benzyl (3S,5S,6R)-3-[4-(bis((tert-butyl)oxycarbonyl)fluoromethyl)phenylmethyl]-(-)-6-oxo-5,6-diphenyl-4-morpholine-carboxylate | 264131-61-5

• 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: benzyl (3S,5S,6R)-3-[4-(bis((tert-butyl)oxycarbonyl)fluoromethyl)phenylmethyl]-(-)-6-oxo-5,6-diphenyl-4-morpholine-carboxylate
• 英文别名: ditert-butyl 2-fluoro-2-[4-[[(3S,5S,6R)-2-oxo-5,6-diphenyl-4-phenylmethoxycarbonylmorpholin-3-yl]methyl]phenyl]propanedioate
• CAS: 264131-61-5
• 化学式: C₄₂H₄₄FNO₈
• 分子量: 709.812
• InChiKey: CJHHIKQPEKLOCF-PUPDPRJKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.5
• 重原子数：
  52
• 可旋转键数：
  14
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  108
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  benzyl (3S,5S,6R)-3-[4-(bis((tert-butyl)oxycarbonyl)fluoromethyl)phenylmethyl]-(-)-6-oxo-5,6-diphenyl-4-morpholine-carboxylate 在 钯 氢气 、 溶剂黄146 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醇 、 水 为溶剂， 20.0 ℃ 、310.27 kPa 条件下， 反应 5.0h， 生成 N^α-Fmoc-4-(bis((tert-butyl)oxycarbonyl)fluoromethyl)-L-phenylalanine
  参考文献：
  名称：

  Inhibition of Grb2 SH2 Domain Binding by Non-Phosphate-Containing Ligands. 2. 4-(2-Malonyl)phenylalanine as a Potent Phosphotyrosyl Mimetic

  摘要：

  Nonhydrolyzable phosphotyrosyl (pTyr) mimetics serve as important components of many competitive Grb2 SH2 domain inhibitors. To date, the most potent of these inhibitors have relied on phosphonate-based structures to replace the 4-phosphoryl group of the parent pTyr residue. Reported herein is the design and evaluation of a new pTyr mimetic, p-malonylphenylalanine (Pmf), which does not contain phosphorus yet, in Grb2 SH2 domain binding systems, approaches the potency of phosphonate-based pTyr mimetics. When incorporated into high affinity Grb2 SH2 domain-directed platforms, Pmf is 15-20 times more potent than the closely related previously reported pTyr mimetic, O-malonyltyrosine (OMT). Pmf-containing inhibitors show inhibition constants as low as 8 nM in extracellular Grb2 binding assays and in whole cell systems, effective blockade of both endogenous Grb2 binding to cognate erbB-2, and downstream MAP kinase activation. Evidence is provided that use of an N-alpha-oxalyl auxiliary enhances effectiveness of Pmf and other inhibitors in both extracellular and intracellular contexts. As one of the most potent Grb2 SH2 domain-directed pTyr mimetics yet disclosed, Pmf may potentially have utility in the design of new chemotherapeutics for the treatment of various proliferative diseases, including breast cancer.

  DOI：

  10.1021/jm9904248
• 作为产物：
  描述：

  Benzyl (3S,5S,6R)-3-((((4-bis(tert-butyl)oxacarbonyl)methyl)phenyl)methyl)-6-oxo-5,6-diphenyl-4-morpholinecarboxylate 在 sodium hydride 、 N-氟苯磺酰胺 作用下， 以 四氢呋喃 为溶剂， 反应 1.0h， 以92%的产率得到benzyl (3S,5S,6R)-3-[4-(bis((tert-butyl)oxycarbonyl)fluoromethyl)phenylmethyl]-(-)-6-oxo-5,6-diphenyl-4-morpholine-carboxylate
  参考文献：
  名称：

  Inhibition of Grb2 SH2 Domain Binding by Non-Phosphate-Containing Ligands. 2. 4-(2-Malonyl)phenylalanine as a Potent Phosphotyrosyl Mimetic

  摘要：

  Nonhydrolyzable phosphotyrosyl (pTyr) mimetics serve as important components of many competitive Grb2 SH2 domain inhibitors. To date, the most potent of these inhibitors have relied on phosphonate-based structures to replace the 4-phosphoryl group of the parent pTyr residue. Reported herein is the design and evaluation of a new pTyr mimetic, p-malonylphenylalanine (Pmf), which does not contain phosphorus yet, in Grb2 SH2 domain binding systems, approaches the potency of phosphonate-based pTyr mimetics. When incorporated into high affinity Grb2 SH2 domain-directed platforms, Pmf is 15-20 times more potent than the closely related previously reported pTyr mimetic, O-malonyltyrosine (OMT). Pmf-containing inhibitors show inhibition constants as low as 8 nM in extracellular Grb2 binding assays and in whole cell systems, effective blockade of both endogenous Grb2 binding to cognate erbB-2, and downstream MAP kinase activation. Evidence is provided that use of an N-alpha-oxalyl auxiliary enhances effectiveness of Pmf and other inhibitors in both extracellular and intracellular contexts. As one of the most potent Grb2 SH2 domain-directed pTyr mimetics yet disclosed, Pmf may potentially have utility in the design of new chemotherapeutics for the treatment of various proliferative diseases, including breast cancer.

  DOI：

  10.1021/jm9904248