PHD Inhibitor, 8{4} | 1241877-28-0

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: PHD Inhibitor, 8{4}
• 英文别名: 2-[[6-[[(2-acetamidoacetyl)amino]methyl]-4-hydroxy-1-methyl-2-oxoquinoline-3-carbonyl]amino]acetic acid
• CAS: 1241877-28-0
• 化学式: C₁₈H₂₀N₄O₇
• 分子量: 404.379
• InChiKey: HXXITULMAJCBPM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.5
• 重原子数：
  29
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  165
• 氢给体数：
  5
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  2-[[6-[[[2-[[(2R)-2-(2,2-dimethylpropanoylamino)-3-phenylpropanoyl]amino]acetyl]amino]methyl]-4-hydroxy-1-methyl-2-oxoquinoline-3-carbonyl]amino]acetic acid 、 乙酸酐 在 哌啶 、 三乙胺 、 三异丙基硅烷 、 水 、 三氟乙酸 作用下， 以 N,N-二甲基甲酰胺 、 二氯甲烷 为溶剂， 反应 1.42h， 以1.6 mg的产率得到PHD Inhibitor, 8{4}
  参考文献：
  名称：

  Dipeptidyl-Quinolone Derivatives Inhibit Hypoxia Inducible Factor-1α Prolyl Hydroxylases-1, -2, and -3 with Altered Selectivity

  摘要：

  Intracellular levels of the hypoxia-inducible transcription factor (HIF) are regulated under normoxic conditions by prolyl hydroxylases (PHD1, 2, and 3). Treatment of cells with PHD inhibitors stabilizes HIF-1 alpha, eliciting an artificial hypoxic response that includes the transcription of genes involved in erythropoiesis, angiogenesis, and glycolysis. The different in vivo roles of the three PHD isoforms are not yet known, making a PHD-selective inhibitor useful as a biological tool. Although several chemical series of PHD inhibitors have been described, significant isoform selectivity has not been reported. Here we report the synthesis and activity of dipeptidyl analogues derived from a potent but non-selective quinolone scaffold. The compounds were prepared by Pd-catalyzed reductive carbonylation of the 6-iodoquinolone derivative to form the aldehyde directly, which was then attached to a solid support via reductive amination. Amino acids were coupled, and the resulting dipeptidyl-quinolone derivatives were screened, revealing retention of PHD inhibitory activity but an altered PHD1, 2, and 3 selectivity profile. The compounds were found to be similar to 10-fold more potent against PHD1 and PHD3 than against PHD2, whereas the specific parent compound had shown no appreciable selectivity among the different PHD isoforms.

  DOI：

  10.1021/cc100073a