N-acetyl-O-[bis(benzyloxy)phosphoryl]-L-tyrosine | 151608-48-9

• 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: N-acetyl-O-[bis(benzyloxy)phosphoryl]-L-tyrosine
• 英文别名: Ac-Tyr(PO3Bzl2)-OH；Ac-Tyr(PO3Bn2)-OH；(2S)-3-(4-{[bis(benzyloxy)phosphoryl]oxy}phenyl)-2-acetamidopropanoic acid；(2S)-2-acetamido-3-[4-bis(phenylmethoxy)phosphoryloxyphenyl]propanoic acid
• CAS: 151608-48-9
• 化学式: C₂₅H₂₆NO₇P
• 分子量: 483.458
• InChiKey: RBNBBKKKJLFHPQ-DEOSSOPVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  34
• 可旋转键数：
  12
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  111
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  N-acetyl-O-[bis(benzyloxy)phosphoryl]-L-tyrosine 在 1-羟基苯并三唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 生成 Phosphoric acid mono-{4-[(S)-2-acetylamino-2-((S)-3-carbamoyl-2-cyclohexylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ylcarbamoyl)-ethyl]-phenyl} ester
  参考文献：
  名称：

  Structure-Based Design of Novel Bicyclic Nonpeptide Inhibitors for the Src SH2 Domain

  摘要：

  DOI：

  10.1021/jm0003337
• 作为产物：
  描述：

  N-乙酰-L-酪氨酸 在 N-甲基吗啉 、 四氮唑 、 叔丁基过氧化氢 、 水 、 溶剂黄146 作用下， 以 四氢呋喃 、 水 、 乙腈 为溶剂， 反应 6.34h， 生成 N-acetyl-O-[bis(benzyloxy)phosphoryl]-L-tyrosine
  参考文献：
  名称：

  Development of Non-Peptide Ligands of Growth Factor Receptor-Bound Protein 2-Src Homology 2 Domain Using Molecular Modeling and NMR Spectroscopy

  摘要：

  We report a novel series of non-peptide ligands that inhibit the growth factor receptor-bound protein 2 (Grb2)-Src homology 2 (SH2) domain binding, designed using a combined computational and NMR-driven approach. We have identified a new lead compound, in (IC50 = 56 mu M), which is cytotoxic in HER2-positive breast cancer cells and disrupts the interaction between HER2 and Grb2. Thus, In can be used as a scaffold for the development of efficient Grb2-SH2 domain binding inhibitors.

  DOI：

  10.1021/jm101478n

文献信息

• Discovery of Potent and Selective SH2 Inhibitors of the Tyrosine Kinase ZAP-70
  作者：Chi B. Vu、Evelyn G. Corpuz、Taylor J. Merry、Selvaluxmi G. Pradeepan、Catherine Bartlett、Regine S. Bohacek、Martyn C. Botfield、Charles J. Eyermann、Berkley A. Lynch、Ian A. MacNeil、Mary K. Ram、Marie Rose van Schravendijk、Shelia Violette、Tomi K. Sawyer

  DOI：10.1021/jm990229t

  日期：1999.10.1

  A series of 1,2,4-oxadiazole analogues has been shown to be potent and selective SH2 inhibitors of the tyrosine kinase ZAP-70, a potential therapeutic target for immune suppression. These compounds typically are 200-400-fold more potent than the native, monophosphorylated tetrapeptide sequences. When compared with the high-affinity xi-1-ITAM peptide (Ac-NQL-pYNELNLGRREE-pYDVLD-NH2, wherein pY refers to phosphotyrosine) some of the best 1,2,4-oxadiazole analogues are approximately 1 order of magnitude less active. This series of compounds displays an unprecedented level of selectivity over the closely related tyrosine kinase Syk, as well as other SH2-containing proteins such as Src and Grb2. Gel shift studies using a protein construct consisting only of C-terminal ZAP-70 SH2 demonstrate that these compounds can effectively engage this particular SH2 domain.
• Structure-activity relationships of a novel class of Src SH2 inhibitors
  作者：John L. Buchanan、Chi B. Vu、Taylor J. Merry、Evelyn G. Corpuz、Selvaluxmi G. Pradeepan、Ukti N. Mani、Michael Yang、Hilary R. Plake、Vaibhav M. Varkhedkar、Berkley A. Lynch、Ian A. MacNeil、Kara A. Loiacono、Choi Lai Tiong、Dennis A. Holt

  DOI：10.1016/s0960-894x(99)00389-3

  日期：1999.8

  The structure-activity relationships (SAR) of a novel class of Src SH2 inhibitors are described. Variation at the pY+1 and pY+3 side chain positions using 2,4- and 2,5-substituted thiazoles and 1,2,4-oxadiazoles as scaffolds resulted in inhibitors that bound as well as the standard tetrapeptide Ac-pYEEI-NH2. (C) 1999 Elsevier Science Ltd. All rights reserved.
• Design and synthesis of conformationally constrained, extended and reverse turn pseudopeptides as Grb2-SH2 domain antagonists
  作者：Hilary R Plake、Thomas B Sundberg、Angela R Woodward、Stephen F Martin

  DOI：10.1016/s0040-4039(03)00013-3

  日期：2003.2

  A series of conformationally constrained and flexible pseudopeptide derivatives of the tripeptide pYVN were prepared as potential antagonists of interactions of phosphotyrosine peptides with the Grb2-SH2 domain. The conformation ally constrained compounds contained trans- and cis-cyclopropanes as replacements to enforce locally extended and reverse turn peptide conformations, respectively. (C) 2003 Elsevier Science Ltd. All rights reserved.
• Discovery of highly potent Src SH2 binders: Structure–activity studies and X-ray structures
  作者：Pierre Deprez、Isabelle Baholet、Stéphane Burlet、Gudrun Lange、Remi Amengual、Bernard Schoot、Annie Vermond、Eliane Mandine、Dominique Lesuisse

  DOI：10.1016/s0960-894x(02)00139-7

  日期：2002.5

  Optimization of the hydrophobic moiety of caprolactam/thiazepinone based compounds led to the identification of potent Src SH2 binders in two different series incorporating a phosphotyrosine group (RU 81843) or a phosphobenzoic group (RU 79181). The X-ray co-structures with the Src SH2 domain revealed different binding modes for RU 81843 and RU 79181, and an excellent fit between RU81843 and the Src SH2 protein thus explaining its high potency (9 nM, 15-fold more potent than pYEE1 reference peptide). (C) 2002 Elsevier Science Ltd. All rights reserved.
• Phosphotyrosine-Containing Dipeptides as High-Affinity Ligands for the p56<i>^lck</i> SH2 Domain
  作者：Montse Llinàs-Brunet、Pierre L. Beaulieu、Dale R. Cameron、Jean-Marie Ferland、Jean Gauthier、Elise Ghiro、James Gillard、Vida Gorys、Martin Poirier、Jean Rancourt、Dominik Wernic、Raj Betageri、Mario Cardozo、Scott Jakes、Suzanne Lukas、Usha Patel、John Proudfoot、Neil Moss

  DOI：10.1021/jm980612i

  日期：1999.2.1

  Src homology-2 (SH2) domains are noncatalytic motifs containing approximately 100 amino acid residues that are involved in intracellular signal transduction. The phosphotyrosine-containing tetrapeptide Ac-pYEEI binds to the SH2 domain of p.56(lck) (Lck) with an affinity of 0.1 mu M. Starting from Ac-pYEEI, we have designed potent antagonists of the Lck SH2 domain which are reduced in peptidic character and in which the three carboxyl groups have been eliminated. The two C-terminal amino acids (EI) have been replaced by benzylamine derivatives and the pY + 1 glutamic acid has been substituted with leucine. The best C-terminal fragment identified, (S)-1-(4-isopropylphenyl)ethylamine, binds to the Lck SH2 domain better than the C-terminal dipeptide EI. Molecular modeling suggests that the substituents at the 4-position of the phenyl ring occupy the pY + 3 lipophilic pocket in the SH2 domain originally occupied by the isoleucine side chain. This new series of phosphotyrosine-containing dipeptides binds to the Lck SH2 domain with potencies comparable to that of tetrapeptide 1.