(S)-2-(1-aminocyclohexane-1-carboxamido)-N¹-((S)-2-(naphthalen-1-ylmethyl)pent-4-en-1-yl)succinamide | 401810-35-3

• 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: (S)-2-(1-aminocyclohexane-1-carboxamido)-N¹-((S)-2-(naphthalen-1-ylmethyl)pent-4-en-1-yl)succinamide
• 英文别名: (s)-2-(1-Aminocyclohexane-1-carboxamido)-n1-((s)-2-(naphthalen-1-ylmethyl)pent-4-en-1-yl)succinamide；(2S)-2-[(1-aminocyclohexanecarbonyl)amino]-N-[(2S)-2-(naphthalen-1-ylmethyl)pent-4-enyl]butanediamide
• CAS: 401810-35-3
• 化学式: C₂₇H₃₆N₄O₃
• 分子量: 464.608
• InChiKey: CFHZPJNOMHXQHC-CVDCTZTESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  34
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.44
• 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：

  (S)-2-(1-aminocyclohexane-1-carboxamido)-N¹-((S)-2-(naphthalen-1-ylmethyl)pent-4-en-1-yl)succinamide 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-[(9S,10S,14S,18S)-7,16,19-triaza-10-(4-{[bis(tert-butoxy)phosphono]methyl}phenyl)-18-(carbamoylmethyl)-14-(naphthylmethyl)-8,17,20-trioxospiro[5.14]icos-11-en-9-yl]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：

  ethyl 3-(naphth-1-yl)propanoate 在 lithium aluminium tetrahydride 、 氯化亚砜 、 双(叔丁氧羰基)胺 、 sodium hexamethyldisilazane 、 sodium hydride 、 caesium carbonate 、 三乙胺 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 三氟乙酸 、 sodium hydroxide 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 二甲基亚砜 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 107.5h， 生成 (S)-2-(1-aminocyclohexane-1-carboxamido)-N¹-((S)-2-(naphthalen-1-ylmethyl)pent-4-en-1-yl)succinamide
  参考文献：
  名称：

  GRB2 SH2结构域单羧酸抑制剂的合成和结构表征

  摘要：

  设计并合成了一种单羧酸抑制剂来破坏 GRB2 和含磷酸酪氨酸的蛋白质之间的蛋白质相互作用 (PPI)。生化表征显示化合物7与 GRB2 的 Src 同源 2 (SH2) 结构域结合，并且比 EGFR 1068磷酸肽 14-mer 更有效。X 射线晶体学研究表明，化合物7占据了含有磷酸酪氨酸序列的 GRB2 结合位点，并揭示了 GRB2 抑制剂结合的关键结构特征。这种具有 –1 正式电荷的化合物为结构优化提供了新的方向，从而为异常 Ras-MAPK 信号级联的这一关键蛋白靶点生成细胞渗透性抑制剂。

  DOI：

  10.1016/j.bmcl.2021.128354

文献信息

• Enantioselective Synthesis of Metathesis-Derived Ureapeptoid Macrocycles
  作者：Terrence R. Burke Jr.、Xiang-Zhu Wang

  DOI：10.1055/s-2004-815425

  日期：——

  Ring-closing metathesis (RCM) was used for the preparation of the first member of a new class of ureapeptoid-containing macrocycles. Key to the approach was the enantioselective syn­thesis of functionalized carbamoyl alkenylglycine equivalents using (-)-B-allyldiisopinocampheylborane [(-)-d-Ipc2 Ball]-mediated asymmetric allylation.

  环闭合易位（RCM）被用于制备一类新型含尿素肽类似物大环的首个成员。该方法的关键在于利用（-）-β-烯丙基二异松烷基硼烷[（-）-d-Ipc2 Ball]介导的不对称烯丙基化反应，进行手性选择性的功能化氨基甲酰基烯丙基甘氨酸类等效物的合成。
• Olefin Metathesis in the Design and Synthesis of a Globally Constrained Grb2 SH2 Domain Inhibitor
  作者：Yang Gao、Chang-Qing Wei、Terrence R. Burke

  DOI：10.1021/ol0157609

  日期：2001.5.1

  sites of ring closure, may be circumvented by incorporation of side chain functionality within the ring-closing olefin segments. This approach is demonstrated in the preparation of a macrocyclic Grb2 SH2 domain antagonist designed as a conformationally constrained beta-bend mimic.

  经常与烯烃复分解介导的肽大环化有关的一个缺点，即在闭环位点的侧链官能度的丧失，可以通过在闭环烯烃链段内掺入侧链官能度来避免。这种方法在大环Grb2 SH2域拮抗剂的制备中得到了证明，该拮抗剂设计为构象约束的β弯曲模拟物。
• 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。
• Macrocyclization in the Design of Non-Phosphorus-Containing Grb2 SH2 Domain-Binding Ligands
  作者：Zhen-Dan Shi、Chang-Qing Wei、Kyeong Lee、Hongpeng Liu、Manchao Zhang、Toshiyuki Araki、Lindsey R. Roberts、Karen M. Worthy、Robert J. Fisher、Benjamin G. Neel、James A. Kelley、Dajun Yang、Terrence R. Burke

  DOI：10.1021/jm030510e

  日期：2004.4.1

  Macrocyclization from the phosphotyrosyl. (pTyr) mimetic's beta-position has previously been shown to enhance Grb2 SH2 domain-binding affinity of phosphonate-based analogues. The current study examined the effects of such macrocyclization using a dicarboxymethyl-based pTyr mimetic. In extracellular assays affinity was enhanced approximately 5-fold relative to an open-chain congener. Enhancement was also observed in whole-cell assays examining blockade of Grb2 binding to the erbB-2 protein-tyrosine kinase.
• US7425537B2
  申请人：——

  公开号：US7425537B2

  公开（公告）日：2008-09-16