4-(1-methyl-3-phenyl-ureido)-3-nitro-benzenesulfonamide | 921195-77-9

• 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: 4-(1-methyl-3-phenyl-ureido)-3-nitro-benzenesulfonamide
• 英文别名: 4-[Methyl(phenylcarbamoyl)amino]-3-nitrobenzene-1-sulfonamide；1-methyl-1-(2-nitro-4-sulfamoylphenyl)-3-phenylurea
• CAS: 921195-77-9
• 化学式: C₁₄H₁₄N₄O₅S
• 分子量: 350.355
• InChiKey: OQPCRPGWMJGDMQ-UHFFFAOYSA-N

物化性质

• 密度：
  1.528±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  147
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-(1-methyl-3-phenyl-ureido)-3-nitro-benzenesulfonamide 、 4-[4-(3,3-二苯基丙-2-烯基)哌嗪-1-基]苯甲酸 在 4-二甲氨基吡啶 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 以87%的产率得到N-{4-[4-(3,3-diphenyl-allyl)-piperazin-1-yl]-benzoyl}-4-(1-methyl-3-phenylureido)-3-nitro-benzenesulfonamide
  参考文献：
  名称：

  Design, Synthesis, and Computational Studies of Inhibitors of Bcl-X_L

  摘要：

  One of the primary objectives in the design of protein inhibitors is to shape the three-dimensional structures of small molecules to be complementary to the binding site of a target protein. In the course of our efforts to discover potent inhibitors of Bcl-2 family proteins, we found a unique folded conformation adopted by tethered aromatic groups in the ligand that significantly enhanced binding affinity to Bcl-X-L. This finding led us to design compounds that were biased by nonbonding interactions present in a urea tether to adopt this bioactive, folded motif. To characterize the key interactions that induce the desired conformational bias, a series of substituted N,N'-diarylureas were prepared and analyzed using X-ray crystallography and quantum mechanical calculations. Stabilizing pi-stacking interactions and destabilizing steric interactions were predicted to work in concert in two of the substitution patterns to promote the bioactive conformation as a global energy minimum and result in a high target binding affinity. Conversely, intramolecular hydrogen bonding present in the third substitution motif promotes a less active, extended conformer as the energetically favored geometry. These findings were corroborated when the inhibition constant of binding to Bcl-X-L was determined for fully elaborated analogues bearing these structural motifs. Finally, we obtained the NMR solution structure of the disubstituted N,N'-diarylurea bound to Bcl-X-L demonstrating the folded conformation of the urea motif engaged in extensive pi-interactions with the protein.

  DOI：

  10.1021/ja0650347
• 作为产物：
  描述：

  N,N-bis-(2,4-dimethoxy-benzyl)-4-methylamino-3-nitro-benzenesulfonamide 在 三乙基硅烷 、 PS-DIEA(R) 、 三氟乙酸 作用下， 以 二氯甲烷 、 甲苯 为溶剂， 反应 26.0h， 生成 4-(1-methyl-3-phenyl-ureido)-3-nitro-benzenesulfonamide
  参考文献：
  名称：

  Design, Synthesis, and Computational Studies of Inhibitors of Bcl-X_L

  摘要：

  One of the primary objectives in the design of protein inhibitors is to shape the three-dimensional structures of small molecules to be complementary to the binding site of a target protein. In the course of our efforts to discover potent inhibitors of Bcl-2 family proteins, we found a unique folded conformation adopted by tethered aromatic groups in the ligand that significantly enhanced binding affinity to Bcl-X-L. This finding led us to design compounds that were biased by nonbonding interactions present in a urea tether to adopt this bioactive, folded motif. To characterize the key interactions that induce the desired conformational bias, a series of substituted N,N'-diarylureas were prepared and analyzed using X-ray crystallography and quantum mechanical calculations. Stabilizing pi-stacking interactions and destabilizing steric interactions were predicted to work in concert in two of the substitution patterns to promote the bioactive conformation as a global energy minimum and result in a high target binding affinity. Conversely, intramolecular hydrogen bonding present in the third substitution motif promotes a less active, extended conformer as the energetically favored geometry. These findings were corroborated when the inhibition constant of binding to Bcl-X-L was determined for fully elaborated analogues bearing these structural motifs. Finally, we obtained the NMR solution structure of the disubstituted N,N'-diarylurea bound to Bcl-X-L demonstrating the folded conformation of the urea motif engaged in extensive pi-interactions with the protein.

  DOI：

  10.1021/ja0650347