(4R,6R)-6-(4-hydroxy-butoxy)-4-thiophen-3-yl-5,6-dihydro-4H-pyran-2-carboxylic acid (2-hydroxyphenyl)-amide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (4R,6R)-6-(4-hydroxy-butoxy)-4-thiophen-3-yl-5,6-dihydro-4H-pyran-2-carboxylic acid (2-hydroxyphenyl)-amide
• 英文别名: (2R,4R)-2-(4-hydroxybutoxy)-N-(2-hydroxyphenyl)-4-thiophen-3-yl-3,4-dihydro-2H-pyran-6-carboxamide
• 化学式: C₂₀H₂₃NO₅S
• 分子量: 389.472
• InChiKey: ZUQDBCDNZZWHGF-HNAYVOBHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  27
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  116
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  1,3-benzodithiol-2-ylium tetrafluoroborate 、 (4R,6R)-6-(4-hydroxy-butoxy)-4-thiophen-3-yl-5,6-dihydro-4H-pyran-2-carboxylic acid (2-hydroxyphenyl)-amide 在 吡啶 作用下， 以 乙腈 为溶剂， 反应 18.0h， 以57.6%的产率得到(4R,6R)-6-[4-(benzo[1,3]dithiol-2-yloxy)-butoxy]-4-thiophen-3-yl-5,6-dihydro-4H-pyran-2-carboxylic acid (2-hydroxy-phenyl)-amide
  参考文献：
  名称：

  Discovery of an Inhibitor of a Transcription Factor Using Small Molecule Microarrays and Diversity-Oriented Synthesis

  摘要：

  Small molecule microarrays were screened to identify a small molecule ligand for Hap3p, a subunit of the yeast Hap2/3/4/5p transcription factor complex. The compound, named haptamide A, was determined to have a KD of 5.03 muM for binding to Hap3p using surface plasmon resonance analysis. Haptamide A also inhibited activation of a GDH1-lacZ reporter gene in a dose-dependent fashion. To explore structure-activity relationships, 11 derivatives of haptamide A were prepared using the same synthetic route that was developed for the original library synthesis. Analysis of dissociation constants and IC50 values for the reporter gene assay revealed a more potent inhibitor, haptamide B, with a KD of 330 nM. Whole-genome transcriptional profiling was used to compare effects of haptamide B with a hap3Delta yeast strain. Treatment with haptamide B, like the deletion mutant, reduced lactate-induced transcription of several genes from wild-type levels. Profiling the genetic "knockout" and the chemical genetic "knockdown" led to the identification of several genes that are regulated by Hap3p under nonfermentative conditions. These results demonstrate that a small molecule discovered using the small molecule microarray binding assay can permeate yeast cells and reach its target transcription factor protein in cells.

  DOI：

  10.1021/ja0352698