(4R,6R)-6-(2-{(1S,2S,6R,8S,8aR)-8-[(4-ethynylbenzyl)carbamoyloxy]-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthyl}ethyl)-4-tert-butyldimethylsilyloxy-3,4,5,6-tetrahydro-2H-pyran-2-one | 1431473-51-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 内酯类
• 英文名称: (4R,6R)-6-(2-{(1S,2S,6R,8S,8aR)-8-[(4-ethynylbenzyl)carbamoyloxy]-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthyl}ethyl)-4-tert-butyldimethylsilyloxy-3,4,5,6-tetrahydro-2H-pyran-2-one
• 英文别名: [(1S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4-[tert-butyl(dimethyl)silyl]oxy-6-oxooxan-2-yl]ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl] N-[(4-ethynylphenyl)methyl]carbamate
• CAS: 1431473-51-6
• 化学式: C₃₅H₄₉NO₅Si
• 分子量: 591.863
• InChiKey: YAHJAESFRLNRDH-RZSQEPJQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.54
• 重原子数：
  42
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  73.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (4R,6R)-6-(2-{(1S,2S,6R,8S,8aR)-8-[(4-ethynylbenzyl)carbamoyloxy]-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthyl}ethyl)-4-tert-butyldimethylsilyloxy-3,4,5,6-tetrahydro-2H-pyran-2-one 、 7-叠氮庚酸 在 copper(ll) sulfate pentahydrate 、 sodium ascorbate 作用下， 以 水 、 叔丁醇 为溶剂， 反应 18.0h， 生成 7-[4-[4-[[[(1S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4-[tert-butyl(dimethyl)silyl]oxy-6-oxooxan-2-yl]ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl]oxycarbonylamino]methyl]phenyl]triazol-1-yl]heptanoic acid
  参考文献：
  名称：

  Design and Synthesis of Dual-Action Inhibitors Targeting Histone Deacetylases and 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase for Cancer Treatment

  摘要：

  A series of dual-action compounds were designed to target histone deacetylase (HDAC) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) by having a hydroxamate group essential for chelation with the zinc ion in the active site of HDAC and the key structural elements of statin for binding with both proteins. In our study, the statin hydroxamic acids prepared by a fused strategy are most promising in cancer treatments. These compounds showed potent inhibitory activities against HDACs and HMGR with IC50 values in the nanomolar range. These compounds also effectively reduced the HMGR activity as well as promoted the acetylations of histone and tubulin in cancer cells, but were not toxic to normal cells.

  DOI：

  10.1021/jm400179b
• 作为产物：
  描述：

  洛伐他汀 在 咪唑 、 盐酸 、 甲醇 、 4-二甲氨基吡啶 、 potassium hydroxide 作用下， 以 吡啶 、 二氯甲烷 、 水 为溶剂， 反应 36.0h， 生成 (4R,6R)-6-(2-{(1S,2S,6R,8S,8aR)-8-[(4-ethynylbenzyl)carbamoyloxy]-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthyl}ethyl)-4-tert-butyldimethylsilyloxy-3,4,5,6-tetrahydro-2H-pyran-2-one
  参考文献：
  名称：

  DUAL ACTION INHIBITORS AGAINST HISTONE DEACETYLASES AND 3-HYDROXY-3-METHYLGLUTARYL COENZYME A REDUCTASE

  摘要：

  本文披露了式（I）的新化合物及其用途。式（I）的化合物是组蛋白去乙酰化酶（HDACs）和3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶（HMGR）的抑制剂。还提供了使用式（I）的化合物抑制HDACs和HMGR活性、治疗与HDACs或HMGR相关的疾病（如癌症、高胆固醇血症、急性或慢性炎症性疾病、自身免疫疾病、过敏性疾病、病原体感染、神经退行性疾病或与氧化应激相关的疾病）的方法。

  公开号：

  US20140206645A1

文献信息

• Design and Synthesis of Dual-Action Inhibitors Targeting Histone Deacetylases and 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase for Cancer Treatment
  作者：Jhih-Bin Chen、Ting-Rong Chern、Tzu-Tang Wei、Ching-Chow Chen、Jung-Hsin Lin、Jim-Min Fang

  DOI：10.1021/jm400179b

  日期：2013.5.9

  A series of dual-action compounds were designed to target histone deacetylase (HDAC) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) by having a hydroxamate group essential for chelation with the zinc ion in the active site of HDAC and the key structural elements of statin for binding with both proteins. In our study, the statin hydroxamic acids prepared by a fused strategy are most promising in cancer treatments. These compounds showed potent inhibitory activities against HDACs and HMGR with IC50 values in the nanomolar range. These compounds also effectively reduced the HMGR activity as well as promoted the acetylations of histone and tubulin in cancer cells, but were not toxic to normal cells.
• DUAL ACTION INHIBITORS AGAINST HISTONE DEACETYLASES AND 3-HYDROXY-3-METHYLGLUTARYL COENZYME A REDUCTASE
  申请人：National Taiwan University

  公开号：US20140206645A1

  公开（公告）日：2014-07-24

  Disclosed herein are novel compounds of formula (I), and uses thereof. The compounds of Formula (I) are inhibitors of histone deacetylases (HDACs) and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR). Also provided are methods of using the compounds of Formula (I) for inhibiting the activity of HDACs and HMGR, treating diseases associated with HDACs or HMGR (e.g., cancer, hypercholesterolemia, an acute or chronic inflammatory disease, autoimmune disease, allergic disease, pathogen infection, neurodegenerative disease, or a disease associated with oxidative stress,

  本文披露了式（I）的新化合物及其用途。式（I）的化合物是组蛋白去乙酰化酶（HDACs）和3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶（HMGR）的抑制剂。还提供了使用式（I）的化合物抑制HDACs和HMGR活性、治疗与HDACs或HMGR相关的疾病（如癌症、高胆固醇血症、急性或慢性炎症性疾病、自身免疫疾病、过敏性疾病、病原体感染、神经退行性疾病或与氧化应激相关的疾病）的方法。