigation (DARTS) was carried out on whole cell lysate to evaluate anticancer activity. Results: The chemical structures of all the synthesized compounds were confirmed by IR, 1H-NMR and Mass spectral analysis. The results of chemical similarity search show that SY series fit it in the chemical space defined by existing Hsp90 inhibitors. In vitro cell proliferation assay, against human melanoma and breast cancer cell lines, identified ‘SY3' as the promising anticancer agent amongst the series. Conclusion: Docking studies, 2D chemical similarity search, resazurin reduction assay and qualitative proteomic analysis identify ‘SY3’as a promising Hsp90 inhibitor amongst the series.

  背景：热休克蛋白90是一种分子伴侣，参与多种促进癌细胞生长和/或存活的目标蛋白的稳定性和功能。Hsp90抑制剂的发现已成为癌症治疗研究中的一个有吸引力的目标。天然产物如胶丹霉素和雷地西酮已被确立为Hsp90抑制剂，但在体内研究中面临着毒性和无活性等限制。然而，它们为设计新型合成或半合成的相关化合物作为Hsp90抑制剂奠定了逻辑起点。 目标：本文聚焦于取代的2-芳基/杂芳基-6-羟基苯并呋喃-3(2H)-酮类似物的结构基础药物设计，以优化和模拟有效Hsp90抑制剂雷地西酮的药效团相互作用。 方法：通过Surflex dock-Geom (SYBYL-X 1.2药物发现套件)进行虚拟对接研究，设计的配体通过传统方法合成，使用对苯二酚和氯对苯二酚作为起始材料。进行二维化学相似性搜索，以识别与已报道Hsp90抑制剂相比的'SY'系列化学空间。采用体外细胞增殖测定（重氮还原法）和蛋白质组学研究（DARTS）对全细胞裂解液进行评估，以评估抗癌活性。 结果：所有合成化合物的化学结构通过红外光谱、1H-NMR和质谱分析得到确认。化学相似性搜索的结果表明，SY系列符合现有Hsp90抑制剂所定义的化学空间。在针对人黑色素瘤和乳腺癌细胞系的体外细胞增殖测定中，'SY3'被识别为该系列中有前景的抗癌剂。 结论：对接研究、二维化学相似性搜索、重氮还原测定和定性蛋白组学分析都确认了'SY3'作为该系列中有前景的Hsp90抑制剂。
• Synthesis and Activity of Aurone and Indanone Derivatives
  作者：Chao Niu、Haji Akber Aisa、Heng Wu、Haiqing Zhao、Tong Lu、Baoxing Xie

  DOI：10.2174/1573406419666230203105246

  日期：2023.2.3

  Gram-positive bacteria. The introduction of electron-withdrawing groups or hydroxyl is beneficial to the activity. It was exciting that the 3-phenylallylbenzofuranone and 3-allylindanone skeletons with antimicrobial activity were first reported in this study. Compounds A5 and E7 were selected for molecular docking studies with targets MetRS (PBD: 7WPI) and PBP (PDB: 6C3K) to determine the binding interactions

  简介：基于生物活性基团剪接、经典生物电子等排和烯烃插入规则，设计并合成了 48 个金酮和茚满酮衍生物。评估了它们对白色念珠菌、大肠杆菌和金黄色葡萄球菌的抑制活性。其中，三十种化合物表现出中等至优异的抗菌活性。方法：最大抑制圈为18 mm（化合物B15、B16和E7），MIC和MBC的最小值分别为15.625 μM（化合物A5和D2）和62.5 μM（化合物A6、A8和E7） . 结果：SAR表明，炔诺酮和茚满酮衍生物能强烈抑制革兰氏阳性菌的生长。吸电子基团或羟基的引入有利于活性。令人兴奋的是，本研究首次报道了具有抗菌活性的 3-苯基烯丙基苯并呋喃酮和 3-烯丙基萘酮骨架。选择化合物 A5 和 E7 与目标 MetRS (PBD: 7WPI) 和 PBP (PDB: 6C3K) 进行分子对接研究，以确定活性位点的结合相互作用。结论：在此基础上，对化合物的理化和药理性质进行了预测和分析。讨论了
• Discovery of aurones bearing two amine functionalities as SHIP2 inhibitors with insulin-sensitizing effect in rat myotubes
  作者：Phei Ching Lim、Beow Keat Yap、Yi Juin Tay、Nur Aziah Hanapi、Siti Rafidah Yusof、Chong-Yew Lee

  DOI：10.1039/d3md00360d

  日期：——

  An aurone bearing two amine functionalities 12a is a micromolar SHIP2 inhibitor with glucose uptake-enhancing property in rat myotubes. 12a showed good permeability across the Caco-2 cell monolayer indicating its potential as an oral insulin sensitizer.

  带有两个胺官能团的醛酮 12a 是一种微摩尔 SHIP2 抑制剂，具有增强大鼠肌管葡萄糖摄取的特性。12a 在 Caco-2 细胞单层中表现出良好的渗透性，这表明它具有作为口服胰岛素增敏剂的潜力。
• Functionalized aurones as inducers of NAD(P)H:quinone oxidoreductase 1 that activate AhR/XRE and Nrf2/ARE signaling pathways: Synthesis, evaluation and SAR
  作者：Chong-Yew Lee、Eng-Hui Chew、Mei-Lin Go

  DOI：10.1016/j.ejmech.2010.03.023

  日期：2010.7

  The chemopreventive potential of functionalized aurones and related compounds as inducers of NAD(P) H:quinone oxidoreductase 1 (NQO1, EC 1.6.99.2) are described. Several 4,6-dimethoxy and 5-hydroxyaurones induced NQO1 activity of Hepa1c1c7 cells by 2-fold at submicromolar concentrations, making these the most potent inducers to be identified from this class. Mechanistically, induction of NQO1 was mediated by the activation of AhR/XRE and Nrf2/ARE pathways, indicating that aurones may be mixed activators of NQO1 induction or agents capable of exploiting the proposed cross-talk between the AhR and Nrf2 gene batteries. QSAR analysis by partial least squares projection to latent structures (PLS) identified size parameters, in particular those associated with non-polar surface areas, as an important determinant of induction activity. These were largely determined by the substitution on rings A and B. A stereoelectronic role for the exocyclic double bond as reflected in the E-LUMO term was also identified. The electrophilicity of the double bond or its effect on the conformation of the target compound are possible key features for induction activity. (c) 2010 Elsevier Masson SAS. All rights reserved.