N-hydroxy-4-(2-methoxy-5-((2-methylquinazolin-4-yl)-amino)phenoxy)butanamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: N-hydroxy-4-(2-methoxy-5-((2-methylquinazolin-4-yl)-amino)phenoxy)butanamide
• 英文别名: N-hydroxy-4-[2-methoxy-5-[(2-methylquinazolin-4-yl)amino]phenoxy]butanamide
• 化学式: C₂₀H₂₂N₄O₄
• 分子量: 382.419
• InChiKey: WPYUKFSQAANHNM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  28
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  106
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  2-甲氧基-5-硝基苯酚 在 盐酸 、 5%-palladium/activated carbon 、 氢气 、 羟胺 、 caesium carbonate 、 sodium hydroxide 作用下， 以 甲醇 、 乙醇 、 二氯甲烷 、 水 、 异丙醇 、 乙腈 为溶剂， 反应 3.5h， 生成 N-hydroxy-4-(2-methoxy-5-((2-methylquinazolin-4-yl)-amino)phenoxy)butanamide
  参考文献：
  名称：

  Discovery of Selective Histone Deacetylase 6 Inhibitors Using the Quinazoline as the Cap for the Treatment of Cancer

  摘要：

  Novel selective histone deacetylase 6 (HDAC6) inhibitors using the quinazoline as the cap were designed, synthesized, and evaluated for HDAC enzymatic assays. N-Hydroxy-4-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)-amino)phenoxy)butanamide, 23bb, was the most potent selective inhibitor for HDAC6 with an IC50 of 17 nM and showed 25-fold and 200-fold selectivity relative to HDAC1 and HDAC8, respectively. In vitro, 23bb presented low nanomolar antiproliferative effects against panel of cancer cell lines. Western blot analysis further confirmed that 23bb increased acetylation level of a-tubulin in vitro. 23bb has a good pharmacokinetic profile with oral bioavailability of 47.0% in rats. In in vivo efficacy evaluations of colorectal HCT116, acute myelocytic leukemia MV4-11, and B cell lymphoma Romas xenografts, 23bb more effectively inhibited the tumor growth than SAI-IA even at a 4-fold reduced dose or ACY-1215 at the same dose. Our results indicated that 23bb is a potent oral anticancer candidate for selective HDAC6 inhibitor and deserves further investigation.

  DOI：

  10.1021/acs.jmedchem.5b01342

文献信息

• Discovery of Selective Histone Deacetylase 6 Inhibitors Using the Quinazoline as the Cap for the Treatment of Cancer
  作者：Zhuang Yang、Taijin Wang、Fang Wang、Ting Niu、Zhuowei Liu、Xiaoxin Chen、Chaofeng Long、Minghai Tang、Dong Cao、Xiaoyan Wang、Wei Xiang、Yuyao Yi、Liang Ma、Jingsong You、Lijuan Chen

  DOI：10.1021/acs.jmedchem.5b01342

  日期：2016.2.25

  Novel selective histone deacetylase 6 (HDAC6) inhibitors using the quinazoline as the cap were designed, synthesized, and evaluated for HDAC enzymatic assays. N-Hydroxy-4-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)-amino)phenoxy)butanamide, 23bb, was the most potent selective inhibitor for HDAC6 with an IC50 of 17 nM and showed 25-fold and 200-fold selectivity relative to HDAC1 and HDAC8, respectively. In vitro, 23bb presented low nanomolar antiproliferative effects against panel of cancer cell lines. Western blot analysis further confirmed that 23bb increased acetylation level of a-tubulin in vitro. 23bb has a good pharmacokinetic profile with oral bioavailability of 47.0% in rats. In in vivo efficacy evaluations of colorectal HCT116, acute myelocytic leukemia MV4-11, and B cell lymphoma Romas xenografts, 23bb more effectively inhibited the tumor growth than SAI-IA even at a 4-fold reduced dose or ACY-1215 at the same dose. Our results indicated that 23bb is a potent oral anticancer candidate for selective HDAC6 inhibitor and deserves further investigation.