4-(((2-amino-4-oxo-3,4-dihydropteridin-6-yl)methyl)amino)-N-(6-(hydroxyamino)-6-oxohexyl)benzamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 蝶啶及其衍生物
• 英文名称: 4-(((2-amino-4-oxo-3,4-dihydropteridin-6-yl)methyl)amino)-N-(6-(hydroxyamino)-6-oxohexyl)benzamide
• 英文别名: 4-[(2-amino-4-oxo-3H-pteridin-6-yl)methylamino]-N-[6-(hydroxyamino)-6-oxohexyl]benzamide
• 化学式: C₂₀H₂₄N₈O₄
• 分子量: 440.462
• InChiKey: LAPSXONRKCNPMH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.7
• 重原子数：
  32
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  184
• 氢给体数：
  6
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  pteroyl hydrazide 在 亚硝酸特丁酯 、 三异丙基硅烷 、 potassium thioacyanate 、 三氟乙酸 、 四甲基胍 作用下， 以 二甲基亚砜 为溶剂， 反应 2.0h， 生成 4-(((2-amino-4-oxo-3,4-dihydropteridin-6-yl)methyl)amino)-N-(6-(hydroxyamino)-6-oxohexyl)benzamide
  参考文献：
  名称：

  Design and structure activity relationship of tumor-homing histone deacetylase inhibitors conjugated to folic and pteroic acids

  摘要：

  Histone deacetylase (HDAC) inhibition has recently emerged as a novel therapeutic approach for the treatment of various pathological conditions including cancer. Currently, two HDAC inhibitors (HDACi) - Vorinostat and Romidepsin - have been approved for the treatment of cutaneous T-cell lymphoma. However, HDACi remain ineffective against solid tumors and are associated with adverse events including cardiotoxicity. Targeted delivery may enhance the therapeutic indices of HDACi and enable them to be efficacious against solid tumors. We showed herein that morphing of folic and pteroic acids into the surface recognition group of HDACi results in hydroxamate and benzamide HDACi which derived tumor homing by targeting folate receptor (FR), a receptor commonly overexpressed in solid tumors. We observed a correlation between the potency of HDAC1 inhibition and cytotoxicity as only the potent pteroate hydroxamates, 11d and 11e, displayed antiproliferative activity against two representative FR-expression cancer cells. Our observation further supports the previous results which suggest that for a drug to be successfully targeted using the FR, it must be extremely potent against its primary target as the FR has a low delivery efficiency. Published by Elsevier Masson SAS.

  DOI：

  10.1016/j.ejmech.2015.04.014

文献信息

• Design and structure activity relationship of tumor-homing histone deacetylase inhibitors conjugated to folic and pteroic acids
  作者：Quaovi H. Sodji、James R. Kornacki、John F. McDonald、Milan Mrksich、Adegboyega K. Oyelere

  DOI：10.1016/j.ejmech.2015.04.014

  日期：2015.5

  Histone deacetylase (HDAC) inhibition has recently emerged as a novel therapeutic approach for the treatment of various pathological conditions including cancer. Currently, two HDAC inhibitors (HDACi) - Vorinostat and Romidepsin - have been approved for the treatment of cutaneous T-cell lymphoma. However, HDACi remain ineffective against solid tumors and are associated with adverse events including cardiotoxicity. Targeted delivery may enhance the therapeutic indices of HDACi and enable them to be efficacious against solid tumors. We showed herein that morphing of folic and pteroic acids into the surface recognition group of HDACi results in hydroxamate and benzamide HDACi which derived tumor homing by targeting folate receptor (FR), a receptor commonly overexpressed in solid tumors. We observed a correlation between the potency of HDAC1 inhibition and cytotoxicity as only the potent pteroate hydroxamates, 11d and 11e, displayed antiproliferative activity against two representative FR-expression cancer cells. Our observation further supports the previous results which suggest that for a drug to be successfully targeted using the FR, it must be extremely potent against its primary target as the FR has a low delivery efficiency. Published by Elsevier Masson SAS.