3-((1-acetylpiperidin-4-yl)methyl)-5-cyclopentylthieno[2,3-d]pyrimidin-4(3H)-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻吩并嘧啶酮衍生物
• 英文名称: 3-((1-acetylpiperidin-4-yl)methyl)-5-cyclopentylthieno[2,3-d]pyrimidin-4(3H)-one
• 英文别名: 3-[(1-Acetylpiperidin-4-yl)methyl]-5-cyclopentylthieno[2,3-d]pyrimidin-4-one；3-[(1-acetylpiperidin-4-yl)methyl]-5-cyclopentylthieno[2,3-d]pyrimidin-4-one
• 化学式: C₁₉H₂₅N₃O₂S
• 分子量: 359.492
• InChiKey: RVVNQLSZGRBWKP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  25
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.63
• 拓扑面积：
  81.2
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  环戊基乙酮 在 吗啉 、 aluminum oxide 、 potassium carbonate 、 sulfur 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 4.25h， 生成 3-((1-acetylpiperidin-4-yl)methyl)-5-cyclopentylthieno[2,3-d]pyrimidin-4(3H)-one
  参考文献：
  名称：

  Identification of the first small-molecule inhibitor of the REV7 DNA repair protein interaction

  摘要：

  DNA interstrand crosslink (ICL) repair (ICLR) has been implicated in the resistance of cancer cells to ICL-inducing chemotherapeutic agents. Despite the clinical significance of ICL-inducing chemotherapy, few studies have focused on developing small-molecule inhibitors for ICLR. The mammalian DNA polymerase zeta, which comprises the catalytic subunit REV3L and the non-catalytic subunit REV7, is essential for ICLR. To identify small-molecule compounds that are mechanistically capable of inhibiting ICLR by targeting REV7, high-throughput screening and structure-activity relationship (SAR) analysis were performed. Compound 1 was identified as an inhibitor of the interaction of REV7 with the REV7-binding sequence of REV3L. Compound 7 (an optimized analog of compound 1) bound directly to REV7 in nuclear magnetic resonance analyses, and inhibited the reactivation of a reporter plasmid containing an ICL in between the promoter and reporter regions. The normalized clonogenic survival of HeLa cells treated with cisplatin and compound 7 was lower than that for cells treated with cisplatin only. These findings indicate that a small-molecule inhibitor of the REV7/REV3L interaction can chemosensitize cells by inhibiting ICLR. (C) 2016 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2016.07.026

文献信息

• Identification of the first small-molecule inhibitor of the REV7 DNA repair protein interaction
  作者：Marcelo L. Actis、Nigus D. Ambaye、Benjamin J. Evison、Youming Shao、Murugendra Vanarotti、Akira Inoue、Ezelle T. McDonald、Sotaro Kikuchi、Richard Heath、Kodai Hara、Hiroshi Hashimoto、Naoaki Fujii

  DOI：10.1016/j.bmc.2016.07.026

  日期：2016.9

  DNA interstrand crosslink (ICL) repair (ICLR) has been implicated in the resistance of cancer cells to ICL-inducing chemotherapeutic agents. Despite the clinical significance of ICL-inducing chemotherapy, few studies have focused on developing small-molecule inhibitors for ICLR. The mammalian DNA polymerase zeta, which comprises the catalytic subunit REV3L and the non-catalytic subunit REV7, is essential for ICLR. To identify small-molecule compounds that are mechanistically capable of inhibiting ICLR by targeting REV7, high-throughput screening and structure-activity relationship (SAR) analysis were performed. Compound 1 was identified as an inhibitor of the interaction of REV7 with the REV7-binding sequence of REV3L. Compound 7 (an optimized analog of compound 1) bound directly to REV7 in nuclear magnetic resonance analyses, and inhibited the reactivation of a reporter plasmid containing an ICL in between the promoter and reporter regions. The normalized clonogenic survival of HeLa cells treated with cisplatin and compound 7 was lower than that for cells treated with cisplatin only. These findings indicate that a small-molecule inhibitor of the REV7/REV3L interaction can chemosensitize cells by inhibiting ICLR. (C) 2016 Elsevier Ltd. All rights reserved.