8-[4-[4-[[[(2S,3R,4S,6R)-2-[[(2R,4R,5R,6R,8R,11R,12S,19R,20R)-11-ethyl-4-methoxy-2,4,6,8,12,19-hexamethyl-7,9,14-trioxo-10,13-dioxa-15,18-diazatricyclo[10.6.2.015,20]icos-1(18)-en-5-yl]oxy]-3-hydroxy-6-methyloxan-4-yl]-methylamino]methyl]phenyl]triazol-1-yl]-N-hydroxyoctanamide | 1236149-44-2

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 8-[4-[4-[[[(2S,3R,4S,6R)-2-[[(2R,4R,5R,6R,8R,11R,12S,19R,20R)-11-ethyl-4-methoxy-2,4,6,8,12,19-hexamethyl-7,9,14-trioxo-10,13-dioxa-15,18-diazatricyclo[10.6.2.015,20]icos-1(18)-en-5-yl]oxy]-3-hydroxy-6-methyloxan-4-yl]-methylamino]methyl]phenyl]triazol-1-yl]-N-hydroxyoctanamide
• CAS: 1236149-44-2
• 化学式: C₄₉H₇₅N₇O₁₁
• 分子量: 938.175
• InChiKey: TYTXOQRHPHSGAQ-SCNQDDDRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  67
• 可旋转键数：
  16
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.73
• 拓扑面积：
  217
• 氢给体数：
  3
• 氢受体数：
  15

反应信息

• 作为产物：
  描述：

  8-[4-[4-[[[(2S,3R,4S,6R)-2-[[(2R,4R,5R,6R,8R,11R,12S,19R,20R)-11-ethyl-4-methoxy-2,4,6,8,12,19-hexamethyl-7,9,14-trioxo-10,13-dioxa-15,18-diazatricyclo[10.6.2.015,20]icos-1(18)-en-5-yl]oxy]-3-hydroxy-6-methyloxan-4-yl]-methylamino]methyl]phenyl]triazol-1-yl]-N-trityloxyoctanamide 在 茴香硫醚 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 以51%的产率得到8-[4-[4-[[[(2S,3R,4S,6R)-2-[[(2R,4R,5R,6R,8R,11R,12S,19R,20R)-11-ethyl-4-methoxy-2,4,6,8,12,19-hexamethyl-7,9,14-trioxo-10,13-dioxa-15,18-diazatricyclo[10.6.2.015,20]icos-1(18)-en-5-yl]oxy]-3-hydroxy-6-methyloxan-4-yl]-methylamino]methyl]phenyl]triazol-1-yl]-N-hydroxyoctanamide
  参考文献：
  名称：

  Non-Peptide Macrocyclic Histone Deacetylase Inhibitors Derived from Tricyclic Ketolide Skeleton

  摘要：

  Inhibition of histone deacetylase (HDAC) function is a validated therapeutic strategy for cancer treatment. Of the several structurally distinct small molecule histone deacetylase inhibitors (HDACi) reported, macrocyclic depsipeptides possess the most complex cap groups and have demonstrated excellent HDAC inhibition potency and isoform selectivity. Unfortunately, the development of macrocyclic depsipeptides has been hampered in part because of development problems characteristic of large peptides and the complex reaction schemes required for their synthesis. Herein we report that tricyclic ketolide TE-802 is an excellent mimetic for the peptide backbone of macrocyclic HDACi. Compounds derived from this template are particularly selective against HDACs 1 and 2 with nanomolar inhibitory activity. Interrogation of the association between a subset of these compounds and key HDAC isoforms, using AutoDock, enables a molecular description of the interaction between the HDAC enzyme's outer rim and the inhibitors' macrocyclic cap group that are responsible for compound affinity and presumably isoform selectivity.

  DOI：

  10.1021/jm100507q

文献信息

• Non-Peptide Macrocyclic Histone Deacetylase Inhibitors Derived from Tricyclic Ketolide Skeleton
  作者：Sandra C. Mwakwari、William Guerrant、Vishal Patil、Shabana I. Khan、Babu L. Tekwani、Zachary A. Gurard-Levin、Milan Mrksich、Adegboyega K. Oyelere

  DOI：10.1021/jm100507q

  日期：2010.8.26

  Inhibition of histone deacetylase (HDAC) function is a validated therapeutic strategy for cancer treatment. Of the several structurally distinct small molecule histone deacetylase inhibitors (HDACi) reported, macrocyclic depsipeptides possess the most complex cap groups and have demonstrated excellent HDAC inhibition potency and isoform selectivity. Unfortunately, the development of macrocyclic depsipeptides has been hampered in part because of development problems characteristic of large peptides and the complex reaction schemes required for their synthesis. Herein we report that tricyclic ketolide TE-802 is an excellent mimetic for the peptide backbone of macrocyclic HDACi. Compounds derived from this template are particularly selective against HDACs 1 and 2 with nanomolar inhibitory activity. Interrogation of the association between a subset of these compounds and key HDAC isoforms, using AutoDock, enables a molecular description of the interaction between the HDAC enzyme's outer rim and the inhibitors' macrocyclic cap group that are responsible for compound affinity and presumably isoform selectivity.