3-(5-chloro-2,4-dihydroxyphenyl)-4-(4-methoxyphenyl)-5-(N-octanoylamino)isoxazole

• 分子结构分类: 有机化合物 - 苯类化合物 - 酚类
• 英文名称: 3-(5-chloro-2,4-dihydroxyphenyl)-4-(4-methoxyphenyl)-5-(N-octanoylamino)isoxazole
• 英文别名: N-(3-(5-chloro-2,4-dihydroxyphenyl)-4-(4-methoxyphenyl)isoxazol-5-yl)octanamide；N-[3-(5-chloro-2,4-dihydroxyphenyl)-4-(4-methoxyphenyl)-1,2-oxazol-5-yl]octanamide
• 化学式: C₂₄H₂₇ClN₂O₅
• 分子量: 458.942
• InChiKey: AYPRMJRBDPUOEQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6
• 重原子数：
  32
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  105
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  4-氯间苯二酚 在 吡啶 、 4-二甲氨基吡啶 、 三氟化硼乙醚 、 盐酸羟胺 、 溴 、 三氯化硼 、 potassium carbonate 、 三乙胺 、 sodium hydroxide 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 水 、 乙腈 为溶剂， 反应 47.0h， 生成 3-(5-chloro-2,4-dihydroxyphenyl)-4-(4-methoxyphenyl)-5-(N-octanoylamino)isoxazole
  参考文献：
  名称：

  Discovery of potent N-(isoxazol-5-yl)amides as HSP90 inhibitors

  摘要：

  HSP90 is ubiquitously overexpressed in a broad spectrum of human cancers and has been recognized as an attractive target for cancer treatment. Here, we described the fragment screening, synthesis and structure-activity relationship studies of small molecule inhibitors with 4,5-diarylisoxazole scaffold targeting HSP90. Among them, the compound N-(3-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-((4-morpholinopiperidin-1-yl)methyl)phenyl)isoxazol-5-yl)cyclopropanecarboxamide (108) showed high affinity for binding to HSP90 (FP binding assay, IC50 = 0.030 mu M) and inhibited the proliferation of various human cancer cell lines with averaging GI(50) about 88 nM. Compound 108 exhibited its functional inhibition of HSP90 by depleting key signaling pathways and concomitantly elevating of HSP70 and HSP27 in U-87MG cells. Further in vivo studies showed that compound 108 strongly suppressed the tumor growth of human glioblastoma xenograft model U-87MG with T/C = 18.35% at 50 mg/kg q3w/2.5w. Moreover, compound 108 also exhibited good pharmacokinetic properties. Together, our study implicates that compound 108 is a promising candidate of HSP90 inhibitor and is currently advanced to preclinical study. (c) 2014 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2014.09.065

文献信息

• [EN] PHENYL 1,2-ISOXAZOLYL OR PHENYL 1,2-PYRAZOLE COMPOUND AND APPLICATION THEREOF<br/>[FR] COMPOSÉ DE PHÉNYL-1,2-ISOXAZOLYLE OU PHÉNYL-1,2-PYRAZOLE ET APPLICATION DE CELUI-CI
  申请人：SHANGHAI INST MATERIA MEDICA

  公开号：WO2014056446A1

  公开（公告）日：2014-04-17

  本发明公开了结构式（I）的苯基1，2-异噁唑或1，2-吡唑类化合物的用途。通过生物活性测试证明，该类化合物具有明显的抑制热休克蛋白90的活性。因此，本发明的苯基1，2-异噁唑或1，2-吡唑类化合物可作为热休克蛋白90的抑制剂而用于治疗癌症。
• Discovery of potent N-(isoxazol-5-yl)amides as HSP90 inhibitors
  作者：Danqi Chen、Aijun Shen、Jian Li、Feng Shi、Wuyan Chen、Jing Ren、Hongchun Liu、Yechun Xu、Xin Wang、Xinying Yang、Yiming Sun、Min Yang、Jianhua He、Yueqin Wang、Liping Zhang、Min Huang、Meiyu Geng、Bing Xiong、Jingkang Shen

  DOI：10.1016/j.ejmech.2014.09.065

  日期：2014.11

  HSP90 is ubiquitously overexpressed in a broad spectrum of human cancers and has been recognized as an attractive target for cancer treatment. Here, we described the fragment screening, synthesis and structure-activity relationship studies of small molecule inhibitors with 4,5-diarylisoxazole scaffold targeting HSP90. Among them, the compound N-(3-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-((4-morpholinopiperidin-1-yl)methyl)phenyl)isoxazol-5-yl)cyclopropanecarboxamide (108) showed high affinity for binding to HSP90 (FP binding assay, IC50 = 0.030 mu M) and inhibited the proliferation of various human cancer cell lines with averaging GI(50) about 88 nM. Compound 108 exhibited its functional inhibition of HSP90 by depleting key signaling pathways and concomitantly elevating of HSP70 and HSP27 in U-87MG cells. Further in vivo studies showed that compound 108 strongly suppressed the tumor growth of human glioblastoma xenograft model U-87MG with T/C = 18.35% at 50 mg/kg q3w/2.5w. Moreover, compound 108 also exhibited good pharmacokinetic properties. Together, our study implicates that compound 108 is a promising candidate of HSP90 inhibitor and is currently advanced to preclinical study. (c) 2014 Elsevier Masson SAS. All rights reserved.