17-(6-(pyrimidine-4-carboxamido)hexylamino)-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-(6-(pyrimidine-4-carboxamido)hexylamino)-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-[6-(pyrimidine-4-carbonylamino)hexylamino]-2-azabicyclo[16.3.1]docosa-1(21),4,6,10,18-pentaen-9-yl] carbamate
• 化学式: C₃₉H₅₄N₆O₉
• 分子量: 750.893
• InChiKey: KSDRIAAIHZTSBQ-OHGVIQRNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  54
• 可旋转键数：
  13
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.51
• 拓扑面积：
  221
• 氢给体数：
  5
• 氢受体数：
  12

反应信息

• 作为产物：
  描述：

  格尔德霉素 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 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 27.5h， 生成 17-(6-(pyrimidine-4-carboxamido)hexylamino)-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

文献信息

• 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.