5-(bromomethyl)-3-(5-chlorofuran-2-yl)-4-phenylisoxazole | 1579976-80-9

• 分子结构分类: 有机化合物 - 有机卤素化合物 - 芳基卤化物
• 英文名称: 5-(bromomethyl)-3-(5-chlorofuran-2-yl)-4-phenylisoxazole
• 英文别名: PM32；5-(Bromomethyl)-3-(5-chlorofuran-2-yl)-4-phenyl-1,2-oxazole；5-(bromomethyl)-3-(5-chlorofuran-2-yl)-4-phenyl-1,2-oxazole
• CAS: 1579976-80-9
• 化学式: C₁₄H₉BrClNO₂
• 分子量: 338.588
• InChiKey: PWRBRIZVVVDOBR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  19
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  39.2
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  5-(bromomethyl)-3-(5-chlorofuran-2-yl)-4-phenylisoxazole 在 四丁基硫酸氢铵 、 对甲苯磺酸 作用下， 以 二氯甲烷 、 水 为溶剂， 反应 5.33h， 生成 methyl 2-[3-(5-chlorofuran-2-yl)-4-phenylisoxazol-5-yl]acetate
  参考文献：
  名称：

  Selective COX-1 inhibition as a target of theranostic novel diarylisoxazoles

  摘要：

  Cyclooxygenase(COX)-1 role in some diseases is increasingly studied. 3-(5-Chlorofuran-2-yl)-5-methy14-phenylisoxazole (P6), a highly selective cyclooxygenase-1 inhibitor, was used as a "lead" to design new isoxazoles (2a-m), differently selective towards COX-1. Those isoxazoles might be useful as novel theranostic agents and also to better clarify COX-1 role in the human physiology and diseases. 2a-m were prepared in fair to good yields developing suitable synthetic strategies. They were evaluated in vitro for their COX-inhibitory activity and selectivity. Structure activity relationship studies of the novel set of diarylisoxazoles allowed to identify new key determinants for COX-1 selectivity, and to uncover compounds appropriate for a deep pharmacokinetic and pharmacodynamic investigation. 3-(5-Chlorofuran2yl)-4-phenylisoxazol-5-amine (2f) was the most active compound of the series, its inhibitory activity was assessed in purified enzyme (COX-1 IC50 = 1.1 mu M; COX-2 IC50 > 50 mu M) and in the ovarian cancer cell line (OVCAR-3) expressing only COX-1 (IC50 = 0.58 mu M). Furthermore, the high inhibitory potency of 2f was rationalized through docking simulations in terms of interactions with a crystallographic model of the COX-1 binding site. We found critical interactions between the inhibitor and constriction residues R120 and Y355 at the base of the active site, as well as with S530 at the top of the side pocket. (C) 2014 Published by Elsevier Masson SAS.

  DOI：

  10.1016/j.ejmech.2013.12.023
• 作为产物：
  描述：

  3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole 在 N-溴代丁二酰亚胺(NBS) 、 偶氮二异丁腈 作用下， 以 四氯化碳 为溶剂， 反应 4.0h， 以95%的产率得到5-(bromomethyl)-3-(5-chlorofuran-2-yl)-4-phenylisoxazole
  参考文献：
  名称：

  PET radiotracer [18F]-P6 selectively targeting COX-1 as a novel biomarker in ovarian cancer: Preliminary investigation

  摘要：

  Cyclooxygenase-1 (COX-1), but not COX-2, is expressed at high levels in the early stages of human epithelial ovarian cancer where it seems to play a key role in cancer onset and progression. As a consequence, COX-1 is an ideal biomarker for early ovarian cancer detection. A series of novel fluorinated COX-1-targeted imaging agents derived from P6 was developed by using a highly selective COX-1 inhibitor as a lead compound. Among these new compounds, designed by structural modification of P6, 3-(5-chlorofuran-2-yl)-5-(fluoromethyl)-4-phenylisoxazole ([(18/19)F]-P6) is the most promising derivative [IC50 = 2.0 μM (purified oCOX-1) and 1.37 μM (hOVCAR-3 cell COX-1)]. Its tosylate precursor was also prepared and, a method for radio[(18)F]chemistry was developed and optimized. The radiochemistry was carried out using a carrier-free K(18)F/Kryptofix 2.2.2 complex, that afforded [(18)F]-P6 in good radiochemical yield (18%) and high purity (>95%). In vivo PET/CT imaging data showed that the radiotracer [(18)F]-P6 was selectively taken up by COX-1-expressing ovarian carcinoma (OVCAR 3) tumor xenografts as compared with the normal leg muscle. Our results suggest that [(18)F]-P6 might be an useful radiotracer in preclinical and clinical settings for in vivo PET-CT imaging of tissues that express elevated levels of COX-1.

  DOI：

  10.1016/j.ejmech.2014.04.074

文献信息

• PET radiotracer [18F]-P6 selectively targeting COX-1 as a novel biomarker in ovarian cancer: Preliminary investigation
  作者：Maria Grazia Perrone、Paola Malerba、Md. Jashim Uddin、Paola Vitale、Andrea Panella、Brenda C. Crews、Cristina K. Daniel、Kebreab Ghebreselasie、Mike Nickels、Mohammed N. Tantawy、H. Charles Manning、Lawrence J. Marnett、Antonio Scilimati

  DOI：10.1016/j.ejmech.2014.04.074

  日期：2014.6

  Cyclooxygenase-1 (COX-1), but not COX-2, is expressed at high levels in the early stages of human epithelial ovarian cancer where it seems to play a key role in cancer onset and progression. As a consequence, COX-1 is an ideal biomarker for early ovarian cancer detection. A series of novel fluorinated COX-1-targeted imaging agents derived from P6 was developed by using a highly selective COX-1 inhibitor as a lead compound. Among these new compounds, designed by structural modification of P6, 3-(5-chlorofuran-2-yl)-5-(fluoromethyl)-4-phenylisoxazole ([(18/19)F]-P6) is the most promising derivative [IC50 = 2.0 μM (purified oCOX-1) and 1.37 μM (hOVCAR-3 cell COX-1)]. Its tosylate precursor was also prepared and, a method for radio[(18)F]chemistry was developed and optimized. The radiochemistry was carried out using a carrier-free K(18)F/Kryptofix 2.2.2 complex, that afforded [(18)F]-P6 in good radiochemical yield (18%) and high purity (>95%). In vivo PET/CT imaging data showed that the radiotracer [(18)F]-P6 was selectively taken up by COX-1-expressing ovarian carcinoma (OVCAR 3) tumor xenografts as compared with the normal leg muscle. Our results suggest that [(18)F]-P6 might be an useful radiotracer in preclinical and clinical settings for in vivo PET-CT imaging of tissues that express elevated levels of COX-1.
• Selective COX-1 inhibition as a target of theranostic novel diarylisoxazoles
  作者：Paola Vitale、Maria Grazia Perrone、Paola Malerba、Antonio Lavecchia、Antonio Scilimati

  DOI：10.1016/j.ejmech.2013.12.023

  日期：2014.3

  Cyclooxygenase(COX)-1 role in some diseases is increasingly studied. 3-(5-Chlorofuran-2-yl)-5-methy14-phenylisoxazole (P6), a highly selective cyclooxygenase-1 inhibitor, was used as a "lead" to design new isoxazoles (2a-m), differently selective towards COX-1. Those isoxazoles might be useful as novel theranostic agents and also to better clarify COX-1 role in the human physiology and diseases. 2a-m were prepared in fair to good yields developing suitable synthetic strategies. They were evaluated in vitro for their COX-inhibitory activity and selectivity. Structure activity relationship studies of the novel set of diarylisoxazoles allowed to identify new key determinants for COX-1 selectivity, and to uncover compounds appropriate for a deep pharmacokinetic and pharmacodynamic investigation. 3-(5-Chlorofuran2yl)-4-phenylisoxazol-5-amine (2f) was the most active compound of the series, its inhibitory activity was assessed in purified enzyme (COX-1 IC50 = 1.1 mu M; COX-2 IC50 > 50 mu M) and in the ovarian cancer cell line (OVCAR-3) expressing only COX-1 (IC50 = 0.58 mu M). Furthermore, the high inhibitory potency of 2f was rationalized through docking simulations in terms of interactions with a crystallographic model of the COX-1 binding site. We found critical interactions between the inhibitor and constriction residues R120 and Y355 at the base of the active site, as well as with S530 at the top of the side pocket. (C) 2014 Published by Elsevier Masson SAS.