N-hydroxy-7-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-5-methylhept-5-enamide | 1001329-43-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异香豆素
• 英文名称: N-hydroxy-7-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-5-methylhept-5-enamide
• 英文别名: (E)-N-hydroxy-7-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1H-2-benzofuran-5-yl)-5-methylhept-5-enamide
• CAS: 1001329-43-6
• 化学式: C₁₈H₂₃NO₆
• 分子量: 349.384
• InChiKey: XPWZUAAQWQREED-JXMROGBWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  25
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  105
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  (E)-7-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1H-2-benzofuran-5-yl)-5-methyl-N-trityloxyhept-5-enamide 在 三乙基硅烷 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 以8%的产率得到N-hydroxy-7-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-5-methylhept-5-enamide
  参考文献：
  名称：

  Dual Inhibitors of Inosine Monophosphate Dehydrogenase and Histone Deacetylases for Cancer Treatment

  摘要：

  Mycophenolic acid (MPA), an inhibitor of IMP-dehydrogenase (IMPDH), is used worldwide in transplantation. Recently, numerous studies showed its importance in cancer treatment. Consequently, MPA entered clinical trials in advanced multiple myeloma patients. Suberoylanilide hydroxamic acid (SAHA), a potent differentiation agent acting through inhibition of histone deacetylases (HDACs), was recently approved for treatment of cutaneous T cell lymphoma. We report herein the synthesis of dual inhibitors of IMPDH and HDACs. We found that mycophenolic hydroxamic acid (9, MAHA) inhibits both IMPDH (K-i = 30 nM) and HDAC (IC50 = 5.0 mu M). A modification of SAHA with groups known to interact with IMPDH afforded a SAHA analogue 14, which inhibits IMPDH (K-i = 1.7 mu M) and HDAC (IC50 = 0.06 mu M). Both MAHA (IC50 = 4.8 mu M) and SAHA analogue 14 (IC50 = 7.7 mu M) were more potent than parent compounds as antiproliferation agents. They were also significantly more potent as differentiation inducers.

  DOI：

  10.1021/jm070864w

文献信息

• Dual Inhibitors of Inosine Monophosphate Dehydrogenase and Histone Deacetylases for Cancer Treatment
  作者：Liqiang Chen、Daniel Wilson、Hiremagalur N. Jayaram、Krzysztof W. Pankiewicz

  DOI：10.1021/jm070864w

  日期：2007.12.27

  Mycophenolic acid (MPA), an inhibitor of IMP-dehydrogenase (IMPDH), is used worldwide in transplantation. Recently, numerous studies showed its importance in cancer treatment. Consequently, MPA entered clinical trials in advanced multiple myeloma patients. Suberoylanilide hydroxamic acid (SAHA), a potent differentiation agent acting through inhibition of histone deacetylases (HDACs), was recently approved for treatment of cutaneous T cell lymphoma. We report herein the synthesis of dual inhibitors of IMPDH and HDACs. We found that mycophenolic hydroxamic acid (9, MAHA) inhibits both IMPDH (K-i = 30 nM) and HDAC (IC50 = 5.0 mu M). A modification of SAHA with groups known to interact with IMPDH afforded a SAHA analogue 14, which inhibits IMPDH (K-i = 1.7 mu M) and HDAC (IC50 = 0.06 mu M). Both MAHA (IC50 = 4.8 mu M) and SAHA analogue 14 (IC50 = 7.7 mu M) were more potent than parent compounds as antiproliferation agents. They were also significantly more potent as differentiation inducers.