6-((3-fluorobenzyl)thio)-5-(3-methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡唑并嘧啶类
• 英文名称: 6-((3-fluorobenzyl)thio)-5-(3-methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one
• 英文别名: 6-[(3-Fluorophenyl)methylsulfanyl]-5-(3-methoxyphenyl)-1-methylpyrazolo[3,4-d]pyrimidin-4-one；6-[(3-fluorophenyl)methylsulfanyl]-5-(3-methoxyphenyl)-1-methylpyrazolo[3,4-d]pyrimidin-4-one
• 化学式: C₂₀H₁₇FN₄O₂S
• 分子量: 396.445
• InChiKey: BGTVGYWDKJYKAS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  85
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  5-氨基-1-甲基吡唑-4-甲酸乙酯 在 sodium hydride 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 2.5h， 生成 6-((3-fluorobenzyl)thio)-5-(3-methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one
  参考文献：
  名称：

  Structure-Based Optimization of a Novel Class of Aldehyde Dehydrogenase 1A (ALDH1A) Subfamily-Selective Inhibitors as Potential Adjuncts to Ovarian Cancer Chemotherapy

  摘要：

  Aldehyde dehydrogenase (ALDH) activity is commonly used as a marker to identify cancer stem-like cells. The three ALDH1A isoforms have all been individually implicated in cancer stem-like cells and in chemoresistance; however, which isoform is preferentially expressed varies between cell lines. We sought to explore the structural determinants of ALDH1A isoform selectivity in a series of small-molecule inhibitors in support of research into the role of ALDH1A in cancer stem cells. An SAR campaign guided by a cocrystal structure of the HTS hit CM39 (7) with ALDH1A1 afforded first-in-class inhibitors of the ALDH1A subfamily with excellent selectivity over the homologous ALDH2 isoform. We also discovered the first reported modestly selective single isoform 1A2 and 1A3 inhibitors. Two compounds, 13g and 13h, depleted the CD133(+) putative cancer stem cell pool, synergized with cisplatin, and achieved efficacious concentrations in vivo following IP administration. Compound 13h additionally synergized with cisplatin in a patient-derived ovarian cancer spheroid model.

  DOI：

  10.1021/acs.jmedchem.8b00930

文献信息

• SMALL MOLECULE INHIBITORS OF ALDH AND USES THEREOF
  申请人：The Regents of the University of Michigan

  公开号：US20190255055A1

  公开（公告）日：2019-08-22

  This invention is in the field of medicinal chemistry. In particular, the invention relates to a new class of small-molecules having a thiopyrimidinone structure which function as inhibitors of ALDH protein, and their use as therapeutics for the treatment of cancer and other diseases.
• Structure-Based Optimization of a Novel Class of Aldehyde Dehydrogenase 1A (ALDH1A) Subfamily-Selective Inhibitors as Potential Adjuncts to Ovarian Cancer Chemotherapy
  作者：Brandt C. Huddle、Edward Grimley、Cameron D. Buchman、Mikhail Chtcherbinine、Bikash Debnath、Pooja Mehta、Kun Yang、Cynthia A. Morgan、Siwei Li、Jeremy Felton、Duxin Sun、Geeta Mehta、Nouri Neamati、Ronald J. Buckanovich、Thomas D. Hurley、Scott D. Larsen

  DOI：10.1021/acs.jmedchem.8b00930

  日期：2018.10.11

  Aldehyde dehydrogenase (ALDH) activity is commonly used as a marker to identify cancer stem-like cells. The three ALDH1A isoforms have all been individually implicated in cancer stem-like cells and in chemoresistance; however, which isoform is preferentially expressed varies between cell lines. We sought to explore the structural determinants of ALDH1A isoform selectivity in a series of small-molecule inhibitors in support of research into the role of ALDH1A in cancer stem cells. An SAR campaign guided by a cocrystal structure of the HTS hit CM39 (7) with ALDH1A1 afforded first-in-class inhibitors of the ALDH1A subfamily with excellent selectivity over the homologous ALDH2 isoform. We also discovered the first reported modestly selective single isoform 1A2 and 1A3 inhibitors. Two compounds, 13g and 13h, depleted the CD133(+) putative cancer stem cell pool, synergized with cisplatin, and achieved efficacious concentrations in vivo following IP administration. Compound 13h additionally synergized with cisplatin in a patient-derived ovarian cancer spheroid model.