(2S)-2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propanoic acid | 1534392-29-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: (2S)-2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propanoic acid
• 英文别名: (2S)-2-(1,3-dioxoisoindol-2-yl)-3-(2-oxo-1H-quinolin-4-yl)propanoic acid
• CAS: 1534392-29-4
• 化学式: C₂₀H₁₄N₂O₅
• 分子量: 362.342
• InChiKey: UNQOGLZDYYMZJO-INIZCTEOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  27
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  104
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  3-(2-oxo-1,2-dihydro-4-quinolinyl)-L-alanine 、 2-[(琥珀酰亚胺氧基)羰基]苯甲酸甲酯 在 sodium carbonate 作用下， 以 水 、 乙腈 为溶剂， 以19%的产率得到(2S)-2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propanoic acid
  参考文献：
  名称：

  Synthesis and Evaluation of Analogues of N-Phthaloyl-l-tryptophan (RG108) as Inhibitors of DNA Methyltransferase 1

  摘要：

  DNA methyltransferases (DNMT) are promising drug targets in cancer provided that new, more specific, and chemically stable inhibitors are discovered. Among the non-nucleoside DNMT inhibitors, N-phthaloyl-L-tryptophan 1 (RG108) was first identified as inhibitor of DNMT1. Here, 1 analogues were synthesized to understand its interaction with DNMT. The indole, carboxylate, and phthalimide moieties were modified. Homologated and conformationally constrained analogues were prepared. The latter were synthesized from prolinohomotryptophan derivatives through a methodology based amino-zinc-ene-enolate cyclization. All compounds were tested for their ability to inhibit DNMT1 in vitro. Among them, constrained compounds 16-18 and NPys derivatives 10-11 were found to be at least 10-fold more potent than the reference compound. The cytotoxicity on the tumor, DU145 cell line of the most potent inhibitors was correlated to their inhibitory potency. Finally, docking studies were conducted in order to understand their binding mode. This study provides insights for the design of the next-generation of DNMT inhibitors.

  DOI：

  10.1021/jm401419p

文献信息

• Synthesis and Evaluation of Analogues of <i>N</i>-Phthaloyl-<scp>l</scp>-tryptophan (RG108) as Inhibitors of DNA Methyltransferase 1
  作者：Saâdia Asgatay、Christine Champion、Gaël Marloie、Thierry Drujon、Catherine Senamaud-Beaufort、Alexandre Ceccaldi、Alexandre Erdmann、Arumugam Rajavelu、Philippe Schambel、Albert Jeltsch、Olivier Lequin、Philippe Karoyan、Paola B. Arimondo、Dominique Guianvarc’h

  DOI：10.1021/jm401419p

  日期：2014.1.23

  DNA methyltransferases (DNMT) are promising drug targets in cancer provided that new, more specific, and chemically stable inhibitors are discovered. Among the non-nucleoside DNMT inhibitors, N-phthaloyl-L-tryptophan 1 (RG108) was first identified as inhibitor of DNMT1. Here, 1 analogues were synthesized to understand its interaction with DNMT. The indole, carboxylate, and phthalimide moieties were modified. Homologated and conformationally constrained analogues were prepared. The latter were synthesized from prolinohomotryptophan derivatives through a methodology based amino-zinc-ene-enolate cyclization. All compounds were tested for their ability to inhibit DNMT1 in vitro. Among them, constrained compounds 16-18 and NPys derivatives 10-11 were found to be at least 10-fold more potent than the reference compound. The cytotoxicity on the tumor, DU145 cell line of the most potent inhibitors was correlated to their inhibitory potency. Finally, docking studies were conducted in order to understand their binding mode. This study provides insights for the design of the next-generation of DNMT inhibitors.