5-(2,4-bis(benzyloxy)-5-chlorophenyl)-4-(3-formylphenyl)-isoxazole-3-carboxylic acid ethylamide | 1001385-63-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 5-(2,4-bis(benzyloxy)-5-chlorophenyl)-4-(3-formylphenyl)-isoxazole-3-carboxylic acid ethylamide
• 英文别名: 5-[5-chloro-2,4-bis(phenylmethoxy)phenyl]-N-ethyl-4-(3-formylphenyl)-1,2-oxazole-3-carboxamide
• CAS: 1001385-63-2
• 化学式: C₃₃H₂₇ClN₂O₅
• 分子量: 567.041
• InChiKey: QXZFRZKZNYVKIE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.7
• 重原子数：
  41
• 可旋转键数：
  11
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  90.7
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  1-乙酰哌嗪 、 5-(2,4-bis(benzyloxy)-5-chlorophenyl)-4-(3-formylphenyl)-isoxazole-3-carboxylic acid ethylamide 在 3 A molecular sieve 、 sodium cyanoborohydride 、 溶剂黄146 作用下， 以 二氯甲烷 为溶剂， 反应 16.0h， 生成 4-[3-[(4-acetylpiperazin-1-yl)methyl]phenyl]-5-[5-chloro-2,4-bis(phenylmethoxy)phenyl]-N-ethyl-1,2-oxazole-3-carboxamide
  参考文献：
  名称：

  4,5-Diarylisoxazole Hsp90 Chaperone Inhibitors: Potential Therapeutic Agents for the Treatment of Cancer

  摘要：

  Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential chemotherapeutic agents for cancer. Here, we describe the structure-based design, synthesis, structure-activity relationships and pharmacokinetics of potent small-molecule inhibitors of Hsp90 based on the 4,5-diarylisoxazole scaffold. Analogues from this series have high affinity for Hsp90, as measured in a fluorescence polarization (FP) competitive binding assay, and are active in cancer cell lines where they inhibit proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Compound 40f (VER-52296/NVP-AUY922) is potent in the Hsp90 FP binding assay (IC50 = 21 nM) and inhibits proliferation of various human cancer cell lines in vitro, with GI50 averaging 9 nM. Compound 40f is retained in tumors in vivo when administered i.p., as evaluated by cassette dosing in tumor-bearing mice. In a human colon cancer xenograft model, 40f inhibits tumor growth by approximately 50%.

  DOI：

  10.1021/jm701018h
• 作为产物：
  描述：

  5-(2,4-bis(benzyloxy)-5-chlorophenyl)-4-bromoisoxazole-3-carboxylic acid ethylamide 、 3-甲酰基苯硼酸 在 bis-triphenylphosphine-palladium(II) chloride 碳酸氢钠 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 生成 5-(2,4-bis(benzyloxy)-5-chlorophenyl)-4-(3-formylphenyl)-isoxazole-3-carboxylic acid ethylamide
  参考文献：
  名称：

  4,5-Diarylisoxazole Hsp90 Chaperone Inhibitors: Potential Therapeutic Agents for the Treatment of Cancer

  摘要：

  Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential chemotherapeutic agents for cancer. Here, we describe the structure-based design, synthesis, structure-activity relationships and pharmacokinetics of potent small-molecule inhibitors of Hsp90 based on the 4,5-diarylisoxazole scaffold. Analogues from this series have high affinity for Hsp90, as measured in a fluorescence polarization (FP) competitive binding assay, and are active in cancer cell lines where they inhibit proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Compound 40f (VER-52296/NVP-AUY922) is potent in the Hsp90 FP binding assay (IC50 = 21 nM) and inhibits proliferation of various human cancer cell lines in vitro, with GI50 averaging 9 nM. Compound 40f is retained in tumors in vivo when administered i.p., as evaluated by cassette dosing in tumor-bearing mice. In a human colon cancer xenograft model, 40f inhibits tumor growth by approximately 50%.

  DOI：

  10.1021/jm701018h