(E)-N-(4-(3-(2,2-bis(3-hydroxypropyl)hydrazinyl)-3-oxoprop-1-en-1-yl)benzyl)-2-(2-methyl-1H-indol-3-yl)ethanaminium 2,2,2-trifluoroacetate

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 肉桂酸及其衍生物
• 英文名称: (E)-N-(4-(3-(2,2-bis(3-hydroxypropyl)hydrazinyl)-3-oxoprop-1-en-1-yl)benzyl)-2-(2-methyl-1H-indol-3-yl)ethanaminium 2,2,2-trifluoroacetate
• 英文别名: (E)-N',N'-bis(3-hydroxypropyl)-3-[4-[[2-(2-methyl-1H-indol-3-yl)ethylamino]methyl]phenyl]prop-2-enehydrazide;2,2,2-trifluoroacetic acid
• 化学式: C₂HF₃O₂*C₂₇H₃₆N₄O₃
• 分子量: 578.632
• InChiKey: PAERSDSKZHRDHY-UEIGIMKUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.55
• 重原子数：
  41
• 可旋转键数：
  14
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  138
• 氢给体数：
  6
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  1H-2-甲基-3-氨乙基吲哚 在 sodium cyanoborohydride 、 potassium carbonate 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 溶剂黄146 、 三乙胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 2.5h， 生成 (E)-N-(4-(3-(2,2-bis(3-hydroxypropyl)hydrazinyl)-3-oxoprop-1-en-1-yl)benzyl)-2-(2-methyl-1H-indol-3-yl)ethanaminium 2,2,2-trifluoroacetate
  参考文献：
  名称：

  Design of Hydrazide-Bearing HDACIs Based on Panobinostat and Their p53 and FLT3-ITD Dependency in Antileukemia Activity

  摘要：

  Here, we present a new series of hydrazide-bearing class I selective HDAC inhibitors designed based on panobinostat. The cap, linker, and zinc-binding group were derivatized to improve HDAC affinity and antileukemia efficacy. Lead inhibitor 13a shows picomolar or low nanomolar IC50 values against HDAC1 and HDAC3 and exhibits differential toxicity profiles toward multiple cancer cells with different FLT3 and p53 statuses. 13a indirectly inhibits the FLT3 signaling pathway and down-regulates master antiapoptotic proteins, resulting in the activation of pro-caspase3 in wt-p53 FLT3-ITD MV4-11 cells. While in the wt-FLT3 and p53-null cells, 13a is incapable of causing apoptosis at a therapeutic concentration. The MDM2 antagonist and the proteasome inhibitor promote 13a-triggered apoptosis by preventing p53 degradation. Furthermore, we demonstrate that apoptosis rather than autophagy is the key contributing factor for 13a-triggered cell death. When compared to panobinostat, 13a is not mutagenic and displays superior in vivo bioavailability and a higher AUC(0-inf) value.

  DOI：

  10.1021/acs.jmedchem.0c00442

文献信息

• Design of Hydrazide-Bearing HDACIs Based on Panobinostat and Their p53 and FLT3-ITD Dependency in Antileukemia Activity
  作者：Xiaoyang Li、Yuqi Jiang、Yuri K. Peterson、Tongqiang Xu、Richard A. Himes、Xin Luo、Guilin Yin、Elizabeth S. Inks、Nathan Dolloff、Stephanie Halene、Sherine S. L. Chan、C. James Chou

  DOI：10.1021/acs.jmedchem.0c00442

  日期：2020.5.28

  Here, we present a new series of hydrazide-bearing class I selective HDAC inhibitors designed based on panobinostat. The cap, linker, and zinc-binding group were derivatized to improve HDAC affinity and antileukemia efficacy. Lead inhibitor 13a shows picomolar or low nanomolar IC50 values against HDAC1 and HDAC3 and exhibits differential toxicity profiles toward multiple cancer cells with different FLT3 and p53 statuses. 13a indirectly inhibits the FLT3 signaling pathway and down-regulates master antiapoptotic proteins, resulting in the activation of pro-caspase3 in wt-p53 FLT3-ITD MV4-11 cells. While in the wt-FLT3 and p53-null cells, 13a is incapable of causing apoptosis at a therapeutic concentration. The MDM2 antagonist and the proteasome inhibitor promote 13a-triggered apoptosis by preventing p53 degradation. Furthermore, we demonstrate that apoptosis rather than autophagy is the key contributing factor for 13a-triggered cell death. When compared to panobinostat, 13a is not mutagenic and displays superior in vivo bioavailability and a higher AUC(0-inf) value.