甲基0328 | 1445251-22-8

• 物质功能分类: 生物化工 - 抑制剂 - DNA损伤(DNA Damage)
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 中文名称: 甲基0328
• 中文别名: (S)-3-(4-氧代-3,4-二氢喹唑啉-2-2)-N-1-苯乙基丙酰胺；3-（4-Oxo-1H-喹唑啉-2-基）-N-[（（1S）-1-苯乙基]丙酰胺；ME0328
• 英文名称: 3,4-dihydro-4-oxo-N-[(1S)-1-phenylethyl]-2-quinazolinepropanamide
• 英文别名: ME0328；3-(4-oxo-3H-quinazolin-2-yl)-N-[(1S)-1-phenylethyl]propanamide
• CAS: 1445251-22-8
• 化学式: C₁₉H₁₉N₃O₂
• 分子量: 321.379
• InChiKey: QIHBWVVVRYYYRO-ZDUSSCGKSA-N

物化性质

• 溶解度：
  DMSO：可溶10mg/mL，澄清

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  24
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  70.6
• 氢给体数：
  2
• 氢受体数：
  3

安全信息

• 危险品标志：
  Xn
• 安全说明：
  S36/37
• 危险类别码：
  R22,R43
• WGK Germany：
  3
• 危险性防范说明：
  P280,P305+P351+P338
• 危险性描述：
  H302

制备方法与用途

生物活性

ME0328 是一种强效的选择性PARP抑制剂，其IC50值为0.89 μM。相比PARP1，ME0328对PARP3的选择性高出约七倍。

体外研究

ME0328 具有良好的溶解性和细胞穿透能力，并且在人肝脏微粒体和大鼠肝细胞中表现出代谢稳定性。实验结果表明，在A549 和MRC5细胞中，10 μM浓度的ME0328通过影响ARTD3显著延迟了γH2AX位点的出现，同时未显示明显的细胞毒性。

靶点

目标蛋白	IC50 (μM)
ARTD3/PARP3	0.89
ARTD1/PARP1	6.3
ARTD2/PARP2	10.8
ARTD6/TNKS2	34.3
ARTD5/TNKS1	47.3
ARTD10/PARP10	71.3

反应信息

• 作为产物：
  描述：

  4-((2-氰基苯基)氨基)-4-氧代丁酸 在 N-羟基-7-氮杂苯并三氮唑 、 过氧化脲素 、 potassium carbonate 、 N,N'-二异丙基碳二亚胺 作用下， 以 水 、 N,N-二甲基甲酰胺 、 丙酮 为溶剂， 反应 19.0h， 生成 甲基0328
  参考文献：
  名称：

  Chemical Probes to Study ADP-Ribosylation: Synthesis and Biochemical Evaluation of Inhibitors of the Human ADP-Ribosyltransferase ARTD3/PARP3

  摘要：

  The racemic 3-(4-oxo-3,4-dihydroquinazolin-2-yl)-N-[1-(pyridin-2-yl)ethyl]propanamide, 1, has previously been identified as a potent but unselective inhibitor of diphtheria toxin-like ADP-ribosyltransferase 3 (ARTD3). Herein we describe synthesis and evaluation of SS compounds in this class. It was found that the stereochemistry is of great importance for both selectivity and potency and that substituents on the phenyl ring resulted in poor solubility. Certain variations at the meso position were tolerated and caused a large shift in the binding pose. Changes to the ethylene linker that connects the quinazolinone to the amide were also investigated but proved detrimental to binding. By combination of synthetic organic chemistry and structure-based design, two selective inhibitors of ARTD3 were discovered.

  DOI：

  10.1021/jm401394u

文献信息

• PHARMACEUTICAL COMBINATION FOR TREATMENT OF CANCER
  申请人：ArQule, Inc.

  公开号：US20200155521A1

  公开（公告）日：2020-05-21

  The present application is drawn to methods of treating a cell proliferative disorder, such as a cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising at least one of Compound 1, Compound 2, and Compound 3, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and at least one second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein the cell proliferative disorder is treated.
• Chemical Probes to Study ADP-Ribosylation: Synthesis and Biochemical Evaluation of Inhibitors of the Human ADP-Ribosyltransferase ARTD3/PARP3
  作者：Anders E. G. Lindgren、Tobias Karlberg、Torun Ekblad、Sara Spjut、Ann-Gerd Thorsell、C. David Andersson、Ton Tong Nhan、Victor Hellsten、Johan Weigelt、Anna Linusson、Herwig Schüler、Mikael Elofsson

  DOI：10.1021/jm401394u

  日期：2013.12.12

  The racemic 3-(4-oxo-3,4-dihydroquinazolin-2-yl)-N-[1-(pyridin-2-yl)ethyl]propanamide, 1, has previously been identified as a potent but unselective inhibitor of diphtheria toxin-like ADP-ribosyltransferase 3 (ARTD3). Herein we describe synthesis and evaluation of SS compounds in this class. It was found that the stereochemistry is of great importance for both selectivity and potency and that substituents on the phenyl ring resulted in poor solubility. Certain variations at the meso position were tolerated and caused a large shift in the binding pose. Changes to the ethylene linker that connects the quinazolinone to the amide were also investigated but proved detrimental to binding. By combination of synthetic organic chemistry and structure-based design, two selective inhibitors of ARTD3 were discovered.