[4-((S)-2-{1-[(S)-2-Carbamoyl-1-(3-naphthalen-1-yl-propylcarbamoyl)-ethylcarbamoyl]-cyclohexylcarbamoyl}-2-{2-[1-(4-methoxy-benzyl)-1H-tetrazol-5-yl]-acetylamino}-ethyl)-phenyl]-acetic acid tert-butyl ester | 364630-88-6

• 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-{1-[(S)-2-Carbamoyl-1-(3-naphthalen-1-yl-propylcarbamoyl)-ethylcarbamoyl]-cyclohexylcarbamoyl}-2-{2-[1-(4-methoxy-benzyl)-1H-tetrazol-5-yl]-acetylamino}-ethyl)-phenyl]-acetic acid tert-butyl ester
• CAS: 364630-88-6
• 化学式: C₅₀H₆₁N₉O₈
• 分子量: 916.09
• InChiKey: BBUBLQAJAPFOSB-YATWDLPUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.97
• 重原子数：
  67.0
• 可旋转键数：
  21.0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  238.62
• 氢给体数：
  5.0
• 氢受体数：
  12.0

反应信息

• 作为反应物：
  描述：

  [4-((S)-2-{1-[(S)-2-Carbamoyl-1-(3-naphthalen-1-yl-propylcarbamoyl)-ethylcarbamoyl]-cyclohexylcarbamoyl}-2-{2-[1-(4-methoxy-benzyl)-1H-tetrazol-5-yl]-acetylamino}-ethyl)-phenyl]-acetic acid tert-butyl ester 在 三乙基硅烷 、 水 、 三氟乙酸 作用下， 反应 1.5h， 以32%的产率得到{4-[(S)-2-{1-[(S)-2-Carbamoyl-1-(3-naphthalen-1-yl-propylcarbamoyl)-ethylcarbamoyl]-cyclohexylcarbamoyl}-2-(2-1H-tetrazol-5-yl-acetylamino)-ethyl]-phenyl}-acetic 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：

  ethyl 2-(5-(4-methoxybenzyl)tetrazolyl)acetate 在 lithium hydroxide 、 草酰氯 作用下， 生成 [4-((S)-2-{1-[(S)-2-Carbamoyl-1-(3-naphthalen-1-yl-propylcarbamoyl)-ethylcarbamoyl]-cyclohexylcarbamoyl}-2-{2-[1-(4-methoxy-benzyl)-1H-tetrazol-5-yl]-acetylamino}-ethyl)-phenyl]-acetic acid tert-butyl ester
  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