(S)-asparagine-3-((1-naphthyl)propyl)amide | 284677-41-4

• 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)-asparagine-3-((1-naphthyl)propyl)amide
• 英文别名: (2S)-2-amino-N-(3-naphthalen-1-ylpropyl)butanediamide
• CAS: 284677-41-4
• 化学式: C₁₇H₂₁N₃O₂
• 分子量: 299.373
• InChiKey: CSMHIUKKTAOGTO-HNNXBMFYSA-N

物化性质

• 沸点：
  630.9±55.0 °C(Predicted)
• 密度：
  1.198±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  22
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  98.2
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (S)-asparagine-3-((1-naphthyl)propyl)amide 在 palladium on activated charcoal 4-aza-1-hydroxybenzotriazole 、 N,N′-二叔丁基碳二亚胺 、 氢气 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 二乙胺 、 二异丙胺 、 N,N-二异丙基乙胺 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 21.25h， 生成 methyl 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：

  1-萘丙胺 在 N-甲基吗啉 、 palladium on activated carbon 、 氢气 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， -30.0~20.0 ℃ 、101.33 kPa 条件下， 反应 16.0h， 生成 (S)-asparagine-3-((1-naphthyl)propyl)amide
  参考文献：
  名称：

  蛋白质-配体相互作用中不同非极性表面的一些热力学效应。

  摘要：

  了解小分子的结构变化如何影响它们对靶蛋白的结合亲和力，对于改进合理的药物设计策略至关重要。为了评估改变非极性基团的性质对结合熵和焓的影响，我们设计并制备了一组 Grb2-SH2 结构域配体 Ac–pTyr–Ac 6 c–Asn–(CH 2 ) n – R，其中R的大小和静电性质pTyr+3 位点的组是不同的。这些配体与 Grb2-SH2 结构域的复合物在一系列研究中进行了评估，其中使用等温滴定量热法确定了结合热力学，并在两种不同复合物的晶体学研究中检查了结合相互作用。值得注意的是，将非极性基团添加到 pTyr+3 位点会导致更高的结合亲和力，但这些影响的大小和能量来源随R取代基的性质而变化。例如，使用脂肪族R基团增强结合亲和力是由结合熵的更有利变化驱动的，而芳基R组通过结合焓和熵的更有利变化的组合来提高结合自由能。然而，焓/熵补偿在这些关联中起着重要作用，并减轻了结合自由能的任何显着变化，结合自由能仅变化

  DOI：

  10.1016/j.ejmech.2020.112771

文献信息

• 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.
• Some thermodynamic effects of varying nonpolar surfaces in protein-ligand interactions
  作者：David L. Cramer、Bo Cheng、Jianhua Tian、John H. Clements、Rachel M. Wypych、Stephen F. Martin

  DOI：10.1016/j.ejmech.2020.112771

  日期：2020.12

  enhancements to binding affinities using aliphatic R groups are driven by more favorable changes in binding entropies, whereas aryl R groups improve binding free energies through a combination of more favorable changes in binding enthalpies and entropies. However, enthalpy/entropy compensation plays a significant role in these associations and mitigates against any significant variation in binding free energies

  了解小分子的结构变化如何影响它们对靶蛋白的结合亲和力，对于改进合理的药物设计策略至关重要。为了评估改变非极性基团的性质对结合熵和焓的影响，我们设计并制备了一组 Grb2-SH2 结构域配体 Ac–pTyr–Ac 6 c–Asn–(CH 2 ) n – R，其中R的大小和静电性质pTyr+3 位点的组是不同的。这些配体与 Grb2-SH2 结构域的复合物在一系列研究中进行了评估，其中使用等温滴定量热法确定了结合热力学，并在两种不同复合物的晶体学研究中检查了结合相互作用。值得注意的是，将非极性基团添加到 pTyr+3 位点会导致更高的结合亲和力，但这些影响的大小和能量来源随R取代基的性质而变化。例如，使用脂肪族R基团增强结合亲和力是由结合熵的更有利变化驱动的，而芳基R组通过结合焓和熵的更有利变化的组合来提高结合自由能。然而，焓/熵补偿在这些关联中起着重要作用，并减轻了结合自由能的任何显着变化，结合自由能仅变化
• Examination of Acylated 4-Aminopiperidine-4-carboxylic Acid Residues in the Phosphotyrosyl+1 Position of Grb2 SH2 Domain-Binding Tripeptides
  作者：Sang-Uk Kang、Won Jun Choi、Shinya Oishi、Kyeong Lee、Rajeshri G. Karki、Karen M. Worthy、Lakshman K. Bindu、Marc C. Nicklaus、Robert J. Fisher、Terrence R. Burke

  DOI：10.1021/jm0614073

  日期：2007.4.1

  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.