19-bromogeldanamycin

• 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: 19-bromogeldanamycin
• 英文别名: 19-BrGA；[(4E,6Z,8S,9S,10E,12S,13R,14S,16R)-21-bromo-13-hydroxy-8,14,19-trimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1]docosa-1(21),4,6,10,18-pentaen-9-yl] carbamate
• 化学式: C₂₉H₃₉BrN₂O₉
• 分子量: 639.541
• InChiKey: JYIHZXNUYFNBCE-UQFWMSAZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  41
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  164
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  19-bromogeldanamycin 、 环丙胺 以 氯仿 为溶剂， 反应 16.0h， 以14%的产率得到19-(cyclopropylamino)geldanamycin
  参考文献：
  名称：

  Inhibition of the oncogene product p185erbB-2 in vitro and in vivo by geldanamycin and dihydrogeldanamycin derivatives

  摘要：

  The erbB-2 oncogene encodes a transmembrane protein tyrosine kinase which plays a pivotal role in signal transduction and has been implicated when overexpressed in breast, ovarian, and gastric cancers. Naturally occurring benzoquinoid ansamycin antibiotics herbimycin A, geldanamycin (GDM), and dihydrogeldanamycin were found to potently deplete p185, the erbB-2 oncoprotein, in human breast cancer SKBR-3 cells in culture. Chemistry efforts to modify selectively the quinoid moiety of GDM afforded derivatives with greater potency in vitro and in vivo. Analogs demonstrated inhibition of p185 phosphotyrosine in cell culture and in vivo after systemic drug administration to nu/nu nude mice bearing Fisher rat embryo cells transfected with human erbB-2 (FRE/erbB-2). Specifically, dosed intraperitoneally at 100 mg/kg, 17-(allylamino)-17-demethoxygeldanamycin and other 17-amino analogs were effective at reducing p185 phosphotyrosine in subcutaneous flank FRE/erbB-2 tumors. Modifications to the 17-19-positions of the quinone ring revealed a broad structure-activity relationship in vitro.

  DOI：

  10.1021/jm00019a010
• 作为产物：
  描述：

  格尔德霉素 在 pyridinium hydrobromide perbromide 作用下， 以 乙醇 、 氯仿 为溶剂， 反应 1.0h， 以87%的产率得到19-bromogeldanamycin
  参考文献：
  名称：

  [EN] HSP90 INHIBITORS WITH MODIFIED TOXICITY
  [FR] INHIBITEURS DE HSP90 AYANT UNE TOXICITÉ MODIFIÉE

  摘要：

  该发明提供了19-取代格尔丹霉素衍生物及其药学上可接受的盐，这些衍生物是强效的Hsp90结合剂，可用于治疗癌症或神经退行性疾病的症状改善。

  公开号：

  WO2013074695A1

文献信息

• [EN] HSP90 INHIBITORS WITH MODIFIED TOXICITY<br/>[FR] INHIBITEURS DE HSP90 AYANT UNE TOXICITÉ MODIFIÉE
  申请人：UNIV COLORADO REGENTS

  公开号：WO2013074695A1

  公开（公告）日：2013-05-23

  The invention provides 19-substituted geldanamycin derivatives, and pharmaceutically acceptable salts thereof that are potent Hsp90 binding agents useful for the treatment of, and/or the amelioration of symptoms of, cancer or neurodegenerative disorders.

  该发明提供了19-取代格尔丹霉素衍生物及其药学上可接受的盐，这些衍生物是强效的Hsp90结合剂，可用于治疗癌症或神经退行性疾病的症状改善。
• Inhibition of the oncogene product p185erbB-2 in vitro and in vivo by geldanamycin and dihydrogeldanamycin derivatives
  作者：R. C. Schnur、M. L. Corman、R. J. Gallaschun、B. A. Cooper、M. F. Dee、J. L. Doty、M. L. Muzzi、J. D. Moyer、C. I. DiOrio

  DOI：10.1021/jm00019a010

  日期：1995.9

  The erbB-2 oncogene encodes a transmembrane protein tyrosine kinase which plays a pivotal role in signal transduction and has been implicated when overexpressed in breast, ovarian, and gastric cancers. Naturally occurring benzoquinoid ansamycin antibiotics herbimycin A, geldanamycin (GDM), and dihydrogeldanamycin were found to potently deplete p185, the erbB-2 oncoprotein, in human breast cancer SKBR-3 cells in culture. Chemistry efforts to modify selectively the quinoid moiety of GDM afforded derivatives with greater potency in vitro and in vivo. Analogs demonstrated inhibition of p185 phosphotyrosine in cell culture and in vivo after systemic drug administration to nu/nu nude mice bearing Fisher rat embryo cells transfected with human erbB-2 (FRE/erbB-2). Specifically, dosed intraperitoneally at 100 mg/kg, 17-(allylamino)-17-demethoxygeldanamycin and other 17-amino analogs were effective at reducing p185 phosphotyrosine in subcutaneous flank FRE/erbB-2 tumors. Modifications to the 17-19-positions of the quinone ring revealed a broad structure-activity relationship in vitro.