4-((E)-4-((S)-1-((S)-2-((R)-5-amino-5-oxopentan-2-ylcarbamoyl)pyrrolidin-1-yl)-4-methyl-1-oxopentan-2-ylamino)-4-oxobut-2-en-2-yl)phenyl dihydrogen phosphate | 1304101-08-3

• 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: 4-((E)-4-((S)-1-((S)-2-((R)-5-amino-5-oxopentan-2-ylcarbamoyl)pyrrolidin-1-yl)-4-methyl-1-oxopentan-2-ylamino)-4-oxobut-2-en-2-yl)phenyl dihydrogen phosphate
• 英文别名: [4-[(E)-4-[[(2S)-1-[(2S)-2-[[(2R)-5-amino-5-oxopentan-2-yl]carbamoyl]pyrrolidin-1-yl]-4-methyl-1-oxopentan-2-yl]amino]-4-oxobut-2-en-2-yl]phenyl] dihydrogen phosphate
• CAS: 1304101-08-3
• 化学式: C₂₆H₃₉N₄O₈P
• 分子量: 566.591
• InChiKey: MSYMDIOCJOFGTP-MWSMYNQTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  39
• 可旋转键数：
  13
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  188
• 氢给体数：
  5
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  (R)-4-FMOC氨基-Γ-戊酸 、 pentachlorophenyl (E)-3-(4-phosphorylphenyl)but-2-enoate 、 Fmoc-L-亮氨酸 、 Fmoc-L-脯氨酸 在 哌啶 、 C₃₃H₃₁N₂O₆Pol 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 1-羟基苯并三唑 、 N,N-二异丙基乙胺 、 N,N'-二异丙基碳二亚胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 以34 mg的产率得到4-((E)-4-((S)-1-((S)-2-((R)-5-amino-5-oxopentan-2-ylcarbamoyl)pyrrolidin-1-yl)-4-methyl-1-oxopentan-2-ylamino)-4-oxobut-2-en-2-yl)phenyl dihydrogen phosphate
  参考文献：
  名称：

  Potent and Selective Phosphopeptide Mimetic Prodrugs Targeted to the Src Homology 2 (SH2) Domain of Signal Transducer and Activator of Transcription 3

  摘要：

  Signal transducer and activator of transcription 3 (Stat3), a target for anticancer drug design, is activated by recruitment to phosphotyrosine residues on growth factor and cytokine receptors via its SH2 domain. We report here structure activity relationship studies on phosphopeptide mimics targeted to the SH2 domain of Stat3. Inclusion of a methyl group on the beta-position of the pTyr mimic 4-phosphocinnamide enhanced affinity 2- to 3-fold. Bis-pivaloyloxymethyl prodrugs containing beta-methylcinnamide, dipeptide scaffolds Haic and Nle-cis-3,4-methanoproline, and glutamine surrogates were highly potent, completely inhibiting phosphorylation of Stat3 Tyr705 at 0.5-1,mu M in a variety of cancer cell lines. The inhibitors were selective for Stat3 over Stat1, Stat5, Src, and p85 of PI3K, indicating ability to discriminate individual SH2 domains in intact cells. At concentrations that completely inhibited Stat3 phosphorylation, the prodrugs were not cytotoxic to a panel of tumor cells, thereby showing clear distinction between cytotoxicity and effects downstream of activated Stat3.

  DOI：

  10.1021/jm2000882