(3S,4S)-3,4-bis-(4-bromobenzenesulfonylamino)pyrrolidine-1-carboxylic acid t-butyl ester | 1323886-51-6

• 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: (3S,4S)-3,4-bis-(4-bromobenzenesulfonylamino)pyrrolidine-1-carboxylic acid t-butyl ester
• CAS: 1323886-51-6
• 化学式: C₂₁H₂₅Br₂N₃O₆S₂
• 分子量: 639.386
• InChiKey: AHEUFDSTBZHCIY-OALUTQOASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.46
• 重原子数：
  34.0
• 可旋转键数：
  6.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  121.88
• 氢给体数：
  2.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  (3S,4S)-3,4-bis-(4-bromobenzenesulfonylamino)pyrrolidine-1-carboxylic acid t-butyl ester 在 四(三苯基膦)钯 、 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 12.5h， 生成 (3S,4S)-3,4-bis-[(4-cyanobenzenesulfonyl)-(3-methyl-but-2-enyl)-amino]pyrrolidinium trifluoroacetate
  参考文献：
  名称：

  Two Solutions for the Same Problem: Multiple Binding Modes of Pyrrolidine-Based HIV-1 Protease Inhibitors

  摘要：

  Structure-based drug design is an integral part of industrial and academic drug discovery projects. Initial lead structures are, in general, optimized in terms of affinity using iterative cycles comprising synthesis, biological evaluation, computational methods, and structural analysis. X-ray crystallography commonly suggests the existence of a single well-defined state, termed binding mode, which is generally assumed to be consistent in a series of similar ligands and therefore used for the following optimization process. During the further development of symmetrically disubstituted 3,4-amino-pyrrolidines as human immunodeficiency virus type 1 protease inhibitors, we discovered that, by modification of the P1/P1' moieties of our lead structure, the activity of the inhibitors towards the active-site mutation 1le84Val was altered, however, not being explainable with the initial underlying structure activity relationship. The cocrystallization of the most potent derivative in complex with the human immunodeficiency virus type 1 protease surprisingly led to two different crystal forms (P2(1)2(1)2(1) and P6(1)22). Structural analysis revealed two completely different binding modes; the interaction of the pyrrolidine nitrogen atom with the catalytic aspartates remains as the only similarity. The study presented clearly demonstrates that structural biology has to escort the entire lead optimization process not to fail by an initially observed binding orientation. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.jmb.2011.04.052
• 作为产物：
  描述：

  (3S,4S)-1-tert-butoxycarbonyl-3,4-diaminopyrrolidine 、 4-溴苯磺酰氯 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 12.0h， 以65%的产率得到(3S,4S)-3,4-bis-(4-bromobenzenesulfonylamino)pyrrolidine-1-carboxylic acid t-butyl ester
  参考文献：
  名称：

  Two Solutions for the Same Problem: Multiple Binding Modes of Pyrrolidine-Based HIV-1 Protease Inhibitors

  摘要：

  Structure-based drug design is an integral part of industrial and academic drug discovery projects. Initial lead structures are, in general, optimized in terms of affinity using iterative cycles comprising synthesis, biological evaluation, computational methods, and structural analysis. X-ray crystallography commonly suggests the existence of a single well-defined state, termed binding mode, which is generally assumed to be consistent in a series of similar ligands and therefore used for the following optimization process. During the further development of symmetrically disubstituted 3,4-amino-pyrrolidines as human immunodeficiency virus type 1 protease inhibitors, we discovered that, by modification of the P1/P1' moieties of our lead structure, the activity of the inhibitors towards the active-site mutation 1le84Val was altered, however, not being explainable with the initial underlying structure activity relationship. The cocrystallization of the most potent derivative in complex with the human immunodeficiency virus type 1 protease surprisingly led to two different crystal forms (P2(1)2(1)2(1) and P6(1)22). Structural analysis revealed two completely different binding modes; the interaction of the pyrrolidine nitrogen atom with the catalytic aspartates remains as the only similarity. The study presented clearly demonstrates that structural biology has to escort the entire lead optimization process not to fail by an initially observed binding orientation. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.jmb.2011.04.052