4-[4-(N-methyl-2,4-dihydroxybenzamido)benzoyl]-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid

• 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: 4-[4-(N-methyl-2,4-dihydroxybenzamido)benzoyl]-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid
• 英文别名: 4-[4-[(2,4-Dihydroxybenzoyl)-methylamino]benzoyl]-2,3-dihydro-1,4-benzoxazine-2-carboxylic acid；4-[4-[(2,4-dihydroxybenzoyl)-methylamino]benzoyl]-2,3-dihydro-1,4-benzoxazine-2-carboxylic acid
• 化学式: C₂₄H₂₀N₂O₇
• 分子量: 448.432
• InChiKey: YJJQLXIDSMWSDE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  33
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  128
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  2,4-二羟基苯甲酸 在 草酰氯 、 硫酸 、 氨 、 水 、 三乙胺 、 N,N-二甲基甲酰胺 、 sodium hydroxide 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 31.5h， 生成 4-[4-(N-methyl-2,4-dihydroxybenzamido)benzoyl]-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid
  参考文献：
  名称：

  Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase

  摘要：

  Libraries of nonpurified resorcinol amide derivatives were screened by surface plasmon resonance (SPR) to determine the binding dissociation constant (off-rate, k(d)) for compounds binding to the pyruvate dehydrogenase kinase (PDHK) enzyme. Parallel off-rate measurements against HSP90 and application of structure-based drug design enabled rapid hit to lead progression in a program to identify pan-isoform ATP-competitive inhibitors of PDHK. Lead optimization identified selective sub-100-nM inhibitors of the enzyme which significantly reduced phosphorylation of the E1 alpha subunit in the PC3 cancer cell line in vitro.

  DOI：

  10.1021/acs.jmedchem.6b01478

文献信息

• Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase
  作者：Paul A. Brough、Lisa Baker、Simon Bedford、Kirsten Brown、Seema Chavda、Victoria Chell、Jalanie D’Alessandro、Nicholas G. M. Davies、Ben Davis、Loic Le Strat、Alba T. Macias、Daniel Maddox、Patrick C. Mahon、Andrew J. Massey、Natalia Matassova、Sean McKenna、Johannes W. G. Meissner、Jonathan D. Moore、James B. Murray、Christopher J. Northfield、Charles Parry、Rachel Parsons、Stephen D. Roughley、Terry Shaw、Heather Simmonite、Stephen Stokes、Allan Surgenor、Emma Stefaniak、Alan Robertson、Yikang Wang、Paul Webb、Neil Whitehead、Mike Wood

  DOI：10.1021/acs.jmedchem.6b01478

  日期：2017.3.23

  Libraries of nonpurified resorcinol amide derivatives were screened by surface plasmon resonance (SPR) to determine the binding dissociation constant (off-rate, k(d)) for compounds binding to the pyruvate dehydrogenase kinase (PDHK) enzyme. Parallel off-rate measurements against HSP90 and application of structure-based drug design enabled rapid hit to lead progression in a program to identify pan-isoform ATP-competitive inhibitors of PDHK. Lead optimization identified selective sub-100-nM inhibitors of the enzyme which significantly reduced phosphorylation of the E1 alpha subunit in the PC3 cancer cell line in vitro.