5-(3,4-dihydroxybenzyl)-1,3-diisobutylpyrimidine-2,4,6-(1H,3H,5H)-trione

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 5-(3,4-dihydroxybenzyl)-1,3-diisobutylpyrimidine-2,4,6-(1H,3H,5H)-trione
• 英文别名: 5-[(3,4-Dihydroxyphenyl)methyl]-1,3-bis(2-methylpropyl)-1,3-diazinane-2,4,6-trione；5-[(3,4-dihydroxyphenyl)methyl]-1,3-bis(2-methylpropyl)-1,3-diazinane-2,4,6-trione
• 化学式: C₁₉H₂₆N₂O₅
• 分子量: 362.426
• InChiKey: RPKZRKUMLOYWSJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  26
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  98.2
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  1,3-双(2-甲基丙基)脲 在 乙酸酐 、 溶剂黄146 、 锌 作用下， 以 乙醇 为溶剂， 反应 2.17h， 生成 5-(3,4-dihydroxybenzyl)-1,3-diisobutylpyrimidine-2,4,6-(1H,3H,5H)-trione
  参考文献：
  名称：

  A Novel Cell-Permeable, Selective, and Noncompetitive Inhibitor of KAT3 Histone Acetyltransferases from a Combined Molecular Pruning/Classical Isosterism Approach

  摘要：

  Selective inhibitors of the two paralogue KAT3 acetyltransferases (CBP and p300) may serve not only as precious chemical tools to investigate the role of these enzymes in physiopathological mechanisms but also as lead structures for the development of further antitumor agents. After the application of a molecular pruning approach to the hardly optimizable and not very cell-permeable garcinol core structure, we prepared many analogues that were screened for their inhibitory effects using biochemical and biophysical (SPR) assays. Further optimization led to the discovery of the benzylidenebarbituric acid derivative 7h (EML425) as a potent and selective reversible inhibitor of CBP/p300, noncompetitive versus both acetyl-CoA and a histone H3 peptide, and endowed with good cell permeability. Furthermore, in human leukemia U937 cells, it induced a marked and time-dependent reduction in the acetylation of lysine H4K5 and H3K9, a marked arrest in the G0/G1 phase and a significant increase in the hypodiploid nuclei percentage.

  DOI：

  10.1021/jm5019687

文献信息

• A Novel Cell-Permeable, Selective, and Noncompetitive Inhibitor of KAT3 Histone Acetyltransferases from a Combined Molecular Pruning/Classical Isosterism Approach
  作者：Ciro Milite、Alessandra Feoli、Kazuki Sasaki、Valeria La Pietra、Amodio Luca Balzano、Luciana Marinelli、Antonello Mai、Ettore Novellino、Sabrina Castellano、Alessandra Tosco、Gianluca Sbardella

  DOI：10.1021/jm5019687

  日期：2015.3.26

  Selective inhibitors of the two paralogue KAT3 acetyltransferases (CBP and p300) may serve not only as precious chemical tools to investigate the role of these enzymes in physiopathological mechanisms but also as lead structures for the development of further antitumor agents. After the application of a molecular pruning approach to the hardly optimizable and not very cell-permeable garcinol core structure, we prepared many analogues that were screened for their inhibitory effects using biochemical and biophysical (SPR) assays. Further optimization led to the discovery of the benzylidenebarbituric acid derivative 7h (EML425) as a potent and selective reversible inhibitor of CBP/p300, noncompetitive versus both acetyl-CoA and a histone H3 peptide, and endowed with good cell permeability. Furthermore, in human leukemia U937 cells, it induced a marked and time-dependent reduction in the acetylation of lysine H4K5 and H3K9, a marked arrest in the G0/G1 phase and a significant increase in the hypodiploid nuclei percentage.