methyl 6-[4-[4-[[[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-hydroxy-6-methyloxan-4-yl]-methylamino]methyl]phenyl]triazol-1-yl]hexanoate | 1093856-92-8

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: methyl 6-[4-[4-[[[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-hydroxy-6-methyloxan-4-yl]-methylamino]methyl]phenyl]triazol-1-yl]hexanoate
• CAS: 1093856-92-8
• 化学式: C₅₃H₈₉N₅O₁₄
• 分子量: 1020.31
• InChiKey: OOMXXLSOGPYYRD-GGXWVIOLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.8
• 重原子数：
  72
• 可旋转键数：
  17
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.81
• 拓扑面积：
  237
• 氢给体数：
  5
• 氢受体数：
  18

反应信息

• 作为反应物：
  描述：

  methyl 6-[4-[4-[[[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-hydroxy-6-methyloxan-4-yl]-methylamino]methyl]phenyl]triazol-1-yl]hexanoate 在 potassium cyanide 、 羟胺 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 反应 24.0h， 以16%的产率得到Azithromycin-N-benzyltriazolylhexahydroxamic Acid
  参考文献：
  名称：

  Non-Peptide Macrocyclic Histone Deacetylase Inhibitors

  摘要：

  Inhibition of histone deacetylase inhibitors (HDACi) hold great promise in cancer therapy because of their demonstrated ability to arrest proliferation of nearly all transformed cell types. Of the several structurally distinct small molecule HDACi reported, macrocyclic depsipeptides have the most complex recognition cap-group moieties and present an excellent opportunity for the modulation of the biological activities of HDACi. Unfortunately, the structure-activity relationship (SAR) studies for this class of compounds have been impaired largely because most macrocyclic HDACi known to date comprise complex peptide macrocycles. In addition to retaining the pharmacologically disadvantaged peptidyl backbone, they offer only limited opportunity for side chain modifications. Here, we report the discovery of a new class of macrocyclic HDAG based on the macrolide antibiotics skeletons. SAR studies revealed that these compounds displayed both linker-length and macrolide-type dependent HDAC inhibition activities with IC50 in the low nanomolar range. In addition, these non-peptide macrocyclic HDACi are more selective against HDACs 1 and 2 relative to HDAC 8, another class I HDAC isoform, and hence have subclass HDAC isoform selectivity.

  DOI：

  10.1021/jm801128g
• 作为产物：
  描述：

  (3'-N-(4-ethynylbenzyl))azithromycin 、 6-叠氮基己酸甲酯 在 copper(l) iodide 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 12.0h， 以92%的产率得到methyl 6-[4-[4-[[[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-hydroxy-6-methyloxan-4-yl]-methylamino]methyl]phenyl]triazol-1-yl]hexanoate
  参考文献：
  名称：

  Non-Peptide Macrocyclic Histone Deacetylase Inhibitors

  摘要：

  Inhibition of histone deacetylase inhibitors (HDACi) hold great promise in cancer therapy because of their demonstrated ability to arrest proliferation of nearly all transformed cell types. Of the several structurally distinct small molecule HDACi reported, macrocyclic depsipeptides have the most complex recognition cap-group moieties and present an excellent opportunity for the modulation of the biological activities of HDACi. Unfortunately, the structure-activity relationship (SAR) studies for this class of compounds have been impaired largely because most macrocyclic HDACi known to date comprise complex peptide macrocycles. In addition to retaining the pharmacologically disadvantaged peptidyl backbone, they offer only limited opportunity for side chain modifications. Here, we report the discovery of a new class of macrocyclic HDAG based on the macrolide antibiotics skeletons. SAR studies revealed that these compounds displayed both linker-length and macrolide-type dependent HDAC inhibition activities with IC50 in the low nanomolar range. In addition, these non-peptide macrocyclic HDACi are more selective against HDACs 1 and 2 relative to HDAC 8, another class I HDAC isoform, and hence have subclass HDAC isoform selectivity.

  DOI：

  10.1021/jm801128g

文献信息

• Non-Peptide Macrocyclic Histone Deacetylase Inhibitors
  作者：Adegboyega K. Oyelere、Po C. Chen、William Guerrant、Sandra C. Mwakwari、Rebecca Hood、Yunzhe Zhang、Yuhong Fan

  DOI：10.1021/jm801128g

  日期：2009.1.22

  Inhibition of histone deacetylase inhibitors (HDACi) hold great promise in cancer therapy because of their demonstrated ability to arrest proliferation of nearly all transformed cell types. Of the several structurally distinct small molecule HDACi reported, macrocyclic depsipeptides have the most complex recognition cap-group moieties and present an excellent opportunity for the modulation of the biological activities of HDACi. Unfortunately, the structure-activity relationship (SAR) studies for this class of compounds have been impaired largely because most macrocyclic HDACi known to date comprise complex peptide macrocycles. In addition to retaining the pharmacologically disadvantaged peptidyl backbone, they offer only limited opportunity for side chain modifications. Here, we report the discovery of a new class of macrocyclic HDAG based on the macrolide antibiotics skeletons. SAR studies revealed that these compounds displayed both linker-length and macrolide-type dependent HDAC inhibition activities with IC50 in the low nanomolar range. In addition, these non-peptide macrocyclic HDACi are more selective against HDACs 1 and 2 relative to HDAC 8, another class I HDAC isoform, and hence have subclass HDAC isoform selectivity.