N1,N6-bis[(1S)-2-Methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-bis[4-(2-phenylethyl)benzyloxy]-3,4-dihydroxyhexanediamide

• 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: N1,N6-bis[(1S)-2-Methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-bis[4-(2-phenylethyl)benzyloxy]-3,4-dihydroxyhexanediamide
• 英文别名: (2R,3R,4R,5R)-3,4-dihydroxy-N,N'-bis[(2S)-3-methyl-1-(methylamino)-1-oxobutan-2-yl]-2,5-bis[[4-(2-phenylethyl)phenyl]methoxy]hexanediamide
• 化学式: C₄₈H₆₂N₄O₈
• 分子量: 823.042
• InChiKey: WSIGESKMDUMSIL-LVFDAWRISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.3
• 重原子数：
  60
• 可旋转键数：
  23
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  175
• 氢给体数：
  6
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  4-bromobenzyl 2,2,2-trichloroacetimidate 在 9-borabicyclo[3.3.1]nonane dimer 、 三氟甲磺酸 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 1,2-二氯乙烷 为溶剂， 反应 54.03h， 生成 N1,N6-bis[(1S)-2-Methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-bis[4-(2-phenylethyl)benzyloxy]-3,4-dihydroxyhexanediamide
  参考文献：
  名称：

  Design and Fast Synthesis of C-Terminal Duplicated Potent C₂-Symmetric P1/P1‘-Modified HIV-1 Protease Inhibitors

  摘要：

  tin analysis of the X-ray structure of a complex of HIV-1 protease with a linear C-2-symmetric C-terminal duplicated inhibitor guided the selection of a series of diverse target compounds. These were synthesized with the objective to identify suitable P1/P1' substituents to provide inhibitors with improved antiviral activity. Groups with various physical properties were attached to the para-positions of the P1/P1' benzyloxy groups in the parent inhibitor. A p-bromobenzyloxy compound, prepared in only three steps from commercially available starting materials, was utilized as a common precursor in all reactions. The subsequent coupling reactions were completed within a few minutes and relied on palladium catalysis and flash heating with microwave irradiation. All of the compounds synthesized exhibited good inhibitory potency in the protease assay, with K-i values ranging from 0.09 to 3.8 nM. A 30-fold improvement of the antiviral effect in cell culture, compared to the parent compound, was achieved with four of the inhibitors. The differences in K-i values were not correlated to the differences in antiviral effect, efficiency against mutant virus, or reduced potency in the presence of human serum. The poorest enzyme inhibitors in fact belong to the group with the best antiviral effect. The binding features of two structurally related inhibitors, cocrystallized with HIV-1 protease, are discussed with special emphasis on the interaction at the enzyme/water phase.

  DOI：

  10.1021/jm9910371

文献信息

• Design and Fast Synthesis of C-Terminal Duplicated Potent <i>C</i>₂-Symmetric P1/P1‘-Modified HIV-1 Protease Inhibitors
  作者：Mathias Alterman、Hans O. Andersson、Neeraj Garg、Göran Ahlsén、Seved Lövgren、Björn Classon、U. Helena Danielson、Ingmar Kvarnström、Lotta Vrang、Torsten Unge、Bertil Samuelsson、Anders Hallberg

  DOI：10.1021/jm9910371

  日期：1999.9.1

  tin analysis of the X-ray structure of a complex of HIV-1 protease with a linear C-2-symmetric C-terminal duplicated inhibitor guided the selection of a series of diverse target compounds. These were synthesized with the objective to identify suitable P1/P1' substituents to provide inhibitors with improved antiviral activity. Groups with various physical properties were attached to the para-positions of the P1/P1' benzyloxy groups in the parent inhibitor. A p-bromobenzyloxy compound, prepared in only three steps from commercially available starting materials, was utilized as a common precursor in all reactions. The subsequent coupling reactions were completed within a few minutes and relied on palladium catalysis and flash heating with microwave irradiation. All of the compounds synthesized exhibited good inhibitory potency in the protease assay, with K-i values ranging from 0.09 to 3.8 nM. A 30-fold improvement of the antiviral effect in cell culture, compared to the parent compound, was achieved with four of the inhibitors. The differences in K-i values were not correlated to the differences in antiviral effect, efficiency against mutant virus, or reduced potency in the presence of human serum. The poorest enzyme inhibitors in fact belong to the group with the best antiviral effect. The binding features of two structurally related inhibitors, cocrystallized with HIV-1 protease, are discussed with special emphasis on the interaction at the enzyme/water phase.