5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)chroman-3-yl 4-methoxybenzoate

• 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-dimethoxy-2-(3,4,5-trimethoxyphenyl)chroman-3-yl 4-methoxybenzoate
• 英文别名: [(2R,3R)-5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-3,4-dihydro-2H-chromen-3-yl] 4-methoxybenzoate
• 化学式: C₂₈H₃₀O₉
• 分子量: 510.541
• InChiKey: BCBGTCAABCWHLH-CLJLJLNGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  37
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  90.9
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  反式-3,4,5-三甲氧基肉桂醇 在 甲醇 、 4-二甲氨基吡啶 、 硫酸 、 三氟化硼乙醚 、 4-甲基苯磺酸吡啶 、 silica gel 、 L-Selectride 、 potassium carbonate 、 戴斯-马丁氧化剂 、 N-甲基吗啉氧化物 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 lithium bromide 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 为溶剂， 反应 31.0h， 生成 5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)chroman-3-yl 4-methoxybenzoate
  参考文献：
  名称：

  Synthesis and Structure–Activity Relationships of EGCG Analogues, a Recently Identified Hsp90 Inhibitor

  摘要：

  Epigallocatechin-3-gallate (EGCG), the principal polyphenol isolated from green tea, was recently shown to inhibit Hsp90; however, structure activity relationships for this natural product have not yet been produced. Herein, we report the synthesis and biological evaluation of EGCG analogues to establish structure activity relationships between EGCG and Hsp90. All four rings as well as the linker connecting the C- and the D-rings were systematically investigated, which led to the discovery of compounds that inhibit Hs90 and display improvement in efficacy over EGCG. Antiproliferative activity of all the analogues was determined against MCF-7 and SKBr3 cell lines and Hsp90 inhibitory activity of the four most potent analogues was further evaluated by Western blot analyses and degradation of Hsp90-dependent client proteins. The prenyl-substituted aryl ester of 3,5-dihydroxychroman-3-ol ring system was identified as a novel scaffold that exhibits Hsp90 inhibitory activity.

  DOI：

  10.1021/jo401027r

文献信息

• Potent and Nontoxic Chemosensitizer of P-Glycoprotein-Mediated Multidrug Resistance in Cancer: Synthesis and Evaluation of Methylated Epigallocatechin, Gallocatechin, and Dihydromyricetin Derivatives
  作者：Iris L. K. Wong、Bao-Chao Wang、Jian Yuan、Liang-Xing Duan、Zhen Liu、Tao Liu、Xue-Min Li、Xuesen Hu、Xiao-Yu Zhang、Tao Jiang、Sheng-Biao Wan、Larry M. C. Chow

  DOI：10.1021/acs.jmedchem.5b00085

  日期：2015.6.11

  We are interested in developing novel natural product-derived P-gp inhibitors to reverse cancer drug resistance. Here, we have synthesized 55 novel derivatives of methylated epigallocatechin (EGC), gallocatechin (GC), and dihydromyricetin (DHM). Three EGC derivatives (23, 35, and 36) and three GC derivatives (50, 51, and 53) are significantly better than epigallocatechin gallate (EGCG) with a relative fold (RF) ranging from 31.4 to 53.6. The effective concentration (EC50) of 23 and 51 ranges from 102 to 195 nM. Compounds 23 and 51 are noncytotoxic to fibroblasts with IC50 > 100 mu M. Compound 23 is specific for P-gp without modulating activity toward MITI or BCRP. Compounds 23 and 51 are non-P-gp substrates. Important pharmacophores for P-gp modulation were identified. In summary, methylated EGC and GC derivatives represent a new class of potent, specific, noncytotoxic, and nonsubstrate P-gp modulators.
• Synthesis and Structure–Activity Relationships of EGCG Analogues, a Recently Identified Hsp90 Inhibitor
  作者：Anuj Khandelwal、Jessica A. Hall、Brian S. J. Blagg

  DOI：10.1021/jo401027r

  日期：2013.8.16

  Epigallocatechin-3-gallate (EGCG), the principal polyphenol isolated from green tea, was recently shown to inhibit Hsp90; however, structure activity relationships for this natural product have not yet been produced. Herein, we report the synthesis and biological evaluation of EGCG analogues to establish structure activity relationships between EGCG and Hsp90. All four rings as well as the linker connecting the C- and the D-rings were systematically investigated, which led to the discovery of compounds that inhibit Hs90 and display improvement in efficacy over EGCG. Antiproliferative activity of all the analogues was determined against MCF-7 and SKBr3 cell lines and Hsp90 inhibitory activity of the four most potent analogues was further evaluated by Western blot analyses and degradation of Hsp90-dependent client proteins. The prenyl-substituted aryl ester of 3,5-dihydroxychroman-3-ol ring system was identified as a novel scaffold that exhibits Hsp90 inhibitory activity.