(1SR,2RS,4SR)-tetrahydrofuran-2-carboxylic acid (1-(3-bromobenzyl)-6-(2,4-dichlorophenyl)-4-(4-fluorophenylsulfanyl)-2-hydroxyhexyl)amide

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二芳基庚烷
• 英文名称: (1SR,2RS,4SR)-tetrahydrofuran-2-carboxylic acid (1-(3-bromobenzyl)-6-(2,4-dichlorophenyl)-4-(4-fluorophenylsulfanyl)-2-hydroxyhexyl)amide
• 英文别名: (2R)-N-[1-(3-bromophenyl)-7-(2,4-dichlorophenyl)-5-(4-fluorophenyl)sulfanyl-3-hydroxyheptan-2-yl]oxolane-2-carboxamide
• 化学式: C₃₀H₃₁BrCl₂FNO₃S
• 分子量: 655.455
• InChiKey: RSGSWWLIEMUMMS-JXOQWRPTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.3
• 重原子数：
  39
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  83.9
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (1SR,2RS,4SR)-tetrahydrofuran-2-carboxylic acid (1-(3-bromobenzyl)-6-(2,4-dichlorophenyl)-4-(4-fluorophenylsulfanyl)-2-hydroxyhexyl)amide 在 间氯过氧苯甲酸 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 生成 (2R)-N-[(1R,2S,4R)-1-[(3-bromophenyl)methyl]-6-(2,4-dichlorophenyl)-4-(4-fluorophenyl)sulfonyl-2-hydroxy-hexyl]tetrahydrofuran-2-carboxamide 、 (2R)-N-[(1S,2R,4S)-1-[(3-bromophenyl)methyl]-6-(2,4-dichlorophenyl)-4-(4-fluorophenyl)sulfonyl-2-hydroxy-hexyl]tetrahydrofuran-2-carboxamide
  参考文献：
  名称：

  Hydroxyethylene Sulfones as a New Scaffold To Address Aspartic Proteases:  Design, Synthesis, and Structural Characterization

  摘要：

  Hydroxyethylene sulfones were developed as novel scaffolds against aspartyl proteases. A diastereoselective synthesis has been established to introduce the required side chain decoration with desired stereochemistry. Depending on the substitution of the hydroxyethylene-sulfone core, micro- to submicromolar inhibition of HIV-1 protease is achieved for the S-configuration at P, and R-configuration at the hydroxy-group-bearing backbone atom. This stereochemical preference is consistent with the S,R configuration of amprenavir. The racemic mixture of the most potent derivative (K-i = 80 nM) was separated by chiral HPLC, revealing the S,R,S-enantiomer to be more active (K-i = 45 nM). Docking studies suggested this isomer as the more active one. The subsequently determined crystal structure with HIV-1 protease, cocrystallized from a racemic mixture, exclusively reveals the S,R,S-enantiomer accommodated to the binding pocket. The transition state mimicking hydroxy group of the inhibitor is centered between both catalytic aspartates, while either its carbonyl or sulfonyl group forms H-bonds to the structurally conserved water mediating interactions between ligand and Ile50NH/Ile50NH' of both flaps. Biological testing of the stereoisomeric hydroxyethylene sulfones against cathepsin D and beta-secretase did not reveal significant inhibition. Most likely, the latter proteases require inverted configuration at the hydroxy group.

  DOI：

  10.1021/jm050224y
• 作为产物：
  描述：

  3-溴苄溴 在 盐酸 、 barium dihydroxide 、 草酰氯 、 三丁基硼 、 sodium ethanolate 、 sodium hydride 、 碳酸氢钠 、 1-羟基苯并三唑 、 二甲基亚砜 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 三乙胺 、 lithium diisopropyl amide 、 氯甲酸异丁酯 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醇 、 二氯甲烷 为溶剂， 反应 38.0h， 生成 (1SR,2RS,4SR)-tetrahydrofuran-2-carboxylic acid (1-(3-bromobenzyl)-6-(2,4-dichlorophenyl)-4-(4-fluorophenylsulfanyl)-2-hydroxyhexyl)amide
  参考文献：
  名称：

  Hydroxyethylene Sulfones as a New Scaffold To Address Aspartic Proteases:  Design, Synthesis, and Structural Characterization

  摘要：

  Hydroxyethylene sulfones were developed as novel scaffolds against aspartyl proteases. A diastereoselective synthesis has been established to introduce the required side chain decoration with desired stereochemistry. Depending on the substitution of the hydroxyethylene-sulfone core, micro- to submicromolar inhibition of HIV-1 protease is achieved for the S-configuration at P, and R-configuration at the hydroxy-group-bearing backbone atom. This stereochemical preference is consistent with the S,R configuration of amprenavir. The racemic mixture of the most potent derivative (K-i = 80 nM) was separated by chiral HPLC, revealing the S,R,S-enantiomer to be more active (K-i = 45 nM). Docking studies suggested this isomer as the more active one. The subsequently determined crystal structure with HIV-1 protease, cocrystallized from a racemic mixture, exclusively reveals the S,R,S-enantiomer accommodated to the binding pocket. The transition state mimicking hydroxy group of the inhibitor is centered between both catalytic aspartates, while either its carbonyl or sulfonyl group forms H-bonds to the structurally conserved water mediating interactions between ligand and Ile50NH/Ile50NH' of both flaps. Biological testing of the stereoisomeric hydroxyethylene sulfones against cathepsin D and beta-secretase did not reveal significant inhibition. Most likely, the latter proteases require inverted configuration at the hydroxy group.

  DOI：

  10.1021/jm050224y

文献信息

• Hydroxyethylene Sulfones as a New Scaffold To Address Aspartic Proteases:  Design, Synthesis, and Structural Characterization
  作者：Edgar Specker、Jark Böttcher、Andreas Heine、Christoph A. Sotriffer、Hauke Lilie、Andreas Schoop、Gerhard Müller、Nils Griebenow、Gerhard Klebe

  DOI：10.1021/jm050224y

  日期：2005.10.1

  Hydroxyethylene sulfones were developed as novel scaffolds against aspartyl proteases. A diastereoselective synthesis has been established to introduce the required side chain decoration with desired stereochemistry. Depending on the substitution of the hydroxyethylene-sulfone core, micro- to submicromolar inhibition of HIV-1 protease is achieved for the S-configuration at P, and R-configuration at the hydroxy-group-bearing backbone atom. This stereochemical preference is consistent with the S,R configuration of amprenavir. The racemic mixture of the most potent derivative (K-i = 80 nM) was separated by chiral HPLC, revealing the S,R,S-enantiomer to be more active (K-i = 45 nM). Docking studies suggested this isomer as the more active one. The subsequently determined crystal structure with HIV-1 protease, cocrystallized from a racemic mixture, exclusively reveals the S,R,S-enantiomer accommodated to the binding pocket. The transition state mimicking hydroxy group of the inhibitor is centered between both catalytic aspartates, while either its carbonyl or sulfonyl group forms H-bonds to the structurally conserved water mediating interactions between ligand and Ile50NH/Ile50NH' of both flaps. Biological testing of the stereoisomeric hydroxyethylene sulfones against cathepsin D and beta-secretase did not reveal significant inhibition. Most likely, the latter proteases require inverted configuration at the hydroxy group.