4,5-Dihydrogeldanamycin | 150270-08-9

• 物质功能分类: 分析化学 - 标准品 - 药典标准品和杂质标准品
• 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: 4,5-Dihydrogeldanamycin
• 英文别名: geldanamycin；[(4E,8S,9S,10E,12S,13R,14S,16R)-13-hydroxy-8,14,19-trimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1]docosa-1(21),4,10,18-tetraen-9-yl] carbamate
• CAS: 150270-08-9
• 化学式: C₂₉H₄₂N₂O₉
• 分子量: 562.66
• InChiKey: JRZJKWGQFNTSRN-UTWVXPODSA-N

物化性质

• 沸点：
  767.9±60.0 °C(Predicted)
• 密度：
  1.22±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于 DMSO（高达 30 mg/ml）或乙醇（高达 10 mg/ml）。

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  40
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.59
• 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：

  4,5-Dihydrogeldanamycin 在 氨 作用下， 以 二氯甲烷 为溶剂， 以75%的产率得到Carbamic acid (4E,10E)-(8S,9S,12S,13R,14S,16R)-19-amino-13-hydroxy-8,14-dimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-aza-bicyclo[16.3.1]docosa-1(21),4,10,18-tetraen-9-yl ester
  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：

  4,5-dihydro-7-O-descarbamoyl-7-hydroxygeldanamycin 以 乙酸乙酯 为溶剂， 反应 72.0h， 生成 格尔德霉素 、 4,5-Dihydrogeldanamycin
  参考文献：
  名称：

  [EN] GELDANAMYCIN DERIVATIVES AND THE METHOD FOR BIOSYNTHESIS THEREOF
  [FR] DERIVES DE GELDANAMYCINE ET PROCEDE DE BIOSYNTHESE DE CEUX-CI

  摘要：

  本发明涉及一种由链霉菌亲湿亚种duamyceticus的基因操作所生物合成的格尔达霉素衍生物苯醌环丝菌素，以及它们的制备方法。更具体地，本发明涉及一种格尔达霉素O-氨甲酰转移酶基因（gel8）失活突变体，其制备方法以及格尔达霉素衍生物，4,5-二氢-7-0-去氨甲酰-7-羟基格尔达霉素和4,5-二氢-7-0-去氨甲酰-7-羟基-17-O-去甲基格尔达霉素。由于本发明的格尔达霉素衍生物像格尔达霉素一样抑制Hsp90，因此它们可以有效地用作抗生素、抗真菌、抗病毒、抗炎和抗肿瘤剂以及免疫抑制剂。

  公开号：

  WO2006016773A1

文献信息

• Synthesis and anticancer activity of geldanamycin derivatives derived from biosynthetically generated metabolites
  作者：Kyeong Lee、Jung S. Ryu、Yinglan Jin、Woncheol Kim、Navneet Kaur、Sang J. Chung、Yong-Jin Jeon、Joon-Tae Park、Ji S. Bang、Hong S. Lee、Tae Y. Kim、Jung J. Lee、Young-Soo Hong

  DOI：10.1039/b713407j

  日期：——

  A new series of geldanamycin derivatives were synthesized using a semi-synthetic approach involving genetically engineered biosynthetic intermediates. These analogues were then evaluated for anti-proliferation activity in human cancer cell lines, SK-Br3 and SK-Ov3. Most of the synthesized compounds exhibited potent in vitro anti-proliferation activity toward both cell lines. Such compounds potently inhibited the expression of the Hsp90 client protein ErbB2.

  一种新系列的甘草酸胺衍生物采用半合成方法合成，涉及基因工程改造的生物合成中间体。这些类似物随后在人体癌细胞系SK-Br3和SK-Ov3中评估了抗增殖活性。大多数合成的化合物对这两个细胞系表现出强效的体外抗增殖活性。这些化合物有效抑制了Hsp90靶蛋白ErbB2的表达。
• WO2008/38964
  申请人：——

  公开号：——

  公开（公告）日：——
• 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.
• [EN] GELDANAMYCIN DERIVATIVES AND THE METHOD FOR BIOSYNTHESIS THEREOF<br/>[FR] DERIVES DE GELDANAMYCINE ET PROCEDE DE BIOSYNTHESE DE CEUX-CI
  申请人：KOREA RES INST OF BIOSCIENCE

  公开号：WO2006016773A1

  公开（公告）日：2006-02-16

  The present invention relates to geldanamycin derivatives, benzoquinone ansamycin biosynthesized by gene manipulation of Streptomyces hygroscopicus subsp. duamyceticus and the method producing them, more particularly to a geldanamycin O-carbamoyl transferase gene ( gel8 )-inactive mutant, the method producing it and geldanamycin derivatives, 4, 5-dihydro-7-0-descarbamoyl-7-hydroxy geldanamycin and 4, 5-dihydro-7-0-descarbamoyl-7-hydroxy- 17-O-demethyl geldanamycin. Since geldanamycin derivatives of the present invention suppress Hsp90 like geldanamycin, they can effectively be used for antibiotic, antifungal, antiviral, antiinflammatory and antitumor agents and an immune su ressant.

  本发明涉及一种由链霉菌亲湿亚种duamyceticus的基因操作所生物合成的格尔达霉素衍生物苯醌环丝菌素，以及它们的制备方法。更具体地，本发明涉及一种格尔达霉素O-氨甲酰转移酶基因（gel8）失活突变体，其制备方法以及格尔达霉素衍生物，4,5-二氢-7-0-去氨甲酰-7-羟基格尔达霉素和4,5-二氢-7-0-去氨甲酰-7-羟基-17-O-去甲基格尔达霉素。由于本发明的格尔达霉素衍生物像格尔达霉素一样抑制Hsp90，因此它们可以有效地用作抗生素、抗真菌、抗病毒、抗炎和抗肿瘤剂以及免疫抑制剂。