3-[N-[2-benzoyl-4-(N^α-tert-butyloxycarbonyl-S-tritylcysteinylamino)phenyl]carbamoyl]propionic acid methyl ester | 265648-50-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 三苯基化合物
• 英文名称: 3-[N-[2-benzoyl-4-(N^α-tert-butyloxycarbonyl-S-tritylcysteinylamino)phenyl]carbamoyl]propionic acid methyl ester
• 英文别名: methyl 4-[2-benzoyl-4-[[(2R)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-tritylsulfanylpropanoyl]amino]anilino]-4-oxobutanoate
• CAS: 265648-50-8
• 化学式: C₄₅H₄₅N₃O₇S
• 分子量: 771.934
• InChiKey: FKCSYQNGWYRLFD-LHEWISCISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8
• 重原子数：
  56
• 可旋转键数：
  18
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  165
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  3-[N-[2-benzoyl-4-(N^α-tert-butyloxycarbonyl-S-tritylcysteinylamino)phenyl]carbamoyl]propionic acid methyl ester 在 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 12.0h， 以66%的产率得到3-[N-[2-benzoyl-4-(N^α-tert-butyloxycarbonyl-S-tritylcysteinylamino)phenyl]carbamoyl]propionic acid
  参考文献：
  名称：

  Synthesis, Molecular Modeling, and Structure−Activity Relationship of Benzophenone-Based CAAX-Peptidomimetic Farnesyltransferase Inhibitors

  摘要：

  Because of the involvement of farnesylated proteins in oncogenesis, inhibition of the protein-modifying enzyme farnesyltransferase is considered a major emerging strategy in cancer therapy. Here, we describe the structure-activity relationship of a novel class of CAAX-peptidomimetic farnesyltransferase inhibitors based on the benzophenone scaffold. 4 ' -Methyl, 4 ' -chloro, 4 ' -bromo, and 4 ' -nitrophenylacetic acid as substituents at the 2-amino group of the benzophenone core structure yield farnesyltransferase inhibitors active in the nanomolar range. Using diphenylacetic acid in this position further improves activity. SEAL superimposition of inhibitor 12a to the enzyme-bound conformation of a CAAX-peptide shows a markedly good resemblance of the molecular properties of the peptide. FlexX docking of 12a confirms the good fit of the molecule into the peptide binding site of farnesyltransferase. The novel benzophenone-based AAX-peptidomimetic substructure described here will be useful for the design of some novel types of farnesyltransferase inhibitors.

  DOI：

  10.1021/jm010872r
• 作为产物：
  描述：

  丁二酸单甲酯酰氯 在 tin(ll) chloride 作用下， 以 乙酸乙酯 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 6.0h， 生成 3-[N-[2-benzoyl-4-(N^α-tert-butyloxycarbonyl-S-tritylcysteinylamino)phenyl]carbamoyl]propionic acid methyl ester
  参考文献：
  名称：

  Synthesis, Molecular Modeling, and Structure−Activity Relationship of Benzophenone-Based CAAX-Peptidomimetic Farnesyltransferase Inhibitors

  摘要：

  Because of the involvement of farnesylated proteins in oncogenesis, inhibition of the protein-modifying enzyme farnesyltransferase is considered a major emerging strategy in cancer therapy. Here, we describe the structure-activity relationship of a novel class of CAAX-peptidomimetic farnesyltransferase inhibitors based on the benzophenone scaffold. 4 ' -Methyl, 4 ' -chloro, 4 ' -bromo, and 4 ' -nitrophenylacetic acid as substituents at the 2-amino group of the benzophenone core structure yield farnesyltransferase inhibitors active in the nanomolar range. Using diphenylacetic acid in this position further improves activity. SEAL superimposition of inhibitor 12a to the enzyme-bound conformation of a CAAX-peptide shows a markedly good resemblance of the molecular properties of the peptide. FlexX docking of 12a confirms the good fit of the molecule into the peptide binding site of farnesyltransferase. The novel benzophenone-based AAX-peptidomimetic substructure described here will be useful for the design of some novel types of farnesyltransferase inhibitors.

  DOI：

  10.1021/jm010872r

文献信息

• Synthesis, Molecular Modeling, and Structure−Activity Relationship of Benzophenone-Based CAAX-Peptidomimetic Farnesyltransferase Inhibitors
  作者：Jacek Sakowski、Markus Böhm、Isabel Sattler、Hans-Martin Dahse、Martin Schlitzer

  DOI：10.1021/jm010872r

  日期：2001.8.1

  Because of the involvement of farnesylated proteins in oncogenesis, inhibition of the protein-modifying enzyme farnesyltransferase is considered a major emerging strategy in cancer therapy. Here, we describe the structure-activity relationship of a novel class of CAAX-peptidomimetic farnesyltransferase inhibitors based on the benzophenone scaffold. 4 ' -Methyl, 4 ' -chloro, 4 ' -bromo, and 4 ' -nitrophenylacetic acid as substituents at the 2-amino group of the benzophenone core structure yield farnesyltransferase inhibitors active in the nanomolar range. Using diphenylacetic acid in this position further improves activity. SEAL superimposition of inhibitor 12a to the enzyme-bound conformation of a CAAX-peptide shows a markedly good resemblance of the molecular properties of the peptide. FlexX docking of 12a confirms the good fit of the molecule into the peptide binding site of farnesyltransferase. The novel benzophenone-based AAX-peptidomimetic substructure described here will be useful for the design of some novel types of farnesyltransferase inhibitors.