(E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methyl-N-(thiazol-2-yl)hex-4-enamide | 1451181-27-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异香豆素
• 英文名称: (E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methyl-N-(thiazol-2-yl)hex-4-enamide
• 英文别名: (4E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-4-methyl-N-(1,3-thiazol-2-yl)hex-4-enamide；(E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1H-2-benzofuran-5-yl)-4-methyl-N-(1,3-thiazol-2-yl)hex-4-enamide
• CAS: 1451181-27-3
• 化学式: C₂₀H₂₂N₂O₅S
• 分子量: 402.471
• InChiKey: JGPADURPJLEMAK-NYYWCZLTSA-N

物化性质

• 密度：
  1.354±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  28
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  126
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  霉酚酸 在 四丁基氟化铵 、 水 、 氯甲酸乙酯 、 溶剂黄146 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 生成 (E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methyl-N-(thiazol-2-yl)hex-4-enamide
  参考文献：
  名称：

  Discovery of N-(2,3,5-triazoyl)mycophenolic amide and mycophenolic epoxyketone as novel inhibitors of human IMPDH

  摘要：

  Syntheses of ten derivatives of mycophenolic acid (MPA) at C-6' position, and structure-activity relationship study among these derivatives, MPA and mycophenolic hydroxamic acid (MPHA) led to discovery of N-(2,3,5-triazolyl)mycophenolic amide 4, (7'S) mycophenolic epoxyketone 9 and (7'R) mycophenolic epoxyketone 10 having potent inhibitory activity against human inosine-5'-monophosphate dehydrogenase (IMPDH) type land II as well as antiproliferative activity on human leukemia K562 cells. Compounds 4, 9, and 10 showed induction activity of erythroid differentiation in K562 cells. Inhibitory effects of 4 and 10 against IMPDH were attenuated by supplemental guanosine in K562 cells. In contrast, attenuation effect by supplemental guanosine was not significant in the case of 9. Compound 9 weakly inhibited the enzyme activity of HDAC in the nuclear lysate of K562 cells at 10 mu M. These observations suggest that the primary target of 4, 9, and 10 is IMPDH, whereas compound 9 partially inhibits a certain type of HDAC. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.07.016

文献信息

• Application of Docking Analysis in the Prediction and Biological Evaluation of the Lipoxygenase Inhibitory Action of Thiazolyl Derivatives of Mycophenolic Acid
  作者：Evangelia Tsolaki、Phaedra Eleftheriou、Victor Kartsev、Athina Geronikaki、Anil K. Saxena

  DOI：10.3390/molecules23071621

  日期：——

  5-LOX inhibition is among the desired characteristics of anti-inflammatory drugs, while 15-LOX has also been considered as a drug target. Similarity in inhibition behavior between soybean LOX-1 and human 5-LOX has been observed and soybean LOX (sLOX) type 1b has been used for the evaluation of LOX inhibition in drug screening for years. After prediction of LOX inhibition by PASS and docking as well as toxicity by PROTOX and ToxPredict sixteen (E)-N-(thiazol-2-yl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enamide derivatives with lengths varying from about 15–20 Å were evaluated in vitro for LOX inhibitory action using the soybean lipoxygenase sLOX 1b. Docking analysis was performed using soybean LOX L-1 (1YGE), soybean LOX-3 (1JNQ), human 5-LOX (3O8Y and 3V99) and mammalian 15-LOX (1LOX) structures. Different dimensions of target center and docking boxes and a cavity prediction algorithm were used. The compounds exhibited inhibitory action between 2.5 μΜ and 165 μΜ. Substituents with an electronegative atom at two-bond proximity to position 4 of the thiazole led to enhanced activity. Docking results indicated that the LOX structures 1JNQ, 3V99 and 1LOX can effectively be used for estimation of LOX inhibition and amino acid interactions of these compounds.

  抑制 5-LOX 是抗炎药物的理想特性之一，而 15-LOX 也被认为是药物靶点之一。已观察到大豆 LOX-1 与人类 5-LOX 的抑制行为具有相似性，因此大豆 LOX（sLOX）1b 型多年来一直被用于药物筛选中 LOX 抑制性的评估。在通过 PASS 和对接预测 LOX 抑制作用以及通过 PROTOX 和 ToxPredict 预测毒性之后，16 个 (E)-N-（噻唑-2-基）-6-（4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢异苯并呋喃-5-基）-4-甲基己-4-烯酰胺衍生物在体外使用大豆脂氧合酶 sLOX 1b 对 LOX 抑制作用进行了评估。利用大豆 LOX L-1 (1YGE)、大豆 LOX-3 (1JNQ)、人类 5-LOX (3O8Y 和 3V99) 和哺乳动物 15-LOX (1LOX) 的结构进行了对接分析。研究采用了不同尺寸的靶中心和对接盒以及空腔预测算法。这些化合物在 2.5 Μ 至 165 Μ 之间表现出抑制作用。在噻唑的第 4 位与一个电负性原子通过双键结合的取代基可提高活性。Docking 结果表明，LOX 结构 1JNQ、3V99 和 1LOX 可有效地用于估计这些化合物的 LOX 抑制作用和氨基酸相互作用。
• Discovery of N-(2,3,5-triazoyl)mycophenolic amide and mycophenolic epoxyketone as novel inhibitors of human IMPDH
  作者：Kazuhiro Sunohara、Shinya Mitsuhashi、Kengo Shigetomi、Makoto Ubukata

  DOI：10.1016/j.bmcl.2013.07.016

  日期：2013.9

  Syntheses of ten derivatives of mycophenolic acid (MPA) at C-6' position, and structure-activity relationship study among these derivatives, MPA and mycophenolic hydroxamic acid (MPHA) led to discovery of N-(2,3,5-triazolyl)mycophenolic amide 4, (7'S) mycophenolic epoxyketone 9 and (7'R) mycophenolic epoxyketone 10 having potent inhibitory activity against human inosine-5'-monophosphate dehydrogenase (IMPDH) type land II as well as antiproliferative activity on human leukemia K562 cells. Compounds 4, 9, and 10 showed induction activity of erythroid differentiation in K562 cells. Inhibitory effects of 4 and 10 against IMPDH were attenuated by supplemental guanosine in K562 cells. In contrast, attenuation effect by supplemental guanosine was not significant in the case of 9. Compound 9 weakly inhibited the enzyme activity of HDAC in the nuclear lysate of K562 cells at 10 mu M. These observations suggest that the primary target of 4, 9, and 10 is IMPDH, whereas compound 9 partially inhibits a certain type of HDAC. (C) 2013 Elsevier Ltd. All rights reserved.