p-(methylthio)octanophenone | 760948-49-0

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: p-(methylthio)octanophenone
• 英文别名: 1-(4-Methylsulfanylphenyl)octan-1-one；1-(4-methylsulfanylphenyl)octan-1-one
• CAS: 760948-49-0
• 化学式: C₁₅H₂₂OS
• 分子量: 250.405
• InChiKey: DVSUOXZLOMLUFA-UHFFFAOYSA-N

物化性质

• 熔点：
  58-60 °C(Solv: dichloromethane (75-09-2); hexane (110-54-3))
• 沸点：
  371.5±25.0 °C(Predicted)
• 密度：
  1.00±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  17
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  42.4
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  p-(methylthio)octanophenone 在 Oxone 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 反应 15.0h， 以81%的产率得到4-(methylsulfonyl)octanophenone
  参考文献：
  名称：

  Synthesis and biological evaluation of acyclic triaryl (Z)-olefins possessing a 3,5-di-tert-butyl-4-hydroxyphenyl pharmacophore: Dual inhibitors of cyclooxygenases and lipoxygenases

  摘要：

  A new class of regioisomeric acyclic triaryl (Z)-olefins possessing a 3,5-di-tert-butyl-4-hydroxyphenyl (DTBHP) 5-lipoxygenase (5-LOX) pharmacophore that is vicinal to a para-methanesulfonylphenyl cyclooxygenase-2 (COX-2) pharmacophore were designed for evaluation as selective COX-2 and/or 5-LOX inhibitors. The target compounds were synthesized via a highly stereoselective McMurry olefination cross-coupling reaction. This key synthetic step afforded a (Z):(E) olefinic mixture with a predominance for the (Z)-olefin stereoisomer. Structure-activity studies for the (Z)-1-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(4-methanesulfonylphenyl)-1-phenylalk-1-ene regioisomers showed that COX-1 inhibition decreased, COX-2 inhibition increased, and the COX-2 selectivity index (SI) increased as the chain length of the alkyl substituent attached to the olefinic double bond was increased (Et -> n-butyl -> n-heptyl). In this group of compounds, inhibition of both 5-LOX and 15-LOX was dependent upon the length of the alkyl substituent with the hex-1-ene compound 9c having a n-butyl substituent exhibiting potent inhibition of both 5-LOX (IC50 = 0.3 mu M) and 15-LOX (IC50 = 0.8 mu M) relative to the inactive (IC50 > 10 mu M) Et and n-heptyl analogs. Compound 9c is of particular interest since it also exhibits a dual inhibitory activity against the COX (COX-1 IC50 = 3.0 mu M, and COX-2 IC50 = 0.36 mu M, COX-2 SI = 8.3) isozymes. A comparison of the relative inhibitory activities of the two groups of regioisomers investigated shows that the regioisomers in which the alkyl substituent is attached to the same olefinic carbon atom (C-2) as the para-methanesulfonylphenyl moiety generally exhibit a greater potency with respect to COX-2 inhibition. The 4-hydroxy substituent in the 3,5-di-tert-butyl-4-hydroxyphenyl moiety is essential for COX and LOX inhibition since 3,5-di-tert-butyl-4-acetoxyphenyl derivatives were inactive inhibitors. These structure-activity data indicate acyclic triaryl (Z)-olefins constitute a suitable template for the design of dual COX-2/LOX inhibitors. (c) 2006 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2006.03.054
• 作为产物：
  描述：

  茴香硫醚 、 辛酰氯 在 三氯化铝 作用下， 以 氯仿 为溶剂， 反应 1.5h， 以72%的产率得到p-(methylthio)octanophenone
  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

• Methylsulfonyl and Hydroxyl Substituents Induce<i>Z</i>-Stereocontrol in the McMurry Olefination Reaction
  作者：Edward E. Knaus、Md. Jashim Uddin、P. N. Rao

  DOI：10.1055/s-2004-829087

  日期：——

  Aryl ketones possessing methylsulfonyl and hydroxyl substituents, that induce stereocontrol, selectively afford Z-olefins using a Zn-TiCl4 catalyzed McMurry reaction.

  具有甲基磺酰基和羟基取代基的芳基酮，能够引导立体控制，在Zn-TiCl4催化的McMurry反应中选择性地生成Z-烯烃。
• 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.
• A new class of acyclic 2-alkyl-1,2-diaryl (E)-olefins as selective cyclooxygenase-2 (COX-2) inhibitors
  作者：Md. Jashim Uddin、P.N. Praveen Rao、Md. Abdur Rahim、Robert McDonald、Edward E. Knaus

  DOI：10.1016/j.bmcl.2004.07.027

  日期：2004.10

  A new class of (E)-2-alkyl-2-(4-methanesulfonylphenyl)-1-phenylethenes were designed for evaluation as selective cyclooxygense-2 (COX-2) inhibitors. The target olefins were synthesized, via a Takeda olefination reaction, followed by oxidation of the respective thiomethyl olefinic intermediate. In vitro COX-1/COX-2 inhibition studies identified (E)-2-(4-methanesulfonylphenyl)-1-phenyloct-1-ene (8d) as a potent (IC50 = 0.77 muM) and selective (Selectivity Index > 130) COX-2 inhibitor. (C) 2004 Elsevier Ltd. All rights reserved.
• Synthesis and biological evaluation of acyclic triaryl (Z)-olefins possessing a 3,5-di-tert-butyl-4-hydroxyphenyl pharmacophore: Dual inhibitors of cyclooxygenases and lipoxygenases
  作者：Anne Moreau、P.N. Praveen Rao、Edward E. Knaus

  DOI：10.1016/j.bmc.2006.03.054

  日期：2006.8

  A new class of regioisomeric acyclic triaryl (Z)-olefins possessing a 3,5-di-tert-butyl-4-hydroxyphenyl (DTBHP) 5-lipoxygenase (5-LOX) pharmacophore that is vicinal to a para-methanesulfonylphenyl cyclooxygenase-2 (COX-2) pharmacophore were designed for evaluation as selective COX-2 and/or 5-LOX inhibitors. The target compounds were synthesized via a highly stereoselective McMurry olefination cross-coupling reaction. This key synthetic step afforded a (Z):(E) olefinic mixture with a predominance for the (Z)-olefin stereoisomer. Structure-activity studies for the (Z)-1-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(4-methanesulfonylphenyl)-1-phenylalk-1-ene regioisomers showed that COX-1 inhibition decreased, COX-2 inhibition increased, and the COX-2 selectivity index (SI) increased as the chain length of the alkyl substituent attached to the olefinic double bond was increased (Et -> n-butyl -> n-heptyl). In this group of compounds, inhibition of both 5-LOX and 15-LOX was dependent upon the length of the alkyl substituent with the hex-1-ene compound 9c having a n-butyl substituent exhibiting potent inhibition of both 5-LOX (IC50 = 0.3 mu M) and 15-LOX (IC50 = 0.8 mu M) relative to the inactive (IC50 > 10 mu M) Et and n-heptyl analogs. Compound 9c is of particular interest since it also exhibits a dual inhibitory activity against the COX (COX-1 IC50 = 3.0 mu M, and COX-2 IC50 = 0.36 mu M, COX-2 SI = 8.3) isozymes. A comparison of the relative inhibitory activities of the two groups of regioisomers investigated shows that the regioisomers in which the alkyl substituent is attached to the same olefinic carbon atom (C-2) as the para-methanesulfonylphenyl moiety generally exhibit a greater potency with respect to COX-2 inhibition. The 4-hydroxy substituent in the 3,5-di-tert-butyl-4-hydroxyphenyl moiety is essential for COX and LOX inhibition since 3,5-di-tert-butyl-4-acetoxyphenyl derivatives were inactive inhibitors. These structure-activity data indicate acyclic triaryl (Z)-olefins constitute a suitable template for the design of dual COX-2/LOX inhibitors. (c) 2006 Elsevier Ltd. All rights reserved.