(2S)-2-amino-N1-[3-(1-naphthalenyl)propyl]butanediamide | 220193-52-2

• 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: (2S)-2-amino-N1-[3-(1-naphthalenyl)propyl]butanediamide
• 英文别名: (2S)-2-[(1-aminocyclohexanecarbonyl)amino]-N-(3-naphthalen-1-ylpropyl)butanediamide
• CAS: 220193-52-2
• 化学式: C₂₄H₃₂N₄O₃
• 分子量: 424.543
• InChiKey: CKNMRZWBBILGTI-FQEVSTJZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  31
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  127
• 氢给体数：
  4
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (2S)-2-amino-N1-[3-(1-naphthalenyl)propyl]butanediamide 在 哌啶 、 N,N′-二叔丁基碳二亚胺 、 1-羟基苯并三唑 作用下， 以 乙腈 为溶剂， 反应 1.17h， 生成 2-trimethylsilylethyl 5-[(2S)-3-[[1-[[(2S)-4-amino-1-(3-naphthalen-1-ylpropylamino)-1,4-dioxobutan-2-yl]carbamoyl]cyclohexyl]amino]-2-[[2-[(2-methylpropan-2-yl)oxy]-2-oxoacetyl]amino]-3-oxopropyl]-2-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethoxy]benzoate
  参考文献：
  名称：

  Potent Inhibition of Grb2 SH2 Domain Binding by Non-Phosphate-Containing Ligands

  摘要：

  Development of Grb2 Src homology 2 (SH2) domain binding inhibitors has important implications for treatment of a variety of diseases, including several cancers. In cellular studies, inhibitors of Grb2 SH2 domain binding have to date been large, highly charged peptides which relied on special transport devices for cell membrane penetration. Work presented in the current study examines a variety of pTyr mimetics in the context of a high-affinity Grb2 binding platform. Among the analogues studied are new norm-phosphorus-containing pTyr mimetics 23a and 23b which, when incorporated into tripeptide structures 18f and 20f, are able to inhibit Grb2 SH2 domain binding with affinities among the best yet reported for non-phosphorus-containing SH2 domain inhibitors (IC50 values of 6.7 and 1.3 mu M, respectively). The present study has also demonstrated the usefulness of the Na-oxalyl group as an auxiliary which enhances the binding potency of both phosphorus- and non-phosphorus-containing pTyr mimetics. When combined with the (phosphonomethyl)phenylalanine (Pmp) residue to give analogues such as L-20d, potent inhibition of Grb2 SH2 domain binding can be achieved both in extracellular assays using isolated Grb2 SH2 domain protein and in intracellular systems measuring the association of endogenous Grb2 with its cognate p185(erbB-2) ligand. These latter effects can be achieved at micromolar to submicromolar concentrations without prodrug derivatization. The oxalyl-containing pTyr mimetics presented in this study should be of general usefulness for the development of other Grb2 SH2 domain antagonists, independent of the beta-bend-mimicking platform utilized for their display.

  DOI：

  10.1021/jm980388x
• 作为产物：
  描述：

  {1-[(S)-2-Carbamoyl-1-(3-naphthalen-1-yl-propylcarbamoyl)-ethylcarbamoyl]-cyclohexyl}-carbamic acid tert-butyl ester 在 三乙基硅烷 、 三氟乙酸 作用下， 反应 1.0h， 生成 (2S)-2-amino-N1-[3-(1-naphthalenyl)propyl]butanediamide
  参考文献：
  名称：

  Potent Inhibition of Grb2 SH2 Domain Binding by Non-Phosphate-Containing Ligands

  摘要：

  Development of Grb2 Src homology 2 (SH2) domain binding inhibitors has important implications for treatment of a variety of diseases, including several cancers. In cellular studies, inhibitors of Grb2 SH2 domain binding have to date been large, highly charged peptides which relied on special transport devices for cell membrane penetration. Work presented in the current study examines a variety of pTyr mimetics in the context of a high-affinity Grb2 binding platform. Among the analogues studied are new norm-phosphorus-containing pTyr mimetics 23a and 23b which, when incorporated into tripeptide structures 18f and 20f, are able to inhibit Grb2 SH2 domain binding with affinities among the best yet reported for non-phosphorus-containing SH2 domain inhibitors (IC50 values of 6.7 and 1.3 mu M, respectively). The present study has also demonstrated the usefulness of the Na-oxalyl group as an auxiliary which enhances the binding potency of both phosphorus- and non-phosphorus-containing pTyr mimetics. When combined with the (phosphonomethyl)phenylalanine (Pmp) residue to give analogues such as L-20d, potent inhibition of Grb2 SH2 domain binding can be achieved both in extracellular assays using isolated Grb2 SH2 domain protein and in intracellular systems measuring the association of endogenous Grb2 with its cognate p185(erbB-2) ligand. These latter effects can be achieved at micromolar to submicromolar concentrations without prodrug derivatization. The oxalyl-containing pTyr mimetics presented in this study should be of general usefulness for the development of other Grb2 SH2 domain antagonists, independent of the beta-bend-mimicking platform utilized for their display.

  DOI：

  10.1021/jm980388x

文献信息

• Synthesis of the First α‐Fluoro‐Phosphotyrosyl Mimetic
  作者：Zhen‐Dan Shi、Hongpeng Liu、Manchao Zhang、Dajun Yang、Terrence R. Burke

  DOI：10.1081/scc-200034770

  日期：2004.12.31

  Abstract The diastereoselective preparation of (2S)‐2‐fluoro‐4‐[[bis(1,1‐dimethylethoxy)phosphinyl]methyl] benzenepropanoic acid (5) is presented as new phosphotyrosyl (pTyr) mimetic suitably protected for incorporation into peptides. Synthesis of 5 utilized electrophilic fluorination under chiral induction provided by the commercially available Evans auxiliary, (S)‐(+)‐4‐phenyl‐2‐oxazolidinone. In

  摘要 (2S)-2-氟-4-[[双(1,1-二甲基乙氧基)膦基]甲基]苯丙酸 (5) 的非对映选择性制备是作为新的磷酸酪氨酰 (pTyr) 模拟物被适当保护以掺入肽中的。5 在手性诱导下合成 5，由市售的 Evans 助剂 (S)-(+)-4-苯基-2-恶唑烷酮提供。为了证明其合成效用，使用类似物 5 来制备信号转导导向的三肽。该肽的设计考虑及其初步生物学评估也包括在内。
• Synthesis of α,α-disubstituted 4-phosphonophenylalanine analogues as conformationally-constrained phosphotyrosyl mimetics
  作者：Shinya Oishi、Sang-Uk Kang、Hongpeng Liu、Manchao Zhang、Dajun Yang、Jeffrey R. Deschamps、Terrence R. Burke

  DOI：10.1016/j.tet.2004.02.005

  日期：2004.3

  Syntheses of N-Boc (S)-4-(diethylphosphono)-(alpha-methyl)phenylalanine [Boc-(alpha-Me)Phe(4-PO3Et2)-OH] (9) and N-Boc (S)-2amino-6-(diethylphosphono)tetralin-2-carboxylic acid [Boc-Atc(6-PO3Et2)-OH] (18) are reported as conformationally-constrained phosphotyrosyl mimetics suitably protected for peptide synthesis. Both syntheses proceeded through chiral arylhalides that are converted to arylphosphonates by palladium-catalyzed cross coupling with diethylphosphite. These amino acid analogues may be useful in the study of cellular signal transduction processes. (C) 2004 Elsevier Ltd. All rights reserved.
• Inhibition of Grb2 SH2 Domain Binding by Non-Phosphate-Containing Ligands. 2. 4-(2-Malonyl)phenylalanine as a Potent Phosphotyrosyl Mimetic
  作者：Yang Gao、Juliet Luo、Zhu-Jun Yao、Ribo Guo、Hong Zou、James Kelley、Johannes H. Voigt、Dajun Yang、Terrence R. Burke

  DOI：10.1021/jm9904248

  日期：2000.3.1

  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.
• Synthesis of N -Fmoc 3-(4-(di-( tert -butyl)phosphonomethyl)phenyl)pipecolic acid as a conformationally constrained phosphotyrosyl mimetic suitably protected for peptide synthesis
  作者：Ding-Guo Liu、Xiang-Zhu Wang、Yang Gao、Bihua Li、Dajun Yang、Terrence R Burke

  DOI：10.1016/s0040-4020(02)01421-7

  日期：2002.12

  Phosphonomethylphenylalanine (Pmp, 2) has shown wide utility as a hydrolytically stable phosphtyrosyl (pTyr, 1) mimetic, particularly in Src homology 2 (SH2) domain-binding peptides. (2S,3R)-3-(4-(phosphonomethyl)phenyl)pipecolic acid (3) represents a variant of Pmp having phi and chi(1) torsion angles constrained through incorporation into the piperidinyl ring structure contained within pipecolic acid. Reported herein is the enantioselective preparation of 3, in an orthogonally protected form (4) suitable for use in peptide synthesis. Stereochemistries at both the 2- and 3-positions are derived inductively from a single chiral center provided by the commercially available Evans chiral auxiliary, (4S)-4-benzyl-1,3-oxazolidin-2-one. Incorporation of 4 into a Grb2 SH2 domain-directed tripeptide (18) showed that Grb2 SH2 domain-binding affinity was reduced relative to the parent Pmp-containing tripeptide (19). Although conformational constraint did not enhance affinity in this case, novel amino acid analogue 4 may serve as a useful tool for the induction of defined phosphotyrosyl geometry in peptides directed at other signal transduction targets. (C) 2002 Elsevier Science Ltd. All rights reserved.
• PHENYLALANINE DERIVATIVES
  申请人：THE GOVERNMENT OF THE UNITED STATES OF AMERICA as represented by the SECRETARY OF THE DEPARTMENT OF HEALTH AND HUMAN SERVICES

  公开号：EP1163262B1

  公开（公告）日：2011-05-11