(2R)-2-[[4-[bis[(2-methylpropan-2-yl)oxy]phosphorylmethyl]phenyl]methyl]-4-[(2-methylpropan-2-yl)oxy]-4-oxobutanoic acid | 491831-48-2

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 苯丙酸
• 英文名称: (2R)-2-[[4-[bis[(2-methylpropan-2-yl)oxy]phosphorylmethyl]phenyl]methyl]-4-[(2-methylpropan-2-yl)oxy]-4-oxobutanoic acid
• CAS: 491831-48-2
• 化学式: C₂₄H₃₉O₇P
• 分子量: 470.543
• InChiKey: VNEAWDXGJDCBIY-LJQANCHMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  32
• 可旋转键数：
  13
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  99.1
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  benzyl 4-amino-4-[[(2S)-4-amino-1-(3-naphthalen-1-ylpropylamino)-1,4-dioxobutan-2-yl]carbamoyl]piperidine-1-carboxylate 、 (2R)-2-[[4-[bis[(2-methylpropan-2-yl)oxy]phosphorylmethyl]phenyl]methyl]-4-[(2-methylpropan-2-yl)oxy]-4-oxobutanoic acid 在 4-aza-1-hydroxybenzotriazole 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 21.25h， 以59%的产率得到benzyl 4-[[(2S)-4-amino-1-(3-naphthalen-1-ylpropylamino)-1,4-dioxobutan-2-yl]carbamoyl]-4-[[(2R)-2-[[4-[bis[(2-methylpropan-2-yl)oxy]phosphorylmethyl]phenyl]methyl]-4-[(2-methylpropan-2-yl)oxy]-4-oxobutanoyl]amino]piperidine-1-carboxylate
  参考文献：
  名称：

  Examination of Acylated 4-Aminopiperidine-4-carboxylic Acid Residues in the Phosphotyrosyl+1 Position of Grb2 SH2 Domain-Binding Tripeptides

  摘要：

  A 4-aminopiperidine-4-carboxylic acid residue was placed in the pTyr+1 position of a Grb2 SH2 domain-binding peptide to form a general platform, which was then acylated with a variety of groups to yield a library of compounds designed to explore potential binding interactions, with protein features lying below the beta D strand. The highest affinities were obtained using phenylethyl carbamate and phenylbutyrylamide functionalities.

  DOI：

  10.1021/jm0614073
• 作为产物：
  描述：

  (R)-3-[4-(Di-tert-butoxy-phosphorylmethyl)-benzyl]-4-oxo-4-((S)-2-oxo-4-phenyl-oxazolidin-3-yl)-butyric acid tert-butyl ester 在 lithium hydroxide 、 双氧水 作用下， 以 四氢呋喃 为溶剂， 以86%的产率得到(2R)-2-[[4-[bis[(2-methylpropan-2-yl)oxy]phosphorylmethyl]phenyl]methyl]-4-[(2-methylpropan-2-yl)oxy]-4-oxobutanoic acid
  参考文献：
  名称：

  Development of a Phosphatase-Stable Phosphotyrosyl Mimetic Suitably Protected for the Synthesis of High-Affinity Grb2 SH2 Domain-Binding Ligands

  摘要：

  Synthesis of (2R)-2-carboxymethyl-3-(4-(phosphonomethyl)phenyl) proprionic acid (5) in tert-butyl-protected form (6) and its use for the preparation of a Grb2 SH2 domain-directed tripeptide (8a) is reported. In extracellular ELISA-based assays, 8a exhibits potent Grb2 SH2 domain binding affinity (IC50=8 nM). Against cultures of MDA-MB-453 breast cancer cells, which overexpress erbB-2 tyrosine kinase, 8a is also antimitogenic at concentrations equivalent to those required to inhibit intracellular association of Grb2 protein with phosphorylated p185(erbB-2) protein (IC50=8 muM). Analogue 6 may be useful for the preparation of a variety of phosphatase-stable SH2 domain-directed ligands. (C) 2002 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(02)00527-9

文献信息

• [EN] MACROCYCLIC SH2 DOMAIN BINDING INHIBITORS<br/>[FR] INHIBITEURS DE LIAISON DE DOMAINE SH2 MACROCYCLIQUE
  申请人：US GOV HEALTH & HUMAN SERV

  公开号：WO2006039527A1

  公开（公告）日：2006-04-13

  Disclosed are compounds for inhibiting the binding of an SH2 domain-containing protein, for example, a compound of formula (I): FORMULA (I) wherein R1 is a lipophile; R2, in combination with the phenyl ring, is a phenylphosphate mimic group or a protected phenylphosphate mimic group; R3 is, for example, hydrogen, azido, amino, oxalylamino, carboxy alkyl, alkoxycarbonyl alkyl, aminocarbonyl alkyl, or alkyl carbonylamino; R6 is a linker; AA is an amino acid; and n is 1 to 6; or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof. Also disclosed are pharmaceutical compositions and methods of use of such compounds.

  本文披露了用于抑制含有SH2结构域蛋白质结合的化合物，例如，具有以下结构的化合物（I）：FORMULA（I）其中R1是脂溶性基团；R2与苯环结合形成苯磷酸酯模拟基团或受保护的苯磷酸酯模拟基团；R3是，例如，氢、偶氮基、氨基、草酰氨基、羧基烷基、烷氧羰基烷基、氨基羰基烷基或烷基羰基氨基；R6是连接基；AA是氨基酸；n为1至6；或其药学上可接受的盐、立体异构体、溶剂合物或水合物。还披露了包括这些化合物的药物组合物和使用方法。
• Sh2 domain binding inhibitors
  申请人：Burke R. Terrence

  公开号：US20060167222A1

  公开（公告）日：2006-07-27

  Disclosed are compounds for SH2 domain binding inhibition, for example, a compound of formula (I), wherein R 1 is a lipophile; R 2 , in combination with the phenyl ring, is a phenylphosphate mimic group or a protected phenylphosphate mimic group; R 3 is hydrogen, azido, amino, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, or alkylcarbonylamino, wherein the alkyl portion of R 3 may be optionally substituted with a substituent selected from the group consisting of halo, hydroxy, carboxyl, amino, aminoalkyl, alkyl, alkoxy, and keto; R 6 is a linker; AA is an amino acid; and n is 1 to 6; or a salt thereof. The conformationally compounds provide enhanced binding affinity with SH2 domain protein. Also disclosed are a pharmaceutical compositions and a method for inhibiting an SH2 domain from binding with a phosphoprotein.

  本发明揭示了用于SH2结构域结合抑制的化合物，例如，式(I)的化合物，其中R1是一个疏水基；R2与苯环结合，是苯基磷酸酯类似物基团或受保护的苯基磷酸酯类似物基团；R3是氢、叠氮基、氨基、羧基烷基、烷氧羰基烷基、氨基羰基烷基或烷基羰基氨基，其中R3的烷基部分可以选择地用来自卤素、羟基、羧基、氨基、氨基烷基、烷基、烷氧基和酮的取代基进行取代；R6是一个连接基；AA是一种氨基酸；n为1至6；或其盐。这些构象化合物提供了与SH2结构域蛋白的增强结合亲和力。本发明还揭示了一种制药组合物和一种抑制SH2结构域与磷酸化蛋白结合的方法。
• Utilization of a nitrobenzoxadiazole (NBD) fluorophore in the design of a Grb2 SH2 domain-binding peptide mimetic
  作者：Zhen-Dan Shi、Rajeshri G. Karki、Shinya Oishi、Karen M. Worthy、Lakshman K. Bindu、Pathirage G. Dharmawardana、Marc C. Nicklaus、Donald P. Bottaro、Robert J. Fisher、Terrence R. Burke

  DOI：10.1016/j.bmcl.2005.01.017

  日期：2005.3

  Fluorescence labeling has become a general technique for studying the intracellular accumulation and localization of exogenously administered materials. Reported herein is a low nanomolar affinity Grb2 SH2 domain-binding antagonist that utilizes the environmentally-sensitive nitrobenzoxadiazole (NBD) fluorophore as a naphthyl replacement. This novel agent should serve as a useful tool to visualize the actions of this class of Grb2 SH2 domain-binding antagonists in whole cell systems. (c) 2005 Elsevier Ltd. All rights reserved.
• Design and Synthesis of Conformationally Constrained Grb2 SH2 Domain Binding Peptides Employing α-Methylphenylalanyl Based Phosphotyrosyl Mimetics
  作者：Shinya Oishi、Rajeshri G. Karki、Sang-Uk Kang、Xiangzhu Wang、Karen M. Worthy、Lakshman K. Bindu、Marc C. Nicklaus、Robert J. Fisher、Terrence R. Burke

  DOI：10.1021/jm0492709

  日期：2005.2.1

  Previous work has shown that incorporation of either I-aminocyclohexanecarboxylic acid (Ac(6)c) or alpha-methyl-p-phosphonophenylalanine ((alpha-Me)Ppp) in the phosphotyrosyl (pTyr) C-proximal position (pY + 1 residue) of Grb2 SH2 domain binding peptides confers high affinity. The tetralin-based (S)-2-amino-6-phosphonotetralin-2-carboxylic acid (Atc(6-(POH2)-H-3)) simultaneously presents structural features of both (a-Me)Ppp and Ac(6)c residues. The current study compares the affinity of this tetralin hybrid Atc(6-PO3H2) versus Ac(6)c and (alpha-Me)Ppp residues when incorporated into the pY + I position of a high-affinity Grb2 SH2 domain binding tripeptide platform. The highest binding affinity (K-D = 14.8 nM) was exhibited by the (alpha-Me)Ppp-containing parent, with the corresponding Ac(6)c-containing peptide being nearly 2-fold less potent (K-D = 23.8 nM). The lower KD value was attributable primarily to a 50% increase in off-rate. Replacement of the Ac(6)c residue with the tetralin-based hybrid resulted in a further 4-fold decrease in binding affnity (K-D = 97.8 nM), which was the result of a further 6-fold increase in off-rate, offset by an approximate 45% increase in on-rate. Therefore, by incorporation of the key structural components found in (alpha-Me)Ppp into the Ac(6)c residue, the tetralin hybrid does enhance binding on-rate. However, net binding affinity is decreased due to an associated increase in binding off-rate. Alternatively, global conformational constraint of an ((alpha-Me)Ppp-containing peptide by beta-macrocyclization did result in pronounced elevation of binding affinity, which was achieved primarily through a decrease in the binding off-rate. Mathematical fitting using a simple model that assumed a single binding site yielded an effective KD of 2.28 nM. However this did not closely approximate the data obtained. Rather, use of a complex model that assumed two binding sites resulted in a very close fit of data and provided KD values of 97 pM and 72 nM for the separate sites, respectively. Therefore, although local conformational constraint in the pY + 1 residue proved to be deleterious, global conformational constraint through beta-macrocyclization achieved higher affinity. Similar beta-macrocyclization may potentially be extended to SH2 domain systems other than Grb2, where bend geometries are required.
• US7425537B2
  申请人：——

  公开号：US7425537B2

  公开（公告）日：2008-09-16