(E)-6-(1,3-dihydro-4,6-dimethoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenohydroxamic acid | 1001329-42-5

• 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: (E)-6-(1,3-dihydro-4,6-dimethoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenohydroxamic acid
• 英文别名: (E)-6-(4,6-dimethoxy-7-methyl-3-oxo-1H-2-benzofuran-5-yl)-N-hydroxy-4-methylhex-4-enamide
• CAS: 1001329-42-5
• 化学式: C₁₈H₂₃NO₆
• 分子量: 349.384
• InChiKey: VEURGGSTVLSJTB-BJMVGYQFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 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：
  94.1
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  (E)-6-(1,3-二氢-4,6-二甲氧基-7-甲基-3-氧代-5-异苯并呋喃基)-4-甲基-4-己烯酸 在 氯甲酸乙酯 、 三乙胺 、 盐酸羟胺 、 盐酸 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 10.75h， 以90%的产率得到(E)-6-(1,3-dihydro-4,6-dimethoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenohydroxamic acid
  参考文献：
  名称：

  Hydroxamic Acid Derivatives of Mycophenolic Acid Inhibit Histone Deacetylase at the Cellular Level

  摘要：

  麦克芬酸（MPA，1）是一种IMP脱氢酶（IMPDH）抑制剂和潜在的PPARγ激动剂，作为一种有效的免疫抑制剂用于临床移植，并且最近已在晚期多发性骨髓瘤患者中进入临床试验。另一方面，亚丁酸（SAHA）是一种非特异性组蛋白去乙酰化酶（HDAC）抑制剂，已被批准用于治疗皮肤T细胞淋巴瘤。MPA似乎具有一个帽结构、一个链接器和一个弱金属结合位点，作为HDAC的潜在抑制剂。因此，设计并合成了具有有效金属结合位点的麦克芬酸氢氧酸衍生物：麦克芬酸氢氧酸（MPHA，2）、7-O-乙酰麦克芬酸（7-O-Ac MPHA，3）和7-O-月桂酰麦克芬酸氢氧酸（7-O-L MPHA，4）。所有这些化合物均抑制组蛋白去乙酰化酶，其IC50值分别为1、0.9和0.5μM，细胞增殖抑制浓度为2、1.5和1μM。

  DOI：

  10.1271/bbb.80303

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.
• Hydroxamic Acid Derivatives of Mycophenolic Acid Inhibit Histone Deacetylase at the Cellular Level
  作者：Daniela I. BATOVSKA、Dong Hoon KIM、Shinya MITSUHASHI、Yoon Sun CHO、Ho Jeong KWON、Makoto UBUKATA

  DOI：10.1271/bbb.80303

  日期：2008.10.23

  Mycophenolic acid (MPA, 1), an inhibitor of IMP-dehydrogenase (IMPDH) and a latent PPARγ agonist, is used as an effective immunosuppressant for clinical transplantation and recently entered clinical trials in advanced multiple myeloma patients. On the other hand, suberoylanilide hydroxamic acid (SAHA), a non-specific histone deacetylase (HDAC) inhibitor, has been approved for treating cutaneous T-cell lymphoma. MPA seemed to bear a cap, a linker, and a weak metal-binding site as a latent inhibitor of HDAC. Therefore, the hydroxamic acid derivatives of mycophenolic acid having an effective metal-binding site, mycophenolic hydroxamic acid (MPHA, 2), 7-O-acetyl mycophenolic acid (7-O-Ac MPHA, 3), and 7-O-lauroyl mycophenolic hydroxamic acid (7-O-L MPHA, 4) were designed and synthesized. All these compounds inhibited histone deacetylase with IC50 values of 1, 0.9 and 0.5 μM, and cell proliferation at concentrations of 2, 1.5 and 1 μM, respectively.

  麦克芬酸（MPA，1）是一种IMP脱氢酶（IMPDH）抑制剂和潜在的PPARγ激动剂，作为一种有效的免疫抑制剂用于临床移植，并且最近已在晚期多发性骨髓瘤患者中进入临床试验。另一方面，亚丁酸（SAHA）是一种非特异性组蛋白去乙酰化酶（HDAC）抑制剂，已被批准用于治疗皮肤T细胞淋巴瘤。MPA似乎具有一个帽结构、一个链接器和一个弱金属结合位点，作为HDAC的潜在抑制剂。因此，设计并合成了具有有效金属结合位点的麦克芬酸氢氧酸衍生物：麦克芬酸氢氧酸（MPHA，2）、7-O-乙酰麦克芬酸（7-O-Ac MPHA，3）和7-O-月桂酰麦克芬酸氢氧酸（7-O-L MPHA，4）。所有这些化合物均抑制组蛋白去乙酰化酶，其IC50值分别为1、0.9和0.5μM，细胞增殖抑制浓度为2、1.5和1μM。