(S)-N-(3-(1H-indol-3-yl)-1-oxo-1-((8-oxo-8-(2-propylhydrazinyl)octyl)amino)propan-2-yl)-4-methoxybenzamide

• 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: (S)-N-(3-(1H-indol-3-yl)-1-oxo-1-((8-oxo-8-(2-propylhydrazinyl)octyl)amino)propan-2-yl)-4-methoxybenzamide
• 英文别名: N-[(2S)-3-(1H-indol-3-yl)-1-oxo-1-[[8-oxo-8-(2-propylhydrazinyl)octyl]amino]propan-2-yl]-4-methoxybenzamide
• 化学式: C₃₀H₄₁N₅O₄
• 分子量: 535.687
• InChiKey: ZCZXFHBXRHZTID-MHZLTWQESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  39
• 可旋转键数：
  17
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  124
• 氢给体数：
  5
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  8-氨基辛酸 在 盐酸 、 sodium cyanoborohydride 、 magnesium sulfate 、 一水合肼 、 三乙胺 、 乙酰氯 作用下， 以 甲醇 、 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 53.0h， 生成 (S)-N-(3-(1H-indol-3-yl)-1-oxo-1-((8-oxo-8-(2-propylhydrazinyl)octyl)amino)propan-2-yl)-4-methoxybenzamide
  参考文献：
  名称：

  Class I HDAC Inhibitors Display Different Antitumor Mechanism in Leukemia and Prostatic Cancer Cells Depending on Their p53 Status

  摘要：

  Previously, we designed and synthesized a series of o-aminobenzamide-based histone deacetylase (HDAC) inhibitors, among which the representative compound 11a exhibited potent inhibitory activity against class I HDACs. In this study, we report the development of more potent hydrazide-based class I selective HDAC inhibitors using 11a as a lead. Representative compound 13b showed a mixed, slow, and tight binding inhibition mechanism for HDAC1, 2, and 3. The most potent compound 13e exhibited low nanomolar IC(50)s toward HDAC1, 2, and 3 and could down-regulate HDAC6 in acute myeloid leukemia MV4-11 cells. The EC50 of 13e against MV4-11 cells was 34.7 nM, which is 26 times lower than its parent compound 11a. In vitro responses to 13e vary significantly and interestingly based on cell type: in p53 wild-type MV4-11 cells, 13e induced cell death via apoptosis and G1/S cell cycle arrest, which is likely mediated by a p53-dependent pathway, while in p53-null PC-3 cells, 13e caused G2/M arrest and inhibited cell proliferation without inducing caspase-3-dependent apoptosis.

  DOI：

  10.1021/acs.jmedchem.8b00136

文献信息

• Class I HDAC Inhibitors Display Different Antitumor Mechanism in Leukemia and Prostatic Cancer Cells Depending on Their p53 Status
  作者：Xiaoyang Li、Yuri K. Peterson、Elizabeth S. Inks、Richard A. Himes、Jiaying Li、Yingjie Zhang、Xiujie Kong、C. James Chou

  DOI：10.1021/acs.jmedchem.8b00136

  日期：2018.3.22

  Previously, we designed and synthesized a series of o-aminobenzamide-based histone deacetylase (HDAC) inhibitors, among which the representative compound 11a exhibited potent inhibitory activity against class I HDACs. In this study, we report the development of more potent hydrazide-based class I selective HDAC inhibitors using 11a as a lead. Representative compound 13b showed a mixed, slow, and tight binding inhibition mechanism for HDAC1, 2, and 3. The most potent compound 13e exhibited low nanomolar IC(50)s toward HDAC1, 2, and 3 and could down-regulate HDAC6 in acute myeloid leukemia MV4-11 cells. The EC50 of 13e against MV4-11 cells was 34.7 nM, which is 26 times lower than its parent compound 11a. In vitro responses to 13e vary significantly and interestingly based on cell type: in p53 wild-type MV4-11 cells, 13e induced cell death via apoptosis and G1/S cell cycle arrest, which is likely mediated by a p53-dependent pathway, while in p53-null PC-3 cells, 13e caused G2/M arrest and inhibited cell proliferation without inducing caspase-3-dependent apoptosis.