(2S,3S)-3-(4-{[bis(tert-butoxy)phosphono]methyl}phenyl)-2-{[(tert-butyl)oxycarbonyl]methyl}pent-4-enoic acid | 495404-40-5

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 苯丙酸
• 英文名称: (2S,3S)-3-(4-{[bis(tert-butoxy)phosphono]methyl}phenyl)-2-{[(tert-butyl)oxycarbonyl]methyl}pent-4-enoic acid
• 英文别名: (2S,3S)-3-[4-[bis[(2-methylpropan-2-yl)oxy]phosphorylmethyl]phenyl]-2-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]pent-4-enoic acid
• CAS: 495404-40-5
• 化学式: C₂₆H₄₁O₇P
• 分子量: 496.581
• InChiKey: LMVKXFQSUQUPCL-RTWAWAEBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  34
• 可旋转键数：
  14
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.62
• 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：

  (2S,3S)-3-(4-{[bis(tert-butoxy)phosphono]methyl}phenyl)-2-{[(tert-butyl)oxycarbonyl]methyl}pent-4-enoic acid 在 Grubbs catalyst first generation 、 N-羟基-7-氮杂苯并三氮唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 tert-butyl 2-[(1S,7S,11S,15S)-3,6,9-triaza-15-(4-{[bis(tert-butoxy)phosphono]methyl}phenyl)-7-(carbamoylmethyl)-4,4-dimethyl-11-(naphthylmethyl)-2,5,8-trioxocyclopentadec-13-enyl]acetate
  参考文献：
  名称：

  Macrocyclization in the Design of Grb2 SH2 Domain-Binding Ligands Exhibiting High Potency in Whole-Cell Systems

  摘要：

  While most SH2 domains bind phosphotyrosyl (pTyr) containing peptides in extended fashion, the growth factor receptor-bound protein 2 (Grb2) SH2 domain preferentially binds ligands in bend conformations. Accordingly, incorporation of bend-inducing functionality into synthetic ligands could potentially enhance their affinity for this SH2 domain. A macrocyclic tripeptide mimetic that contains a simplified pTyr surrogate lacking an alpha-nitrogen has recently been shown to exhibit high Grb2 SH2 domain-binding affinity in extracellular ELISA-based assays. However, the same compound is largely ineffective in whole-cell assays. It is known that acidic functionality originating from the alpha-nitrogen of pTyr residues or from the alpha-position of P-0 pTyr mimetics not only increases binding affinity of peptides to Grb2 SH2 domains in extracellular assays but also enhances potency in cell-based systems. Such functionality is absent from the previously reported macrocycle. Therefore, the current study was undertaken to examine the effects of introducing carboxylic functionality at the pTyr mimetic alpha-position of macrocyclic ligands. It was found that such a modification not only enhanced Grb2 SH2 domain binding in extracellular assays but also conferred high efficacy in whole-cell systems. The most potent compound of the current study exhibited an IC50 value of 0.002 muM in an extracellular ELISA-based assay, and in MDA-MB-453 cells, it both inhibited the association of Grb2 with p185(erbB-2) and exhibited antimitogenic effects with submicromolar IC50 values.

  DOI：

  10.1021/jm0203635
• 作为产物：
  描述：

  3-[(3R)-3-(4-{[bis(tert-butoxy)phosphono]methyl}phenyl)pent-4-enoyl]-(4S)-4-phenyl-1,3-oxazolidin-2-one 在 lithium hydroxide 、 双氧水 、 sodium hexamethyldisilazane 作用下， 以 四氢呋喃 为溶剂， 反应 2.5h， 生成 (2S,3S)-3-(4-{[bis(tert-butoxy)phosphono]methyl}phenyl)-2-{[(tert-butyl)oxycarbonyl]methyl}pent-4-enoic acid
  参考文献：
  名称：

  Macrocyclization in the Design of Grb2 SH2 Domain-Binding Ligands Exhibiting High Potency in Whole-Cell Systems

  摘要：

  While most SH2 domains bind phosphotyrosyl (pTyr) containing peptides in extended fashion, the growth factor receptor-bound protein 2 (Grb2) SH2 domain preferentially binds ligands in bend conformations. Accordingly, incorporation of bend-inducing functionality into synthetic ligands could potentially enhance their affinity for this SH2 domain. A macrocyclic tripeptide mimetic that contains a simplified pTyr surrogate lacking an alpha-nitrogen has recently been shown to exhibit high Grb2 SH2 domain-binding affinity in extracellular ELISA-based assays. However, the same compound is largely ineffective in whole-cell assays. It is known that acidic functionality originating from the alpha-nitrogen of pTyr residues or from the alpha-position of P-0 pTyr mimetics not only increases binding affinity of peptides to Grb2 SH2 domains in extracellular assays but also enhances potency in cell-based systems. Such functionality is absent from the previously reported macrocycle. Therefore, the current study was undertaken to examine the effects of introducing carboxylic functionality at the pTyr mimetic alpha-position of macrocyclic ligands. It was found that such a modification not only enhanced Grb2 SH2 domain binding in extracellular assays but also conferred high efficacy in whole-cell systems. The most potent compound of the current study exhibited an IC50 value of 0.002 muM in an extracellular ELISA-based assay, and in MDA-MB-453 cells, it both inhibited the association of Grb2 with p185(erbB-2) and exhibited antimitogenic effects with submicromolar IC50 values.

  DOI：

  10.1021/jm0203635

文献信息

• SH2 domain binding inhibitors
  申请人：Burke R. Terrence

  公开号：US20050119163A1

  公开（公告）日：2005-06-02

  Disclosed are compounds represented by the formula: or a pharmaceutically acceptable salt or isomer thereof, wherein R 1 -R 6 are as defined in the specification. These compounds are targeted for use as inhibitors of SH2 domain binding with a phosphoprotein, and are contemplated for use in a number of diseases including cancer. Also disclosed are pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier.

  揭示了由以下公式表示的化合物：或其药学上可接受的盐或异构体，其中R1-R6如规范中所定义。这些化合物被用作SH2结构域与磷酸蛋白结合的抑制剂，并可用于多种疾病，包括癌症。还揭示了包括本发明化合物和药学上可接受的载体的药物组合物。
• Synthesis of a 5-Methylindolyl-Containing Macrocycle That Displays Ultrapotent Grb2 SH2 Domain-Binding Affinity
  作者：Zhen-Dan Shi、Kyeong Lee、Chang-Qing Wei、Lindsey R. Roberts、Karen M. Worthy、Robert J. Fisher、Terrence R. Burke

  DOI：10.1021/jm030440b

  日期：2004.2.1

  The growth factor receptor-bound protein 2 (Grb2) is an SH2 domain-containing docking module that represents an attractive target for anticancer therapeutic intervention. Here, a ring-closing metathesis approach is utilized to synthesize a 5-methylindolyl-containing tetrapeptide mimetic (6) that exhibits unprecedented in vitro Grb2 SH2 domain-binding affinity (K(d) = 93 pM). Key to the preparation

  生长因子受体结合蛋白2（Grb2）是包含SH2域的对接模块，代表抗癌治疗干预的有吸引力的目标。在这里，采用一种闭环复分解方法来合成含5-甲基吲哚基的四肽模拟物（6），该模拟物表现出前所未有的体外Grb2 SH2结构域结合亲和力（K（d）= 93 pM）。制备6的关键是作为两个闭环链段之一的（2S）-2-（3-（5-（5-甲基吲哚基）甲基）戊-4-烯胺（12）的对映选择性合成。
• Utilization of achiral alkenyl amines for the preparation of high affinity Grb2 SH2 domain-binding macrocycles by ring-closing metathesis
  作者：Fa Liu、Karen M. Worthy、Lakshman Bindu、Alessio Giubellino、Donald P. Bottaro、Robert J. Fisher、Terrence R. Burke Jr.

  DOI：10.1039/b611887a

  日期：——

  A family of previously reported ring-closing metathesis (RCM)-derived macrocycles that exhibit potent Grb2 SH2 domain-binding affinity is characterized by stereoselectively-introduced upper ring junctions that bear bicyclic aryl substituents. However, the synthetic complexity of these macrocycles presents a potential limit to their therapeutic application. Therefore, the current study was undertaken

  展示有力的Grb2 SH2域结合亲和力的一系列先前报道的闭环易位（RCM）衍生的大环化合物，其特征在于带有双环芳基取代基的立体选择性引入的上环连接。然而，这些大环化合物的合成复杂性对其治疗应用提出了潜在的限制。因此，目前的研究是通过使用非手性4-戊烯酰胺作为成环组分来简化这些大环的。制备了一系列大环（5a-f），其在上环结处带有开放和环状结构。这些大环的Grb2 SH2域结合亲和力各不相同，其中环取代基的亲和力更高。最有效的类似物（5d）含有一个环己基基团，并显示出与母体大环（2）几乎相等的Grb2 SH2域结合亲和力（K（D）= 1.3 nM），该亲本大环在其骨架上具有立体选择性引入的萘基甲基取代基。上环结（K（D）= 0.9 nM）。这项研究的结果提出了应促进Grb2 SH2域结合拮抗剂开发的设计考虑。
• [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。
• Structural Examination of Ring-Closing Metathesis-Derived 15-Member Macrocycles as Grb2 SH2 Domain-Binding Tetrapeptide Mimetics
  作者：Fa Liu、Karen M. Worthy、Lakshman K. Bindu、Robert J. Fisher、Terrence R. Burke

  DOI：10.1021/jo701831q

  日期：2007.12.1

  exhibited low nanomolar Grb2 SH2 domain-binding affinities in spite of the fact that differing ring junction stereochemistries and geometries of the RCM-derived double bond were employed. The finding that significant latitude exists in the structural requirements for ring closure may facilitate the development of therapeutically relevant macrocyle-based Grb2 SH2 domain-binding antagonists. The synthetic approaches

  采用闭环复分解 (RCM) 将羧基末端的链烯基甘氨酸侧链与附加到氨基末端磷酸酪氨酰 (pTyr) 模拟物的 β-亚甲基的乙烯基和烯丙基官能团连接在一起。这需要合成各种新的 pTyr 模拟物，包括一种新的含氮杂类似物。尽管采用了不同的环结立体化学和 RCM 衍生双键的几何结构，但许多由此产生的 15 成员大环四肽模拟物表现出低纳摩尔 Grb2 SH2 域结合亲和力。环闭合的结构要求存在显着差异的发现可能促进治疗相关的基于大环的 Grb2 SH2 结构域结合拮抗剂的开发。