17-(tetrahydropiperazin-4'-yl-methylmino)-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-(tetrahydropiperazin-4'-yl-methylmino)-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-(piperidin-4-ylmethylamino)-2-azabicyclo[16.3.1]docosa-1(21),4,6,10,18-pentaen-9-yl] carbamate
• 化学式: C₃₄H₅₀N₄O₈
• 分子量: 642.793
• InChiKey: GITXJMAXOAAKCV-SAROKQDASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  46
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  178
• 氢给体数：
  5
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  异烟酸 、 17-(tetrahydropiperazin-4'-yl-methylmino)-17-demethoxygeldanamycin 在 N-羟基丁二酰亚胺 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 生成 17-(1-N-isonicotinoylpiperidin-4-methylamino)-17-demethoxygeldanamycin
  参考文献：
  名称：

  Discovery of Novel 17-Phenylethylaminegeldanamycin Derivatives as Potent Hsp90 Inhibitors

  摘要：

  Twenty‐six 17‐phenylethylamine‐modified geldanamycin derivatives were synthesized and evaluated for antiproliferation activity in human cancer cell lines, LNCaP and MDA‐MB‐231. Five derivatives (2j, 2q, 2v, 2x, and 2y) showed excellent in vitro antitumor activities. Among them, compound 2y was the most potent lead, with IC50 values of 0.27 ± 0.11 and 0.86 ± 0.23 μm for LNCaP and MDA‐MB‐231, respectively. In particular, compound 2y was more active than its precursor geldanamycin against LNCap cells. Liver injury test in mice demonstrated that 2y group showed no significant difference for serum alanine aminotransferase (ALT) activity versus vehicle control, indicating that 2y was a promising antitumor candidate. Preliminary structure–activity relationship (SAR) and molecular dynamics (MD) simulations of this new series of geldanamycin derivatives were also investigated, suggesting a theoretical model of 17‐phenylethylaminegeldanamycins binding to Hsp90.

  DOI：

  10.1111/cbdd.12371
• 作为产物：
  描述：

  4-氨甲基哌啶 、 格尔德霉素 以 二氯甲烷 为溶剂， 反应 1.0h， 以32%的产率得到17-(tetrahydropiperazin-4'-yl-methylmino)-17-demethoxygeldanamycin
  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

文献信息

• 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.
• METHODS, COMPOSITIONS, AND KITS FOR THE TREATMENT OF CANCER
  申请人：Haggerty Timothy J.

  公开号：US20140335050A1

  公开（公告）日：2014-11-13

  The invention features methods, compositions, and kits for the administration of an HSP90 inhibitor, OBAA, flunarizine, aphidicolin, damnacanthal, dantrolene, or an analog thereof, alone, or in combination with, e.g., a TAA, an antigen-binding scaffold (e.g., an antibody, a soluble T cell receptor, or a chimeric receptor) specific for a TAA, a cell (e.g., a white blood cell that targets a cancer cell), and/or an IFN-β receptor agonist or an IFN-γ receptor agonist, for the treatment of cancer.
• Discovery of Novel 17-Phenylethylaminegeldanamycin Derivatives as Potent Hsp90 Inhibitors
  作者：Zhenyu Li、Lejiao Jia、Jifeng Wang、Xingkang Wu、Guowei Shi、Chunhua Lu、Yuemao Shen

  DOI：10.1111/cbdd.12371

  日期：2015.2

  Twenty‐six 17‐phenylethylamine‐modified geldanamycin derivatives were synthesized and evaluated for antiproliferation activity in human cancer cell lines, LNCaP and MDA‐MB‐231. Five derivatives (2j, 2q, 2v, 2x, and 2y) showed excellent in vitro antitumor activities. Among them, compound 2y was the most potent lead, with IC50 values of 0.27 ± 0.11 and 0.86 ± 0.23 μm for LNCaP and MDA‐MB‐231, respectively. In particular, compound 2y was more active than its precursor geldanamycin against LNCap cells. Liver injury test in mice demonstrated that 2y group showed no significant difference for serum alanine aminotransferase (ALT) activity versus vehicle control, indicating that 2y was a promising antitumor candidate. Preliminary structure–activity relationship (SAR) and molecular dynamics (MD) simulations of this new series of geldanamycin derivatives were also investigated, suggesting a theoretical model of 17‐phenylethylaminegeldanamycins binding to Hsp90.