[4-((S)-2-Amino-2-{1-[(S)-2-carbamoyl-1-(3-naphthalen-1-yl-propylcarbamoyl)-ethylcarbamoyl]-cyclohexylcarbamoyl}-ethyl)-benzyl]-phosphonic acid di-tert-butyl ester | 220193-83-9

• 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: [4-((S)-2-Amino-2-{1-[(S)-2-carbamoyl-1-(3-naphthalen-1-yl-propylcarbamoyl)-ethylcarbamoyl]-cyclohexylcarbamoyl}-ethyl)-benzyl]-phosphonic acid di-tert-butyl ester
• CAS: 220193-83-9
• 化学式: C₄₂H₆₀N₅O₇P
• 分子量: 777.941
• InChiKey: UGZLNVJYVXYFGM-PXLJZGITSA-N

物化性质

• 沸点：
  1027.967±65.00 °C(Press: 760.00 Torr)(predicted)
• 密度：
  1.215±0.10 g/cm3(Temp: 25 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.96
• 重原子数：
  55.0
• 可旋转键数：
  17.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  191.94
• 氢给体数：
  5.0
• 氢受体数：
  8.0

反应信息

• 作为反应物：
  描述：

  [4-((S)-2-Amino-2-{1-[(S)-2-carbamoyl-1-(3-naphthalen-1-yl-propylcarbamoyl)-ethylcarbamoyl]-cyclohexylcarbamoyl}-ethyl)-benzyl]-phosphonic acid di-tert-butyl ester 在 三乙基硅烷 、 水 、 三氟乙酸 作用下， 反应 1.0h， 生成 [4-((S)-2-(3-Amino-benzyloxycarbonylamino)-2-{1-[(S)-2-carbamoyl-1-(3-naphthalen-1-yl-propylcarbamoyl)-ethylcarbamoyl]-cyclohexylcarbamoyl}-ethyl)-benzyl]-phosphonic acid
  参考文献：
  名称：

  N-Terminal carboxyl and tetrazole-containing amides as adjuvants to Grb2 SH2 domain ligand binding

  摘要：

  High affinity binding of peptides to Src homology 2 (SH2) domains, often requires the presence of phosphotyrosyl (pTyr) or pTyr-mimicking moieties in the N-terminal position of the binding ligand. Several reports have shown that N-alpha-acylation of the critical pTyr residue can result in increased SH2 domain binding potency. For Grb2 SH2 domains which recognize pTyr-Xxx-Asn-NH2 motifs, significant potency enhancement can be incurred by N-alpha-(3-amino)Z derivatization of tripeptides such as pTyr-Xxe-Asn-NH2. Using ligands based on the high affinity pY-Ac(6)c-Asn-(naphthylpropylamide) motif, (where Ac(6)c = 1-aminocyclohex-anecarboxylic acid), additional reports have shown moderate potentiating effects of N-alpha-oxalyl derivatization. The current study examined variations of the N-alpha-oxalyl theme in the context of a Xxx-Ac(6)c-Asn-(naphthylpropylamide) platform, where Xxx = the hydrolytically stable pTyr mimetics phosphonomethyl phenylalanine (Pmp) or carboxymethyl phenylalanine (Cmf). The effects of N-alpha-(3-amino)Z derivatization were also investigated for this platform, to ascertain whether the large binding enhancement reported for tripeptides such as pTyr-Ile-Asn-NH2 could be observed. In ELISA-based extracellular Grb2 SH2 domain binding assays, it was found for the Pmp-based series, that extending the oxalyl carboxyl out by one methylene unit or replacing carboxyl functionality with a tetrazole isostere, resulted in binding potency greater than the parent N-alpha-acetyl-containing compound, with enhancement approximating that observed for the N-alpha-oxalyl derivative. When Cmf was used as the pTyr mimetic, only modest differences in IC50 values were observed for the series. Examination of the N-alpha-(3-amino)Z derivatized Pmp-Ac(6)c-Asn-(naphthylpropylamide), showed that binding affinity was reduced relative to the parent N-alpha-acetyl analogue, in contrast to the reported significant enhancement of affinity observed with other peptide ligands. Treatment of MDA-453 tumor cells, which are mitogenically driven through erbB-2 tyrosine kinase-dependent pathways, with Pmp-containing inhibitors resulted in growth inhibition, with the N-alpha-oxalyl and N-alpha-malonyl-containing compounds exhibiting IC50 values (4.3 and 4.6 muM, respectively) approximately five-fold lower than the parent N-alpha-acetyl-containing compound. Tetrazole and N-alpha-(3-amino)Z-containing inhibitors were from two- to four-fold less potent than these latter analogues in the growth inhibition assays. (C) 2001 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(01)00014-1
• 作为产物：
  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 2.17h， 生成 [4-((S)-2-Amino-2-{1-[(S)-2-carbamoyl-1-(3-naphthalen-1-yl-propylcarbamoyl)-ethylcarbamoyl]-cyclohexylcarbamoyl}-ethyl)-benzyl]-phosphonic acid di-tert-butyl ester
  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

• 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。