N^α-Fmoc-4-(di-tert-butoxycarbonyl-methyl)-L-phenylalanine | 261513-67-1

• 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^α-Fmoc-4-(di-tert-butoxycarbonyl-methyl)-L-phenylalanine
• 英文别名: N-Fmoc 4-(bis((tert-butyl)oxycarbonyl)methyl)-L-phenylalanine；N-Fmoc-4-(di-tert-butoxycarbonyl-methyl)-L-phenylalanine；(2S)-3-[4-[1,3-bis[(2-methylpropan-2-yl)oxy]-1,3-dioxopropan-2-yl]phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid
• CAS: 261513-67-1
• 化学式: C₃₅H₃₉NO₈
• 分子量: 601.697
• InChiKey: LUMXGQZLTMJFND-NDEPHWFRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.5
• 重原子数：
  44
• 可旋转键数：
  14
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  128
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  N^α-Fmoc-4-(di-tert-butoxycarbonyl-methyl)-L-phenylalanine 在 哌啶 、 N,N′-二叔丁基碳二亚胺 、 1-羟基苯并三唑 作用下， 以 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 3.17h， 生成 2-[4-((S)-2-Amino-2-{1-[(S)-2-carbamoyl-1-(3-naphthalen-1-yl-propylcarbamoyl)-ethylcarbamoyl]-cyclohexylcarbamoyl}-ethyl)-phenyl]-malonic acid di-tert-butyl ester
  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：

  2-(4-Diethoxymethyl-phenyl)-malonic acid di-tert-butyl ester 在 palladium on activated charcoal bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate 、 1,1,2,3-四甲基胍 、 水 、 氢气 、 sodium carbonate 、 (+)-1,2-双((2S,5S)-2,5-二甲基磷烷)苯 、 柠檬酸 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 水 为溶剂， -78.0~25.0 ℃ 、1.01 MPa 条件下， 反应 40.0h， 生成 N^α-Fmoc-4-(di-tert-butoxycarbonyl-methyl)-L-phenylalanine
  参考文献：
  名称：

  适用于固相肽合成的丙二酰基苯丙氨酰基和丙二酰基甲基苯丙氨酰基衍生物的新型高效对映选择性合成

  摘要：

  开发了对映体纯的丙二酰基苯丙氨酰基和丙二酰基甲基苯丙氨酰基衍生物的新合成，其中使用Rh（I）-（S，S）-Me-DuPHOS系统通过不对称氢化处理了相应的手性烯酰胺。这些非天然氨基酸被适当地保护并且可以用于固相肽合成中。

  DOI：

  10.1016/j.tetlet.2005.03.105

文献信息

• LARGE SCALE PREPARATION OF CELL PERMEABLE, NON-PHOSPHATE-CONTAINING GRB2 SH2 DOMAIN INHIBITORS
  作者：Ding-Guo Liu、Zhu-Jun Yao、Yang Gao、Terrence R. Burke

  DOI：10.1080/00304940009356287

  日期：2000.4

  Inhibitors of cellular signal transduction are emerging as important new therapeutics for several diseases including cancers' and diabetes.' Antagonists of aberrant protein-tyrosine kinasedependent signalling are particularly interesting7 with analogues l4 and 2s representing two noteworthy examples which have been reported recently to potently inhibit Grb2 SH2 domain binding both in extracellular

  细胞信号转导抑制剂正在成为包括癌症和糖尿病在内的多种疾病的重要新疗法。异常蛋白酪氨酸激酶依赖性信号传导的拮抗剂特别令人感兴趣 7，其中类似物 14 和 2s 代表了两个值得注意的例子，最近据报道它们在细胞外测定和全细胞制备中均能有效抑制 Grb2 SH2 结构域结合。Grb2 SH2 结构域在多种癌症（包括乳腺癌和白血病）中发挥的核心作用，使 1 和 2 成为有用的药理学工具和治疗剂的潜在价值。以前 1 和 2 都仅以毫克级制备。然而，由于需要显着更大的数量，本文报道了它们通过适用于相关信号转导抑制剂放大的技术在数百毫克规模上的合成。特别值得注意的是应用径向压缩技术以实现近 1 g 规模的最终产品 HPLC 纯化。
• PHENYLALANINE DERIVATIVES
  申请人：Burke R. Terrence

  公开号：US20070219194A1

  公开（公告）日：2007-09-20

  The present invention provides phenylalanine derivatives that inhibit SH2 domain binding with a phosphoprotein. These derivatives include compounds of the formula: W—Y-(AA) n -Z wherein n is 0 to 15; Y is a phenylalanyl radical having a phenyl ring, an amine end, and a carboxyl end, the phenyl ring having one or more substituents, e.g., hydroxyl, carboxyl, formyl, carboxyalkyl, carboxyalkyloxy, dicarboxyalkyl, dicarboxyalkyloxy, dicarboxyhaloalkyl, dicarboxyhaloalkyloxy, and phosphonoalkyl, or phosphonohaloalkyl; W is a moiety attached to the nitrogen of Y and is, e.g., alkylcarbonyl, oxalyl, alkylaminooxalyl, arylaminooxalyl, arylalkylaminooxalyl, or alkoxyoxalyl; AA is an amino acid, the amine end of which is attached to the carboxyl end of Y; and Z is an arylalkylamino or arylheterocyclyl alkylamino; or a salt thereof; with the proviso that W is not arylalkylamino when the phenyl ring of phenylalanyl contains a phosphonoalkyl or phosphonohaloalkyl substituent at a position para to the alkylamido group and the ortho and meta positions are unsubstituted. The present invention further provides precursors suitable for preparing the phenylalanine derivatives and a method for the preparation of the precursors. The present invention further provides conjugates comprising a precursor and a conjugant that are covalently linked. These conjugates have biological and/or pharmacological properties.

  本发明提供苯丙氨酸衍生物，其抑制SH2域与磷酸化蛋白结合。这些衍生物包括以下公式的化合物：W—Y-(AA)n-Z，其中n为0至15；Y是具有苯环、胺端和羧基端的苯丙氨酰基基团，苯环具有一个或多个取代基，例如羟基、羧基、甲酰基、羧基烷基、羧基烷氧基、二羧基烷基、二羧基烷氧基、二羧基卤代烷基、二羧基卤代烷氧基、磷酸烷基或磷酸卤代烷基；W是连接到Y的氮上的基团，例如烷基羰基、草酰基、烷基氨基草酰基、芳基氨基草酰基、芳基烷基氨基草酰基或烷氧基草酰基；AA是一种氨基酸，其胺端连接到Y的羧基端；Z是芳基烷基氨基或芳基杂环基烷基氨基；或其盐；但是，当苯丙氨酰基的苯环在烷基酰基基团的对位上含有磷酸烷基或磷酸卤代烷基取代基，并且邻位和间位未取代时，W不是芳基烷基氨基。本发明还提供适用于制备苯丙氨酸衍生物的前体以及制备前体的方法。本发明还提供共价连接的前体和结合物的共轭物。这些共轭物具有生物和/或药理学性质。
• Phenylalanine derivatives
  申请人：United States of America, represented by the Secretary, Department of Health and Human Services

  公开号：US07226991B1

  公开（公告）日：2007-06-05

  Disclosed herein are phenylalanine derivative compounds of the following formula W—Y—(AA)n—Z wherein Y is a phenylalanyl radical, AA is an amino acid, n is an integer of 1 to 15, and substituent variables W and Z are as described herein. The compounds can be used to inhibit SH2 binding with phosphoproteins, and to inhibit proliferation of tumor cells.

  本文披露了以下公式的苯丙氨酸衍生物化合物W-Y-(AA)n-Z，其中Y是苯丙氨酰基，AA是氨基酸，n是1到15的整数，取代变量W和Z如本文所述。这些化合物可用于抑制SH2与磷酸化蛋白结合，并抑制肿瘤细胞增殖。
• Phenylanine derivatives
  申请人：The United States of America as represented by the Department of Health and Human Services

  公开号：US07825216B2

  公开（公告）日：2010-11-02

  The present invention provides phenylalanine derivatives that inhibit SH2 domain binding with a phosphoprotein. These derivatives include compounds of the formula: W—Y-(AA)n-Z wherein n is 0 to 15; Y is a phenylalanyl radical having a phenyl ring, an amine end, and a carboxyl end, the phenyl ring having one or more substituents, e.g., hydroxyl, carboxyl, formyl, carboxyalkyl, carboxyalkyloxy, dicarboxyalkyl, dicarboxyalkyloxy, dicarboxyhaloalkyl, dicarboxyhaloalkyloxy, and phosphonoalkyl, or phosphonohaloalkyl; W is a moiety attached to the nitrogen of Y and is, e.g., alkylcarbonyl, oxalyl, alkylaminooxalyl, arylaminooxalyl, arylalkylaminooxalyl, or alkoxyoxalyl; AA is an amino acid, the amine end of which is attached to the carboxyl end of Y; and Z is an arylalkylamino or arylheterocyclyl alkylamino; or a salt thereof; with the proviso that W is not arylalkylamino when the phenyl ring of phenylalanyl contains a phosphonoalkyl or phosphonohaloalkyl substituent at a position para to the alkylamido group and the ortho and meta positions are unsubstituted. The present invention further provides precursors suitable for preparing the phenylalanine derivatives and a method for the preparation of the precursors. The present invention further provides conjugates comprising a precursor and a conjugant that are covalently linked. These conjugates have biological and/or pharmacological properties.

  本发明提供了苯丙氨酸衍生物，可以抑制SH2结构域与磷酸化蛋白质的结合。这些衍生物包括以下化合物：W-Y-(AA)n-Z，其中n为0至15；Y是具有苯环、胺端和羧基端的苯丙氨酰基基团，苯环具有一个或多个取代基，例如羟基、羧基、甲酰基、羧基烷基、羧基烷氧基、二羧基烷基、二羧基烷氧基、二羧基卤代烷基、二羧基卤代烷氧基、磷酸烷基或磷酸卤代烷基；W是连接到Y的氮上的基团，例如烷基羰基、草酰基、烷基氨氧草酰基、芳基氨氧草酰基、芳基烷基氨氧草酰基或烷氧草酰基；AA是一种氨基酸，其胺端连接到Y的羧基端；Z是芳基烷基氨基或芳基杂环基烷基氨基；或其盐；但是，若苯丙氨酰基的苯环在离烷基酰胺基团的对位上含有磷酸烷基或磷酸卤代烷基取代基且邻位和间位未被取代，则W不是芳基烷基氨基。本发明还提供了适用于制备苯丙氨酸衍生物的前体物以及制备前体物的方法。本发明还提供了共价连接的前体和结合物的共轭物。这些共轭物具有生物和/或药理学性质。
• Selectivity and Mechanism of Action of a Growth Factor Receptor-Bound Protein 2 Src Homology 2 Domain Binding Antagonist
  作者：Alessio Giubellino、Zhen-Dan Shi、Lisa M. Miller Jenkins、Karen M. Worthy、Lakshman K. Bindu、Gagani Athauda、Benedetta Peruzzi、Robert J. Fisher、Ettore Appella、Terrence R. Burke、Donald P. Bottaro

  DOI：10.1021/jm800523u

  日期：2008.12.11

  We have shown previously that a potent synthetic antagonist of growth factor receptor-bound protein 2 (Grb2) Src homology 2 (SH2) domain binding (1) blocks growth factor stimulated motility, invasion, and angiogenesis in cultured cell models, as well as tumor metastasis in animals. To characterize the selectivity of I for the SH2 domain of Grb2 over other proteins containing similar structural binding motifs, we synthesized a biotinylated derivative (3) that retained high affinity Grb2 SH2 domain binding and potent biological activity. To investigate the selectivity of 1 and 3 for Grb2, the biotinylated antagonist 3 was used to immobilize target proteins from cell extracts for subsequent identification by mass spectrometry. Nonspecific binding was identified in parallel using a biotinylated analogue that lacked a single critical binding determinant. The mechanism of action of the antagonist was further characterized by immunoprecipitation, immunoblotting, and light microscopy. This approach to defining protein binding antagonist selectivity and molecular basis of action should be widely applicable in drug development.