1-(4-hydroxyphenyl)-1-phenyl-2-(4-methylsulfonyphenyl)but-1-ene

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二苯乙烯类
• 英文名称: 1-(4-hydroxyphenyl)-1-phenyl-2-(4-methylsulfonyphenyl)but-1-ene
• 英文别名: 4-[2-(4-methylsulfonylphenyl)-1-phenylbut-1-enyl]phenol
• 化学式: C₂₃H₂₂O₃S
• 分子量: 378.492
• InChiKey: NCYNUGBKDQITPZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.16
• 重原子数：
  27.0
• 可旋转键数：
  5.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  54.37
• 氢给体数：
  1.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  乙酰氯 、 1-(4-hydroxyphenyl)-1-phenyl-2-(4-methylsulfonyphenyl)but-1-ene 在 三乙胺 作用下， 以 乙醚 为溶剂， 反应 1.5h， 生成 Acetic acid 4-[(Z)-2-(4-methanesulfonyl-phenyl)-1-phenyl-but-1-enyl]-phenyl ester 、 (E)-1-(4-acetoxyphenyl)-1-phenyl-2-(4-methylsulfonylphenyl)but-1-ene
  参考文献：
  名称：

  Design and synthesis of acyclic triaryl (Z)-olefins: a novel class of cyclooxygenase-2 (COX-2) inhibitors

  摘要：

  A group of acyclic 2-alkyl-1, 1-diphenyl-2-(4-methylsulfonylphenyl)ethenes was designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1 and COX-2 isozyme inhibition structure-activity studies identified 1,1-diphenyl-2(4-methylsulfonylphenyl)hex-1-ene as a highly potent (IC50 = 0.014muM), and an extremely selective [COX-2 selectivity index (SI) >7142], COX-2 inhibitor that showed superior anti-inflammatory (A1) activity (ID50 = 2.5 mg/kg) relative to celecoxib (ID50 = 10.8mg/kg). This initial study was extended to include the design of a structurally related group of acyclic triaryl (Z)-olefins possessing an acetoxy (OAc) substituent at the para-position of the C-1 phenyl ring that is cis to a C-2 4-methylsulfonylphenyl substituent. COX-1 and COX-2 inhibition studies showed that (Z)-1-(4-acetoxyphenyl)-1-phenyl-2-(4-methylsulfonylphenyl)but-1-ene [(Z)-13b] is a potent (COX-1 IC50 = 2.4muM; COX-2 IC50 = 0.03 muM), and selective (COX-2 SI = 81), COX-2 inhibitor which is a potent AI agent (ID50 = 4.1 mg/kg) with equipotent analgesic activity to celecoxib. A molecular modeling (docking) study showed that the SO2Me substituent of (Z)-13b inserts deep inside the 2degrees-pocket of the COX-2 active site where one of the O-atoms of SO, group undergoes a H-bonding interaction with Phe(518). The p-OAc substituent on the C-1 phenyl ring is oriented in a hydrophobic pocket comprised of Met(522), Gly(526), Trp(387), Tyr(348), and Tyr(385), and the C-2 ethyl substituent is oriented towards the mouth of the COX-2 channel in the vicinity of amino acid residues Arg(12)0, Leu(531), and Val(349). Structure-activity data acquired indicate that a (Z)olefin having cis C-1 4-acetoxyphenyl (phenyl) and C-2 4-methylsulfonylphenyl substituents, and a C-1 phenyl substituent in conjunction with either a C-2 hydrogen or short alkyl substituent provides a novel template to design acyclic olefinic COX-2 inhibitors that, like aspirin, have the potential to acetylate COX-2. (C) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2004.08.021
• 作为产物：
  描述：

  4-羟基-二苯甲酮 在 Oxone 、 四氯化钛 、 锌 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 反应 17.5h， 生成 1-(4-hydroxyphenyl)-1-phenyl-2-(4-methylsulfonyphenyl)but-1-ene
  参考文献：
  名称：

  Design and synthesis of acyclic triaryl (Z)-olefins: a novel class of cyclooxygenase-2 (COX-2) inhibitors

  摘要：

  A group of acyclic 2-alkyl-1, 1-diphenyl-2-(4-methylsulfonylphenyl)ethenes was designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1 and COX-2 isozyme inhibition structure-activity studies identified 1,1-diphenyl-2(4-methylsulfonylphenyl)hex-1-ene as a highly potent (IC50 = 0.014muM), and an extremely selective [COX-2 selectivity index (SI) >7142], COX-2 inhibitor that showed superior anti-inflammatory (A1) activity (ID50 = 2.5 mg/kg) relative to celecoxib (ID50 = 10.8mg/kg). This initial study was extended to include the design of a structurally related group of acyclic triaryl (Z)-olefins possessing an acetoxy (OAc) substituent at the para-position of the C-1 phenyl ring that is cis to a C-2 4-methylsulfonylphenyl substituent. COX-1 and COX-2 inhibition studies showed that (Z)-1-(4-acetoxyphenyl)-1-phenyl-2-(4-methylsulfonylphenyl)but-1-ene [(Z)-13b] is a potent (COX-1 IC50 = 2.4muM; COX-2 IC50 = 0.03 muM), and selective (COX-2 SI = 81), COX-2 inhibitor which is a potent AI agent (ID50 = 4.1 mg/kg) with equipotent analgesic activity to celecoxib. A molecular modeling (docking) study showed that the SO2Me substituent of (Z)-13b inserts deep inside the 2degrees-pocket of the COX-2 active site where one of the O-atoms of SO, group undergoes a H-bonding interaction with Phe(518). The p-OAc substituent on the C-1 phenyl ring is oriented in a hydrophobic pocket comprised of Met(522), Gly(526), Trp(387), Tyr(348), and Tyr(385), and the C-2 ethyl substituent is oriented towards the mouth of the COX-2 channel in the vicinity of amino acid residues Arg(12)0, Leu(531), and Val(349). Structure-activity data acquired indicate that a (Z)olefin having cis C-1 4-acetoxyphenyl (phenyl) and C-2 4-methylsulfonylphenyl substituents, and a C-1 phenyl substituent in conjunction with either a C-2 hydrogen or short alkyl substituent provides a novel template to design acyclic olefinic COX-2 inhibitors that, like aspirin, have the potential to acetylate COX-2. (C) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2004.08.021

文献信息

• Design and synthesis of acyclic triaryl (Z)-olefins: a novel class of cyclooxygenase-2 (COX-2) inhibitors
  作者：Md. Jashim Uddin、P.N. Praveen Rao、Edward E. Knaus

  DOI：10.1016/j.bmc.2004.08.021

  日期：2004.11

  A group of acyclic 2-alkyl-1, 1-diphenyl-2-(4-methylsulfonylphenyl)ethenes was designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1 and COX-2 isozyme inhibition structure-activity studies identified 1,1-diphenyl-2(4-methylsulfonylphenyl)hex-1-ene as a highly potent (IC50 = 0.014muM), and an extremely selective [COX-2 selectivity index (SI) >7142], COX-2 inhibitor that showed superior anti-inflammatory (A1) activity (ID50 = 2.5 mg/kg) relative to celecoxib (ID50 = 10.8mg/kg). This initial study was extended to include the design of a structurally related group of acyclic triaryl (Z)-olefins possessing an acetoxy (OAc) substituent at the para-position of the C-1 phenyl ring that is cis to a C-2 4-methylsulfonylphenyl substituent. COX-1 and COX-2 inhibition studies showed that (Z)-1-(4-acetoxyphenyl)-1-phenyl-2-(4-methylsulfonylphenyl)but-1-ene [(Z)-13b] is a potent (COX-1 IC50 = 2.4muM; COX-2 IC50 = 0.03 muM), and selective (COX-2 SI = 81), COX-2 inhibitor which is a potent AI agent (ID50 = 4.1 mg/kg) with equipotent analgesic activity to celecoxib. A molecular modeling (docking) study showed that the SO2Me substituent of (Z)-13b inserts deep inside the 2degrees-pocket of the COX-2 active site where one of the O-atoms of SO, group undergoes a H-bonding interaction with Phe(518). The p-OAc substituent on the C-1 phenyl ring is oriented in a hydrophobic pocket comprised of Met(522), Gly(526), Trp(387), Tyr(348), and Tyr(385), and the C-2 ethyl substituent is oriented towards the mouth of the COX-2 channel in the vicinity of amino acid residues Arg(12)0, Leu(531), and Val(349). Structure-activity data acquired indicate that a (Z)olefin having cis C-1 4-acetoxyphenyl (phenyl) and C-2 4-methylsulfonylphenyl substituents, and a C-1 phenyl substituent in conjunction with either a C-2 hydrogen or short alkyl substituent provides a novel template to design acyclic olefinic COX-2 inhibitors that, like aspirin, have the potential to acetylate COX-2. (C) 2004 Elsevier Ltd. All rights reserved.