diphenyl 1-[(N-benzyloxycarbonyl-O-tert-butyl-D-seryl)-L-alanyl]amino-2-(4-(N,N'-bis(tert-butyloxycarbonyl)guanidino)phenyl)ethanephosphonate | 695172-16-8

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: diphenyl 1-[(N-benzyloxycarbonyl-O-tert-butyl-D-seryl)-L-alanyl]amino-2-(4-(N,N'-bis(tert-butyloxycarbonyl)guanidino)phenyl)ethanephosphonate
• CAS: 695172-16-8
• 化学式: C₄₉H₆₃N₆O₁₂P
• 分子量: 959.046
• InChiKey: GWJDCWKDBDSLOR-JHHOSHMASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.87
• 重原子数：
  68.0
• 可旋转键数：
  17.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  230.31
• 氢给体数：
  5.0
• 氢受体数：
  12.0

反应信息

• 作为反应物：
  描述：

  diphenyl 1-[(N-benzyloxycarbonyl-O-tert-butyl-D-seryl)-L-alanyl]amino-2-(4-(N,N'-bis(tert-butyloxycarbonyl)guanidino)phenyl)ethanephosphonate 、 三氟乙酸 以 二氯甲烷 为溶剂， 反应 3.0h， 以85%的产率得到diphenyl 1-[(N-benzyloxycarbonyl-D-seryl)-L-alanyl]amino-2-(4-guanidinophenyl)ethanephosphonate trifluoroacetate
  参考文献：
  名称：

  Diphenyl Phosphonate Inhibitors for the Urokinase-Type Plasminogen Activator:  Optimization of the P4 Position

  摘要：

  This paper describes the structure-activity relationship in a series of tripeptidyl diphenyl phosphonate irreversible urokinase plasminogen activator (uPA) inhibitors, originally derived from an arginyltripeptide. uPA is considered an interesting target in anticancer drug design. The selectivity of these inhibitors for uPA is enhanced by the optimization of the P4 position. The most interesting compound shows an IC50 of 5 nM, with a selectivity index of more than 3000 toward other Arg/Lys-specific proteases such as tissue-type plasminogen activator, plasmin, factor Xa, and thrombin. A synthetic strategy for the preparation of small libraries of diphenyl phosphonate analogues of capped tripeptides is described. It is shown that uPA is irreversibly inhibited, and interactions with the active site were modeled. Finally, a diparacetamol phosphonate analogue was developed to circumvent the release of cytotoxic phenol.

  DOI：

  10.1021/jm060622g
• 作为产物：
  描述：

  4-氨基苯乙醇 在 palladium on activated charcoal PS-carbodiimide 、 氢气 、 copper(II) bis(trifluoromethanesulfonate) 、 1-羟基苯并三唑 、 戴斯-马丁氧化剂 、 三乙胺 、 三氟乙酸 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 乙腈 为溶剂， 反应 18.17h， 生成 diphenyl 1-[(N-benzyloxycarbonyl-O-tert-butyl-D-seryl)-L-alanyl]amino-2-(4-(N,N'-bis(tert-butyloxycarbonyl)guanidino)phenyl)ethanephosphonate
  参考文献：
  名称：

  Diphenyl Phosphonate Inhibitors for the Urokinase-Type Plasminogen Activator:  Optimization of the P4 Position

  摘要：

  This paper describes the structure-activity relationship in a series of tripeptidyl diphenyl phosphonate irreversible urokinase plasminogen activator (uPA) inhibitors, originally derived from an arginyltripeptide. uPA is considered an interesting target in anticancer drug design. The selectivity of these inhibitors for uPA is enhanced by the optimization of the P4 position. The most interesting compound shows an IC50 of 5 nM, with a selectivity index of more than 3000 toward other Arg/Lys-specific proteases such as tissue-type plasminogen activator, plasmin, factor Xa, and thrombin. A synthetic strategy for the preparation of small libraries of diphenyl phosphonate analogues of capped tripeptides is described. It is shown that uPA is irreversibly inhibited, and interactions with the active site were modeled. Finally, a diparacetamol phosphonate analogue was developed to circumvent the release of cytotoxic phenol.

  DOI：

  10.1021/jm060622g

文献信息

• Development of Irreversible Diphenyl Phosphonate Inhibitors for Urokinase Plasminogen Activator
  作者：J. Joossens、P. Van der Veken、A.-M. Lambeir、K. Augustyns、A. Haemers

  DOI：10.1021/jm0499209

  日期：2004.5.1

  In this letter we report the synthesis and biochemical evaluation of selective, irreversible diphenyl phosphonate inhibitors for urokinase plasminogen activator (uPA). A diphenyl phosphonate group was introduced on the substratelike peptide Z-D-Ser-Ala-Arg, and modification of the guanidine side chain was investigated. A guanylated benzyl group appeared the most promising side chain modification. A k(app) value in the 10(3) M-1 s(-1) range for uPA was obtained, together with a selectivity index higher than 240 toward other trypsin-like proteases such as tPA, thrombin, plasmin, and FXa.