rac-(1S,2R,4S)-N-(1-(3-bromobenzyl)-4-(4-fluorophenylsulfonyl)-2-hydroxy-6-methylheptyl)-2-(2,6-dimethylphenoxy)acetamide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: rac-(1S,2R,4S)-N-(1-(3-bromobenzyl)-4-(4-fluorophenylsulfonyl)-2-hydroxy-6-methylheptyl)-2-(2,6-dimethylphenoxy)acetamide
• 英文别名: N-[(2R,3S,5R)-1-(3-bromophenyl)-5-(4-fluorophenyl)sulfonyl-3-hydroxy-7-methyloctan-2-yl]-2-(2,6-dimethylphenoxy)acetamide
• 化学式: C₃₁H₃₇BrFNO₅S
• 分子量: 634.607
• InChiKey: RVHWPGAHEOLZNT-NLDZOOGBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.2
• 重原子数：
  40
• 可旋转键数：
  13
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  101
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  rac-(1S,2R,4S)-N-(1-(3-bromobenzyl)-4-(4-fluorophenylsulfonyl)-2-hydroxy-6-methylheptyl)-2-(2,6-dimethylphenoxy)acetamide 、 甲胺 以 四氢呋喃 为溶剂， 160.0 ℃ 、200.0 kPa 条件下， 反应 5.0h， 以87%的产率得到rac-(1S,2R,4S)-N-(1-(3-bromobenzyl)-2-hydroxy-6-methyl-4-(methylaminobenzenesulfonyl)heptyl)-2-(2,6-dimethylphenoxy)acetamide
  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 、 间氯过氧苯甲酸 、 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 40.0h， 生成 rac-(1S,2R,4S)-N-(1-(3-bromobenzyl)-4-(4-fluorophenylsulfonyl)-2-hydroxy-6-methylheptyl)-2-(2,6-dimethylphenoxy)acetamide
  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.