8-mercapto-3-methyl-7-propyl-3,7-dihydro-1H-purine-2,6-dione

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: 8-mercapto-3-methyl-7-propyl-3,7-dihydro-1H-purine-2,6-dione
• 英文别名: 3-methyl-7-propyl-8-sulfanylidene-9H-purine-2,6-dione
• 化学式: C₉H₁₂N₄O₂S
• mdl: MFCD00630786
• 分子量: 240.286
• InChiKey: MYKSZEXFUYXPKE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.2
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.444
• 拓扑面积：
  96.8
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  8-mercapto-3-methyl-7-propyl-3,7-dihydro-1H-purine-2,6-dione 、 (2-nitrophenyl)methanethiol 在 potassium carbonate 作用下， 以 乙腈 为溶剂， 以63%的产率得到3-Methyl-8-[(2-nitrophenyl)methylsulfanyl]-7-propylpurine-2,6-dione
  参考文献：
  名称：

  Ligand-based design, synthesis and biological evaluation of xanthine derivatives as LSD1/KDM1A inhibitors

  摘要：

  Histone lysine specific demethylase 1 (LSD1) has been recognized as an important epigenetic target for disease treatment. To date, a large number of LSD1 inhibitors have been developed, some of which are currently being evaluated in clinical trials for the treatment of cancers, virus infection, and neurodegenerative diseases. In this paper, we for the first time reported the ligand-based design of fragment-like xanthine derivatives as LSD1 inhibitors, of which compound 4 possessed acceptable pharmacological inhibition against LSD1 (IC50 = 6.45 mu M) and favorable fragment-like nature, and therefore could be used as a promising template to design new LSD1 inhibitors. Interestingly, compounds 6c and 6i strongly suppressed growth of MGC-803 cells partly dependent on their LSD1 inhibition, and were also found to be able to inhibit BRD4 and IDOL. The docking studies were performed to rationalize the biochemical potency against LSD1 and to explain the observed activity discrepancy. The proof-of-concept work may provide an example for other natural ligand-based drug design. (C) 2018 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2018.11.035
• 作为产物：
  描述：

  6-氨基-1-甲基尿嘧啶 在 溴 、 碳酸氢钠 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 8.0h， 生成 8-mercapto-3-methyl-7-propyl-3,7-dihydro-1H-purine-2,6-dione
  参考文献：
  名称：

  发现可可碱衍生物MQS-14主要通过ROS介导的机制诱导MGC-803细胞死亡

  摘要：

  活性氧（ROS）在维持氧化还原平衡和调节生理过程中起着至关重要的作用，癌细胞中的ROS水平相对高于正常细胞中的ROS。因此，升高细胞ROS水平可能是选择性杀死癌细胞的可行策略。在这项工作中，我们合成了一系列新的可可碱衍生物，并评估了它们对胃癌细胞MGC-803，SGC-7901和HGC-27的细胞毒性。特别是，MQS-14在低微摩尔水平下有效抑制MGC-803，SGC-7901和HGC-27细胞的细胞生长。机理研究表明，化合物CQS-14降低了MGC-803细胞的细胞活力，并抑制了CFDA和EdU染色检测所揭示的细胞分裂。MQS-14增加细胞ROS水平并激活MAPK途径，同时降低p-ERK和增加p-JNK表达。MQS-14还诱导了MGC-803细胞中的DNA损伤和凋亡。总之，MQS-14部分通过升高细胞ROS水平诱导MGC-803细胞的细胞死亡。

  DOI：

  10.1016/j.ejmech.2019.04.044

文献信息

• Discovery of the theobromine derivative MQS-14 that induces death of MGC-803 cells mainly through ROS-mediated mechanisms
  作者：Ting Ma、Qi-Sheng Ma、Bin Yu、Hong-Min Liu

  DOI：10.1016/j.ejmech.2019.04.044

  日期：2019.7

  levels in cancer cells are relatively higher than those in normal cells. Therefore, elevating cellular ROS levels may be a viable strategy for selective killing of cancer cells. In this work, we synthesized a series of new theobromine derivatives and evaluated their cytotoxicity against gastric cancer cells MGC-803, SGC-7901 and HGC-27. Particularly, MQS-14 potently inhibited cell growth of MGC-803

  活性氧（ROS）在维持氧化还原平衡和调节生理过程中起着至关重要的作用，癌细胞中的ROS水平相对高于正常细胞中的ROS。因此，升高细胞ROS水平可能是选择性杀死癌细胞的可行策略。在这项工作中，我们合成了一系列新的可可碱衍生物，并评估了它们对胃癌细胞MGC-803，SGC-7901和HGC-27的细胞毒性。特别是，MQS-14在低微摩尔水平下有效抑制MGC-803，SGC-7901和HGC-27细胞的细胞生长。机理研究表明，化合物CQS-14降低了MGC-803细胞的细胞活力，并抑制了CFDA和EdU染色检测所揭示的细胞分裂。MQS-14增加细胞ROS水平并激活MAPK途径，同时降低p-ERK和增加p-JNK表达。MQS-14还诱导了MGC-803细胞中的DNA损伤和凋亡。总之，MQS-14部分通过升高细胞ROS水平诱导MGC-803细胞的细胞死亡。
• 黄嘌呤类LSD1抑制剂及其制备方法和应用
  申请人：郑州大学

  公开号：CN107936022A

  公开（公告）日：2018-04-20

  本发明属于药物化学领域，公开了含有黄嘌呤结构的LSD1抑制剂、合成方法及相关应用。本发明结构通式如下所示，其中R1为苄基，R2为1‑3的烃基、羧酸衍生物，R3为杂原子取代六元环。通过LSD1酶活性检测，发现该系列黄嘌呤类化合物对其具有较好抑制作用，可作为先导化合物，进一步设计新型LSD抑制剂。。
• Ligand-based design, synthesis and biological evaluation of xanthine derivatives as LSD1/KDM1A inhibitors
  作者：Qi-Sheng Ma、Yongfang Yao、Yi-Chao Zheng、Siqi Feng、Junbiao Chang、Bin Yu、Hong-Min Liu

  DOI：10.1016/j.ejmech.2018.11.035

  日期：2019.1

  Histone lysine specific demethylase 1 (LSD1) has been recognized as an important epigenetic target for disease treatment. To date, a large number of LSD1 inhibitors have been developed, some of which are currently being evaluated in clinical trials for the treatment of cancers, virus infection, and neurodegenerative diseases. In this paper, we for the first time reported the ligand-based design of fragment-like xanthine derivatives as LSD1 inhibitors, of which compound 4 possessed acceptable pharmacological inhibition against LSD1 (IC50 = 6.45 mu M) and favorable fragment-like nature, and therefore could be used as a promising template to design new LSD1 inhibitors. Interestingly, compounds 6c and 6i strongly suppressed growth of MGC-803 cells partly dependent on their LSD1 inhibition, and were also found to be able to inhibit BRD4 and IDOL. The docking studies were performed to rationalize the biochemical potency against LSD1 and to explain the observed activity discrepancy. The proof-of-concept work may provide an example for other natural ligand-based drug design. (C) 2018 Elsevier Masson SAS. All rights reserved.