3-[(benzyloxy)(6-bromohexanoyl)amino]propanoic acid tert-butyl ester | 1239468-30-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 3-[(benzyloxy)(6-bromohexanoyl)amino]propanoic acid tert-butyl ester
• 英文别名: tert-butyl 3-[(benzyloxy)(6-bromohexanoyl)amino]propanoate；tert-butyl 3-[N-(benzyloxy)-6-bromohexanamido]propanoate；Tert-butyl 3-[6-bromohexanoyl(phenylmethoxy)amino]propanoate
• CAS: 1239468-30-4
• 化学式: C₂₀H₃₀BrNO₄
• 分子量: 428.366
• InChiKey: AUZAGPIFUVGHHE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  26
• 可旋转键数：
  13
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  55.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-[(benzyloxy)(6-bromohexanoyl)amino]propanoic acid tert-butyl ester 在 盐酸 、 5%-palladium/activated carbon 、 氢气 、 sodium iodide 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 乙酸乙酯 、 丙酮 为溶剂， 生成 3-{6-[butyl(methyl)amino]-N-hydroxyhexanamido}propanoic acid
  参考文献：
  名称：

  Identification of Jumonji AT-Rich Interactive Domain 1A Inhibitors and Their Effect on Cancer Cells

  摘要：

  Jumonji AT-rich interactive domain IA (JARID1A), one of the jumonji C domain-containing histone demethylase (JHDM) family members, plays key roles in cancer cell proliferation and development of drug tolerance. Therefore, selective JARIDIA inhibitors are potential anticancer agents. In this study, we searched for cell-active JARID1A inhibitors by screening hydroxamate compounds in our in-house library and the structural optimization based on docking study of the hit-compound to a homology model of JARID1A. As a result, we identified compound 6j, which selectively inhibits JARID1A over three other JHDM family members. Compound 7j, a prodrug form of compound 6j, induced a selective increase in the level of trimethylation of histone H3 lysine 4, a substrate of JARID1A. Furthermore, compound 7j synergistically enhanced A549 human lung cancer cell growth inhibition induced by vorinostat, a histone deacetylase inhibitor. These findings support the idea that JARIDIA inhibitors have potential as anticancer agents.

  DOI：

  10.1021/acsmedchemlett.5b00083
• 作为产物：
  描述：

  6-溴己酰氯 、 tert-butyl 3-(benzyloxyamino)propanoate 在 4-二甲氨基吡啶 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 以83%的产率得到3-[(benzyloxy)(6-bromohexanoyl)amino]propanoic acid tert-butyl ester
  参考文献：
  名称：

  Identification of Jumonji AT-Rich Interactive Domain 1A Inhibitors and Their Effect on Cancer Cells

  摘要：

  Jumonji AT-rich interactive domain IA (JARID1A), one of the jumonji C domain-containing histone demethylase (JHDM) family members, plays key roles in cancer cell proliferation and development of drug tolerance. Therefore, selective JARIDIA inhibitors are potential anticancer agents. In this study, we searched for cell-active JARID1A inhibitors by screening hydroxamate compounds in our in-house library and the structural optimization based on docking study of the hit-compound to a homology model of JARID1A. As a result, we identified compound 6j, which selectively inhibits JARID1A over three other JHDM family members. Compound 7j, a prodrug form of compound 6j, induced a selective increase in the level of trimethylation of histone H3 lysine 4, a substrate of JARID1A. Furthermore, compound 7j synergistically enhanced A549 human lung cancer cell growth inhibition induced by vorinostat, a histone deacetylase inhibitor. These findings support the idea that JARIDIA inhibitors have potential as anticancer agents.

  DOI：

  10.1021/acsmedchemlett.5b00083

文献信息

• Design, Synthesis, Enzyme-Inhibitory Activity, and Effect on Human Cancer Cells of a Novel Series of Jumonji Domain-Containing Protein 2 Histone Demethylase Inhibitors
  作者：Shohei Hamada、Takayoshi Suzuki、Koshiki Mino、Koichi Koseki、Felix Oehme、Ingo Flamme、Hiroki Ozasa、Yukihiro Itoh、Daisuke Ogasawara、Haruka Komaarashi、Aiko Kato、Hiroki Tsumoto、Hidehiko Nakagawa、Makoto Hasegawa、Ryuzo Sasaki、Tamio Mizukami、Naoki Miyata

  DOI：10.1021/jm1003655

  日期：2010.8.12

  Selective inhibitors of Jumonji domain-containing protein (JMJD) histone demethylases are candidate anticancer agents as well as potential tools for elucidating the biological functions of JMJDs. On the basis of the crystal structure of JMJD2A and a homology model of JMJD2C, we designed and prepared a series of hydroxamate analogues bearing a tertiary amine. Enzyme assays using JMJD2C, JMJD2A, and prolyl hydroxylases revealed that hydroxamate analogue 8 is a potent and selective JMJD2 inhibitor, showing 500-fold greater JMJD2C-inhibitory activity and more than 9100-fold greater JMJD2C-selectivity compared with the lead compound N-oxalylglycine 2. Compounds 17 and 18, prodrugs of compound 8, each showed synergistic growth inhibition of cancer cells in combination with an inhibitor of lysine-specific demethylase I (LSD1). These findings suggest that combination treatment with JMJD2 inhibitors and LSD I inhibitors may represent a novel strategy for anticancer chemotherapy.