17-(2-thienyl)-17-demethoxygeldanamycin

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酰胺类
• 英文名称: 17-(2-thienyl)-17-demethoxygeldanamycin
• 英文别名: [(4E,6Z,8S,9S,10E,12S,13R,14S,16R)-13-hydroxy-8,14-dimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-19-thiophen-2-yl-2-azabicyclo[16.3.1]docosa-1(21),4,6,10,18-pentaen-9-yl] carbamate
• 化学式: C₃₂H₄₀N₂O₈S
• 分子量: 612.744
• InChiKey: HMVJRAYGBDOBFZ-ZLYWGBLGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  43
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  183
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  格尔德霉素 在 barium dihydroxide 、 caesium bromide 、 N,N-二异丙基乙胺 、 cesium fluoride 、 bis(dibenzylideneacetone)-palladium⁽⁰⁾ 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 12.5h， 生成 17-(2-thienyl)-17-demethoxygeldanamycin
  参考文献：
  名称：

  Synthesis and Biological Evaluation of a New Class of Geldanamycin Derivatives as Potent Inhibitors of Hsp90

  摘要：

  The heat shock protein Hsp90 has increasingly become an important therapeutic target especially for treatment of cancers. Inhibition of the ATPase activity of Hsp90 by natural products (e.g., 17-allylaminogeldanamycin or radicicol) leads to the ubiquitination of oncogenic client proteins such as Her-2, Raf-1, and p-Akt; followed by their proteasomal degradation. Rsp90 inhibitors simultaneously target multiple oncogenic proteins and provide an advantage For cancer therapy due to the potential for increased efficacy and overcoming drug resistance. In an effort to convert geldanamycin into a druglike compound with better pharmacokinetic properties and efficacy in human tumor xenograft; models, geldanamycin was derivatized on the 17-position to prepare new analogues such as 17-geldanamycin amides, carbamates, and areas and 17-arylgeldanamycins. All the compounds were first evaluated ex vivo using a cell-based Her-2 degradation assay and in vitro using biochemical assays that measure recombinant Hsp90 (rHsp90) competitive binding and changes in rHsp90 conformation. In addition, we confirmed the selectivity of geldanamycin analogues for Hsp90 derived from tumor cells using a novel cell lysate binding assay.

  DOI：

  10.1021/jm0306125

文献信息

• US7465718B2
  申请人：——

  公开号：US7465718B2

  公开（公告）日：2008-12-16
• Synthesis and Biological Evaluation of a New Class of Geldanamycin Derivatives as Potent Inhibitors of Hsp90
  作者：Jean-Yves Le Brazidec、Adeela Kamal、David Busch、Lia Thao、Lin Zhang、Gregg Timony、Roy Grecko、Katy Trent、Rachel Lough、Tim Salazar、Samina Khan、Francis Burrows、Marcus F. Boehm

  DOI：10.1021/jm0306125

  日期：2004.7.1

  The heat shock protein Hsp90 has increasingly become an important therapeutic target especially for treatment of cancers. Inhibition of the ATPase activity of Hsp90 by natural products (e.g., 17-allylaminogeldanamycin or radicicol) leads to the ubiquitination of oncogenic client proteins such as Her-2, Raf-1, and p-Akt; followed by their proteasomal degradation. Rsp90 inhibitors simultaneously target multiple oncogenic proteins and provide an advantage For cancer therapy due to the potential for increased efficacy and overcoming drug resistance. In an effort to convert geldanamycin into a druglike compound with better pharmacokinetic properties and efficacy in human tumor xenograft; models, geldanamycin was derivatized on the 17-position to prepare new analogues such as 17-geldanamycin amides, carbamates, and areas and 17-arylgeldanamycins. All the compounds were first evaluated ex vivo using a cell-based Her-2 degradation assay and in vitro using biochemical assays that measure recombinant Hsp90 (rHsp90) competitive binding and changes in rHsp90 conformation. In addition, we confirmed the selectivity of geldanamycin analogues for Hsp90 derived from tumor cells using a novel cell lysate binding assay.